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Highlights in Chronic Lymphocytic Leukemia From the 23rd Congress of the European Hematology Association
• June 14-17, 2018 • Stockholm, Sweden
Clinical Implications of the 2018 iwCLL Guidelines Update
Susan M. O’Brien, MD
Associate Director for Clinical Sciences
Chao Family Comprehensive Cancer Center
Medical Director, Sue and Ralph Stern Center for Clinical Trials & Research
Professor of Medicine, Division of Hematology/Oncology
Department of Medicine
University of California, Irvine
Orange, California
H&O When were guidelines from the iwCLL first published?
SO The original guidelines for chronic lymphocytic leukemia (CLL) were published in the 1980s by a working group from the National Cancer Institute.1 The first guidelines from the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) were published in 2008.2 The iwCLL consists of a group of experts from various countries. The guidelines that were published in 2008 were intended to standardize the assessment of patients. The guidelines were adopted by the US Food and Drug Administration (FDA) and the European Medicines Agency for the evaluation of new drugs. Since 2008, there have been many changes in the field of CLL, particularly in treatment. There are now several classes of therapies. Chemoimmunotherapy includes the combination of fludarabine, cyclophosphamide, and rituximab (FCR), bendamustine plus rituximab, and chlorambucil plus an antibody, either obinutuzumab or ofatumumab.3,4 The newer small-molecule therapies include the Bruton tyrosine kinase inhibitor ibrutinib, the phosphoinositide 3-kinase δ inhibitor idelalisib, and the BCL-2 inhibitor venetoclax.5-7 Ibrutinib is the only small molecule with FDA approval in the frontline setting for CLL.8 The patterns of response to these drugs differ from those seen with chemotherapy.
H&O What are the key changes in the most recent update to the iwCLL guidelines?
SO The 2018 guidelines now highlight the relevance of genomic alterations, particularly the deletions in TP53 and 17p, and the immunoglobulin heavy chain variable (IGHV) mutation.9 Many physicians are aware of the relevance of the 17p deletion and appreciate the importance of administering the test for this mutation. Patients with the 17p deletion respond poorly to chemotherapy, even as upfront therapy.10 These patients are therefore treated with small-molecule agents. What some physicians may not know is that patients without the 17p deletion may still have a TP53 mutation, which carries the same relevance in terms of outcome.11 Fluorescence in situ hybridization (FISH) provides information on some of the prognostically important cytogenetic abnormalities in CLL, including the 17p deletion. However, we also encourage physicians to test for the TP53 mutation, which excludes the use of chemotherapy even in patients who do not have a 17p deletion.
The iwCLL guidelines now recommend that all patients with CLL undergo testing of their IGHV mutation status.9 We have known for many years that the IGHV mutation status has prognostic significance.12 Among patients under active surveillance with watch and wait, those without a mutated IGHV gene tended to need treatment more rapidly than those with the mutation. After treatment with chemoimmunotherapy, response rates were the same regardless of the IGHV status, but patients with unmutated IGHV had a much shorter time to progression with chemoimmunotherapy. In several studies of FCR, patients with a mutated IGHV gene exhibited a plateau on the progression-free survival (PFS) curve; these patients can have very long remissions and may even be cured.13,14 The longest follow-up data were published by the MD Anderson Cancer Center, which developed the FCR regimen.14 This study showed that in patients with a mutated IGHV gene, the plateau on the PFS curve was 60% at 10 to 16 years. Many of these patients tested negative for minimal residual disease, again suggesting that there could be a cure fraction. Patients without the mutated IGHV gene had a PFS of approximately 3 years, which is a reasonably good response to chemotherapy, although nowhere near the long-term benefits seen in patients with the mutated gene.
Until recently, the significance of IGHV status was limited to prognosis. That changed with the advent of small-molecule therapies, which are equally effective regardless of the patient’s IGHV mutation status.5,6 For patients with an unmutated IGHV gene, most physicians suggest treatment with investigational approaches or a small-molecule therapy, such as ibrutinib, rather than chemotherapy. Therefore, it is now important to ascertain a patient’s IGHV mutation status before selection of treatment.
H&O How is IGHV tested?
SO The test sequences the IGHV gene in CLL cells. It can be performed on peripheral blood, like any test in CLL. Bone marrow is not needed. Most of the major laboratories now test for IGHV. A mutated IGHV gene is defined as one that differs by more than 2% from the known germline sequences.15 This difference indicates that the cell has gone through the germinal center, encountered an antigen, and mutated in response to the antigen to develop specificity for it.
