What are the guideline sources, guidelines and references for Chronic lymphocytic leukemia ?
Guideline sources The following summarized guidelines for the evaluation and management of chronic lymphocytic leukemia (CLL) are prepared by our editorial team based on guidelines from the British Society for Haematology (BSH 2022; 2018), the European Society of Medical Oncology (ESMO 2021), the International Workshop on Chronic Lymphocytic Leukemia (iwCLL 2018), and the American Association of Family Physicians (AAFP 2014). 1 2 3 4 5 6 7 8 9 9 10 Definition CLL is a lymphoproliferative malignancy characterized by peripheral lymphocytosis due to the proliferation of clonal B cells. 7 Epidemiology CLL is caused by somatic gene mutations involving multipotent and self-renewing hematopoietic stem cells, which leads to clonal proliferation and accumulation of mature B cells. 9 Pathophysiology The incidence of CLL in the United States is estimated at 4.83 per 100,000 person-years. 8 https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 1/11 6/23/23, 3:26 AM Chronic lymphocytic leukemia Pathway Disease course Accumulation of B cells in the bone marrow, blood, lymph nodes, and spleen can result in cytopenias, lymphadenopathy, splenomegaly, hepatomegaly, susceptibility to infection, bone marrow failure, and death. 9 Prognosis and risk of recurrence The overall survival at 5-years for patients with low-risk, intermediate-risk, high-risk, and very-high risk CLL is 93.2%, 79.4%, 63.6%, and 23.3%, respectively. 10 Calculator Calculator Calculator Eastern Cooperative Oncology G International prognostic index fo Karnofsky Guidelines 1. Screening and diagnosis Indications for screening: do not obtain routine screening for CLL in the general population nor in relatives of patients with CLL. D Diagnostic criteria: As per ESMO 2021 guidelines, consider establishing the diagnosis of CLL solely based on immunophenotyping of peripheral blood. B As per iwCLL 2018 guidelines, diagnose CLL in the presence of B lymphocytes in the peripheral blood at a concentration 5 10 cells/L, sustained for 3 months, with confirmation of clonality via flow cytometry. E As per AAFP 2014 guidelines, suspect CLL in older adult patients with a markedly elevated WBC count and an enlarged liver or spleen. B Patients with Richter's transformation, biopsy: as per BSH 2022 guidelines, ensure specialist hematopathology review, clinicopathological correlation, and multidisciplinary review when evaluating Richter's transformation. B Show 3 more Differential diagnosis: suspect common causes such as infection, inflammation, and stress response when evaluating a patient with leukocytosis. Obtain peripheral blood smear in patients with a WBC count > 20, 000/ L and with associated anemia, thrombocytopenia, thrombocytosis, enlarged liver, spleen or lymph nodes, or constitutional symptoms. B 2. Diagnostic investigations https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 2/11 6/23/23, 3:26 AM Chronic lymphocytic leukemia Pathway History and physical examination: As per ESMO 2021 guidelines, elicit history and perform physical examinations, including careful palpation of all lymph node areas, spleen, and liver, in asymptomatic patients with early- stage disease, as well as before initiating treatment in patients with advanced or symptomatic stage disease. B As per iwCLL 2018 guidelines: Assess performance status by the ECOG (ECOG) score as an essential baseline test. E Record the bidimensional diameters of the largest palpable lymph nodes in each of the following sites: cervical, axillary, and inguinal. Moreover, record the dimensions of the liver and spleen below their respective costal margins, as assessed by palpation. Be aware of the fact that any of these manifestations of CLL, in particular hepatomegaly, could be caused by a variety of other diseases. E Laboratory testing: As per ESMO 2021 guidelines, obtain CBC with differential in patients with early, asymptomatic stage disease, as well as before initiating treatment in patients with advanced or symptomatic stage disease. B Show 2 more As per iwCLL 2018 