University of Wisconsin Hematology

Chronic lymphocytic leukemia

Review articles

  1. Hallek et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018;131:2745
  2. Hallek et al. Chronic lymphocytic leukemiia. Lancet 2018;391:1524

Monoclonal B-cell lymphocytosis

  1. Strati and Shanafelt. Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Blood 2015;126:454
  2. Ghia and Caligaris-Cappio. Monoclonal B-cell lymphocytosis: right track or red herring? Blood 2012;119:4358
  3. Shim et al. Monoclonal B-cell lymphocytosis in healthy blood donors: an unexpectedly common finding. Blood 2014;123:1319 (7% of apparently healthy blood donors over 45 yo had MBL)
  4. Slager et al. Progression and survival of MBL: a screening study of 10 139 individuals. Blood 2022;140:1702 (17% prevalence in people over 40, higher in men.  8-fold increased risk of lymphoid malignancy; B-cell count > 500 increased risk)
  5. Rawstron et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. NEJM 2008;359:575 (5% of adults have circulating monoclonal B-cells with a CLL phenotype; they develop frank CLL at a rate of about 1% per year. See also the accompanying editorial)
  6. Shanafelt et al. B-cell count and survival: differentiating chronic lymphocytic leukemia from monoclonal B-cell lymphocytosis based on clinical outcome. Blood 2009;113:4188 (B-cell count > 11K independent predictor of need for eventual treatment)
  7. Shanafelt et al. Brief Report: Natural History of Individuals With Clinically Recognized Monoclonal B-Cell Lymphocytosis Compared With Patients With Rai 0 Chronic Lymphocytic Leukemia. J Clin Oncol 2009;27:3959 (MBL pts had lower likelihood of requiring treatment than stage 0 CLL pts. Circulating B-cell count predicts time to treatment)
  8. Fazi et al. General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood 2011;118:6618
  9. Landgren et al. B-Cell Clones as Early Markers for Chronic Lymphocytic Leukemia. NEJM 2009;360:659(almost all patients diagnosed with CLL have clonal B-cell population in blood prior to diagnosis; with editorial)
  10. Slager et al. Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families. Blood 2021;137:2046(3.5% incidence of MBL; progression to CLL in about 1%/yr)
  11. Parikh et al The CLL International Prognostic Index predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL. Blood 2021;138:149
  12. Oliva-Ariza et al. High frequency of low-count monoclonal B-cell lymphocytosis in hospitalized COVID-19 patients. Blood 2023;141:309

