<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01700946</url>
  </required_header>
  <id_info>
    <org_study_id>ALLR18</org_study_id>
    <secondary_id>NCI-2012-00587</secondary_id>
    <nct_id>NCT01700946</nct_id>
  </id_info>
  <brief_title>Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma</brief_title>
  <official_title>A Phase II Study of Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St. Jude Children's Research Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Cookies for Kids' Cancer</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Assisi Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>St. Jude Children's Research Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_unapproved_device>Yes</is_unapproved_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The overall objective of this protocol is to improve the cure rate of relapsed precursor&#xD;
      B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma.&#xD;
&#xD;
      This phase II trial is studying risk-directed therapy for B-lymphoblastic leukemia or&#xD;
      lymphoma in first relapse. Standard risk (SR) and high risk (HR) participants will receive&#xD;
      different therapy. Treatment will consist of chemotherapy for SR participants, and&#xD;
      chemotherapy followed by hematopoietic stem cell transplant (HSCT) for HR in first relapse.&#xD;
      Induction therapy consists of three blocks of chemotherapy. The first block is a novel&#xD;
      immunotherapy regimen that includes chemotherapy, rituximab and infusion of haploidentical&#xD;
      natural killer (NK) cells. SR participants will continue to receive chemotherapy for a total&#xD;
      duration of approximately 2 years. HR participants will be candidates for HSCT and will&#xD;
      proceed to transplant once a suitable donor is found and their minimal residual disease (MRD)&#xD;
      is negative.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary objective&#xD;
&#xD;
        -  To estimate the 3-year survival rate of participants with first relapse or primary&#xD;
           refractory precursor B-cell ALL and lymphoblastic lymphoma treated with risk-directed&#xD;
           therapy.&#xD;
&#xD;
      Secondary objectives&#xD;
&#xD;
        -  To determine minimal residual disease (MRD) levels at the end of remission induction&#xD;
           therapy for participants with relapsed precursor B-cell ALL and compare the results with&#xD;
           those in protocol ALLR17&#xD;
&#xD;
        -  To estimate levels of CD20 expression at baseline, during treatment with&#xD;
           dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of&#xD;
           remission induction therapy for relapsed precursor B-cell ALL.&#xD;
&#xD;
      STUDY DESCRIPTION:&#xD;
&#xD;
      The general treatment plan will consist of chemotherapy for standard-risk participants and&#xD;
      chemotherapy followed by HSCT for high risk participants in first relapse of B-precursor ALL&#xD;
      or lymphoblastic lymphoma. Remission induction for all participants consists of three blocks&#xD;
      of therapy, wherein the first block is a novel immunotherapy regimen that includes cytotoxic&#xD;
      chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells.&#xD;
      Standard-risk patients will continue to receive chemotherapy for a total duration of&#xD;
      approximately 2 years. High-risk patients will be candidates for HSCT and will proceed to&#xD;
      transplant once a suitable donor is found and the patient achieves negative MRD.&#xD;
&#xD;
      Participants will be assigned to the standard arm if they experience late relapse (&gt; or = 6&#xD;
      months after completion of frontline therapy) AND maximum residual disease (MRD) is &lt;0.01% at&#xD;
      the end of Block II of remission induction therapy. Provisional standard risk participants&#xD;
      (i.e., late relapse) will be re-assigned to high risk if MRD is &gt; or = 0.01% at the end of&#xD;
      Block II. Participants with lymphoma must be in complete remission at the end of Block III.&#xD;
&#xD;
      High risk participants will meet one of the following criteria:&#xD;
&#xD;
        -  Early relapse (on therapy or &lt;6 months after completion of frontline therapy), OR&#xD;
&#xD;
        -  Any relapse after hematopoietic stem cell transplant, OR&#xD;
&#xD;
        -  MRD &gt; or = 0.01% at the end of Block II of remission induction therapy, OR&#xD;
&#xD;
        -  Re-emergence of MRD at any time after attaining negative MRD on this clinical trial.&#xD;
&#xD;
      Natural killer (NK) cell collection: Donors who meet eligibility criteria will undergo&#xD;
      apheresis once. The cells obtained will be purified for CD56+ cells utilizing the CliniMACS&#xD;
      selection system. The NK cell product will undergo quality control testing following standard&#xD;
      operating procedures of the St. Jude Human Applications Laboratory.&#xD;
&#xD;
      OUTLINE (STANDARD RISK):&#xD;
&#xD;
      REMISSION INDUCTION:&#xD;
&#xD;
      BLOCK I: Patients receive dexamethasone orally (PO) or intravenously (IV) thrice daily (TID)&#xD;
      on days 1-8 and 21-28; vincristine sulfate IV on days 1, 21, 28, and 35; rituximab IV on days&#xD;
      4, 13, 20, and 27; clofarabine, cyclophosphamide, and etoposide IV on days 6-10; aldesleukin&#xD;
      subcutaneously (SC) once every other day (QOD) on days 11-19; and pegaspargase IV on days 21&#xD;
      and 35. Patients also undergo natural killer (NK) cell infusion on day 12. Patients may&#xD;
      receive triple intrathecal therapy comprising methotrexate, therapeutic hydrocortisone, and&#xD;
      cytarabine on days 1, 5, 8, 11, 21, and 28. Patients continue on to Block II after count&#xD;
      recovery.&#xD;
&#xD;
      BLOCK II: Patients receive methotrexate IV over 24 hours on days 1 and 8 and mercaptopurine&#xD;
      PO on days 1-21. Patients also receive triple intrathecal therapy on day 1. High-risk&#xD;
      patients with negative MRD continue on to transplantation. All patients with positive MRD&#xD;
      continue on to Block III after count recovery.&#xD;
&#xD;
      BLOCK III: Patients receive cytarabine IV over 2 hours twice daily (BID) on days 1-4 and&#xD;
      mitoxantrone hydrochloride IV over 1 hour on days 3-5. Patients also receive triple&#xD;
      intrathecal therapy on day 7.&#xD;
&#xD;
      INTERIM CONTINUATION (for patients unable to tolerate dose intensive chemotherapy): Patients&#xD;
      receive etoposide and cyclophosphamide IV on day 1, methotrexate IV on day 8, mercaptopurine&#xD;
      PO on days 8-14, teniposide and cytarabine IV on day 15, dexamethasone PO TID on days 22-26,&#xD;
      and vinblastine IV on day 22.&#xD;
&#xD;
      RE-INDUCTION THERAPY: Patients receive clofarabine, cyclophosphamide, and etoposide IV on&#xD;
      days 1-5; dexamethasone PO on days 1-6; and pegaspargase on days 6 and 20 and vincristine&#xD;
      sulfate IV on days 6, 13, and 20. Patients may also receive triple intrathecal therapy on&#xD;
      days 1 and 15. Patients continue on to continuation treatment after count recovery.&#xD;
&#xD;
      CONTINUATION TREATMENT: Patients receive methotrexate IV over 2 hours on day 1 and&#xD;
      mercaptopurine PO on days 1-7 of weeks 1, 2, 5, and 6; teniposide and cytarabine IV on day 1&#xD;
      of weeks 3 and 7; vincristine sulfate IV on day 1 of week 4; dexamethasone PO TID on days 1-5&#xD;
      of weeks 4 and 8; and vinblastine IV on day 1 of week 8. Treatment repeats every 8 weeks for&#xD;
      up to 10 courses in the absence of disease progression or unacceptable toxicity. Patients may&#xD;
      also receive triple intrathecal therapy on day 1 of week 1 of all courses and day 1 of week&#xD;
      5, courses 1-5.&#xD;
&#xD;
      Due to the unavailability of the drug Teniposide (VM-26), etoposide (VP-16) will be&#xD;
      substituted for the remaining doses for patients currently on this study. The protocol&#xD;
      Section 5.1.3 allows this substitution.&#xD;
&#xD;
      OUTLINE: GROUP 2 (high risk defined as participants not meeting the standard risk criteria&#xD;
      noted above):&#xD;
&#xD;
      Patients receive Remission Induction (Blocks I, II, and III) treatment as described above for&#xD;
      Group 1. Patients then undergo allogeneic hematopoietic stem cell transplantation (HSCT) as&#xD;
      soon as they have negative MRD. Patients with negative MRD may continue chemotherapy until a&#xD;
      suitable donor is found.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 4 months for 1 year,&#xD;
      every 6 months for 1 year, and then yearly for up to 10 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 15, 2013</start_date>
  <completion_date type="Actual">July 24, 2021</completion_date>