IGHV is mutated in approximately half of patients with CLL.16 In clinical trials, however, the population usually has a higher percentage of unmutated patients, who tend to progress and need treatment more quickly. These patients also have a shorter PFS after treatment with chemotherapy, and are therefore more likely to enroll in a clinical trial.
H&O Does the IGHV status change over time?
SO The mutation status of IGHV does not change, so the test does not need to be repeated. In contrast, FISH testing of chromosome abnormalities can change owing to clonal evolution.
H&O What do the new guidelines recommend about progressive disease?
SO The new guidelines suggest that patients who develop asymptomatic progressive disease may not need treatment at relapse, but can be monitored instead.9 It is possible to detect progressive disease that meets the established criteria, but is in fact minimal. For example, say a patient is in complete remission after treatment. Then, the lymphocyte count rises to 10,000 µL, or small lymph nodes develop. This patient may still be asymptomatic, just like at diagnosis. The recommendation is to reinstitute watch and wait and initiate treatment only when required, as is done in the upfront setting. This recommendation applies to all patients with CLL, but particularly those in a clinical trial. Because PFS is often an endpoint of clinical trials, enrolled patients tend to undergo more close assessment for progressive disease.
H&O Have the indications for treatment changed?
SO They have not changed. Essentially, treatment is required when the disease starts to cause a problem. For example, constitutional symptoms may be a reason to treat. In general, lymphocytosis by itself is not an indication for treatment. Patients with CLL can be completely asymptomatic, even with very high lymphocyte counts. Treatment of CLL is not necessarily required for autoimmune complications. If patients respond poorly to other interventions for these conditions, such as corticosteroids or rituximab, treatment might then be indicated.
H&O What did the CLL10 and CLL11 trials show?
SO These trials evaluated chemoimmunotherapy. The CLL10 trial (First-Line Chemoimmunotherapy With Bendamustine and Rituximab Versus Fludarabine, Cyclophosphamide, and Rituximab in Patients With Advanced Chronic Lymphocytic Leukaemia) compared bendamustine plus rituximab vs FCR.3 The FCR regimen produced a significantly longer PFS—more than a year longer—but at the expense of more myelosuppression and infections. The randomized CLL11 trial (A Study of Obinutuzumab [RO5072759 (GA101)] With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia [Stage 1a]) had 3 arms: chlorambucil, chlorambucil plus rituximab, and chlorambucil plus obinutuzumab.4 In this trial, both antibody arms produced better outcomes compared with single-agent chlorambucil. PFS was better with obinutuzumab vs rituximab. An update of the CLL11 trial, presented at the 23rd Congress of the European Hematology Association, also showed a benefit in overall survival with obinutuzumab vs rituximab.17
Both of these trials consistently showed that patients with a mutated IGHV gene had significantly better PFS than patients who were unmutated, as would be expected with chemoimmunotherapy.3,4
H&O What did the RESONATE-2 trial show?
SO RESONATE-2 (Randomized, Multicenter, Open-Label, Phase 3 Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Versus Chlorambucil in Patients 65 Years or Older With Treatment-Naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma [PCYC-1115/1116]) was a randomized trial in the frontline setting that compared ibrutinib vs chlorambucil in patients who were older than 70 years or who were ages 65 years to 70 years and had a contraindication to chemotherapy.5 After a median follow-up of 18.4 months, the median PFS was not reached with ibrutinib vs 18.9 months with chlorambucil. At 24 months, the estimated survival rate was 98% with ibrutinib vs 85% with chlorambucil, and the relative risk of death was 84% lower with ibrutinib vs chlorambucil (hazard ratio, 0.16; P=.001). The overall response rate was 86% with ibrutinib vs 35% with chlorambucil (P<.001). The results of RESONATE-2 led to the approval of ibrutinib in the frontline setting in CLL. Interestingly, although the eligibility for the trial was restricted to older patients, the frontline indication is not age-restricted. The response rate, PFS, and overall survival were better with ibrutinib than chlorambucil.
