Revised MRC prognostic classifi cation based on multivariable analyzes. Favorable risk cytogenetics \200 t(15;17)(q22;q21): 15% adults <45 years, rare older; fus ion gene PML- RAR ( \200\230FAB M3 \200\231). t(8;21)(q22;q22) Irrespective of additional cytogenetic abnormalities. 5 \200\2238% adults <55 years, rare older; fusion gene AML1/ETO. ( \200\230FAB M2 \200\231). inv(16)(p13q22)/t(16;16)(p13;q22). 10% adults <45 years, rare older; fusion gene CBF /MYH11. ( \200\230FAB M4Eo \200\231). Intermediate risk cytogenetics, \200\230standard risk \200\231 Entities not classifi ed as favorable or adverse. 130 CHAPTER 4 Leukemia Adverse cytogenetics, \200\230poor risk \200\231 \200 abn(3q), excluding t(3;5)(q21725;q 31 \200\22335). \200 inv(3)(q21q26)/t(3;3)(q21;q26). \200 add(5q), del(5q), \210\2225. \200 \210\2227, add(7q)/del(7q), excluding favorable karyotype cases. \200 t(6;11)(q2 7;q23). \200 t(10;11)(p11713;q23). \200 t(11q23), excluding t(9;11)(p21722;q23) and t(1 1;19)(q23;p13). \200 t(9;22)(q34;q11). \200 \210\22217/abn(17p). \200 Complex ( \211 4 unrelated abnormalities). Molecular analysis FISH and RT-PCR methods add sensitivity and precision to the detection o f translocations, deletions, and aneuploidy in cases where conventional cytogenetics fails or gives normal results. RT-PCR detects minimal residual disease overlooked by conventional methods and monitoring b y quantifi cation of PML-RARA transcript numbers in APL can identify patients at higher ris k of relapse. This may also be useful in patients with t(8;21) or inv(16). Presence of an activating mutation of the FLT3 gene with internal tandem repeats (25 \200 \22330% of all AML patients) is predictive for poor outcome in all cytogenetic subgroups. Mutations of the nucleophosmin (NPM) gene which normally produces a protein with diverse fu nctions including regulation of the p53 pathway, are found in many cases with a \200\230no rmal \200\231 karyotype and are associated with a favorable response to induction therapy. Abnormal localization of NPM in the cytoplasm can be detected by immunohistochemistry (NPMc +).6 Clinical features \200 Acute presentation usual; often critically ill due to eff ects of BM failure. Symptoms of anemia: weakness, lethargy, breathlessness, lightheadedness, and palpitations. Infection: particularly chest, mouth, perianal, skin (Staphylococcus, Pseudomonas, HSV, Candida). Fever, malaise, sweats. \200 Hemorrhage (especially APL due to DIC): purpura, menorrhagia and epistaxis, bleeding gums, rectal, retina. Gum hypertrophy and skin infi ltration (monocytic leukaemias (M4, M5)) (see Fig. 4.6). Signs of leucostasis, e.g. hypoxia, retinal hemorrhage, confusion, or diff use pulmonary shadowing. Hepatomegaly occurs in 20%, splenomegaly in 24%; the latter should raise the question of transformed CML; lymphadenopathy is infrequent (17%). CNS involvement at presentation is rare in adults with AML. 131 ACUTE MYELOBLASTIC leukemia (AML) Fig. 4.6 Gum hypertrophy in AML (E see color plate section). Investigations and diagnosis \200 FBC and blood fi lm. \200 EBV, CMV and HIV serology. \200 BM aspirate biopsy. BM infi ltrated with blasts ( \211 20%). \200 BM cytogeneti cs and molecular analysis. \200 Immunophenotyping of blood or marrow aspirate. \200 WBC usually i with blasts on fi lm \200\224but WBC may be low. \200 Hb, neutrophils, and pla telets usually d. Diff erential diagnosis ALL, blast crisis of CML, infectious mononucleosis (in younger pati ents), Megaloblastic anemia. Emergency treatment \200 Seek expert help immediately and refer to AML treatment center i f appropriate. Intensive cardiovascular and respiratory resuscitation may be needed for septic shock or massive hemorrhage. Immediate empirical broad-spectrum antibiotic treatment for neutropenic sepsis. Leucapheresis if peripheral blast count high or signs of leucostasis (clinical, diff use pulmonary shadowing on CXR, or hypoxia). Note: not in APL. Intensive hydration to prevent acute tumor lysis syndrome in patients with a high peripheral blast cell count Urgent chemotherapy; can usually be delayed until necessary clinical and laboratory assessments available. The exception is APL. 132 CHAPTER 4 Leukemia Supportive treatment \200 Explain diagnosis and off er counseling \200\224the word \200 \230leukemia \200\231 and prospect of prolonged chemotherapy are distressing. RBC and platelet transfusion support will continue through treatment: \200 CMV \210\222v e products? Most countries have switched to use of CMV unselected products due to leucodepletion at source. Irradiated products for patients treated with purine analogs. \200 Platelet transfusion t o maintain count >10 \227 109/L, unless septic, haemorrhagic or other haemostatic abnormal ity (>20 \227 109/L); in bleeding APL >50 \227 109/L. Start neutropenic infection