guidelines, obtain the following essential baseline investigations: complete blood cell count and differential leukocyte count creatinine, bilirubin, transaminases and ALP LDH and haptoglobin -2 microglobulin serum immunoglobulin levels direct antiglobulin test human immunodeficiency virus, CMV, HBV, and HCV serologies. E Screening for viral infections: Assess history and status of relevant infections (HBV, HCV, human immunodeficiency virus, CMV) to prevent virus reactivation before initiating treatment in patients with advanced or symptomatic stage disease. B Consider obtaining HEV testing before initiating treatment in patients with advanced or symptomatic stage disease, especially if HBV-positive. C Diagnostic imaging: As per ESMO 2021 guidelines: Obtain chest imaging before initiating treatment in patients with advanced or symptomatic stage disease. B Do not obtain routine imaging during a watch-and-wait period unless there are clinical symptoms. D As per iwCLL 2018 guidelines, obtain a CXR when a CT scan is not performed, as an essential baseline investigation. E https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 3/11 6/23/23, 3:26 AM Chronic lymphocytic leukemia Pathway 3. Diagnostic procedures Biopsy: As per ESMO 2021 guidelines: Consider performing lymph node biopsy and/or bone marrow biopsy if immunophenotyping is not conclusive for the diagnosis of CLL. B Consider performing bone marrow examination for the diagnostic evaluation of unclear cytopenia or in the presence of a non-conclusive phenotype before initiating treatment in patients with advanced or symptomatic stage disease. Consider performing a bone marrow biopsy as a baseline parameter to assess treatment response. C As per iwCLL 2018 guidelines, perform a unilateral marrow aspirate and biopsy before initiating treatment within in a clinical trial. Consider comparing repeat marrow biopsies with the baseline marrow specimen to assess the cause of cytopenias. E Cytogenetic analysis: As per ESMO 2021 guidelines, obtain FISH for the detection of chromosome 17 deletion affecting the tumor protein p53 expression, and obtain TP53 sequencing, at least exons 4-10, exons 2-11, for the detection of TP53 gene mutation in the absence of chromosome 17 deletion before initiating treatment in patients with advanced or symptomatic stage disease. B Obtain analysis as close as possible, such as < 6 months, to initiation of therapy because genetic lesions may evolve throughout the disease. B Show 4 more As per BSH 2018 guidelines: Assess for TP53 disruption in all patients with CLL before initiating any line of therapy. Assess for both mutation and deletion detection, B and ideally also for subclonal TP53 mutations. B Consider assessing the IgHV mutation status in patients with CLL. C As per iwCLL 2018 guidelines, perform examination of leukemia-cell cytogenetics and analysis for inactivating mutations in TP53 before any line of therapy. E 4. Medical management General principles: Decide on treatment choice and aims in discussion with the patient and a CLL expert B and based on the patient's wishes, comorbidities, and potential drug side effects. B Offer the opportunity to participate in a clinical trial, where available, in all patients with CLL. Watchful waiting: As per ESMO 2021 guidelines, offer a watch-and-wait approach in patients with early disease. A Do not obtain routine imaging during a watch-and-wait period unless there are clinical symptoms B https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 4/11 6/23/23, 3:26 AM Chronic lymphocytic leukemia Pathway As per AAFP 2014 guidelines, consider monitoring asymptomatic patients with early-stage CLL (no anemia or thrombocytopenia and with < 3 areas of nodal involvement) without treatment. C Indications for treatment: As per ESMO 2021 guidelines: Consider using the Binet and Rai staging systems with clinical symptoms to decide on treatment indications. B Decide on the type of front-line treatment based on TP53 mutation or del(17p), IgHV mutational status, age, comorbidities, and comedication. B As per iwCLL 2018 guidelines: Initiate therapy in patients