  <primary_completion_date type="Actual">July 24, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>3-year Overall Survival Rate of Patients With Relapsed ALL</measure>
    <time_frame>3 years of follow-up since the on-study date</time_frame>
    <description>Estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>3-year Event-free Survival Rates in Patients With Relapsed ALL</measure>
    <time_frame>3 years of follow-up since the on-study date</time_frame>
    <description>Estimate the 3-year event-free survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of Participants With Positive Minimal Residual Disease</measure>
    <time_frame>At end of induction (approximately 3 months)</time_frame>
    <description>To determine minimal residual disease (MRD) levels at the end of remission induction therapy for participants with relapsed precursor B-cell ALL and compare the results with those in protocol ALLR17 (NCT00186875).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean of CD20 Expression Levels</measure>
    <time_frame>Baseline and at the end of Block I (approximately 5 weeks after the on-study date)</time_frame>
    <description>To estimate mean levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median CD20 Expression Levels</measure>
    <time_frame>Baseline and at the end of Block I (approximately 5 weeks after the on-study date)</time_frame>
    <description>To estimate median levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">80</enrollment>
  <condition>Recurrent B-Cell Childhood Acute Lymphoblastic Leukemia</condition>
  <condition>Recurrent Childhood B-Lymphoblastic Lymphoma</condition>
  <arm_group>
    <arm_group_label>Standard Risk</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Interventions: dexamethasone, vincristine sulfate, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, teniposide, vinblastine, natural killer cell infusion, laboratory biomarker analysis, therapeutic hydrocortisone&#xD;
Cells for infusion are prepared using the CliniMACS System.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Interventions: dexamethasone, vincristine, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, natural killer cell infusion, allogeneic hematopoietic stem cell transplantation, laboratory biomarker analysis, therapeutic hydrocortisone&#xD;
Cells for infusion are prepared using the CliniMACS System.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>dexamethasone</intervention_name>
    <description>given intravenously or orally</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>Decadron(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>vincristine sulfate</intervention_name>
    <description>given intravenously</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>Oncovin(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>rituximab</intervention_name>
    <description>given intravenously</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>Rituxan(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>clofarabine</intervention_name>
    <description>given intravenously</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>Clolar(TM)</other_name>
    <other_name>clofarex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>cyclophosphamide</intervention_name>
    <description>given intravenously</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>Cytoxan(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>etoposide</intervention_name>
    <description>given intravenously</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>VP-16</other_name>
    <other_name>Vepesid(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>aldesleukin</intervention_name>
    <description>given subcutaneously</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>IL-2</other_name>
    <other_name>interleukin-2</other_name>
    <other_name>Proleukin (R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>pegaspargase</intervention_name>
    <description>given intravenously</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>PEG-ASP</other_name>
    <other_name>Peg-L-asparaginase</other_name>
    <other_name>PEG-asparaginase</other_name>
    <other_name>Oncaspar(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>methotrexate</intervention_name>
    <description>given intrathecally or intravenously</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>MTX</other_name>
    <other_name>HDMTX</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>mercaptopurine</intervention_name>
    <description>given orally</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>6-MP</other_name>
    <other_name>Purinethol(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>cytarabine</intervention_name>
    <description>given intrathecally or intravenously</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>Ara-C</other_name>
    <other_name>Cytosar-U(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>mitoxantrone</intervention_name>
    <description>given intravenously</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>Novantrone(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>teniposide</intervention_name>
    <description>given intravenously</description>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>VM-26</other_name>
    <other_name>Vumon(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>vinblastine</intervention_name>
    <description>given intravenously</description>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>Velban(R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>natural killer cell infusion</intervention_name>
    <description>undergo allogeneic natural killer cell infusion</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>NK cell infusion</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>laboratory biomarker analysis</intervention_name>
    <description>correlative studies</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>therapeutic hydrocortisone</intervention_name>
    <description>given intrathecally</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>Cortef</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>allogeneic hematopoietic stem cell transplantation</intervention_name>
    <description>undergo allogeneic HSCT</description>
    <arm_group_label>High Risk</arm_group_label>
    <other_name>HSCT</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>CliniMACS</intervention_name>
    <description>The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.</description>
    <arm_group_label>High Risk</arm_group_label>
    <arm_group_label>Standard Risk</arm_group_label>
    <other_name>Cell Selection System</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION CRITERIA:&#xD;
&#xD;
          -  Must have relapsed or refractory precursor B-cell acute lymphoblastic leukemia or&#xD;
             acute lymphoblastic lymphoma.&#xD;
&#xD;
          -  Participants with leukemia must meet one of the following:&#xD;
&#xD;
               1. In first hematologic relapse, defined as the reappearance (in a patient who has&#xD;
                  previously achieved remission) of leukemia blasts in the bone marrow or&#xD;
                  peripheral blood, OR&#xD;
&#xD;
               2. Refractory to one or two courses of frontline induction therapy (≥ 5% blasts in&#xD;
                  the bone marrow or peripheral blood confirmed by flow cytometric analysis).&#xD;
&#xD;
          -  Participant with lymphoma must meet one of the following:&#xD;
&#xD;
               1. In first relapse, OR&#xD;
&#xD;
               2. Refractory to one or two courses of frontline induction therapy with measurable&#xD;
                  disease&#xD;
&#xD;
                    -  Should flow cytometric analyses suggest relapse (by the reappearance of a&#xD;
                       similar immunophenotype to the original leukemia) in the presence of &lt;5%&#xD;
                       blasts morphologically, a repeat bone marrow test is recommended to confirm&#xD;
                       relapse.&#xD;
&#xD;
                    -  Molecular or genetic relapse is characterized by the reappearance of a&#xD;
                       cytogenetic or molecular abnormality.&#xD;
&#xD;
                    -  Early relapse is defined as relapse on therapy or &lt; 6 months after&#xD;
                       completion of frontline therapy. Late relapse is defined as relapse&#xD;
                       occurring ≥ 6 months after completion of frontline therapy.&#xD;
&#xD;
          -  Participant's age is &lt; 22 years at time of enrollment (e.g. participant is eligible&#xD;
             until 22nd birthday).&#xD;
&#xD;
          -  Prior therapy:&#xD;
&#xD;
               1. There is no waiting period for participants who relapse while receiving frontline&#xD;
                  therapy and are free from side effects attributable to such therapy.&#xD;
&#xD;