prophylaxis regimen. Prompt antibiotic treatment might be required if febrile/septic. Start hydration aiming for urine output >100mL/h throughout induction therapy. Start allopurinol or consider rasburicase (200mcg/kg for up to 7d) to prevent hyperuricaemia/tumor lysis syndrome. Insert tunneled central venous catheter. \200 Routine use of growth factors is not recomm ended. Chemotherapy Where available patients should be entered into clinical trials. Initial aim o f chemotherapy7 is to eliminate leukaemic cells and achieve complete hematological remissio n (CR), defi ned as normal BM cellu- larity (blast cells <5% and normal representation of t rilineage haemat- opoiesis), normalization of peripheral blood count with no blast cells, n eutrophils \211 1.5 \227 109/L, platelets \211 100 \227 109/L and Hb >10g/dL. Leukemia is undetectable by conventional morphology but may be demonstrated by more sensitive molecu lar techniques (when available). CR is not synonymous with cure. Standard treatment is with 4 cycles of intensive combination chemotherapy, each cycle followed by a 2 \200\2233- week period of profound myelosuppression, during which good sup- portive therapy is essential. AML treatment consists of two phases: 1. Remission induction to achieve CR: usually 2 cours es of anthracycline- containing combination chemotherapy; assess BM response after 3 \200 \2234 weeks. \200 DA: daunorubicin 35 \200\22360mg/m2 IV \227 3d plus cytarabine 100mg/ m2/d as 12h IV infusion or divided dose bd bolus \227 8 \200\22310d. 2. Consolidation therapy: essential to reduce risk of relapse; optimum number unknown and p art of ongoing trials. Standard 2 cycles, i.e. HD cytarabine. \200 Enter patient into nat ional or international multicentre clinical trial if possible. Randomized studies are based on large patient numbers and compare increm ental experimental therapy with best treatment arm from previous trials. Allows access to n ovel therapies. Treatment protocols are generally age related; patients >60 \200\22370 years will only tolerate less intensive treatments and rarely transplantation. 133 ACUTE MYELOBLASTIC leukemia (AML) Risk stratifi cation using prognostic factors may determine consolidation therapy in some clinical trials or indeed for patients off -study. Patients who have resistant disease with >5% BM blasts after course 1 or adverse risk cytog enetic or molecular features should be considered for alternative treatment for high-risk A ML preferably within study. This would include intensifi cation of treatment with an aim to move to allo-SCT. Major complications are infective episodes which may be bacterial (Gram +ve and Gram \210 \222ve) or fungal (Candida and Aspergillus); less commonly viral (esp. HSV, HZV) and hemorr hage. No role for maintenance treatment. \200 Eff ectiveness of therapy assessed by CR rate, re lapse-free or disease-free survival, and overall survival. Stem cell transplantation (SCT) \200 Allogeneic SCT7 from a HLA-compatible donor should b e off ered to younger/fi tter patients with poor-risk AML in 1st CR. Relapse risk falls to 20% from 50% with conventional chemotherapy but transplant- related mortality (TRM, 7 \200 \22325%) erodes this advantage, although this is signifi cantly lower with reduced intensit y conditioning allo-SCT. \200 Allo-SCT is an option for those with intermediate (standard ) risk AML. Intensive consolidation is the preferred option for patients with favorable cytogeneti cs for whom SCT should be reserved as salvage treatment in the event of relapse. Some older patients with poor risk AML or beyond 1st CR may benefi t from allogeneic SCT wi th reduced intensity conditioning. Autologous transplantation in AML has been abandoned. \200 Haplo-identical SCT may be und ertaken in younger patients with poor-risk AML or beyond 1st CR in the context of a clinica l trial. Prognosis \200 70 \200\22380% of patients aged <60 years will achieve a CR; more intensiv e induction and consolidation regimens reduce the risk of relapse. \200 Relapse risk at 5 y ears in patients <60 years with favorable risk cytogenetics is 29 \200\22342%; intermediate risk 39 \200\22360%; poor risk 68 \200\22390%. 50 \200\22360% of patients aged \211 60 years achieve CR with induction treatment (rate dr ops with each decade) but relapse occurs in 80 \200\22390%; a higher proportion have poor r isk karyotype, previous myelodysplasia and co-morbidity; treatment-related morbidity and mo rtality is higher. Prognostic factors The most important prognostic factors predicting for achievement of remi ssion and for subsequent relapse are: \200 Advancing patient age: <50 years favorable; >6 0 years unfavorable. \200 Presence of specifi c cytogenetic abnormalities classifi es \200\230favorable \200\231, \200\230intermediate \200\231, and \200\230poor risk \200\231 groups. Failure to achieve CR with 1st cycle of induction therapy predicts for refractoriness/relapse. 