with CLL in whom active disease is clearly documented and at least 1 of the following criteria are met: evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Cutoff levels of Hgb < 10 g/dL or platelet counts < 100 10 /L are generally regarded as indication for treatment. However, in some patients, platelet counts < 100 10 /L may remain stable over a long period; this situation does not automatically require therapeutic intervention massive, such as 6 cm below the left costal margin, or progressive or symptomatic splenomegaly massive nodes 10 cm in longest diameter, or progressive or symptomatic lymphadenopathy progressive lymphocytosis with an increase of 50% over a 2-month period, or lymphocyte doubling time < 6 months. Exclude factors contributing to lymphocytosis other than CLL autoimmune complications including anemia or thrombocytopenia poorly responsive to corticosteroids symptomatic or functional extranodal involvement disease-related symptoms as defined by any of the following: unintentional weight loss 10% within the previous 6 months significant fatigue fevers 100.5 F or 38.0 C for 2 weeks without evidence of infection night sweats for 1 month without evidence of infection. E Avoid restarting therapy on the basis of disease relapse alone unless the disease is symptomatic. Avoid restarting therapy on the basis of asymptomatic increases of lymphocyte counts alone without other signs of progression. Follow the same indications for second- and subsequent-line treatment decisions as those used for first-line treatment. D Initial treatment: As per BSH 2022 guidelines, offer venetoclax-obinutuzumab or acalabrutinib as initial therapy in patients unsuitable for chemoimmunotherapy, irrespective of TP53 status. B Show 5 more As per ESMO 2021 guidelines, offer ibrutinib in fit patients with CLL with unmutated IgHV status and without TP53 mutation or chromosome 17p deletion. Consider offering https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 5/11 6/23/23, 3:26 AM Chronic lymphocytic leukemia Pathway chemoimmunotherapy if other options are not available. A Show 4 more As per BSH 2018 guidelines, offer fludarabine, cyclophosphamide, and rituximab (FCR) as initial therapy in previously untreated fit patients without TP53 disruption. B Show 5 more Chimeric antigen receptor therapy: As per BSH 2022 guidelines, offer chimeric antigen receptor T-cell therapy only in the setting of a clinical trial. As per ESMO 2021 guidelines, consider offering chimeric antigen receptor T-cell therapy or bi- specific T-cell engager antibodies as an alternative to allo-SCT in the setting of a clinical trial. C Management of cytopenias: As per ESMO 2021 guidelines, consider administering high-dose corticosteroids in patients with autoimmune cytopenia, specifically in patients with warm autoantibodies. C Show 2 more As per BSH 2018 guidelines, treat autoimmune complications in patients with otherwise asymptomatic CLL not requiring therapy and concurrent autoimmune cytopenias. B Show 3 more As per iwCLL 2018 guidelines, administer growth factors such as G-CSF while patients are under myelosuppressive chemotherapy. E Management of hypogammaglobulinemia: As per BSH 2022 guidelines, offer immunoglobulin replacement therapy in patients with low IgG levels (< 4 g/L), recurrent or serious infection despite 6 months of prophylactic antibiotics, and a documented failure to respond to vaccination. As per ESMO 2021 guidelines, offer prophylactic systemic immunoglobulin replacement therapy only in patients with severe hypogammaglobulinemia and repeated or severe infections. A As per BSH 2018 guidelines, offer immunoglobulin replacement therapy in patients with reduced IgG (< 5 g/L) and recurrent infections failed a 3-month trial of broad spectrum prophylactic antibiotic (according to local antimicrobial protocols). B As per iwCLL 2018 guidelines, reserve intravenous IgAdministration for individual situations of hypogammaglobulinemia and repeated infections. E Management of tumor lysis syndrome: monitor patients in early-phase clinical trials for possible tumor lysis syndrome, and treat