               2. Emergent radiation therapy, one dose of intrathecal chemotherapy, and up to 7&#xD;
                  days of steroids for treatment of relapse are permitted before start of treatment&#xD;
                  in participants who relapse after completion of frontline therapy.&#xD;
&#xD;
               3. At least 90 days have elapsed since bone marrow transplant and participant is off&#xD;
                  immune suppression for a minimum of 2 weeks, if applicable. Participants with ALL&#xD;
                  or NHL who were transplanted in first remission are eligible for this study.&#xD;
&#xD;
        Organ function requirements&#xD;
&#xD;
          -  Hepatic: Total bilirubin ≤ upper limit of normal (ULN) for age, or if total bilirubin&#xD;
             is &gt; ULN, direct bilirubin ≤ 1.4 mg/dl&#xD;
&#xD;
          -  Cardiac: Shortening fraction ≥ 28%&#xD;
&#xD;
          -  Renal: Glomerular filtration rate &gt;50cc/min/1.73 m^2, OR maximum serum creatinine (SC)&#xD;
             based on age as follows:&#xD;
&#xD;
               -  If age is 1 to 2 years, then maximum SC is 0.6 mg/dL&#xD;
&#xD;
               -  If age is 2 to 6 years, then maximum SC is 0.8 mg/dL&#xD;
&#xD;
               -  If age is 6 to 10 years, then maximum SC is 1 mg/dL&#xD;
&#xD;
               -  If age is 10 to &lt;13 years, then maximum SC is 1.2 mg/dL&#xD;
&#xD;
               -  If age is 13 to 16 years, then maximum SC is 1.5 mg/dL for males and 1.4 mg/dL&#xD;
                  for females&#xD;
&#xD;
               -  If age is &gt;16 years, then maximum SC is 1.7 mg/dL for males and 1.4 mg/dL for&#xD;
                  females&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Leukemia participants ages 1 to 5 years with induction failure AND favorable&#xD;
             cytogenetics (i.e., hyperdiploidy defined as DNA index ≥1.16 or modal chromosome&#xD;
             number ≥51, or ETV6-RUNXI).&#xD;
&#xD;
          -  Hepatitis B or HIV infection.&#xD;
&#xD;
          -  Pregnant or breast-feeding&#xD;
&#xD;
          -  Inability or unwillingness or research participant or legal guardian/representative to&#xD;
             give written informed consent.&#xD;
&#xD;
        INCLUSION CRITERIA FOR NK CELL DONORS:&#xD;
&#xD;
          -  Donor is at least 18 years of age.&#xD;
&#xD;
          -  Donor is a family member.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sima Jeha, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>St. Jude Children's Research Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Rady Children's Hospital and Health Center</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92123</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Jude Children's Research Hospital</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cook Children's Medical Center</name>
      <address>
        <city>Fort Worth</city>
        <state>Texas</state>
        <zip>76104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.stjude.org</url>
    <description>St. Jude Children's Research Hospital</description>
  </link>
  <link>
    <url>http://www.stjude.org/protocols</url>
    <description>Clinical Trials Open at St. Jude</description>
  </link>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>October 1, 2012</study_first_submitted>
  <study_first_submitted_qc>October 2, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 4, 2012</study_first_posted>
  <results_first_submitted>June 7, 2022</results_first_submitted>
  <results_first_submitted_qc>September 13, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">September 28, 2022</results_first_posted>
  <last_update_submitted>September 13, 2022</last_update_submitted>
  <last_update_submitted_qc>September 13, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>leukemia</keyword>
  <keyword>lymphoma</keyword>
  <keyword>Non-Hodgkins</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Aldesleukin</mesh_term>
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Hydrocortisone</mesh_term>
    <mesh_term>Hydrocortisone 17-butyrate 21-propionate</mesh_term>
    <mesh_term>Hydrocortisone acetate</mesh_term>
    <mesh_term>Hydrocortisone hemisuccinate</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Methotrexate</mesh_term>
    <mesh_term>Etoposide</mesh_term>
    <mesh_term>Vincristine</mesh_term>
    <mesh_term>Interleukin-2</mesh_term>
    <mesh_term>Asparaginase</mesh_term>
    <mesh_term>Mitoxantrone</mesh_term>
    <mesh_term>Mercaptopurine</mesh_term>
    <mesh_term>Clofarabine</mesh_term>
    <mesh_term>Vinblastine</mesh_term>
    <mesh_term>Pegaspargase</mesh_term>
    <mesh_term>Teniposide</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 18, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/46/NCT01700946/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Eighty (80) participants were enrolled on study. Forty-two (42) participants for the outcome measures and thirty-eight (38) donors who are not included in the analysis.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>STANDARD RISK</title>
          <description>Late relapse (≥ 6 months after completion of frontline therapy) AND&#xD;
MRD &lt; 0.01% at the end of Block II of remission induction therapy.&#xD;
Provisional standard risk participants (i.e., late relapse) will be re-assigned to High risk if MRD ≥ 0.01% at the end of Block II.&#xD;
Participants with lymphoma must be in complete remission at the end of Block III.</description>
        </group>
        <group group_id="P2">
          <title>HIGH RISK</title>
          <description>Early relapse (on therapy or &lt; 6 months after completion of frontline therapy), OR&#xD;
Any relapse after hematopoietic stem cell transplant, OR&#xD;
MRD ≥ 0.01% at the end of Block II of remission induction therapy, OR&#xD;
Re-emergence of MRD at any time after attaining negative MRD on ALLR18</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="17"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Failed to achieve Complete Remission after Induction Block III</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Relapse</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Unacceptable toxicity</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All participants enrolled on study.</population>
      <group_list>
        <group group_id="B1">
          <title>STANDARD RISK</title>
          <description>Late relapse (≥ 6 months after completion of frontline therapy) AND&#xD;
MRD &lt; 0.01% at the end of Block II of remission induction therapy.&#xD;
Provisional standard risk participants (i.e., late relapse) will be re-assigned to High risk if MRD ≥ 0.01% at the end of Block II.&#xD;
Participants with lymphoma must be in complete remission at the end of Block III.</description>
        </group>
        <group group_id="B2">
          <title>HIGH RISK</title>
          <description>Early relapse (on therapy or &lt; 6 months after completion of frontline therapy), OR&#xD;
Any relapse after hematopoietic stem cell transplant, OR&#xD;
MRD ≥ 0.01% at the end of Block II of remission induction therapy, OR&#xD;
Re-emergence of MRD at any time after attaining negative MRD on ALLR18</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="18"/>
            <count group_id="B2" value="24"/>
            <count group_id="B3" value="42"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>1 to 9 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>&gt;=10 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Black</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>3-year Overall Survival Rate of Patients With Relapsed ALL</title>
        <description>Estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.</description>
        <time_frame>3 years of follow-up since the on-study date</time_frame>
        <group_list>
          <group group_id="O1">
            <title>STANDARD RISK</title>
            <description>Late relapse (≥ 6 months after completion of frontline therapy) AND&#xD;
MRD &lt; 0.01% at the end of Block II of remission induction therapy.&#xD;
Provisional standard risk participants (i.e., late relapse) will be re-assigned to High risk if MRD ≥ 0.01% at the end of Block II.&#xD;
Participants with lymphoma must be in complete remission at the end of Block III.</description>
          </group>
          <group group_id="O2">
            <title>HIGH RISK</title>
            <description>Early relapse (on therapy or &lt; 6 months after completion of frontline therapy), OR&#xD;
Any relapse after hematopoietic stem cell transplant, OR&#xD;
MRD ≥ 0.01% at the end of Block II of remission induction therapy, OR&#xD;
Re-emergence of MRD at any time after attaining negative MRD on ALLR18</description>
          </group>
          <group group_id="O3">
            <title>All Patients Enrolled on the Study</title>