134 CHAPTER 4 Leukemia Mutation of FLT3 gene predicts for poor outcome in all cytogenetic subgroups. History of antecedent MDS or leukaemogenic therapy: unfavorable. \200 Presenting blast co unt: <25 \227 109/L favorable; >100 \227 109/L unfavorable. Management of relapse \200 50% of patients in CR after conventional chemotherapy will rel apse.7 \200 Most relapses occur in the fi rst 2 \200\2233 years; <50% achieve 2nd CR. \200 Younger age and longer duration of 1st CR (> 6 months) are good prognostic factors for achieving 2nd CR. 750% of patients achieve 2nd CR with further therapy containing intermediate to high dose cytarabine (e.g. FLAG, FLAG-Ida, Vancouver DA); <10% survive > 3 years without a transplant. Allogeneic SCT is the treatment of choice for a younger/fi tter patient who achieves 2nd CR after relapse. Patients who achieve 2nd CR with chemotherapy should proceed to allograft a s soon as possible thereafter. Long-term DFS rates of 40 \200\22350% have been achieved. RI C allo-SCTs have i the patients eligible for transplant. In younger patients with relapsed AML refractory to 2 cycles of conventional chemotherapy, allogeneic SCT can achieve prolonged DFS in 20 \200\22330%. Donor lymphocyte infusion (DLI) may be used to treat recurrence after an allogeneic transplant. AML in the elderly \200 Older patients have a signifi cantly poorer prognosis, less frequ ent favorable cytogenetics, more frequent unfavorable cytogenetics, more frequent 2 leukemia, more frequent MDR overexpression, i resistance to chemotherapy, and i treatment-related to xicity. Standard chemotherapy regimens may be appropriate in patients <70 years with good performan ce status, aggressive salvage for relapse is rarely appropriate. Non-intensive chemotherapy in combination with good supportive care may control the WBC, mi nimize hospitalization, and provide optimum quality of life. The aim is palliative and to i mprove QoL. Schedules used: Low-dose SC cytarabine. \200 Oral hydroxycarbamide or etoposide. \200 Azacitidine: lice nsed for use in AML with 20 \200\22330% blasts. In some, if not the majority of elderly patients, supportive care alone, including transfusion support, may be appropriate. AML in pregnancy \200 Chemotherapy should be avoided in the 1st trimester if possible due to the high risk of fetal malformation. The option of termination should be discussed w ith the mother. Chemotherapy in the 2nd and 3rd trimesters is associated with i risk of abortion, premature delivery, fetal growth retardation, and neonatal pancytopenia. Early induction of labor be tween cycles should be discussed. Single-agent ATRA is the safest approach for APL in 2nd or 3rd trimesters; Avoid in 1st trimester as teratogenic. 135 ACUTE MYELOBLASTIC leukemia (AML) Extramedullary disease \200 Ranges from gum and skin infi ltration in monocytic (M4/M5) A ML to tumor-like masses (chloroma, granulocytic sarcoma) at any site. \200 Chloroma assoc iated with t(8;21). Usually high presenting WBC but may occur without evidence of marrow or blood involvement by AML. Chloroma may be misdiagnosed as DLBCL no blasts in blood; immunohistochemistry will diff erentiate. Treat with AML chemotherapy. CNS disease \200 Occurs in 0.5% at diagnosis; 5% of AML patients in CR relapse in CNS. Often followed by BM relapse if not already evident. \200 IT prophylaxis shows no benefi t in AML. \200 Treat with IT cytarabine and systemic re-induction chemotherapy. \200 Ve ry poor prognosis. Acute promyelocytic leukemia (APL/APML) APL (FAB M3) requires a diff erent therapeutic appr oach that relates to its biology. Risk of DIC prior to and during initial therapy due to re lease of thromboplastins from leukaemic cells is an indication for urgent treatment. Rapid confi rmation of presence of PML-RARA fusion protein (due to t(15,17) by PML immunofl uores cence or FISH analysis predicts favorable response to all-trans-retinoic acid (ATRA) or ars enic trioxide (ATO). The variant PLZF-RARA fusion (t(11;17) 1%) confers resistance. ATRA sh ould be started as soon as APL is suspected. Dose: 45 mg/m2 daily in 2 divided doses. ATRA induces diff erentiation of abnormal clone by overcoming molecular block resulting from t(1 5;17) translocation and reduces the risk of DIC. ATRA alone can induce remission, but this is not sustained. In combination with anthracycline chemotherapy, 70% of patients may be cu red. Current 1st-line therapy is ATRA + anthracycline induction followed by consolidation. ATRA syndrome is a complication that may follow ATRA therapy: marked neutrophilia, fever, p ulmonary infi ltrates, hypoxia, and fl uid overload. Treat with dexamethasone 10mg bd IV. D iscontinue ATRA in severe cases. Some centers treat preventatively but this is not supporte d in the literature. Molecular monitoring is useful as persistence of the abnormal PML-RARA fusion product after therapy detected by RT-PCR predicts relapse. Arsenic trioxide (ATO) is a useful agent to achieve 2nd CR in patients with PML-RARA-positi ve APL who relapse, but this should be consoli- dated by transplantation. 