A Review of Selected Presentations From the 60th American Society of
Hematology Annual Meeting • December 1-4, 2018 • San Diego, California
Ibrutinib Alone or in Combination With Rituximab Produces Superior Progression-Free Survival Compared With Bendamustine Plus Rituximab in Untreated Older Patients With Chronic Lymphocytic Leukemia: Results of Alliance North American Intergroup Study A041202
The randomized phase 3 RESONATE-2 trial (Open-Label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil in Patients 65 Years or Older With Treatment-Naive CLL or SLL) compared ibrutinib vs chlorambucil as first-line therapy in older patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1,2 After stratification according to Eastern Cooperative Oncology Group (ECOG) performance status and Rai disease stage, 269 patients were randomly assigned into each arm. The trial met its primary endpoint, demonstrating a median progression-free survival (PFS) that was not reached in the ibrutinib arm vs 15 months in the chlorambucil arm (hazard ratio [HR], 0.121; 95% CI, 0.074-0.198; P<.0001). The estimated 24-month overall survival (OS) was 95% with ibrutinib vs 84% with chlorambucil. The findings led to regulatory approval of ibrutinib as first-line treatment in this setting. A single-center trial evaluated ibrutinib with or without rituximab in patients with CLL.3 The study enrolled 181 patients with relapsed CLL and 27 treatment-naive patients with high-risk disease. After a median follow-up of 36 months, the estimated PFS rates were 86.0% for patients treated with ibrutinib alone vs 86.9% for patients who also received rituximab.
At the Plenary Session of the 60th American Society of Hematology (ASH) meeting, Dr Jennifer Woyach presented results from the Alliance North American Intergroup Study A041202 (Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia), a phase 3 trial that evaluated the efficacy and safety of ibrutinib monotherapy, ibrutinib plus rituximab, and bendamustine plus rituximab in elderly patients with treatment-naive CLL.4,5 Eligible patients were ages 65 years or older, required treatment for CLL, and had an ECOG performance status of 0 to 2.6 After randomization for disease risk, chromosomal deletion, and degree of Zap70 methylation, patients were randomly assigned into the 3 treatment arms. In the bendamustine/rituximab arm, the dose of bendamustine was 90 mg/m2 on days 1 and 2, and the dose of rituximab was 375 mg/m2 on day 0 of cycle 1, then 500 mg/m2 on day 1 of cycles 2 through 6. In the monotherapy arm, the dose of ibrutinib was 420 mg daily. Patients in the ibrutinib/rituximab arm received 420 mg of ibrutinib plus rituximab at 375 mg/m2 weekly for 4 weeks starting on day 1 of cycle 2, then 375 mg/m2 on day 1 of cycles 3 through 6. Patients enrolled in the bendamustine/rituximab arm who progressed and required therapy could cross over to the ibrutinib arm. The primary endpoint was PFS.
The 547 enrolled patients had a median age of 71 years (range, 65-89 years), and two-thirds were male. Ninety-seven percent of the patients had an ECOG performance status of 0 or 1, and the median white blood cell count was 82 × 103/µL. Genomic aberrations included unmutated immunoglobulin heavy chain variable (IGHV; 61%), unmethylated Zap70 (53%), the complex karyotype (29%), the TP53 mutation (10%), deletion of chromosome 11q (19%), and deletion of chromosome 17p (6%). Seventy-four percent of eligible patients participated in a Geriatric Assessment Correlative Study. No significant differences emerged among the 3 treatment arms at baseline, based on scores for activities of daily living (mean, 13.7), number of coexisting conditions (mean, 2.5), and falling at least once in the prior 6 months (12.7%).
Ibrutinib with or without rituximab demonstrated a superior PFS compared with bendamustine plus rituximab. The estimated PFS at 24 months was 74% (95% CI, 66%-80%) with bendamustine plus rituximab, 87% (95% CI, 81%-92%) with ibrutinib monotherapy, and 88% (95% CI, 81%-92%) with ibrutinib plus rituximab (Figure 1). Compared with bendamustine plus rituximab, the HR for PFS was 0.39 (95% CI, 0.26-0.58; P<.001) with ibrutinib monotherapy and 0.38 (95% CI, 0.25-0.59; P<.001) with ibrutinib plus rituximab. Comparison of ibrutinib plus rituximab vs ibrutinib monotherapy yielded an HR of 1.00 (95% CI, 0.62-1.62; P=.49). Patients with deletion of 17p13.1 had an estimated 24-month PFS of 75% (95% CI, 31%-93%) with ibrutinib monotherapy and of 73% (95% CI, 37%-90%) with ibrutinib plus rituximab, vs 0% with bendamustine plus rituximab (Figure 2). Among patients with the complex karyotype, the estimated 24-month PFS was also superior with ibrutinib monotherapy (91%; 95% CI, 75%-97%) or ibrutinib plus rituximab (87%; 95% CI, 75%-94%) vs bendamustine plus rituximab (59%; 95% CI, 42%-73%). The overall response rates (ORRs) were 93% (95% CI, 88%-96%) with ibrutinib monotherapy, 94% (95% CI, 89%-97%) with ibrutinib plus rituximab, and 81% (95% CI, 75%-87%) with bendamustine plus rituximab.