Biology, prognosis

  1. Chiorazzi and Ferrarini. Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. Blood 2011;117:1781
  2. Kleinstern et al. Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Blood 2018;131:2541
  3. Shanafelt T. Predicting clinical outcome in CLL: how and why. Hematology 2009;421
  4. Pflug et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood 2014;124:49
  5. Condoluci et al. International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia. Blood 2020;135:1859(IGHV mutation status, lymphocyte count and node involvement have prognostic value)
  6. Grever et al. Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997. J Clin Oncol 2007;25:799(del 17p and del 11q22 were the most significant negative prognostic indicators)
  7. Baliakas et al. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood 2019;133:1205
  8. Guièze and Wu. Genomic and eipgenomic heterogeneity in chronic lymphocytic leukemia. Blood 2015;126:445
  9. Parikh et al. Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis. Blood 2016;127:1753(Yes, although the results do not determine the decision to treat outside of a clinical trial)
  10. Lia et al. Functional dissection of the chromosome 13q14 tumor-suppressor locus using transgenic mouse lines. Blood 2012;119:2981(Size of deletion determines phenotype; larger deletions worse)
  11. Tsai et al. Evidence of serum immunoglobulin abnormalities up to 9.8 years before diagnosis of chronic lymphocytic leukemia: a prospective study. Blood 2009;114:4928
  12. Maurer et al. Monoclonal and polyclonal serum free light chains and clinical outcome in chronic lymphocytic leukemia. Blood 2011;118:2821(FLC abnormalities associated with worse prognosis)
  13. Dagklis et al. The immunoglobulin gene repertoire of low-count chronic lymphocytic leukemia (CLL)–like monoclonal B lymphocytosis is different from CLL: diagnostic implications for clinical monitoring. Blood 2009;114: 26
  14. Forconi and Moss. Perturbation of the normal immune system in patients with CLL. Blood 2015;126:573(New treatments targeting B-cell receptor signaling may allow immune reconstitution in CLL)
  15. Nieto et al. Increased frequency (12%) of circulating chronic lymphocytic leukemia–like B-cell clones in healthy subjects using a highly sensitive multicolor flow cytometry approach. Blood 2009;114:33
  16. Shanafelt et al. Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL. Blood 2004;103:1202
  17. Deaglio et al. In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia. Blood 2006;108:1135
  18. Malavasi et al. CD38 and chronic lymphocytic leukemia: a decade later. Blood 2011;118:3470
  19. Lin et al. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood 2009;113:3168(unmutated IgVH best predictor of short remission)
  20. Rassenti et al.  ZAP-70 compared with immunoglobulin heavy-chain mutation status as a predictor of disease progression in chronic lymphocytic leukemia.  NEJM 2004;351:893
  21. Del Principe et al. Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood 2006; 108:853
  22. Rassenti et al. Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia. Blood 2008;112:1923(ZAP-70 expression strongest risk factor)
  23. Claus et al. Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia. Blood 2014;124:42
  24. Bulian et al. CD49d Is the Strongest Flow Cytometry–Based Predictor of Overall Survival in Chronic Lymphocytic Leukemia. J Clin Oncol 2014;32:897
  25. Tissino et al. CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression. Blood 2020;135:1244
  26. Kwok et al. Minimal residual disease is an independent predictor for 10-year survival in CLL. Blood 2016;128:2770
  27. Letestu et al. Prognosis of Binet stage A chronic lymphocytic leukemia patients: the strength of routine parameters. Blood 2010;116:4588
  28. Brenner et al. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood 2008;111:4916
  29. Tsimberidou et al. Assessment of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma by Absolute Lymphocyte Counts in 2,126 Patients: 20 Years of Experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol 2007;25:4648(No difference in treatment outcome between CLL and SLL without lymphocytosis)
  30. Calin et al. A MicroRNA Signature Associated with Prognosis and Progression in Chronic Lymphocytic Leukemia. NEJM 2005;353:1793
  31. Baliakas et al. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia 2015;29:329(SF3B1 and TTP53 mutations carried worst prognosis)
  32. Klein et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 2001;194:1625
  33. Hamblin et al. Unmutated Ig Vh genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999;94:1848
  34. Rosenwald et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001;194:1639
  35. Fabbri et al. Association of a MicroRNA/TP53 Feedback Circuitry With Pathogenesis and Outcome of B-Cell Chronic Lymphocytic Leukemia. JAMA 2011;305:59(Establishes a molecular link between 13q deletion, p53 function and ZAP70 expression)
  36. Gonzalez et al. Mutational Status of the TP53 Gene As a Predictor of Response and Survival in Patients With Chronic Lymphocytic Leukemia: Results From the LRF CLL4 Trial. J Clin Oncol 2011;29:2223(TP53 mutations associated with lower treatment response rates and shorter OS)
  37. Rossi et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood 2012;119:521(About 11% of CLL patients have NOTCH1 mutations; prognosis similar to that with p53 mutations)
  38. Villamor et al. NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia 2013;27:1100
  39. Wang et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. NEJM 2011;365:2497
  40. Jeromin et al. SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia 2014;28:18
  41. Wan and Wu. SF3B1 mutations in chronic lymphocytic leukemia. Blood 2013;121:4627
  42. Meier-Abt et al. The protein landscape of chronic lymphocytic leukemia. Blood 2021;138:2514
  43. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology 2011:96
  44. Nowakowski et al. Percentage of smudge cells on routine blood smear predicts survival in chronic lymphocytic leukemia. J Clin Oncol 2009;27:1844(10 year survival 50% with 30% or fewer smudge cells, 80% for more than 30% smudge cells)
  45. Shanafelt et al. Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia. Blood 2011;117:1492
  46. Mauro et al. Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases. Blood 1999;94:448
  47. Abrisqueta et al. Improving survival in patients with chronic lymphocytic leukemia (1980-2008): the Hospital Clínic of Barcelona experience. Blood 2009;114:2044
  48. Foon et al. Genetic relatedness of lymphoid malignancies. Transformation of chronic lymphocytic leukemia as a model. Ann Intern Med 1993;119:63
  49. Goldin and Slager. Familial CLL: Genes and environment. Hematology 2007:339
  50. Del Giudice et al. Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood 2009;114:638