136 CHAPTER 4 Leukemia References 1. Bennett, J.M. et al. (1985). Proposed revised criteria for the classifi catio n of acute myeloid leukemia. Annals of Internal Medicine, 103, 626 \200\2239. 2. Bennett, J.M. et al (1985). Criteria for the diagnosis of acute leukemia of megakaryocyt ic lineage (M7). A report of the French-American-British Cooperative Group. Annals of Inter nal Medicine, 103, 460 \200\2232. 3. Bennett, J.M. et al. (1991). Proposals for the recognition of minimally diff erentiated acute myeloid leukemia (AML-M0). British Journal of Hematology, 78, 325 \200\2239. Jaff e, E.S. e t al. (2001). Tumors of Haematopoietic and Lymphoid Tissues. World Health Organization Clas sifi cation of Tumors. Lyon: IARC Press. 4. 5. Bain, B.J. et al. (2002) Revised guideline on immunophenotyping in acute leukaemias and chronic lymphoproliferative disorders. Clin Lab Haematol, 24, 1 \200\22313. M http://www. b cshguidelines.com/pdf/CLH135.PDF 6. Dohner, K. et al. (2005). Mutant nucleophosmin (NPM1) predicts favorable prognosis in yo unger adults with acute myeloid leukemia and normal cytogenetics: interaction with other ge ne mutations. Blood, 106, 3740 \200\2236. 7. Milligan, D.W. et al. (2006). Guidelines on the management of acute myeloid leukemia in adults. British Journal of Hematology, 135, 450 \200\22374. Further reading Grimwade D. et al. (2010). Refi nement of cytogenetic classifi cation in ac ute myeloid leukemia: determination of prognostic signifi cance of rare recurring chromosom al abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Re search Council trials. Blood, 116, 354 \200\22365. Swerdlow, S.H. et al. (2008). WHO Classi fi cations of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. Vardiman J . et al. (2009). The 2008 revision of the World Health Organization (WHO) classifi cation o f myeloid neoplasms and acute leukemia: rationale and important changes. Blood, 114, 937 \200\22351. 137 ACUTE MYELOBLASTIC leukemia (AML) 138 CHAPTER 4 Leukemia Acute lymphoblastic leukemia (ALL) Malignant tumor of haemopoietic precursor cells of lymph oid lineage. Incidence Most common malignancy in childhood with the majority of cases in the 2 \200\2231 0 years age group (median 3.5 years). Five times more frequent in childhood than AML. Rare leukemia in adults, 0.7 \200\2231.8/100,000 annually. In adults, peaks at 15 \200\22324 yea rs with further peak in older age (2.3/100,000 >80 years). Etiology Unknown. Predisposing factors are ionizing radiation (AML is more common) and cong enital predisposition in Down syndrome (20-fold in childhood), Bloom, Klinefelter, and Fanc oni syndromes. Chemicals, pol- lution, viruses, urban/rural population movements, father \200\231s radiation exposure, and radon levels have all been postulated. Immunophenotyping A panel of monoclonal antibodies diff erentiates ALL from AML (E Table 4. 3). A further panel of B-and T-lineage markers and lympho- cyte maturation markers subclass ify ALL. Immunological classi \201 cation of ALL B lineage 785% \200 Pro B-ALL (early precursor B -ALL): HLA-DR+, TdT+, CD19+ (5% children; 11% adults). Common ALL: HLA-DR+, TdT+, CD19+, CD10+ (65% children; 51% adults). Pre B-ALL (precursor B-ALL): HLA-DR+, TdT+, CD19+, CD10 , cytoplasmic IgM+. (15% children; 10% adults). B-cell ALL: HLA-DR+, TdT-, CD19+, CD10 , surface IgM+ (3% children; 4% adults) T lineage 715% \200 Pre-T ALL: TdT+, cytoplasmic CD3+, CD7+ (1% children; 7% adults). \200 T-cell ALL: TdT+, cytoplasmic CD3+, CD1a/2/3+, CD5+ (11% children; 17% adults). Classi \201 cation Historically ALL classifi cation was by morphology (FAB classifi cation ). The FAB classifi cation has since been superseded by the WHO classi- fi cation, which in cludes cytogenetic, immunophenotypic and molecular information (Tables 4.4 and 4.5). Both c lassifi cations, however, are included for historical context. 