The control arm in RESONATE-2 may lead some physicians to question the relevance of the results for younger, fit patients, who they would not treat with chlorambucil. For these patients, some physicians might want to see data from a randomized trial comparing ibrutinib vs FCR or bendamustine plus rituximab. Data are forthcoming from 2 large US Intergroup trials. One is a 2-arm randomized trial of FCR vs ibrutinib and rituximab,18 and the other is a 3-arm trial of ibrutinib alone vs rituximab plus ibrutinib vs rituximab plus bendamustine.19 These trials are fully accrued and will provide important information.
H&O How does your new treatment algorithm differ from the traditional approach?
SO Before the new algorithm, treatment was usually based on the patient’s age and comorbidities. This approach was developed when all treatment options were chemotherapy-based. Patients were divided into 3 groups: younger, fit patients who might otherwise have a normal lifespan; patients who were older but relatively fit; and patients who were unfit and/or elderly. The German CLL Study Group coined phrases to describe the treatment approach in these patients: “go-go” for the younger, fit patients; “slow-go” for the less fit, somewhat older patients; and “no-go” for the older, unfit patients, who should receive palliative therapy.20 It made sense to view patients along a spectrum of tolerance to chemotherapy, and to avoid this treatment in older patients and/or those with comorbidities.
The advent of small-molecule therapy, particularly ibrutinib in the upfront setting, changed the approach to treatment in CLL. In the new algorithm, we suggest that the first step in selecting treatment is to determine whether the patient has a 17p deletion or a TP53 mutation (Figure).21 As I mentioned earlier, these patients are not candidates for chemotherapy. They should receive ibrutinib. In the future, if other small molecules are approved in the frontline setting, then there will be other options.
The second step in the algorithm recommends testing for the IGHV mutation. There appears to be long-term survival, if not a cure, among the subset of patients with a mutated IGHV who are treated with chemotherapy. The survival plateau is less strong among patients without the mutation. The algorithm therefore asks if a patient with the IGHV mutation is amenable to chemotherapy; if so, then treatment with chemotherapy can be initiated. Patients without the mutation should be treated with ibrutinib. This is a major change from the historical treatment approach. Previously, we knew that the IGHV mutation status was prognostically important, but it did not impact treatment selection because the only options were chemotherapy-based. We knew that patients without the mutation would do less well on chemotherapy, but it did not matter because there were no other options. However, now ibrutinib is available. Patients with unmutated IGHV should skip chemotherapy and go straight to ibrutinib.
Disclosure
Dr O’Brien is a consultant for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc, Vaniam Group LLC, AbbVie, and Alexion. She has received research support from Kite, Regeneron, and Acerta. She is a consultant and/or has received research support from Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis.
References
1. Cheson BD, Bennett JM, Rai KR, et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute–sponsored working group. Am J Hematol. 1988;29(3):152-163.
2. Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
3. Eichhorst B, Fink AM, Bahlo J, et al; international group of investigators; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928-942.
4. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110.
5. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med.
2015;373(25):2425-2437.
6. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.
7. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.
8. Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics; 2018.
9. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.
10. Strati P, Keating MJ, O’Brien SM, et al. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion. Haematologica. 2014;99(8):1350-1355.
11. Le Garff-Tavernier M, Veronese L, Nguyen-Khac F, et al. P53 functional assessment and correlation with 17p deletion and/or TP53 mutation status in chronic lymphocytic leukemia (CLL). A preliminary report of the ICLL001 Bomp trial on behalf of the French CLL Intergroup (GCFLLC/MW – GOELAMS) [ASH abstract 4173]. Blood. 2013;122(21 suppl).
12. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94(6):1840-1847.
13. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215.
14. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303-309.
15. Patten PE, Chu CC, Albesiano E, et al. IGHV-unmutated and IGHV-mutated chronic lymphocytic leukemia cells produce activation-induced deaminase protein with a full range of biologic functions. Blood. 2012;120(24):4802-4811.
16. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848-1854.
17. Goede V, Fischer K, Dyer MJS, et al. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study. Presented at: the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S151.
18. Collett L, Howard DR, Munir T, et al. Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial. Trials. 2017;18(1):387.
19. ClinicalTrials.gov. Rituximab and bendamustine hydrochloride, rituximab and ibrutinib, or ibrutinib alone in treating older patients with previously untreated chronic lymphocytic leukemia. https://clinicaltrials.gov/ct2/show/NCT01886872. Identifier: NCT01886872. Accessed July 9, 2018.
20. Eichhorst B, Goede V, Hallek M. Treatment of elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2009;50(2):171-178.