Complications

  1. Vitale et al. Preexisting and treatment-emergent autoimmune cytopenias in patients with CLL treated with targeted drugs. Blood 2021;137:3507(80% of patients with pre-existing AIC improved with targeted therapy)
  2. Mauro et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 2000;95:2786
  3. Borthakur et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab – incidence and predictors. Br J Haematol 2007;136:800(6.5% incidence of AIHA or PRCA)
  4. Dearden et al. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood 2008;111:1820
  5. Visco et al. Impact of immune thrombocytopenia on the clinical course of chronic lymphocytic leukemia. Blood 2008;111:1110(5% incidence of ITP, correlated with worse survival; chemotherapy superior to IVIG as Rx)
  6. Moreno et al. Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. Blood 2010;116:4771(Autoimmune cytopenia not an independent adverse prognostic factor in CLL)
  7. Morrison V. Management of infectious complications in patients with chronic lymphocytic leukemia. Hematology 2007:338
  8. Ahn et al. Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. Blood 2016;128:1940
  9. Tsimberidou et al. Other Malignancies in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. J Clin Oncol 2009;27:904(Risk of 2nd cancer about twice the expected value in CLL patients)
  10. Gade et al. Venous thromboembolism in chronic lymphocytic leukemia: a Danish nationwide cohort study. Blood Adv 2018;2:3034(Second primary cancer is major risk factor)