            <description>All patients who received the protocol-specified therapy.</description>
          </group>
        </group_list>
        <measure>
          <title>3-year Overall Survival Rate of Patients With Relapsed ALL</title>
          <description>Estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="94.4" lower_limit="66.6" upper_limit="99.2"/>
                    <measurement group_id="O2" value="55.5" lower_limit="33.0" upper_limit="73.2"/>
                    <measurement group_id="O3" value="72.63" lower_limit="55.95" upper_limit="83.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.035</p_value>
            <method>Log Rank</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>3-year Event-free Survival Rates in Patients With Relapsed ALL</title>
        <description>Estimate the 3-year event-free survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.</description>
        <time_frame>3 years of follow-up since the on-study date</time_frame>
        <group_list>
          <group group_id="O1">
            <title>STANDARD RISK</title>
            <description>Late relapse (≥ 6 months after completion of frontline therapy) AND&#xD;
MRD &lt; 0.01% at the end of Block II of remission induction therapy.&#xD;
Provisional standard risk participants (i.e., late relapse) will be re-assigned to High risk if MRD ≥ 0.01% at the end of Block II.&#xD;
Participants with lymphoma must be in complete remission at the end of Block III.</description>
          </group>
          <group group_id="O2">
            <title>HIGH RISK</title>
            <description>Early relapse (on therapy or &lt; 6 months after completion of frontline therapy), OR&#xD;
Any relapse after hematopoietic stem cell transplant, OR&#xD;
MRD ≥ 0.01% at the end of Block II of remission induction therapy, OR&#xD;
Re-emergence of MRD at any time after attaining negative MRD on ALLR18</description>
          </group>
          <group group_id="O3">
            <title>All Patients Enrolled on the Study</title>
            <description>All patients who received the protocol-specified therapy.</description>
          </group>
        </group_list>
        <measure>
          <title>3-year Event-free Survival Rates in Patients With Relapsed ALL</title>
          <description>Estimate the 3-year event-free survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="83.3" lower_limit="56.8" upper_limit="94.3"/>
                    <measurement group_id="O2" value="55.7" lower_limit="33.2" upper_limit="73.4"/>
                    <measurement group_id="O3" value="67.83" lower_limit="51.04" upper_limit="79.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.105</p_value>
            <method>Log Rank</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Participants With Positive Minimal Residual Disease</title>
        <description>To determine minimal residual disease (MRD) levels at the end of remission induction therapy for participants with relapsed precursor B-cell ALL and compare the results with those in protocol ALLR17 (NCT00186875).</description>
        <time_frame>At end of induction (approximately 3 months)</time_frame>
        <population>On ALLR18, a total of 42 patients enrolled. Of them, 24 patients had MRD data at the end of Remission Induction. On ALLR17, a total of 40 patients enrolled. Of them, 32 patients had MRD data at the end of Remission Induction</population>
        <group_list>
          <group group_id="O1">
            <title>STANDARD RISK</title>
            <description>Late relapse (≥ 6 months after completion of frontline therapy) AND&#xD;
MRD &lt; 0.01% at the end of Block II of remission induction therapy.&#xD;
Provisional standard risk participants (i.e., late relapse) will be re-assigned to High risk if MRD ≥ 0.01% at the end of Block II.&#xD;
Participants with lymphoma must be in complete remission at the end of Block III.</description>
          </group>
          <group group_id="O2">
            <title>HIGH RISK</title>
            <description>Early relapse (on therapy or &lt; 6 months after completion of frontline therapy), OR&#xD;
Any relapse after hematopoietic stem cell transplant, OR&#xD;
MRD ≥ 0.01% at the end of Block II of remission induction therapy, OR&#xD;
Re-emergence of MRD at any time after attaining negative MRD on ALLR18</description>
          </group>
          <group group_id="O3">
            <title>ALLR18</title>
            <description>All patients who had MRD data at the end of Remission Induction</description>
          </group>
          <group group_id="O4">
            <title>ALLR17</title>
            <description>All patients who had MRD data at the end of Remission Induction</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Participants With Positive Minimal Residual Disease</title>
          <description>To determine minimal residual disease (MRD) levels at the end of remission induction therapy for participants with relapsed precursor B-cell ALL and compare the results with those in protocol ALLR17 (NCT00186875).</description>
          <population>On ALLR18, a total of 42 patients enrolled. Of them, 24 patients had MRD data at the end of Remission Induction. On ALLR17, a total of 40 patients enrolled. Of them, 32 patients had MRD data at the end of Remission Induction</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="24"/>
                <count group_id="O4" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>MRD end-induction: Negative</title>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="6"/>
                    <measurement group_id="O3" value="20"/>
                    <measurement group_id="O4" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>MRD end-induction: Positive</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="4"/>
                    <measurement group_id="O3" value="4"/>
                    <measurement group_id="O4" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1181</p_value>
            <method>Fisher Exact</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean of CD20 Expression Levels</title>
        <description>To estimate mean levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.</description>
        <time_frame>Baseline and at the end of Block I (approximately 5 weeks after the on-study date)</time_frame>
        <population>Of the 42 patients enrolled, 34 patients had At Baseline data; 42 patients had data At Block I</population>
        <group_list>
          <group group_id="O1">
            <title>STANDARD RISK</title>
            <description>Late relapse (≥ 6 months after completion of frontline therapy) AND&#xD;
MRD &lt; 0.01% at the end of Block II of remission induction therapy.&#xD;
Provisional standard risk participants (i.e., late relapse) will be re-assigned to High risk if MRD ≥ 0.01% at the end of Block II.&#xD;
Participants with lymphoma must be in complete remission at the end of Block III.</description>
          </group>
          <group group_id="O2">
            <title>HIGH RISK</title>
            <description>Early relapse (on therapy or &lt; 6 months after completion of frontline therapy), OR&#xD;
Any relapse after hematopoietic stem cell transplant, OR&#xD;
MRD ≥ 0.01% at the end of Block II of remission induction therapy, OR&#xD;
Re-emergence of MRD at any time after attaining negative MRD on ALLR18</description>
          </group>
          <group group_id="O3">
            <title>All Patients Enrolled on the Study</title>
            <description>All patients who received the protocol-specified therapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean of CD20 Expression Levels</title>
          <description>To estimate mean levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.</description>
          <population>Of the 42 patients enrolled, 34 patients had At Baseline data; 42 patients had data At Block I</population>
          <units>percentage of CD20 Antigen</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>At Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="20"/>
                    <count group_id="O3" value="34"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.10" spread="9.82"/>
                    <measurement group_id="O2" value="39.82" spread="7.9"/>
                    <measurement group_id="O3" value="36.23" spread="6.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At Block I</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                    <count group_id="O2" value="24"/>
                    <count group_id="O3" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.54" spread="4.93"/>
                    <measurement group_id="O2" value="20.10" spread="3.44"/>
                    <measurement group_id="O3" value="19.43" spread="2.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median CD20 Expression Levels</title>