Complete responses (CRs) were seen in 26% of the bendamustine/rituximab arm (95% CI, 20%-33%), 12% of the ibrutinib/rituximab arm (95% CI, 8%-18%), and 7% of the ibrutinib monotherapy arm (95% CI, 4%-12%). Dr Woyach noted that responses achieved with ibrutinib tend to deepen over time, and the CR rate may increase in the ibrutinib arms. Minimal residual disease (MRD) in the bone marrow was negative at 9 months in 8% (95% CI, 5%-13%) of patients receiving bendamustine plus rituximab, 4% (95% CI, 2%-8%) of those treated with ibrutinib plus rituximab, and 1% (95% CI, <1%-3%) of those receiving ibrutinib monotherapy. After a median follow-up of 38 months, the estimated 24-month OS was similar for the 3 arms, at 95% with bendamustine plus rituximab (95% CI, 91%-98%), 90% with ibrutinib monotherapy (95% CI, 85%-94%), and 94% with ibrutinib plus rituximab (95% CI, 89%-97%).
Grade 3, 4, or 5 hematologic toxicities occurred in 61% of the bendamustine/rituximab arm, 41% of the ibrutinib monotherapy arm, and 38% of the ibrutinib/rituximab arm (P<.001). Grade 3, 4, or 5 nonhematologic toxicities occurred in 63%, 74%, and 74% (P=.04), respectively.
References
1. Barr PM, Robak T, Owen C, et al. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018;103(9):1502-1510.
2. 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.
3. Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib versus ibrutinib plus rituximab in patients with chronic lymphocytic leukemia [published online December 7, 2018]. Blood. doi:10.1182/blood-2018-10-879429.
4. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202 [ASH abstract 6]. Blood. 2018;132(suppl 1).
5. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
6. 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.
A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients With Chronic Lymphocytic Leukemia: A Trial of the ECOG-ACRIN Cancer Research Group (E1912)
The treatment landscape for patients with CLL or SLL has changed dramatically in the past several years.1 The development of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) improved PFS and OS compared with chemotherapy alone and is the first-line standard of care for CLL patients who are younger than 65 years and who do not have comorbidities.2 Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK), which mediates B-cell receptor signaling. Treatment with ibrutinib has led to durable responses and improved survival in patients with relapsed or refractory CLL and in older patients who are treatment-naive.3,4
In the Late-Breaking Abstract session of the 60th ASH meeting, Dr Tait Shanafelt presented results from the ECOG/American College of Radiology Imaging Network (ACRIN) group phase 3 E1912 trial (Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma), which compared ibrutinib plus rituximab vs FCR in young patients who were treatment-naive.5 Eligible patients were ages 70 years or younger, did not harbor the chromosome 17p deletion, had adequate creatinine clearance, and required treatment based on the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2008 recommendations.6 Prior to randomization, patients were stratified based on age, performance status, disease stage, and status of chromosome 11q22.3 (ataxia telangiectasia mutated). Patients were randomly assigned 2:1 to receive ibrutinib (420 mg daily) or 6 courses of intravenous fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2) on days 1 through 3 every 28 days. All patients also received rituximab (50 mg/m2 on day 1, then 325 mg/m2 on day 2, followed by 500 mg/m2 on day 1 of subsequent cycles). Rituximab was administered during cycles 1 to 6 for patients in the FCR arm and during cycles 2 through 7 in the ibrutinib/rituximab arm. Patients in the ibrutinib/rituximab arm continued to receive daily ibrutinib (420 mg) after completion of 7 cycles of ibrutinib plus rituximab. The primary endpoint was PFS, with a secondary endpoint of OS. All randomized patients were included in the primary analysis.
The study randomly assigned 354 patients to ibrutinib plus rituximab and 175 to FCR. Patient characteristics were well-balanced between the 2 arms. Patients had a median age of 58 years, and 40.6% were ages 60 years or older. One-third of patients were female, and 63.3% had an ECOG performance status of 0. Rai stage III/IV disease was noted in 43.1% of patients. Based on fluorescence in situ hybridization, chromosome 11q deletion was observed in 22.2% of patients, trisomy 12 in 18.3%, and chromosome 13q deletion in 33.8%. A ß2 microglobulin level exceeding 3.5 mg/mL was observed in 50.6%, and IGHV was unmutated in 71.1%.