Treatment

  1. Burger JA. Treatment of chronic lymphocytic leukemia. NEJM 2020;383:460
  2. Woyach J. Treatment-naive CLL: lessons from phase 2 and phase 3 clinical trials. Blood 2019;134:1796
  3. Munir et al. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. NEJM 2024;390:326 (Ibrutinib-venetoclax superior to FCR)
  4. Langerbeins et al. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia. Blood 2022;139:177 (Ibruitinib effective, but toxicity is significant; watch-and-wait still preferable)
  5. Eichhorst et al. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. NEJM 2023;388:1739 (Venetoclax/obinotuzumab with or without ibrutinib superior to FCR and BR; with editorial)
  6. Stephens DM. Venetoclax and obinutuzumab for frontline treatment of chronic lymphocytic leukemia. Blood 2019;134:1691
  7. Fischer et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. NEJM 2019;380:2225
  8. Al-Sawaf et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood 2024:144:1924
  9. van der Straten et al. Fixed-duration venetoclax plus obinutuzumab improves quality of life and geriatric impairments in FCR-unfit patients with CLL. Blood 2023;142:1131
  10. Huber et al. Obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) frontline treatment for high-risk chronic lymphocytic leukemia. Blood 2022;139:1318
  11. Yazdy et al. Combinations or sequences of targeted agents in CLL: is the whole greater than the sum of its parts (Aristotle, 360 BC)? Blood 2019;133:121
  12. Hallek et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018;131:2745
  13. Jain and O’Brien. Initial treatment of CLL: integrating biology and functional status. Blood 2015;126:463
  14. Dreger et al. High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies. Blood 2018;132:892
  15. Thompson and Wierda. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood 2016;127:279
  16. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood 2012;120:4684
  17. Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology 2013:158
  18. Dighiero et al. Chlorambucil in chronic lymphocytic leukemia. NEJM 1998;338:1506
  19. Hillmen et al. Rituximab Plus Chlorambucil As First-Line Treatment for Chronic Lymphocytic Leukemia: Final Analysis of an Open-Label Phase II Study. J Clin Oncol 2014;32:1236(Median PFS 24 mo)
  20. Woyach et al. Impact of Age on Outcomes After Initial Therapy With Chemotherapy and Different Chemoimmunotherapy Regimens in Patients With Chronic Lymphocytic Leukemia: Results of Sequential Cancer and Leukemia Group B Studies. J Clin Oncol 2013;31:440(Older adults did as well with chlorambucil as with fludarabine; rituximab beneficial at all ages)
  21. Eichorst et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382
  22. Flinn et al. Phase III Trial of Fludarabine Plus Cyclophosphamide Compared With Fludarabine for Patients With Previously Untreated Chronic Lymphocytic Leukemia: US Intergroup Trial E2997. J Clin Oncol 2007;25:793(FC gave better CR rate and longer PFS, with more heme toxicity but no increase in infection)
  23. Smith et al. Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lymphocytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow-up of US Intergroup Study E2997. Blood 2011;118:3525(4.7% incidence of myeloid neoplasia, higher incidence with FC vs F alone)
  24. Woyach et al. Chemoimmunotherapy With Fludarabine and Rituximab Produces Extended Overall Survival and Progression-Free Survival in Chronic Lymphocytic Leukemia: Long-Term Follow-Up of CALGB Study 9712. J Clin Oncol 2011;29:1349
  25. Tam et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008;112:975(OR rate 95%, median TTP 80 mo, 6 year OS 77%)
  26. Thompson et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2016;127:303(PFS at 12.8 yrs 53% for pts with mutated IGHV, 9% for those with unmutated IGHV)
  27. Lamanna et al. Sequential Therapy With Fludarabine, High-Dose Cyclophosphamide, and Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia Produces High-Quality Responses: Molecular Remissions Predict for Durable Complete Responses. J Clin Oncol 2009; 27:491
  28. Fischer et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 2016;127:208
  29. Chai-Adisaksopha et al. FCR achieves long-term durable remissions in patients with IGHV-mutated CLL. Blood 2017;130:2278
  30. Thompson et al. Sustained remissions in CLL after frontline FCR treatment with very-long-term follow-up. Blood 2023;142:1784 (“Functional cure” in many patients with rearranged Ig heavy chain; 6.3% incidence of therapy-related myeloid neoplasm)
  31. Abrisqueta et al. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood 2013;122:3951
  32. Fischer et al. Bendamustine in Combination With Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012;30:3209
  33. Chanan-Khan et al. Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL). Blood 2005;106:3348  (55% CR rate)
  34. Badoux et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 2011;118:3489(65% overall response rate; treatment increased immunoglobulin levels)
  35. Strati et al Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood 2013;122:734(58% had response lasting > 36 mo)
  36. Kay et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 2006;109:405    (91% OR, 41% CR)
  37. Lepretre et al. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood 2012;119:5104(Similar efficacy to FCR with more toxicity)
  38. Woyach and Johnson. Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood 2015;126:471
  39. Brown JR. How I treat CLL patients with ibrutinib. Blood 2018;131:379
  40. Michallet et al. A fixed-duration, measurable residual disease–guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial. Blood 2021;137:1019