        <description>To estimate median levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.</description>
        <time_frame>Baseline and at the end of Block I (approximately 5 weeks after the on-study date)</time_frame>
        <population>Of the 42 patients enrolled, 34 patients had At Baseline data; 42 patients had data At Block I</population>
        <group_list>
          <group group_id="O1">
            <title>STANDARD RISK</title>
            <description>Late relapse (≥ 6 months after completion of frontline therapy) AND&#xD;
MRD &lt; 0.01% at the end of Block II of remission induction therapy.&#xD;
Provisional standard risk participants (i.e., late relapse) will be re-assigned to High risk if MRD ≥ 0.01% at the end of Block II.&#xD;
Participants with lymphoma must be in complete remission at the end of Block III.</description>
          </group>
          <group group_id="O2">
            <title>HIGH RISK</title>
            <description>Early relapse (on therapy or &lt; 6 months after completion of frontline therapy), OR&#xD;
Any relapse after hematopoietic stem cell transplant, OR&#xD;
MRD ≥ 0.01% at the end of Block II of remission induction therapy, OR&#xD;
Re-emergence of MRD at any time after attaining negative MRD on ALLR18</description>
          </group>
          <group group_id="O3">
            <title>All Patients Enrolled on the Study</title>
            <description>All patients who received the protocol-specified therapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Median CD20 Expression Levels</title>
          <description>To estimate median levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.</description>
          <population>Of the 42 patients enrolled, 34 patients had At Baseline data; 42 patients had data At Block I</population>
          <units>percentage of CD20 Antigen</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>At Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="20"/>
                    <count group_id="O3" value="34"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16.40" lower_limit="3.30" upper_limit="36.8"/>
                    <measurement group_id="O2" value="23.13" lower_limit="8.75" upper_limit="67.25"/>
                    <measurement group_id="O3" value="22.0" lower_limit="4.30" upper_limit="61.20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At Block 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                    <count group_id="O2" value="24"/>
                    <count group_id="O3" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.83" lower_limit="1.50" upper_limit="22.15"/>
                    <measurement group_id="O2" value="19.58" lower_limit="2.6" upper_limit="30.67"/>
                    <measurement group_id="O3" value="15.58" lower_limit="1.50" upper_limit="30.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Through one month after therapy completion, approximately 22 months. If participant proceeds to transplant, until the first day of conditioning therapy.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>STANDARD RISK</title>
          <description>Late relapse (≥ 6 months after completion of frontline therapy) AND&#xD;
MRD &lt; 0.01% at the end of Block II of remission induction therapy.&#xD;
Provisional standard risk participants (i.e., late relapse) will be re-assigned to High risk if MRD ≥ 0.01% at the end of Block II.&#xD;
Participants with lymphoma must be in complete remission at the end of Block III.</description>
        </group>
        <group group_id="E2">
          <title>HIGH RISK</title>
          <description>Early relapse (on therapy or &lt; 6 months after completion of frontline therapy), OR&#xD;
Any relapse after hematopoietic stem cell transplant, OR&#xD;
MRD ≥ 0.01% at the end of Block II of remission induction therapy, OR&#xD;
Re-emergence of MRD at any time after attaining negative MRD on ALLR18</description>
        </group>
        <group group_id="E3">
          <title>All Patients Enrolled on the Study</title>
          <description>All patients who received the protocol-specified therapy.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE v4</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE v4</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="41" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="35" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Eye pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="34" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="28" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="22" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="16" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Rectal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Anal fistula</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Fecal incontinence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Oral hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pancreatitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Proctitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Stomach pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="20" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Injection site reaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic reaction</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Cytokine release syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infections and infestations - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="20" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Enterocolitis infectious</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Mucosal infection</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Catheter related infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Anorectal Infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Meningitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Bladder infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Encephalitis infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Bone infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Infective myositis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Lip infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Otitis externa</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Otitis media</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="21" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="39" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="21" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="38" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="18" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>GGT increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Cardiac troponin T increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="22" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="40" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="40" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="35" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="35" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="34" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="33" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="25" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="21" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypertriglyceridemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Metabolism and nutrition disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Acidosis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Alkalosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Tumor lysis syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Neuralgia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Delirium</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Personality change</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Suicidal ideation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Cystitis noninfective</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Renal and urinary disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pulmonary hypertension</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pulmonary fibrosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Periorbital edema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Sima Jeha, MD</name_or_title>
      <organization>St. Jude Children's Research Hospital</organization>
      <phone>(901) 595-3901</phone>
      <email>sima.jeha@stjude.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01700946
org study id: ALLR18
secondary id: NCI-2012-00587
nct id: NCT01700946
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: Yes
is unapproved device: Yes
The overall objective of this protocol is to improve the cure rate of relapsed precursor
      B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma.