After a median follow-up of 33.4 months, the intention-to-treat analysis showed a superior PFS with ibrutinib plus rituximab vs FCR (HR, 0.35; 95% CI, 0.22-0.50; P<.0001; Figure 3), with similar results in the eligible study population. Patients with unmutated IGHV experienced a prolonged PFS from ibrutinib plus rituximab compared with FCR (HR, 0.26; 95% CI, 0.14-0.50; P<.00001; Figure 4), but the difference was not significant in the smaller group of patients with mutated IGHV (HR, 0.44; 95% CI, 0.14-1.36; P=.07). OS was significantly improved with ibrutinib plus rituximab vs FCR based on intention-to-treat analysis (HR, 0.17; 95% CI, 0.05-0.54; P<.0003), again with similar results observed in the eligible study population. Deaths were reported in 4 patients (1.1%) in the ibrutinib/rituximab arm and 10 (5.7%) in the FCR arm. The deaths were attributed to CLL in 1 vs 6, respectively.
Grade 3 to 5 adverse events (AEs) occurred in 72.1% of the FCR arm and 58.5% of the ibrutinib/rituximab arm (P=.004). Patients in the FCR arm were more likely to experience neutropenia (P<.001), anemia (P<.001), thrombocytopenia (P<.001), any infection (P<.001), neutropenic fever (P<.001), atrial fibrillation (P=.04), and hypertension (P=.01). In the Alliance A041202 trial, patients who received first-line ibrutinib plus rituximab had a median age of 71 years, and these patients experienced a higher rate of grade 3 to 5 AEs than the younger patients in E1912 (7% vs 1%).7 Compared with patients in the E1912 trial, patients in the Alliance trial were more likely to develop infection (19% vs 5%), atrial fibrillation (6% vs 3%), bleeding (4% vs 1%), and hypertension (34% vs 7%) with ibrutinib plus rituximab.
References
1. Jain N. Selecting frontline therapy for CLL in 2018. Hematology Am Soc Hematol Educ Program. 2018;2018(1):242-247.
2. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2019. National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Updated October 5, 2018. Accessed December 31, 2018.
3. 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.
4. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.
5. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912) [ASH abstract LBA-4]. Blood. 2018;132(suppl 1).
6. 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.
7. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
MURANO Trial Establishes Feasibility of Time-Limited Venetoclax-Rituximab Combination Therapy in Relapsed/Refractory Chronic Lymphocytic Leukemia
The randomized, open-label, 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]) compared venetoclax plus rituximab vs bendamustine plus rituximab in patients with relapsed or refractory CLL.1,2 The trial enrolled 389 patients. All patients received rituximab for 6 months. Patients who were randomly assigned to the venetoclax/rituximab arm also received venetoclax for up to 2 years, and patients in the bendamustine/rituximab arm received bendamustine for 6 months.
After a median of 23.8 months of follow-up, 2-year PFS rates were 84.9% with venetoclax plus rituximab vs 36.3% with bendamustine plus rituximab (HR for progression or death, 0.17; 95% CI, 0.11-0.25; P<.001). Venetoclax plus rituximab demonstrated a benefit over bendamustine plus rituximab for all subgroups examined, including patients with the chromosome 17p deletion. After a median follow-up of 36 months, 30 patients in the venetoclax/rituximab arm and 63 in the bendamustine/rituximab arm had discontinued treatment, and venetoclax plus rituximab continued to show a clinically meaningful improvement in OS compared with bendamustine plus rituximab (87.9% vs 79.5%; HR, 0.50; 95% CI, 0.30-0.85). In the bendamustine/rituximab arm, most patients who progressed subsequently received active therapy that included ibrutinib or venetoclax.
At a median follow-up of 9.9 months (range, 1.4-22.5 months) after cessation of venetoclax monotherapy, the estimated 1-year PFS was 87.4% (95% CI, 81.1%-93.8%).4 MRD is predictive of improved outcomes, including PFS and OS, in CLL patients who receive treatment with chemo-immunotherapy, and MRD negativity is a more robust endpoint than CR.3 MRD status at the end of 24 months of venetoclax plus rituximab was available for 130 patients. Among these patients, at a median of 9.9 months of posttreatment follow-up, the median PFS was 97.6% in those with undetectable MRD, 87.0% in those with low MRD, and 21.4% in those with high MRD. MRD status was found to be a predictor of disease progression by univariate analysis (P<.0001).