139 ACUTE LYMPHOBLASTIC leukemia (ALL) Table 4.4 WHO classifi cation of acute lymphoblastic leukemia/ lymphomaa B-lymphoblastic leukemia/lymphoma, NOS B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities: \200 ALL with t(9 ;22)(q34;q11.2); BCR-ABL (Philadelphia chromosome) \200 ALL with t(v;11q23). MLL rearrang ed \200 ALL with t(1;19)(q23;p13.3); TCF3-PBX1 (E2A-PBX1) \200 ALL with t(12;21)(p13;q2 2); ETV6-RUNX1 (TEL-AML1) \200 Hyperdiploid >50 \200 Hypodiploid \200 ALL with t(5;14 )(q31;q32); IL3-IGH T-lymphoblastic leukemia/lymphoma a 2008 classifi cation. Table 4.5 Historical morphological classifi cation (French \200\223American \200\223 Britis h, FAB) L1 Small monomorphic type \200\224small homogeneous blasts, single inconspicuous nucleolus, re gular nuclear outline; commonest subtype in children; <50% of adults. L2 Large heterogeneous type \200\224larger blasts, more pleomorphic and multinucleolate, irreg ular frequently clefted nuclei with conspicuous nucleoli; commonest in adults. L3 Burkitt cell type \200\224large homogeneous blasts, prominent nucleoli, abundant strongly b asophilic cytoplasm with vacuoles; associated with B-cell phenotype. Cytogenetic analysis \200 Provides important prognostic information in both children and adults. Abnormalities detected in up to 85%. Each has an incidence in the order of 5 \200\22310% or less in adults. If no structural abnormalities present, abnormalities are classifi ed by the modal chromoso me number: <46 (hypodiploid); 46 with other structural abnormalities (pseudodiploid); 47 \200\22350 (hyperdiploid); >50 (hyper-hyperdiploid). t(9;22)(q34;q11), the Philadelphia (Ph) chromosome, found in 5% of children and 25% of adul ts with ALL; very strong adverse prognostic factor in both; resultant BCR-ABL hybrid produc t is same 210 kDa protein detected in CML in 33% but is smaller 180 kDa protein in 66%; can be used for MRD detection. Ph+ ALL rarely cured by chemotherapy alone. t(1;19) associated with precursor B-cell ALL. 140 CHAPTER 4 Leukemia t(v;11q23), MLL rearranged. Occurs in 80% of infants with ALL and 6% of adults; fuses the M LL gene from 11q23; all these abnormalities associated with refractory disease and early re lapse. t(8;14) is associated with B-cell ALL ( \200\230L3 morphology \200\231) and occurs in 5% of cases (dysregulates the c-myc proto-oncogene); variant c-myc translocations occur in t(2;8 ) & t(8;22). t(12;21)(p13;q22) is most common specifi c abnormality in childhood ALL (725%); associated with TEL-AML1 translocation and good prognosis; much less common in adults (72%). Hyper-hyperdiploidy (>50 chromosomes) confers favorable prognosis (725% children; 75% adults); combined +4, +10 confers a favorable outcome in B-ce ll precursor ALL; patients with hypoploidy (<46 chromosomes) and pseudodiploidy have a poor prognosis. \200 t(11;19) with MLL-ENL fusion and overexpression of HOX11 confers good prognosis in T-cell ALL. Molecular analysis FISH and RT-PCR methods add sensitivity and precision to the detection o f prognostically signifi cant translocations, deletions, and aneuploidy in cases where cyto genetics fails or gives normal results. Analysis of spe- cifi c translocations, Ig, or T-ce ll receptor rearrangements allows detec- tion of MRD permitting risk-stratifi ed consolidat ion therapy. Clinical features \200 Acute presentation usual; often critically ill due to BM failure: Anemia: weakness, lethargy, breathlessness, lightheadedness, and palpitations. Infection: particularly chest, mouth, perianal, skin (Staphylococcus, Pseudomonas, HSV, Candida). Fever, malaise, sweats. \200 Hemorrhage: purpura, menorrhagia, and epistaxis, bleeding gums, rectal, retina. Signs of leucostasis e.g. hypoxia, retinal hemorrhage, confusion, or diff use pulmonary shadowing. Bone or joint pain is more common in children. \200 Mediastinal involvement in 15%; may c ause SVC obstruction especially T-ALL (see Fig 4.7). CNS involvement in 6% at presentation; may cause cranial nerve palsies especially facial nerve, sensory disturbances, and meningism. \200 Signs include widespread lymphadenopathy in 55%, mild-to-moderate splenomegaly (49%), hepatomegaly (45%), and orchidomegaly. Diff erential diagnosis \200 In adults: AML, aplastic anemia, infectious mononucleosis, lymphoma with blood spill, transformed CML. In childhood: AML, aplastic anemia, infectious mononucleosis, pertussis, neuroblastoma, rha bdomyosarcoma, Ewing sarcoma. Investigations and diagnosis \200 FBC and blood fi lm. \200 BM aspirate biopsy. 141 ACUTE LYMPHOBLASTIC leukemia (ALL) BM cytogenetics and molecular analysis. \200 Immunophenotyping of blood or marrow blasts. \200 Total WBC usually high with blast cells on fi lm but may be low ( \200\230aleukaemic leukemia \200\231). Hb, neutrophils, and platelets often low; clotting may be deranged. \200 BM heavily infi ltrated with blasts ( \211 20%) (Figs 4.8 and 4.9). \200 CXR and CT scan needed if ALL ha s B-cell or T-cell phenotype for abdominal or mediastinal lymphadenopathy respectively. Lumbar puncture mandatory to detect occult CNS involvement but (may be) postponed until tre atment reduces high peripheral blast count to prevent seeding. Diagnostic LP combined with 1st intra- thecal CNS directed therapy. Note: fundoscopy, CT scan of head, and platelet tra nsfusion usually required. Fig. 4.7 Mediastinal mass in T-ALL. Fig. 4.8 BM: lymphoblasts in ALL L1 (E see color plate section). 