21. Strati P, Jain N, O’Brien S. Chronic lymphocytic leukemia: diagnosis and treatment. Mayo Clin Proc. 2018;93(5):651-664.
Highlights in Chronic Lymphocytic Leukemia From the 23rd Congress of the European Hematology Association
June 14-17, 2018 • Stockholm, Sweden
Ibrutinib Lead-In Followed by Venetoclax in Patients With Chronic Lymphocytic Leukemia: Phase 2 CAPTIVATE Early Safety and Efficacy Results
The phase 2 CAPTIVATE trial (PCYC-1142; Ibrutinib Plus Venetoclax in Subjects With Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma) is evaluating the combination of ibrutinib plus venetoclax as first-line therapy in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. The treatment regimen begins with ibrutinib alone (420 mg) for 3 months, for debulking, followed by ibrutinib (420 mg) plus venetoclax (ramp up to 400 mg). After a year of combination treatment, patients will undergo assessment of minimal residual disease (MRD). Those who are MRD-negative will be randomly assigned to continue ibrutinib alone or to stop treatment entirely. Patients who are MRD-positive will be randomly assigned to treatment with ibrutinib alone or in combination with venetoclax. The overall objective of the study is to determine whether MRD negativity will permit treatment holidays.
Dr Paolo Ghia presented preliminary results of the CAPTIVATE trial at the 23rd Congress of the European Hematology Association (EHA).1 Among the 14 patients who completed 1 year of combination therapy, the objective response rate (ORR) was 100%. The rate of bone marrow MRD negativity was 86%. After 6 cycles of ibrutinib plus venetoclax, 77% of patients were MRD-negative according to testing in peripheral blood. After 12 cycles of ibrutinib plus venetoclax, a confirmed undetectable MRD was reported in 79% of patients.
Analysis of tumor lysis syndrome was available for nearly 80 patients. Three cycles of ibrutinib lead-in treatment reduced the risk of tumor lysis syndrome and bulky disease. Among the 40 patients at high risk for tumor lysis syndrome, 36 (90%) shifted to low or medium risk. Among 37 patients at medium risk of tumor lysis syndrome and with a creatinine clearance of less than 80 mL/min, 7 patients shifted to low risk. No patients developed clinical tumor lysis syndrome. Laboratory tumor lysis syndrome was reported as an adverse event in 2 patients (neither met the Howard criteria). One additional case of laboratory tumor lysis syndrome was not reported as an adverse event (but met Howard Criteria). The combination was well-tolerated, with adverse events reflecting those seen with each agent alone.
Reference
1. Ghia P, Tam C, Siddiqi T, et al. Ibrutinib lead-in followed by venetoclax in patients with chronic lymphocytic leukemia: phase 2 CAPTIVATE early safety and efficacy results. Presented at: the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S806.
Overall Survival Benefit of Obinutuzumab Over Rituximab When Combined With Chlorambucil in Patients With Chronic Lymphocytic Leukemia and Comorbidities: Final Survival Analysis of the CLL11 Study
The randomized phase 3 CLL11 trial (A Study of Obinutuzumab [RO5072759 (GA101)] With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia [Stage 1a]) evaluated chlorambucil alone or with rituximab or obinutuzumab among treatment-naive patients with CLL and comorbidities. A previous analysis showed that both antibody arms were superior to single-agent chlorambucil.1 The final analysis of the CLL11 trial, presented at the EHA meeting, showed improvements in overall survival and progression-free survival (PFS) with obinutuzumab vs rituximab.2
After a median observation of 59.4 months, the median PFS was 28.9 months with obinutuzumab plus chlorambucil (n=333) vs 15.7 months with rituximab plus chlorambucil (n=330; P<.0001). Obinutuzumab plus chlorambucil reduced the risk of progressive disease or death by 79% as compared with chlorambucil alone and by 51% compared with rituximab plus chlorambucil. The median overall survival was not reached vs 73.1 months, respectively (P=.0245). This difference translated into a reduction in the risk of death of 32% compared with chlorambucil alone and of 24% compared with rituximab plus chlorambucil. The time to new treatment was 56.4 months in patients treated with obinutuzumab plus chlorambucil vs 34.9 months with rituximab plus chlorambucil. The analysis identified no new safety signals, and no new late-onset toxicity was reported.
References
1. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110.
2. Goede V, Fischer K, Dyer MJS, et al. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study. Presented at: the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S151.