Dr Arnon Kater presented an analysis of MRD.4 After completion of 6 months of combination therapy, 63% of patients in the venetoclax/rituximab arm vs 15% in the bendamustine/rituximab arm had undetectable MRD.5 At 24 months, undetectable MRD was again observed in 48% of the venetoclax/rituximab arm vs 2% of the bendamustine/rituximab arm. Consistently high rates of undetectable MRD were observed in the venetoclax/rituximab arm across all subgroups. Patients with undetectable MRD at the end of combination treatment in the venetoclax/rituximab arm had a prolonged PFS (HR, 0.38; 95% CI, 0.20-0.72; Figure 5), as did patients in the bendamustine/rituximab arm (HR, 0.27; 95% CI, 0.14-0.52).4 Similarly, in both arms, PFS was prolonged in patients with a low MRD status. MRD status was a stronger predictor of PFS than clinical response. In patients with undetectable MRD after treatment, rates of progressive disease and emergence of MRD-positivity were low. The findings represent the first data to demonstrate undetectable MRD as a predictive marker of improved outcome for a fixed-duration, chemotherapy-free treatment regimen.
In the venetoclax/rituximab arm, most grade 3/4 AEs occurred during the 6 months when patients were receiving both drugs. The most common grade 3/4 AE with venetoclax plus rituximab was neutropenia (58.8%), followed by anemia (10.8%). Grade 3/4 tumor lysis syndrome occurred in 3.1% of patients in the venetoclax/rituximab arm.
References
1. Seymour JF, Kipps TJ, Eichhorst B, et al. MURANO trial establishes feasibility of time-limited venetoclax-rituximab (VenR) combination therapy in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) [ASH abstract 184]. Blood. 2018;132(suppl 1).
2. 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.
3. Owen C, Christofides A, Johnson N, Lawrence T, MacDonald D, Ward C. Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia. Leuk Lymphoma. 2017;58(12):2777-2785.
4. Kater AP, Hillmen P, Langerak AW, et al. First prospective data on impact of minimal residual disease on long-term clinical outcomes after venetoclax plus rituximab vs bendamustine plus rituximab: phase III MURANO study [ASH abstract 695]. Blood. 2018;132(suppl 1).
5. High MRD-negative status seen with venetoclax plus rituximab combination in CLL. Targeted Oncology. https://www.targetedonc.com/news/high-mrdnegative-status-seen-with-venetoclax-plus-rituximab-combination-in-cll. Published December 13, 2018. Accessed December 31, 2018.
Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab as First-Line Treatment in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: Results From Phase 3 iLLUMINATE
The open-label, multicenter phase 3 iLLUMINATE trial (A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment Naïve CLL or SLL) evaluated obinutuzumab in combination with chlorambucil or ibrutinib as first-line treatment in patients with CLL.1,2 This study enrolled patients ages 65 years or older regardless of comorbidities, as well as patients younger than 65 years with at least 1 coexisting condition, such as a CIRS score higher than 6, a creatinine clearance of less than 70 mL/min, and the TP53 mutation/chromosome 17p deletion. Patients were randomly assigned to receive chlorambucil (0.5 mg/kg on days 1 and 15) for 6 cycles of 28 days or ibrutinib (420 mg daily) until disease progression or unacceptable toxicity. Patients in both arms also received obinutuzumab (1000 mg, split on days 1-2, plus 1000 mg on days 8 and 15 during cycle 1; then 1000 mg on day 1 for subsequent cycles). The primary endpoint was PFS as assessed by independent review.
The trial enrolled 113 patients in the ibrutinib/obinutuzumab arm and 116 in the chlorambucil/obinutuzumab arm. The median follow-up was 31.3 months (range, 0.2-36.9 months). According to independent assessment, PFS was not reached with ibrutinib plus obinutuzumab vs 19.0 months with chlorambucil plus obinutuzumab (HR, 0.231; 95% CI, 0.145-0.367; P<.0001; Figure 6). The estimated 30-month PFS was 79% with ibrutinib plus obinutuzumab vs 31% with chlorambucil plus obinutuzumab. After excluding patients with the chromosome 17p deletion, the ibrutinib combination was associated with a 74% reduction in the risk of progression or death. The ibrutinib combination also showed a consistent benefit over chlorambucil/obinutuzumab in patients with an unmutated IGHV, the chromosome 11q deletion, the chromosome 17p deletion, and/or the TP53 mutation.