appropriately. If observed, record the occurrence and severity of tumor lysis syndrome in clinical trials using established criteria. E Management of infection: evaluate for infection source in patients with leukemia, fever with neutropenia (< 500/ L) and initiate empiric broad-spectrum antibiotics. B 5. Therapeutic procedures Stem cell transplantation: https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 6/11 6/23/23, 3:26 AM Chronic lymphocytic leukemia Pathway As per BSH 2022 guidelines, consider offering allo-SCT in suitable patients with high-risk CLL defined by either of the following: failed two out of chemoimmunotherapy, B-cell receptor inhibitors or BCL-2 inhibitors irrespective of TP53 status C failed either B-cell receptor inhibitors or BCL-2 inhibitors therapy and harboring a TP53 disruption. C As per ESMO 2021 guidelines: Do not perform ASCT in patients with CLL. D Consider offering allo-SCT in patients with any of the following: refractory to chemoimmunotherapy with TP53 mutation or del(17p) but fully responsive to novel inhibitor therapy; discuss allo-SCT with the patient as an option for curative treatment if the risk of transplantation is low refractory to chemoimmunotherapy and to novel inhibitor therapy, even in patients with a higher risk of non-relapse mortality (HSCT-Specific Comorbidity Index score 3) (III, B) richter's transformation in remission after therapy and clonally related to CLL. As per BSH 2018 guidelines: Consider offering allo-SCT in patients with CLL with any of the following: failed chemoimmunotherapy and B-cell receptor inhibitor therapy, irrespective of TP53 status not responding or losing response to B-cell receptor inhibitor therapy and harboring a TP53 disruption. C Consider offering allo-SCT in all eligible patients with Richter's transformation. C 6. Specific circumstances Frail patients: consider offering chlorambucil monotherapy in extremely frail patients intolerant to anti-CD20 antibodies or when IV therapy is deemed unsuitable. Consider offering corticosteroid monotherapy. C Show 2 more Patients with chronic hepatitis B or C: Administer prophylactic antiviral agents to patients found to be chronic carriers of HBV, while undergoing therapy for chronic lymphocutic leukemia with immunosuppressive drugs. E Initiate antiviral therapy before antileukemic treatment in patients with high titers of HBV or HCV DNA. E Patients with CMV infection: monitor patients treated with immune-suppressive agents for CMV and consider for antiviral therapy if found to have increased levels of CMV in the blood by the PCR, even in the absence of clinical symptoms. Moreover, initiate antiviral therapy for infected patients with clinical symptoms of active CMV infection. E Patients with AIHA or ITP: treat immune thrombocytopenia and autoimmune hemolytic anemia as a single abnormality caused by CLL initially with corticosteroids and not initially with https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 7/11 6/23/23, 3:26 AM Chronic lymphocytic leukemia Pathway chemotherapy or targeted agents. Rituximab, splenectomy, IVIG, and/or immunosuppressive therapy are the second-line treatment options for autoimmune hemolytic anemia. E Patients with COVID-19 infection: Administer monoclonal antibody therapy against the spike protein (or antiviral therapy if monoclonal antibody therapy is unavailable) in patients developing COVID-19 infection and presenting within 5 days of symptom onset. Offer COVID-19 vaccination in all patients and household members. Patients with Richter's transformation, biopsy: as per ESMO 2021 guidelines, perform a lymph node biopsy or excision and histopathological examination to confirm the diagnosis of Richter's transformation. Consider obtaining PET-CT to guide biopsy. B Patients with Richter's transformation (mutational analysis): Obtain TP53 mutation and 17p deletion analysis in patients with CLL. B Obtain IgHV rearrangement analysis of CLL and Richter's transformation tissue, if available and possible, to establish the relatedness of the clone. B Patients with Richter's transformation (screening for viral