142 CHAPTER 4 Leukemia Fig. 4.9 BM: T-cell ALL showing numerous lymphoblasts (E see color plate section). Emergency treatment Seek expert help immediately. \200 Cardiovascular and respiratory res uscitation may be needed if septic shock or massive hemorrhage. Immediate empirical broad-spectrum antibiotic treatment for neutropenic sepsis. Leucapheresis may be needed if peripheral blast count high or signs of leucostasis (retinal hemorrhage, reduced conscious level, diff use pulmonary shadowing on CXR or hypoxia). LP if meningism (note precautions discussed on E Protocols and procedures, p.699). Supportive treatment \200 Provide explanation and off er counseling \200\224the word \200\230leukemia \200\231 and prospect of prolonged chemotherapy are often distressing. RBC and platelet transfusion support will continue through treatment: \200 Irradiated pro ducts for patients treated with purine analogs. \200 Platelet transfusion to maintain cou nt >10 \227 109/L, unless septic, on antibiotics, haemorrhagic or other haemostatic abnorm ality (>20 \227 109/L). Start neutropenic regimen as prophylaxis against infections. \200 Start hydration aiming for urine output >100mL/h throughout induction therapy. Tumor lysis syndrome: a particular problem in B-cell or T-cell ALL. Start IV fl uids and allopurinol or rasburicase in high counts. Note: interaction with 6-mercaptopurine: discontinue allopurinol or reduce dose of 6-MP or give rasburicase instead. Insert tunneled central venous catheter. 143 ACUTE LYMPHOBLASTIC leukemia (ALL) Chemotherapy Adult ALL regimens have evolved from successful treatments for child- hood ALL . Initial aim of chemotherapy is to eliminate leukaemic cells and achieve complete hematolo gical remission (CR), defi ned as normal BM cellularity (blast cells <5% and normal represe ntation of trilineage haematopoiesis), normalization of peripheral blood count with no blas t cells, neutrophils \211 1.5 \227 109/L, platelets \211 100 \227 109/L and Hb>10g/ dL. Leukemia is undetectable by conventional morphology but may be demonstrated by more sensit ive molecular techniques and CR is not synonymous with cure. \200 Major treatment related complications are infective episodes which may be bacterial (Gram +ve and Gram \210\222ve ), viral (esp. HSV, HZV), and fungal (Candida and Aspergillus). In the longer term, relapse is the main complication. Enroll in high-quality multicentre trial if possible: Treatment for ALL consists of 4 conti guous phases:1 \200\2233 1. Remission induction \200 Vincristine, prednisolone (or dexamethasone), dauno/doxorubic in, other cytostatics, and (peg-)asparaginase to achieve CR. More intensive induction: anthracycline improves leukemia-free survival. 2. Consolidation therapy \200 To further reduce or eliminate tumor burden and risk of rel apse and development of drug-resistant cells; consists of alternating cycles of induction a gents and other cytotoxics. Usually includes several \200\230intensi \201 cation \200\231 phases; combinations of met hotrexate at high dose, cytarabine, etoposide, m-amsacrine, mitoxantrone (mitozantrone), an d idarubicin. 3. CNS prophylaxis \200 Can include craniospinal irradiation (18 \200\22324Gy in 12 fract ions over 2 weeks) plus IT chemotherapy (methotrexate cytarabine or prednisolone) early in the consolidation phase. Irradiation avoided in childhood ALL due to side eff ects and replaced by high-dose systemic methotrexate plus IT therapy. IT therapy continued in consolidation and maintenance phases. \200 CNS prophylaxis reduce s CNS relapse from 30% to 5%. \200 Simultanous administration of IV vincristine and IT me thotrexate must be avoided as errors can be fatal. 4. Maintenance therapy \200 Necessary for all patients who do not proceed to SCT. \200 Daily 6-MP PO and weekly methotrexate PO with doses to limits of tolerance plus cyclical IV vincristine, oral prednisolone, and IT methotrexate for 2 years in girls and 3 years in bo ys. Allogeneic stem cell transplantation \200 Ph+ ALL: allogeneic SCT transplant recommended in CR1 for all eligible patients. 144 CHAPTER 4 Leukemia Consider allogeneic SCT in all adults with a compatible sibling or VUD (volunteer unrelated donor) in CR1, especially in MRD+ve patients and patients with poor risk cytogenetics. Leukemia-free survival superior after 1st remission allograft in patients with high-risk disease (40% vs <10% for Ph/BCR-ABL+ ALL); RIC-allografts have sign ifi cantly reduced treatment-related mortality. In low/good risk young/pediatric patients SCT can be reserved for second CR. Ph+/BCR-ABL+ ALL \200 TKI (tyrosine kinase inhibitor): imatinib mesylate is included in r egimen of patients with Ph+ ALL.4 Improved CR, LFS, and OS. Also considered post-allogeneic transplant. Eligible patients should receive SCT early in 1st CR. Mature B-cell ALL/Burkitt cell