For the subpopulation of patients with high-risk disease, which included those with an unmutated IGHV, the chromosome 11q deletion, the chromosome 17p deletion, and/or the TP53 mutation, ibrutinib plus obinutuzumab reduced the risk of disease progression or death by 85%. According to independent review, the ORR was 88% with ibrutinib plus obinutuzumab vs 73% with chlorambucil plus obinutuzumab. The rates of CR/CR with incomplete bone marrow recovery (CRi), were 19% vs 8%, respectively. In the high-risk subpopulation, the ORR was 90% with ibrutinib plus obinutuzumab vs 68% with chlorambucil plus obinutuzumab, with CR/CRi rates of 14% vs 4%, respectively. Rates of undetectable MRD in the bone marrow and/or peripheral blood were 35% with ibrutinib plus obinutuzumab vs 25% with chlorambucil plus obinutuzumab. OS was similar for both arms. However, 40% of patients in the chlorambucil arm crossed over to receive single-agent ibrutinib.
Grade 3/4 AEs were observed in 77% of patients in the ibrutinib/obinutuzumab arm vs 72% in the chlorambucil/obinutuzumab arm. The most common events were neutropenia (36% vs 46%) and thrombocytopenia (19% vs 10%).
References
1. Moreno C, Greil R, Demirkan F, et al. Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE [ASH abstract 691]. Blood. 2018;132(suppl 1).
2. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-56.
Comparison of Efficacy and Toxicity of CD19-Specific Chimeric Antigen Receptor T Cells Alone or in Combination With Ibrutinib for Relapsed and/or Refractory CLL
The safety and feasibility of therapy with CD-19–directed chimeric antigen receptor (CAR) T cells were evaluated among CLL patients who had previously received ibrutinib.1 Ibrutinib therapy was discontinued prior to study enrollment. CAR T-cell therapy was administered at 3 doses: 2 × 105 cells/kg, 2 × 106 cells/kg, and 2 × 107 cells/kg. Four weeks after the CAR T-cell infusion, the ORR was 71% (17/24). Twenty patients (83%) developed cytokine release syndrome and 8 (33%) developed neurotoxicity (which led to death in 1 patient). Among 19 patients who received the CAR T-cell infusion and were restaged, the ORR at 4 weeks was 74% and included 4 CRs. Among 12 patients who underwent deep sequencing of the IGH locus, 7 (58%) had no evidence of malignant IGH in the bone marrow.
At the 60th ASH Meeting, Dr Jordan Gauthier provided results of a retrospective study evaluating the outcomes in this cohort of patients in comparison with a cohort of CLL patients who received CD19-directed CAR T-cell therapy plus concurrent ibrutinib.2 Patients in the concurrent-ibrutinib cohort received ibrutinib at 420 mg daily from at least 2 weeks prior to leukapheresis until at least 3 months after the CAR T-cell infusion. Dose reductions were permitted. The no-ibrutinib cohort included 24 patients and the concurrent-ibrutinib cohort included 19 patients. In the concurrent-ibrutinib cohort, 13 patients (68%) received ibrutinib as planned. One patient died from presumed cardiac arrhythmia after 4 days of ibrutinib therapy.
Among evaluable patients, the ORR was 83% with concurrent ibrutinib vs 65% with no ibrutinib (P=.38). Based on bone marrow analysis by flow cytometry, the CR rate was 72% with concurrent ibrutinib vs 74% with no ibrutinib, a difference that was not significant. However, based on sequencing of the IGH region, the bone marrow CR rate was 85% (11/13) in the concurrent-ibrutinib cohort vs 50% (7/14) in the no-ibrutinib cohort (P=.10). Cross-sectional tumor area (based on the sum of the product of the diameter of up to 6 dominant lesions) was associated with a higher probability of a bone marrow CR by flow cytometry, and successful CAR T-cell expansion was a strong predictor of response according to iwCLL criteria and assessment of nodes and bone marrow (Figure 7).
Cytokine release syndrome of any grade occurred in 74% of patients in the concurrent-ibrutinib cohort vs 92% in the no-ibrutinib cohort (P=.21). However, cytokine release syndrome of grade 3 or higher was less common with concurrent ibrutinib (0% vs 25%; P=.03). Grade 3 or higher neurotoxicity was observed in 26% vs 29%, respectively.
References
1. Turtle CJ, Hay KA, Hanafi LA, 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(26):3010-3020.
2. Gauthier J, Hirayama AV, Hay KA, et al. Comparison of efficacy and toxicity of CD19-specific chimeric antigen receptor T-cells alone or in combination with ibrutinib for relapsed and/or refractory CLL [ASH abstract 299]. Blood. 2018;132(suppl 1).