  41. Farooqui et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2015;16:169
  42. Burger et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. NEJM 2015;373:2425(Risk of progression or death 84% lower with ibrutinib than with chlorambucil)
  43. Burger et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood 2019;133:1011(Faster responses, but no improvement in PFS when rituximab added to ibrutinib)
  44. Byrd et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125:2497(High response rates, modest toxicity)
  45. O’Brien et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 2018;131:1910(92% 5-yr PFS in treatment-naïve patients)
  46. Patel et al. Cost-effectiveness of first-line vs third-line ibrutinib in patients with untreated chronic lymphocytic leukemia. Blood 2020;136:1946(More cost-effective to delay use of ibrutinib)
  47. Ahn et al. Ibrutinib for Chronic Lymphocytic Leukemia with TP53 Alterations. NEJM 2020;383:498(2 yr PFS 85%)
  48. Woyach et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. NEJM 2018;379:2517 (Ibrutinib superior to Benda/ritux, no difference between ibrutinib/ritux and ibrutinib alone)
  49. Woyach et al. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood 2024;143:1616
  50. Shanafelt et al. Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. NEJM 2019;381:432(3 year PFS and OS superior with I/R, fewer infectious complications)
  51. Shanafelt et al. Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood 2022;140:112
  52. Jain et al. Ibrutinib and Venetoclax for First-Line Treatment of CLL. NEJM 2019;380:2095(88% CR, 61% with no MRD detectable in a group of high risk patients; with editorial)
  53. Tam et al. Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort. Blood 2022;139:3278 (55% CR, 95% 2-yr PFS)
  54. Davids et al. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol 20196:e419(Undetectable MRD achieved in 84% of pts)
  55. Stephens and Byrd. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood 2019;133:1298
  56. Thompson et al. Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study. Br J Haem 2016;175:462
  57. Byrd et al. Acalabrutinib in treatment-naive chronic lymphocytic leukemia. Blood 2021;137:3327(90% PR, 7% CR)
  58. Brown et al. Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. NEJM 2025;392:748
  59. Sharman et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial. Lancet 2020;395:1278
  60. Tam et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood 2019;134:851(Less toxic than ibrutinib)
  61. Wierda et al. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood 2011;118:5119
  62. Hillmen et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet 2015;385:1873(Addition of ofatumumab increased median PFS from 13 to 22 mo)
  63. Danese et al. An observational study of outcomes after initial infused therapy in Medicare patients diagnosed with chronic lymphocytic leukemia. Blood 2011;117:3505(Initial therapy containing rituximab as effective in patients older than 66 as in younger patients)
  64. Wierda et al. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood 2011;117:6450(Ofatumumab, fludarabine + cyclophosphamide; 50% CR in one arm)
  65. Goede et al. Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions. NEJM 2014;370:1101(Better PFS and OS with obinutuzumab aka GA101 + Chl vs rituximab + Chl)
  66. Langerak et al. Prognostic value of MRD in CLL patients with comorbidities receiving chlorambucil plus obinutuzumab or rituximab. Blood 2019;133:494(O+Chl more likely to yield undetectable MRD than R+Chl, MRD a good predictor of PFS and OS)
  67. Brown et al. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood 2015;125:2779(Both combinations effective, reasonably safe)
  68. Byrd et al. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood 2015;127:79(67% OR, 20% CR with 2000 mg dose, well-tolerated)
  69. Flinn et al. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood 2019;133:2765 (91% of previously untreated pts had undetectable MRD at 3 mo after last obinutuzumab dose)
  70. Stilgenbauer et al. Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial. J Clin Oncol 2018;36:1973
  71. Huber et al. Final analysis of the CLL2-GIVe trial: obinutuzumab, ibrutinib, and venetoclax for untreated CLL with del(17p)/TP53mut. Blood 2023;142:961
  72. Wierda and Tambaro. How I manage CLL with venetoclax-based treatments. Blood 2020;135:1421
  73. Friedberg et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010;115:2578(55% overall response rate in CLL)
  74. Pettitt et al. Alemtuzumab in Combination With Methylprednisolone Is a Highly Effective Induction Regimen for Patients With Chronic Lymphocytic Leukemia and Deletion of TP53: Final Results of the National Cancer Research Institute CLL206 Trial. J Clin Oncol 2012;30:1647
  75. Cheah and Fowler. Idelalisib in the management of lymphoma. Blood 2016;128:331
  76. O’Brien et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood 2015;126:2686(97% response rate, 19% CR; well-tolerated)
  77. Lampson et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood 2016;128:195
  78. Strati et al. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL. Blood 2014;123: 3727
  79. Weeks et al. Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia. NEJM 1991;325:81
  80. Eichhorst et al. Limited clinical relevance of imaging techniques in the follow-up of patients with advanced chronic lymphocytic leukemia: results of a meta-analysis. Blood 2011;117:1817
  81. Jain et al. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol 2017;4:e67(Ruxolitinib significantly lessened constitutional symptoms)