leukemia \200 Old \200\230FAB L3 \200\231 classifi cation ; Burkitt cell type: distinct treatment approach. No longer ALL in WHO classifi cation: Burkitt lymphoma/ Burkitt cell leukemia.5 T reatment as for Burkitt lymphoma. \200 Improved prognosis; 75% CR; >65% LFS at 1 year: 40 % DFS. T-cell ALL \200 Higher incidence of CNS disease at diagnosis and relapse.6 \200 High cu re rates when treated with cyclophosphamide-containing regimens yielding DFS of 50 \200\22370%. CNS leukemia \200 i risk with high-risk genetics, T-cell ALL, and high blast count. \200 Presents with headache, vomiting, lethargy, nuchal rigidity, or cranial or peripheral nerve dysfunction. Clinical examination may reveal papilloedema, meningism, neurological defi cit, and LP shows blasts in CSF. Treat with intensifi ed IT triple therapy plus craniospinal irradiation; IT methotrexate, c ytarabine, and hydrocortisone 2 \200\2233 \227 times weekly over 3 \200\2234 weeks until 2 consecutive CSF samples are \210\222ve; insertion of an Ommaya reservoir facilitates such frequent IT therapy. If relapse, will require systemic re-induction as BM relapse often present or follows. Poor prognosis. Minimal residual disease detection Flow cytometry for clonal immunophenotypes or FISH or RT -PCR for fusion proteins or clonal Ig/TCR gene rearrangements identifi ed at diagnosis can detect minimal residual disease (MRD) at a sensitivity of 10 \210\2223 \200\22310 \210\2226 . Morphological and molecular CR can be distinguished. MRD \210\222ve status post-initial induction phase (d28 \200\22335) has very strong prognostic indications. MRD \210\222ve pa tients carry a much better prog- nosis. MRD can be repeated at additional time-points depen ding on the regimen used. MRD +ve patients have a very high risk of relapse and are candida tes for allogeneic SCT. 145 ACUTE LYMPHOBLASTIC leukemia (ALL) Prognosis \200 Overall 775% of adults with ALL achieve a CR with a modern regimen and goo d supportive care; more intensive induction and consolidation reduces relapse risk but adds toxicity; results in patients >50 years are less good. Relapse rates remain high. Median remission duration of CR is around 15 months. 35 \200\22340% of adults with ALL treated with intensive chemotherapy survive 2 years. \200 In contrast to high cure rate in childhood ALL, leukemia-free survival (LFS) in adult ALL in general is <3 0% at 5 years (patients >50 years 10 \200\22320%). LFS after chemotherapy in patients witho ut adverse risk factors is >50% but <10% for very high-risk Ph/BCR-ABL+ ALL; hence latter s hould have an allograft in 1st CR if possible. Prognostic factors Prognosis in adult ALL is much poorer than childhood ALL (cure rate 780% ) due to higher frequency of poor prognostic features and treat- ment-related toxicity. The most important prognostic factors are listed. These are useful for risk stratifi cation to identify patients who require more intensive therapy and SCT in 1st CR. \200 Patient age (<50 years CR >80%, LFS >30%; \211 50 years CR <60%, LFS <20%). High leucocyte count (>30 \227 109/L in B precursor-ALL; >100 \227 109/L in T-ALL) poor risk. Immunophenotype: pro-B-ALL and pro-T-ALL have poorer outcomes; common pre-B-ALL still poor; mature B-cell ALL and T-cell ALL have better outcome s due to the use of more intensive regimens. Cytogenetics: Ph/BCR-ABL+ very poor prognosis: <10% LFS after chemotherapy; Long time to CR (>4 weeks): poor risk. \200 High MRD level after induction (>10 \210\2223 ); persistent/increasing MRD during consolidation: poor risk. Management of relapse \200 Relapse rate highest within fi rst 2 years but may occur after 7 years. \200 20% occur outside BM, generally CNS; testis and other sites occur in 5%. \200 Isolated extramedullary relapse often followed by hematological relapse; these patients require local treatment followed by systemic re-induction therapy. Best predictive factor for response is duration of 1st CR (better >18 months). 50 \200\22360% of patients achieve a short 2nd CR (generally <6 months). \200 Prompt SCT off ers only prospect of LFS and cure. \200 Patients with BCR-ABL+ALL on maintenance imat inib at relapse have prospect (70%) of up to 6 months \200\231 hematological response to dasatinib. Clofarabine and nelarabine-containing regimens can be used. 146 CHAPTER 4 Leukemia References 1. Finiewicz, K.J. and Larson, R.A. (1999). Dose-intensive therapy for adult acu te lymphoblastic leukemia. Semin Oncol, 26, 6 \200\22320. 2. Thomas, X. et al. (2004). Outcome of treatment of adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol, 22, 4075 \200\22386. 3. Pui, C.-H. and Evans, W.E. (2006). Treatment of acute lymphoblastic leukemia. N Engl J Med, 354, 166 \200\22378. 4. Wassmann, B. et al. (2006). Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia ( Ph+ ALL). Blood, 108, 1469 \200\22377. 