A Phase II Trial of Nivolumab Combined With Ibrutinib for Patients With Richter Transformation
A phase 2 study evaluated nivolumab plus ibrutinib in patients with Richter transformation.1 Patients received nivolumab (3 mg/kg every 3 weeks) for all treatment cycles, and concomitant ibrutinib (420 mg daily) was administered starting with cycle 2. Eligible patients had Richter transformation characterized by a diagnosis of diffuse large B-cell lymphoma, and an ECOG performance status of 0 to 2. The 24 enrolled patients had a median age of 64.5 years (range, 47-88 years), and 58% were male. Forty-two percent of patients had received prior treatment for Richter transformation, and 83% had received prior treatment for CLL. Based on fluorescence in situ hybridization data from 20 patients, chromosomal abnormalities included the chromosome 17p deletion (45%), the chromosome 11q deletion (20%), and trisomy 12 (20%). Genetic testing identified an unmutated IGHV in 72% (13/18), the complex karyotype in 63% (12/19), the TP53 mutation in 47% (8/17), and the NOTCH1 mutation in 24% (4/17).
A response was observed in 42% of patients (10/24), including 8 patients with a complete metabolic response and 2 with a partial response. Four additional patients underwent subsequent salvage therapy followed by allogeneic stem cell transplant. Among 13 patients with prior exposure to a BTK inhibitor, the median number of prior therapies was 4, and 3 of these patients (23%) had a response. Among 11 patients with no prior exposure to a BTK inhibitor, the median number of prior therapies was 1, and the response rate was 64% (7/11).
Among 10 patients, the median duration of response was 9.3 months with censoring for allogeneic stem cell transplant and was not reached without censoring for this factor (Figure 8). The median OS was 13.8 months. Among 2 patients who responded to the combination treatment, both had no detectable programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) expression at baseline. Among 3 patients who did not respond, 2 had PD-1 expression on their tumor cells at baseline. The study protocol has been amended to include treatment with ipilimumab, an anti–CTLA-4 antibody.
The combination of nivolumab plus ibrutinib was generally well-tolerated. The most common AEs were grade 1/2 and included skin rash (33%), arthralgia (25%), easy bruising (21%), diarrhea (13%), and atrial fibrillation (4%). Other AEs of interest included grade 4 elevated lipase and amylase in 1, grade 3 pneumonia/pneumonitis or transaminitis in 3, and grade 2 uveitis in 1.
Reference
1. Jain N, Ferrajoli A, Basu S, et al. A phase II trial of nivolumab combined with ibrutinib for patients with Richter transformation [ASH abstract 296]. Blood. 2018;132(suppl 1).
Highlights in Chronic Lymphocytic Leukemia From the 60th
American Society of Hematology Annual Meeting: Commentary
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
Presentations in chronic lymphocytic leukemia (CLL) at the 60th American Society of Hematology (ASH) annual meeting provided important new data. Several studies evaluated the role of ibrutinib in frontline management.
At the plenary session, Dr Jennifer Woyach presented results from the Alliance North American Intergroup Study A041202 (Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia), which compared ibrutinib alone or in combination with rituximab vs bendamustine and rituximab as frontline therapy of CLL in patients older than 65 years.1 The patients’ median age was 71 years. Ibrutinib has a frontline approval that is very broad and not age-restricted.2 The approval was based on the RESONATE-2 trial (Open-Label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil in Patients 65 Years or Older With Treatment-Naive CLL or SLL), a randomized comparison of ibrutinib vs chlorambucil.3 Ibrutinib produced significantly longer progression-free survival (PFS). In fact, a recently published 2-year follow-up analysis showed that median PFS was still not reached for ibrutinib vs approximately 15 months for chlorambucil.4 There was a difference in overall survival in favor of ibrutinib, although it should be mentioned that crossover was allowed in this trial. The RESONATE-2 trial clearly demonstrated that ibrutinib is better than chlorambucil. However, many physicians would treat a patient older than 65 years with a better chemotherapy regimen than chlorambucil. In that setting, the most common regimen is probably bendamustine plus rituximab. The A041202 study therefore compared ibrutinib against this combination, with a primary endpoint of PFS. The trial also evaluated overall survival and whether the addition of rituximab to ibrutinib improves outcomes. Phase 2 data have shown that the addition of rituximab to ibrutinib accelerates the response to ibrutinib.5 The underlying reason is that in most patients, single-agent ibrutinib causes lymphocytosis, which resolves completely over time.6 The addition of rituximab abrogates the lymphocytosis.7 However, it was not known whether the addition of the antibody leads to more deep or durable remissions. A randomized trial from MD Anderson attempted to address this question.5 The study compared ibrutinib with or without rituximab in patients with CLL; most had relapsed disease. The primary endpoint was 24-month PFS. The trial found that there was no long-term benefit with the addition of rituximab; the Kaplan-Meier curves for PFS overlapped completely. A caveat to this study finding is that with a population of patients who have relapsed disease, it might be expected that most patients would have already received rituximab as part of their frontline chemoimmunotherapy regimen and theoretically might have some degree of resistance to this agent.