      This phase II trial is studying risk-directed therapy for B-lymphoblastic leukemia or
      lymphoma in first relapse. Standard risk (SR) and high risk (HR) participants will receive
      different therapy. Treatment will consist of chemotherapy for SR participants, and
      chemotherapy followed by hematopoietic stem cell transplant (HSCT) for HR in first relapse.
      Induction therapy consists of three blocks of chemotherapy. The first block is a novel
      immunotherapy regimen that includes chemotherapy, rituximab and infusion of haploidentical
      natural killer (NK) cells. SR participants will continue to receive chemotherapy for a total
      duration of approximately 2 years. HR participants will be candidates for HSCT and will
      proceed to transplant once a suitable donor is found and their minimal residual disease (MRD)
      is negative.
Primary objective

        -  To estimate the 3-year survival rate of participants with first relapse or primary
           refractory precursor B-cell ALL and lymphoblastic lymphoma treated with risk-directed
           therapy.

      Secondary objectives

        -  To determine minimal residual disease (MRD) levels at the end of remission induction
           therapy for participants with relapsed precursor B-cell ALL and compare the results with
           those in protocol ALLR17

        -  To estimate levels of CD20 expression at baseline, during treatment with
           dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of
           remission induction therapy for relapsed precursor B-cell ALL.