5. Lee, E.J. et al. (2001). Brief-duration high-intensity chemotherapy for patients with sm all noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukem ia group B study 9251. J Clin Oncol, 19, 4014 \200\22322. 6. Larson, R.A. et al. (1995). A fi ve-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B stu dy 8811. Blood, 85, 2025 \200\22337. Further reading Lukenbill, J. et al. (2013). The treatment of adolescents and young adults with acute lymphoblastic leukemia. Curr Hematol Malig Rep, 8(2), 91 \200\2237. NCCN (2013). NCCN Guidelines on ALL. Version 1.2013. Fort Washington, PA: NCCN. Mwww.NCCN.org. Salami, K. et al. (2013). Hematopoietic stem cell transplant versus chemotherapy plus tyrosine kina se inhibitor in the treatment of pediatric Philadelphia chromosome-positive acute lymphobla stic leukemia (ALL). Hematol Oncol Stem Cell Ther, 6(1), 34 \200\22341. Swerdlow, S.H. et a l. (2008). WHO Classifi cations of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. L yon: IARC. Wood, BL. (2013). Flow cytometric monitoring of residual disease in acute leukem ia. Methods Mol Biol, 999, 123 \200\22336. 147 ACUTE LYMPHOBLASTIC leukemia (ALL) 148 CHAPTER 4 Leukemia Chronic myeloid leukemia (CML) Malignant tumor of pluripotent haemopoietic stem cell. The c lonal marker is found in all 3 myeloid lineages and in some B and T lympho- cytes demonstra ting a primitive origin. Characterized by ii granulocytes with left shift and the presence of the Ph chromosome. Incidence Rare disease. Frequency 1.25 per 100,000. Accounts for 15% adult leu- kaemias. Ra re in children. Median age of onset 50 years. Slight \231\202 excess. Etiology Unknown. Irradiation is only known epidemiological factor. BCR-ABL fusion proteins appear to play a role in the pathogenesis of CML and have been shown to transform haemopoi etic progenitor cells in vivo and in vitro. Classi \201 cation Classifi ed as a myeloproliferative disorder (WHO classifi cation) with which it shares a number of clinical features but it also has unique bio- logical features . Natural history \200 Biphasic or triphasic disease: chronic phase (CP), accelerated phase (AP), and blast crisis (BC); 50% transform directly from CP to BC. \200 >85% patients pr esent in CP: defi ned by absence of features of AP or BC. AP characterized by blood counts and organomegaly becoming increasingly refractory to therapy; some have constitutional symptoms. \200 BC resembles acute leukemia with >20% blasts and promyelocytes in blood or marrow; rapidly fatal (Tables 4.6 and 4.7). Clinical symptoms and signs \200 30% asymptomatic at diagnosis; present after routine FBC . \200 Fatigue, lethargy, weight loss, sweats. \200 Splenomegaly in >75%; may cause (L) hypochondrial pain, (early) satiety, and sensation of abdominal fullness. Gout, bruising/bleeding, splenic infarction, and occasionally priapism. \200 hepatomegaly (2%), lymphadenopathy unusual. \200 Occasional signs of leucostasis at presentation. Diagnosis and investigations \200 FBC and blood fi lm show i WBC (generally >25 \227 109 /L, often 100 \200\223300 \227 109/L): predominantly neutrophils and myelocytes; basophili a; sometimes eosinophilia (see Figs. 4.10 and 4.11). Anemia common; platelets typically n or i. \200 Historical: low neutrophil alkaline phosp hatase (NAP) score (no longer used). LDH and urate levels i. \200 BM shows marked hypercellularity due to granulocytic hyperpl asia (blasts <10% in chronic phase; >10% in AP; >20% blasts in BC); trephine biopsy useful to assess marrow fi brosis. \200 Cytogenetic analysis of blood or marrow for t(9;22). 149 CHRONIC MYELOID leukemia (CML) Molecular analysis by real-time quantitative reverse transcription polymerase chain reactio n (RQ-PCR) for BCR-ABL transcripts to obtain baseline for subsequent monitoring. FISH analy sis of blood or marrow will confi rm presence of BCR-ABL. Table 4.6 WHO criteria for accelerated phase Blasts 10 \200\22319% of WBCs in peripheral blood and/or nucleated BM cells Peripheral bloo d basophils \211 20% Persistent thrombocytopenia (<100 \227 109/L) unrelated to therapy o r persistent thrombocytosis (>1000 \227 109/L) unresponsive to therapy i spleen size and i WBC count unresponsive to therapy Cytogenetic evidence of clonal evolution Table 4.7 WHO criteria for blast crisis Blasts \211 20% of peripheral blood WBCs in or of nucleated BM cells Extramedullary blast proliferation Large foci or clusters of blasts in the BM biopsy Fig. 4.10 Peripheral blood fi lm in CML: note large numbers of granulocytic cells at all st ages of diff erentiation (low power) (E see color plate section). 150 CHAPTER 4 Leukemia Fig. 4.11 Peripheral blood fi lm in CML (high power) (E see color plate section). Cytogenetic and molecular analysis \200 Characterized in >80% patients by the presence of the Ph