The A041202 study evaluated frontline therapy, so resistance was not an issue.1 This large trial enrolled more than 500 patients. The population was older, with a median age of approximately 71 years. PFS, the primary endpoint, was dramatically different in the ibrutinib arms vs the bendamustine/rituximab arm. At the 24-month estimate, the PFS was 74% with bendamustine/rituximab, 87% with ibrutinib monotherapy, and 88% with ibrutinib/rituximab. Therefore, the trial showed no difference in outcomes with the addition of rituximab to ibrutinib, but both of these regimens were significantly better than bendamustine/rituximab. This improvement was particularly evident in 17p-deleted patients. Currently, patients with the 17p deletion are no longer treated with chemotherapy, and they would now be excluded from this type of trial. The superiority of the ibrutinib arms was also evident in patients with a complex karyotype. Benefits were unclear, however, in patients with the mutated immunoglobulin heavy chain variable (IGHV) gene, who respond best to chemotherapy. In this group, there was not a large difference among the treatment arms, but there was a trend toward improvement with ibrutinib. Longer follow-up may identify a difference.
The response rates overall were 93% with ibrutinib monotherapy and 94% with ibrutinib/rituximab, compared with 81% with bendamustine/rituximab. The complete response rate, however, was higher with bendamustine/rituximab, at 26%, vs 7% with ibrutinib monotherapy and 12% with ibrutinib/rituximab. So far, the overall survival rates did not differ according to treatment; in this frontline population, the 24-month survival exceeded 90% in all arms. This lack of a difference is not surprising because most patients who progress on bendamustine/rituximab can go on to receive ibrutinib-based therapy as a salvage regimen.
As expected, there was more hematologic toxicity, predominantly neutropenia, with chemotherapy. There was also more febrile neutropenia with the chemotherapy, which again is not surprising. The only toxicity that was significantly higher in the ibrutinib arms was hypertension. This known side effect can usually be addressed with antihypertensive agents.3
The real question is whether the results of this trial are practice-changing: will physicians who use bendamustine/rituximab as frontline therapy switch to ibrutinib, without evidence of a survival benefit? Physicians might still reserve ibrutinib for use as a salvage regimen, based on the following rationale. Most patients with CLL cannot be cured. (There may be a cure fraction among patients with the IGHV mutation who are treated with fludarabine, cyclophosphamide, and rituximab [FCR].8) The goal, therefore, is to sequence treatments—getting a certain number of years from each—to keep patients alive long enough so that they die from other causes. In this study, the median PFS was 41 months with bendamustine/rituximab.1 Therefore, this regimen provides approximately 3 and a half years until disease progression, and possibly even more time until the next therapy is needed. It may make sense to use chemotherapy as upfront treatment because administration only becomes more problematic as a patient ages. Ibrutinib is a great salvage regimen associated with long remissions. The results of this study could give physicians the confidence to use bendamustine/rituximab as upfront treatment.
A late-breaking abstract from the Eastern Cooperative Oncology Group (ECOG)/American College of Radiology Imaging Network (ACRIN) group provided results from another important large, randomized trial in the frontline setting for CLL.9 The study compared ibrutinib and rituximab vs FCR in previously untreated patients with CLL. There was no single-agent ibrutinib arm. FCR is the gold standard for these patients. The head-to-head German CLL10 study showed that PFS was approximately 1 year longer with FCR than bendamustine/rituximab.10 In the United States, however, FCR is used less often than bendamustine/rituximab because FCR is more difficult to administer, a clinical perception that was confirmed by the CLL10 trial. FCR is more likely to cause myelosuppression and grade 3 to 4 infection,11 so most physicians reserve it for younger, fit patients.
The ECOG-ACRIN trial enrolled patients younger than 70 years who did not have deletion 17p.9 More than 500 patients were randomly assigned to treatment with ibrutinib/rituximab or standard-dose FCR. The primary endpoint was PFS. The patients’ median age was 58 years, which was much younger than that in the Alliance trial1 and reflects the fact that younger, fit patients are the better candidates for FCR.11
As in the Alliance trial, PFS was significantly better with ibrutinib/rituximab vs FCR, although no median PFS was reached for either arm.9 The study also analyzed results according to the patients’ mutational status. Those with the IGHV mutation had a trend toward improvement with ibrutinib/rituximab that was not statistically significant. Among patients with an unmutated IGHV, ibrutinib/rituximab significantly improved PFS.
The trial did not resolve whether ibrutinib will recreate the plateau that exists for FCR, partly because the follow-up duration was short. A plateau was also not seen among patients with the IGHV mutation treated with FCR, again because it is too early.