Relapsed & Refractory CLL

  1. Lew et al. How I treat chronic lymphocytic leukemia after venetoclax. Blood 2021;138:361
  2. Grainger et al. Doubling down: the new deal in the clinical management of double-refractory chronic lymphocytic leukemia. Blood 2025;146:146
  3. Arnason and Brown. Alemtuzumab Use In Relapsed and Refractory Chronic Lymphocytic Lymphoma. Hematology 2011:119
  4. Wierda et al. Chemoimmunotherapy With Fludarabine, Cyclophosphamide, and Rituximab for Relapsed and Refractory Chronic Lymphocytic Leukemia. J Clin Oncol 2005;23:4070
  5. Badoux et al. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol 2013;31:584(12% CR, 12% PR; 70% alive @ 36 mo)
  6. Badoux et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011;117:3016
  7. Tam et al. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood 2014;124:3059(Poor survival with salvage regimens if relapse within 3 yrs)
  8. Fischer et al. Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2011;29:3559
  9. Woyach and Johnson. Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood 2015;126:471
  10. Byrd et al. Targeting BTK with ibruitnib in relapsed chronic lymphocytic leukemia. NEJM 2013;369:32(PFS 75% at 26 mo; with editorial)
  11. Farooqui et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2015;16:169
  12. Barr et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood 2017;129:2612(Poor adherence or stopping drug > 1 week associated with adverse events)
  13. Lin et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood 2020;135:2266
  14. Chen et al. A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia. Blood 2018;132:2249
  15. Ryan et al. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood 2016;128:2899
  16. Woyach J. How I manage ibrutinib-refractory chronic lymphocytic leukemia. Blood 2017;129:1270
  17. Furman et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. NEJM 2014;370:997(Adding PI3K inhibitor idelalisib increased OR rate from 13% to 81% – with editorial)
  18. Sharman et al. Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia. J Clin Oncol 2019;37:1391(Adding idelalisib significantly improved PFS and OS with acceptable safety profile)
  19. Woyach et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014;123:1810
  20. Woyach et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibruitinib. NEJM 2014;370:2286
  21. Brown et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood 2015;125:2915(Ibruntinib + benda/rituximab or FCR; PFS 86% at 1 year, 70% at 3 years)
  22. Byrd et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125:2497(High response rates, modest toxicity)
  23. O’Brien et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 2018;131:1910(5-yr PFS 44% in R/R patients)
  24. Jaglowski et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood 2015;126:842(Faster and more durable responses than with single-agent ibrutinib)
  25. Byrd et al. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. NEJM 2014;371:213(Ibrutinib superior)
  26. Byrd et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood 2019;133:2031(Extended ibrutinib treatment gave sustained PFS)
  27. Mato et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood 2016;128:2199(Many patients who fail one KI due to toxicity or disease progression respond to an alternative one)
  28. Byrd et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. NEJM 2016;374:323(ORR 95%, 100% in those with 17p deletion; with editorial)
  29. Byrd et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results. Blood 2020;135:1204
  30. Ghia et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol 2020;38:2849 (Acalabrutinib had best PFS of these 3 regimens)
  31. Byrd et al. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol 2021;39:3441 (Similar efficacy, fewer cardiac events with acalabrutinib)
  32. Seymour et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood 2023;142:687 (Acalabrutinib less toxic)