infections): assess viral serology for human immunodeficiency virus, HBV, HCV, EBV, and CMV in patients with chronic lymphocytic leukemi. B Patients with Richter's transformation (enrollment in clinical trials): offer enrollment in clinical trials when available in all patients with Richter's transformation because of the poor outcome of most patients, including those with relapse. B Patients with Richter's transformation, systemic therapy: As per BSH 2022 guidelines, offer rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients deemed appropriate for anthracycline-based treatment. B Show 3 more As per ESMO 2021 guidelines, offer therapies used in diffuse large B-cell lymphomas (such as R-CHOP) in patients with Richter's transformation. Do not offer more intense treatment regimens (such as R-hyperCVAD or OFAR). B Show 2 more Patients with Richter's transformation, stem cell transplantation: As per BSH 2022 guidelines: Consider offering either autologous or allo-SCT as consolidation in fit patients, typically < 70 years old, in first remission. C Avoid performing autologous or allo-SCT in patients with Hodgkin's lymphoma-Richter's transformation in first remission. D As per BSH 2022 guidelines, consider offering allo-SCT in suitable patients with Richter's transformation. C As per BSH 2022 guidelines, consider offering allo-SCT in all eligible patients with Richter's transformation. C https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 8/11 6/23/23, 3:26 AM Chronic lymphocytic leukemia Pathway As per ESMO 2021 guidelines: Consider offering allo-SCT in patients with Richter's transformation in remission after therapy and clonally related to CLL. Offer allo-SCT in all patients with clonally-related Richter's transformation with an available donor and sufficient fitness. B Patients with Richter's transformation (palliative care): consider offering early palliative care support in heavily pretreated patients with CLL and comorbidities developing diffuse large B-cell lymphoma-Richter's transformation on targeted inhibitor therapy. C 7. Preventative measures Routine immunizations: As per BSH 2022 guidelines, offer routine immunizations at diagnosis in all patients, keep a vaccine logbook, and avoid administering live vaccines. B Show 4 more As per ESMO 2021 guidelines, offer pneumococcal vaccination and seasonal flu vaccination in patients with early-stage CLL. B As per BSH 2018 guidelines, offer seasonal Influenza vaccination in all patients with CLL. Show 2 more As per iwCLL 2018 guidelines, provide routine immunizations before initiation of treatment if possible. Prefer conjugate vaccines as they have proved to be highly immunogenic, where available, in patients with CLL. Show 2 more Antimicrobial prophylaxis: As per BSH 2022 guidelines: Administer prophylactic antibiotics in patients with recurrent or serious infections. B Consider administering P. jirovecii prophylaxis in patients at risk. C As per ESMO 2021 guidelines: Consider administering antibiotic and antiviral prophylaxis mostly in patients with recurrent infections and/or very high risk of developing infections (for example, pneumocystis prophylaxis with co-trimoxazole during treatment with chemoimmunotherapy based on purine analogs or idelalisib). C Insufficient evidence to support the use of prophylactic antibiotics in patients with early-stage CLL. I As per BSH 2018 guidelines, consider administering prophylactic co-trimoxazole or nebulized pentamidine to reduce the risk of P. jirovecii pneumonia in patients receiving treatment for relapsed CLL. Consider administering prophylactic aciclovir to reduce the risk of herpes zoster reactivation. C https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 9/11 6/23/23, 3:26 AM Chronic lymphocytic leukemia Pathway 8. Follow-up and surveillance Assessment of treatment resopnse: As per ESMO 2021 guidelines: Obtain response assessment with a careful physical examination and blood cell count. Perform a bone marrow biopsy and obtain minimal residual disease assessment to define complete remission and minimal residual disease status within clinical trials, B