      STUDY DESCRIPTION:

      The general treatment plan will consist of chemotherapy for standard-risk participants and
      chemotherapy followed by HSCT for high risk participants in first relapse of B-precursor ALL
      or lymphoblastic lymphoma. Remission induction for all participants consists of three blocks
      of therapy, wherein the first block is a novel immunotherapy regimen that includes cytotoxic
      chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells.
      Standard-risk patients will continue to receive chemotherapy for a total duration of
      approximately 2 years. High-risk patients will be candidates for HSCT and will proceed to
      transplant once a suitable donor is found and the patient achieves negative MRD.

      Participants will be assigned to the standard arm if they experience late relapse (> or = 6
      months after completion of frontline therapy) AND maximum residual disease (MRD) is <0.01% at
      the end of Block II of remission induction therapy. Provisional standard risk participants
      (i.e., late relapse) will be re-assigned to high risk if MRD is > or = 0.01% at the end of
      Block II. Participants with lymphoma must be in complete remission at the end of Block III.

      High risk participants will meet one of the following criteria:

        -  Early relapse (on therapy or <6 months after completion of frontline therapy), OR

        -  Any relapse after hematopoietic stem cell transplant, OR

        -  MRD > or = 0.01% at the end of Block II of remission induction therapy, OR

        -  Re-emergence of MRD at any time after attaining negative MRD on this clinical trial.

      Natural killer (NK) cell collection: Donors who meet eligibility criteria will undergo
      apheresis once. The cells obtained will be purified for CD56+ cells utilizing the CliniMACS
      selection system. The NK cell product will undergo quality control testing following standard
      operating procedures of the St. Jude Human Applications Laboratory.

      OUTLINE (STANDARD RISK):

      REMISSION INDUCTION:

      BLOCK I: Patients receive dexamethasone orally (PO) or intravenously (IV) thrice daily (TID)
      on days 1-8 and 21-28; vincristine sulfate IV on days 1, 21, 28, and 35; rituximab IV on days
      4, 13, 20, and 27; clofarabine, cyclophosphamide, and etoposide IV on days 6-10; aldesleukin
      subcutaneously (SC) once every other day (QOD) on days 11-19; and pegaspargase IV on days 21
      and 35. Patients also undergo natural killer (NK) cell infusion on day 12. Patients may
      receive triple intrathecal therapy comprising methotrexate, therapeutic hydrocortisone, and
      cytarabine on days 1, 5, 8, 11, 21, and 28. Patients continue on to Block II after count
      recovery.

      BLOCK II: Patients receive methotrexate IV over 24 hours on days 1 and 8 and mercaptopurine
      PO on days 1-21. Patients also receive triple intrathecal therapy on day 1. High-risk
      patients with negative MRD continue on to transplantation. All patients with positive MRD
      continue on to Block III after count recovery.

      BLOCK III: Patients receive cytarabine IV over 2 hours twice daily (BID) on days 1-4 and
      mitoxantrone hydrochloride IV over 1 hour on days 3-5. Patients also receive triple
      intrathecal therapy on day 7.

      INTERIM CONTINUATION (for patients unable to tolerate dose intensive chemotherapy): Patients
      receive etoposide and cyclophosphamide IV on day 1, methotrexate IV on day 8, mercaptopurine
      PO on days 8-14, teniposide and cytarabine IV on day 15, dexamethasone PO TID on days 22-26,
      and vinblastine IV on day 22.

      RE-INDUCTION THERAPY: Patients receive clofarabine, cyclophosphamide, and etoposide IV on
      days 1-5; dexamethasone PO on days 1-6; and pegaspargase on days 6 and 20 and vincristine
      sulfate IV on days 6, 13, and 20. Patients may also receive triple intrathecal therapy on
      days 1 and 15. Patients continue on to continuation treatment after count recovery.

      CONTINUATION TREATMENT: Patients receive methotrexate IV over 2 hours on day 1 and
      mercaptopurine PO on days 1-7 of weeks 1, 2, 5, and 6; teniposide and cytarabine IV on day 1
      of weeks 3 and 7; vincristine sulfate IV on day 1 of week 4; dexamethasone PO TID on days 1-5
      of weeks 4 and 8; and vinblastine IV on day 1 of week 8. Treatment repeats every 8 weeks for
      up to 10 courses in the absence of disease progression or unacceptable toxicity. Patients may
      also receive triple intrathecal therapy on day 1 of week 1 of all courses and day 1 of week
      5, courses 1-5.

      Due to the unavailability of the drug Teniposide (VM-26), etoposide (VP-16) will be
      substituted for the remaining doses for patients currently on this study. The protocol
      Section 5.1.3 allows this substitution.

      OUTLINE: GROUP 2 (high risk defined as participants not meeting the standard risk criteria
      noted above):

      Patients receive Remission Induction (Blocks I, II, and III) treatment as described above for
      Group 1. Patients then undergo allogeneic hematopoietic stem cell transplantation (HSCT) as
      soon as they have negative MRD. Patients with negative MRD may continue chemotherapy until a
      suitable donor is found.