A Phase Ib/II Study of Duvelisib in Combination With FCR (DFCR) for Frontline Therapy of Younger CLL Patients
A phase 1b/2 study evaluated the addition of duvelisib to fludarabine, cyclophosphamide, and rituximab (FCR) as frontline therapy for younger patients with CLL. Dr Matthew Davids presented the results at the EHA meeting.1 Duvelisib is a dual phosphoinositide 3-kinase inhibitor that targets both the δ and γ isoforms. The trial enrolled 32 patients, whose median age was 55 years (range, 45-65 years). Duvelisib was administered at 25 mg once or twice daily for 1 week, with FCR added on day 8. Patients received up to 6 cycles of this regimen, followed by duvelisib maintenance for up to 2 years.
The phase 1 portion of the study identified the dose of duvelisib as 25 mg twice daily. Among the 29 patients who were evaluable for response after FCR, the ORR was 97%, which consisted of a complete response (CR)/incomplete CR (CRi) in 28% and a partial response in 69%. Approximately 76% of patients achieved MRD-negative bone marrow. The best rate of MRD negativity in the bone marrow in patients with at least 1 evaluation was 81%. The primary efficacy endpoint, the rate of CR/CRi with bone marrow MRD negativity, was 28%. Two patients with the 17p deletion achieved an MRD-positive partial response, and one achieved an MRD-positive complete response after 12 months of duvelisib maintenance. The 2-year rates of PFS and OS were both 97%. At a median follow-up of 21 months, there were 2 cases of progressive disease. One patient developed asymptomatic progression 6 months after the end of maintenance, and the other, who had a baseline 17p deletion and complex karyotype, developed Richter syndrome and died 29 months after enrolling in the study.
A median of 5.5 cycles of FCR were given, and 10 patients (31%) discontinued chemotherapy early based on toxicity. Nine patients (28%) required a reduction in the dose of duvelisib. Serious adverse events included transaminitis (grade 3 in 5 patients and grade 4 in 4 patients), febrile neutropenia (grade 3 in 7 patients), colitis (grade 2 in 1 patient and grade 3 in 1 patient), and pneumonia (occurring in 6 patients, including 3 cases of Pneumocystis jirovecii pneumonia despite planned prophylaxis).
Reference
1. Davids M, Fisher D, Tyekucheva S, et al. A phase Ib/II study of duvelisib in combination with FCR (DFCR) for frontline therapy of younger CLL patients. Presented at: the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S807.
High, Durable Minimal Residual Disease Negativity With Venetoclax + Rituximab in Relapsed/Refractory CLL: MRD Kinetics and Responses in Cytogenetic Risk Groups in Patients From the Phase 3 MURANO Study
The phase 3 MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]) randomly assigned 389 patients with relapsed/refractory CLL to treatment with venetoclax plus rituximab for 6 months followed by single-agent venetoclax for up to 1.5 years or to bendamustine plus rituximab for 6 months.1 After a median follow-up of 23.8 months, the rate of investigator-assessed PFS was significantly higher with venetoclax plus rituximab (32 events of progression or death in 194 patients) vs bendamustine plus rituximab (114 events in 195 patients). The 2-year rates of PFS were 84.9% and 36.3%, respectively (P<.001).
An analysis of the MURANO trial presented at the EHA meeting focused on MRD.2 A high concordance of MRD in peripheral blood and bone marrow was seen with venetoclax plus rituximab in patients with paired samples (84%). A higher agreement in MRD negativity between bone marrow and peripheral blood was seen among patients treated with venetoclax plus rituximab (90%) vs bendamustine plus rituximab (30%). Rates of best MRD negativity (at any time during the study) were 84% with venetoclax plus rituximab vs 23% with bendamustine plus rituximab. Among 121 patients who achieved undetectable MRD at the end of treatment with venetoclax plus rituximab (n=194), 83% remained MRD negative and were progression-free at 13.8 months of follow-up. The rates of undetectable MRD were not impacted by the presence of 17p deletion, the immunoglobulin heavy chain variable (IGHV) mutation, or TP53 mutations.
References
1. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.
2. Hillmen P, Seymour JF, Langerak AW, et al. High, durable minimal residual disease (MRD) negativity with venetoclax + rituximab in relapsed/refractory CLL: MRD kinetics and responses in cytogenetic risk groups in patients from phase 3 MURANO study. Presented at: the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S805.