  33. Fürstenau et al. Acalabrutinib, venetoclax, and obinutuzumab in relapsed/refractory CLL: final efficacy and ctDNA analysis of the CLL2-BAAG trial. Blood 2024;144:272 (3-yr PFS 85%; analysis of circulating tumor DNA useful to detect relapse)
  34. Brown et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. NEJM 2023;388:319 (Better PFS and fewer cardiac problems with zanubrutinib)
  35. Brown et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE. Blood 2024;144:2706
  36. Fürstenau et al. MRD-guided zanubrutinib, venetoclax, and obinutuzumab in relapsed CLL: primary end point analysis from the CLL2-BZAG trial. Blood 2025;145:1282
  37. Roberts et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. NEJM 2016;374:311(79% ORR, 20% CR; with editorial)
  38. Seymour et al. Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. NEJM 2018;378:1107(2-yr PFS 85%, vs 36% with bendamustine + rituximab)
  39. Kater et al. Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. J  Clin Oncol 2020;38:4042 (4-year followup of above trial, showing sustained benefit of Ven-R regimen)
  40. Ma et al. Efficacy of venetoclax plus rituximab for relapsed CLL: 5-year follow-up of continuous or limited- duration therapy. Blood 2021;138;836
  41. Kater et al. Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. J Clin Oncol 2019;37:269
  42. Seymour et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood 2022;140:839 
  43. Stilgenbauer et al. Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial. J Clin Oncol 2018;36:1973
  44. Scarfò et al. Minimal residual disease–driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL. Blood 2022;140:2348
  45. Cartron et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood 2014;124:2196
  46. Hillmen et al. Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study. J Clin Oncol 2019;37:2722(51% CR, 36% were MRD negative in marrow)
  47. Sharman et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood 2015;125:2336
  48. Ding et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood 2017;129:3419
  49. Rogers et al. Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood 2018;132:1568(92% ORR, 42% CR)
  50. Flinn et al The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood 2018;132:2446(Duvelisib superior to ofatumumab)
  51. Lunning et al. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2019;134:1811
  52. Mato et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet 2021;397:892
  53. Mato et al. Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. NEJM 2023;389:33 (73% OR rate; with editorial)
  54. Roeker et al. Fixed-duration pirtobrutinib plus venetoclax with or without rituximab in relapsed/refractory CLL: the phase 1b BRUIN trial. Blood 2024;144:1374

CAR T/NK cells in CLL

  1. Kalos et al. T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia. Sci Transl Med 2011;95:95ra73(Dramatic responses in 3 patients with refractory CLL)
  2. Porter et al. Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia. NEJM 2011;365:725(More detailed description of one of 3 patients described in previous paper)
  3. Frey et al. Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. J Clin Oncol 2020;38:2862
  4. Fraietta et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 2018;24:563
  5. Turtle et al. Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor–Modified T Cells After Failure of Ibrutinib. J Clin Oncol 2017;35:3010
  6. Gauthier et al. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure. Blood 2020;135:1650
  7. Liu et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. NEJM 2020;382:545(High response rates, little toxicity)
  8. Siddiqi et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study. Lancet 2023;402:641

B-Prolymphocytic leukemia

  1. Dearden C. How I treat prolymphocytic leukemia. Blood 2012;120:538
  2. van der Velden et al. B-cell prolymphocytic leukemia: a specific subgroup of mantle cell lymphoma. Blood 2014;124:412(Many B-PLL cases whether or not they have t(11;14) have characteristics in common with MCL)

Stem Cell Transplantation in CLL

Richter syndrome