      After completion of study treatment, patients are followed up every 4 months for 1 year,
      every 6 months for 1 year, and then yearly for up to 10 years.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 3-year Overall Survival Rate of Patients With Relapsed ALL
time frame: 3 years of follow-up since the on-study date
description: Estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.
measure: 3-year Event-free Survival Rates in Patients With Relapsed ALL
time frame: 3 years of follow-up since the on-study date
description: Estimate the 3-year event-free survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.
measure: Proportion of Participants With Positive Minimal Residual Disease
time frame: At end of induction (approximately 3 months)
description: To determine minimal residual disease (MRD) levels at the end of remission induction therapy for participants with relapsed precursor B-cell ALL and compare the results with those in protocol ALLR17 (NCT00186875).
measure: Mean of CD20 Expression Levels
time frame: Baseline and at the end of Block I (approximately 5 weeks after the on-study date)
description: To estimate mean levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.
measure: Median CD20 Expression Levels
time frame: Baseline and at the end of Block I (approximately 5 weeks after the on-study date)
description: To estimate median levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.
arm group label: Standard Risk
arm group type: Active Comparator
description: Interventions: dexamethasone, vincristine sulfate, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, teniposide, vinblastine, natural killer cell infusion, laboratory biomarker analysis, therapeutic hydrocortisone
Cells for infusion are prepared using the CliniMACS System.
arm group label: High Risk
arm group type: Active Comparator
description: Interventions: dexamethasone, vincristine, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, natural killer cell infusion, allogeneic hematopoietic stem cell transplantation, laboratory biomarker analysis, therapeutic hydrocortisone
Cells for infusion are prepared using the CliniMACS System.
intervention type: Drug
intervention name: dexamethasone
description: given intravenously or orally
arm group label: High Risk
arm group label: Standard Risk
other name: Decadron(R)
intervention type: Drug
intervention name: vincristine sulfate
description: given intravenously
arm group label: High Risk
arm group label: Standard Risk
other name: Oncovin(R)
intervention type: Biological
intervention name: rituximab
description: given intravenously
arm group label: High Risk
arm group label: Standard Risk
other name: Rituxan(R)
intervention type: Drug
intervention name: clofarabine
description: given intravenously
arm group label: High Risk
arm group label: Standard Risk
other name: Clolar(TM)
other name: clofarex
intervention type: Drug
intervention name: cyclophosphamide
description: given intravenously
arm group label: High Risk
arm group label: Standard Risk
other name: Cytoxan(R)
intervention type: Drug
intervention name: etoposide
description: given intravenously
arm group label: High Risk
arm group label: Standard Risk
other name: VP-16
other name: Vepesid(R)
intervention type: Biological
intervention name: aldesleukin
description: given subcutaneously
arm group label: High Risk
arm group label: Standard Risk
other name: IL-2
other name: interleukin-2
other name: Proleukin (R)
intervention type: Drug
intervention name: pegaspargase
description: given intravenously
arm group label: High Risk
arm group label: Standard Risk
other name: PEG-ASP
other name: Peg-L-asparaginase
other name: PEG-asparaginase
other name: Oncaspar(R)
intervention type: Drug
intervention name: methotrexate
description: given intrathecally or intravenously
arm group label: High Risk
arm group label: Standard Risk
other name: MTX
other name: HDMTX
intervention type: Drug
intervention name: mercaptopurine
description: given orally
arm group label: High Risk
arm group label: Standard Risk
other name: 6-MP
other name: Purinethol(R)
intervention type: Drug
intervention name: cytarabine
description: given intrathecally or intravenously
arm group label: High Risk
arm group label: Standard Risk
other name: Ara-C
other name: Cytosar-U(R)
intervention type: Drug
intervention name: mitoxantrone
description: given intravenously
arm group label: High Risk
arm group label: Standard Risk
other name: Novantrone(R)
intervention type: Drug
intervention name: teniposide
description: given intravenously
arm group label: Standard Risk
other name: VM-26
other name: Vumon(R)
intervention type: Drug
intervention name: vinblastine
description: given intravenously
arm group label: Standard Risk
other name: Velban(R)
intervention type: Biological
intervention name: natural killer cell infusion
description: undergo allogeneic natural killer cell infusion
arm group label: High Risk
arm group label: Standard Risk
other name: NK cell infusion
intervention type: Other
intervention name: laboratory biomarker analysis
description: correlative studies
arm group label: High Risk
arm group label: Standard Risk
intervention type: Drug
intervention name: therapeutic hydrocortisone
description: given intrathecally
arm group label: High Risk
arm group label: Standard Risk
other name: Cortef
intervention type: Procedure
intervention name: allogeneic hematopoietic stem cell transplantation
description: undergo allogeneic HSCT
arm group label: High Risk
other name: HSCT
intervention type: Device
intervention name: CliniMACS
description: The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.
arm group label: High Risk
arm group label: Standard Risk
other name: Cell Selection System
criteria: 
gender: All
minimum age: N/A
maximum age: 21 Years
healthy volunteers: No
last name: Sima Jeha, MD
role: Principal Investigator
affiliation: St. Jude Children's Research Hospital
facility: 
facility: 
facility: 
country: United States
url: http://www.stjude.org
description: St. Jude Children's Research Hospital
url: http://www.stjude.org/protocols
description: Clinical Trials Open at St. Jude
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Recurrence
mesh term: Cytarabine
mesh term: Aldesleukin
mesh term: Dexamethasone
mesh term: Hydrocortisone
mesh term: Hydrocortisone 17-butyrate 21-propionate
mesh term: Hydrocortisone acetate
mesh term: Hydrocortisone hemisuccinate
mesh term: Cyclophosphamide
mesh term: Rituximab
mesh term: Methotrexate
mesh term: Etoposide
mesh term: Vincristine
mesh term: Interleukin-2
mesh term: Asparaginase
mesh term: Mitoxantrone
mesh term: Mercaptopurine
mesh term: Clofarabine
mesh term: Vinblastine
mesh term: Pegaspargase
mesh term: Teniposide
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 