as well as obtain CT. B Do not obtain routine minimal residual disease measurement, except after allo-SCT. D As per BSH 2018 guidelines, avoid withdrawing B-cell receptor inhibitors early in patients otherwise gaining apparent clinical benefit. D As per iwCLL 2018 guidelines, include a careful physical examination and evaluation of the blood and bone marrow in the assessment of response. E Management of relapsed/refractory disease: As per BSH 2022 guidelines, offer targeted inhibitors (BTK inhibitors or BCL-2 inhibitors alone or in combination with rituximab) in patients with relapsed CLL. B Show 6 more As per ESMO 2021 guidelines, offer one of the following options in patients with relapse: venetoclax plus rituximab for 24 months ibrutinib or acalabrutinib or other BTK inhibitors (if available) as continuous therapy. A Show 6 more As per BSH 2018 guidelines, offer idelalisib with rituximab or ibrutinib monotherapy in patients refractory to chemoimmunotherapy, relapsed after chemoimmunotherapy, or if retreatment with chemoimmunotherapy is inappropriate. B Do not add bendamustine to B-cell receptor inhibitor therapy. B Show 3 more Surveillance for malignancy: obtain serial CBC monitoring and age- and sex-specific cancer screening as leukemia survivors are at increased risk of secondary malignancies. B References 1. Hallek M, Cheson BD, Catovsky D et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018 Jun 21;131 25 2745 2760. Open 2. Anna H Schuh, Nilima Parry-Jones, Niamh Appleby et al. Guideline for the treatment of chronic lymphocytic leukaemia: A British Society for Haematology Guideline. Br J Haematol. 2018 Aug;182 3 344 359. Open 3. B Eichhorst, T Robak, E Montserrat et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Jan;32 1 23 33. Open https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 10/11 6/23/23, 3:26 AM Chronic lymphocytic leukemia Pathway 4. Amanda S Davis, Anthony J Viera, Monica D Mead. Leukemia: an overview for primary care. 2014 May 1;89 9 731 8.2014 May 1;89 9 731 8. Open 5. Toby A Eyre, John C Riches, Piers E M Patten et al. Richter transformation of chronic lymphocytic leukaemia: a British Society for Haematology Good Practice Paper. Br J Haematol. 2022 Feb;196 4 864 870. Open 6. Renata Walewska, Nilima Parry-Jones, Toby A. Eyre et al. Guideline for the treatment of chronic lymphocytic leukaemia. BSH. 2022 Mar 21. Open 7. Parikh SA. Chronic lymphocytic leukemia treatment algorithm 2018. Blood Cancer J. 2018 Oct 3;8 10 93. Open 8. O'Reilly A, Murphy J, Rawe S et al. Chronic Lymphocytic Leukemia: A Review of Front-line Treatment Options, With a Focus on Elderly CLL Patients. Clin Lymphoma Myeloma Leuk. 2018 Apr;18 4 249 256. Open 9. Hallek M, Shanafelt TD, Eichhorst B. Chronic lymphocytic leukaemia. Lancet. 2018 Apr 14;391 10129 1524 1537. Open 10. Sharma S, Rai KR. Chronic lymphocytic leukemia CLL treatment: So many choices, such great options. Cancer. 2019 May 1;125 9 1432 1440. Open 11. American Society of Hematology. Choosing Wisely ASH recommendations. Choosing Wisely. 2014. Open 12. J L Binet, M Leporrier, G Dighiero et al. A clinical staging system for chronic lymphocytic leukemia: prognostic significance. Cancer. 1977 Aug;40 2 855 64. Open 13. Sameer A Parikh, Kari G Rabe, Neil E Kay et al. The CLL-international prognostic index CLL IPI predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL. Blood. 2021 Apr 19;blood.2020009813. Open 14. N Zengin, A Kars, E Kansu et al. Comparison of Rai and Binet Classifications in Chronic Lymphocytic Leukemia. Hematology. 1997;2 2 125 9. Open 15. International CLL IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia CLL IPI a meta-analysis of individual patient data. Lancet Oncol. 2016 Jun;17 6 779 790. Open 16. M Hutchings, M Ladetto, C Buske et al. ESMO Consensus Conference on malignant lymphoma: management of 'ultra-high-risk' patients. Ann Oncol. 2018 Aug 1;29 8 1687 1700. Open 17. C Buske, M Hutchings, M Ladetto et al. ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma. Ann Oncol. 2018 Mar 1;29 3 544 562. Open https://web.pathway.md/diseases/recYUAKoqA4dHHW8E 11/11