A surprising finding was a survival advantage with ibrutinib/rituximab.9 There were 4 deaths in the ibrutinib/rituximab arm vs 10 in the FCR arm. The data were reported early, however, and the low number of deaths overall may have skewed the P value. With longer follow-up, the outcome may become more similar. FCR is known to be associated with grade 3 to 4 infections,11 but infections were not the primary cause of death in the FCR arm. In the FCR arm, 6 of the deaths were caused by progressive CLL. This finding raises the question of why the patients developed progressive disease so early. One possible explanation is that the trial excluded patients with the 17p deletion, but it did not screen for the TP53 mutation. It is possible that the trial enrolled patients with the TP53 mutation, who respond poorly to chemotherapy. The presentation at ASH did not specify why the patients with progressive disease did not cross over to the ibrutinib arm.
In terms of the toxicity, as expected, there was significantly more neutropenia, anemia, thrombocytopenia, and infections with FCR. In the ibrutinib arm, there was more atrial fibrillation, a known side effect, and hypertension.
This interesting trial clearly showed that ibrutinib led to a better PFS than the best chemoimmunotherapy regimen now available. Like the Alliance trial, however, the results may not be practice-changing, for the following reasons. In the United States, most patients treated in the community setting are older than 71 years and would not be candidates for FCR. The one setting where many experts still use FCR is in the IGHV-mutated population. In the past 2 years, 3 publications showed a plateau in the PFS curve with FCR among patients with the IGHV mutation.8,12,13 A study from MD Anderson, where the FCR regimen was developed, had the longest follow-up.8 At 10 to 16 years, approximately 60% of these patients were free of progression. Many patients also showed no minimal residual disease, which suggests that there may be a cure fraction. It is not yet known whether physicians will change their treatment approach based on the results of this trial. A confounding factor is the survival advantage seen with ibrutinib, which requires further explanation.
The frontline randomized iLLUMINATE study (A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment Naïve CLL or SLL) compared ibrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab.14 A criticism of the RESONATE-2 trial3 (which led to the approval of ibrutinib as a single agent when it showed superiority over single-agent chlorambucil) was that the standard of care was chlorambucil/obinutuzumab by the time the results were reported. As with any type of chemotherapy in lymphoid malignancies, there are now strong data from randomized trials, including CLL11, showing that obinutuzumab plus chlorambucil is better than chlorambucil alone.15 The CLL11 trial had a third arm of chlorambucil and rituximab, and this regimen was clearly inferior to chlorambucil and obinutuzumab (which is approved for the frontline treatment of CLL). In the RESONATE-2 trial, however, the superiority of ibrutinib over chlorambucil was so large that it is hard to imagine it would not have remained so even with the addition of obinutuzumab to chlorambucil. Therefore, a randomized trial was probably not needed to confirm that ibrutinib was better. In the frontline CLL11 trial, chlorambucil and obinutuzumab produced a median PFS of approximately 26 months.15 This PFS was significantly better than chlorambucil with or without rituximab, but far inferior to that of ibrutinib, which was still not reached after 24 months of follow-up.4
An interesting aspect to the iLLUMINATE trial was that it combined obinutuzumab with ibrutinib. Nearly all of the other trials that combined ibrutinib with an antibody used rituximab, and showed no improvement in outcome.5,7 (In contrast, the addition of antibodies to chemotherapy always improves outcome in lymphoid malignancies.) More than 200 patients were randomly assigned to receive ibrutinib/obinutuzumab or chlorambucil/obinutuzumab.14 iLLUMINATE is a registration trial. The patients’ median age was approximately 71 years, so this trial enrolled an older population, as would be expected. According to an independent review committee, the PFS at 2 and a half years was 79% with ibrutinib/obinutuzumab vs 31% with chlorambucil/obinutuzumab. The median PFS with chlorambucil/obinutuzumab was 19 months as assessed by the independent review committee and 22 months by investigator assessment.
The difference was even more dramatic among high-risk patients: those with unmutated IGHV, the deletion 11q, the deletion 17p, or the TP53 mutation. If this trial were being designed now, it would exclude patients with the 17p deletion or the TP53 mutation, who do not respond well to any type of chemotherapy.
The overall response rate was higher with ibrutinib/obinutuzumab, at 88%, vs 73% with chlorambucil/obinutuzumab. Interestingly, the complete response rate was higher with ibrutinib/obinutuzumab at 19%, vs 8% with the chemotherapy combination.
The rate of undetectable minimal residual disease, meaning less than 1 CLL cell in 10,000 cells, was higher with ibrutinib/obinutuzumab. Rates of undetectable minimal residual disease (MRD) were approximately 20% in the bone marrow and 30% in the peripheral blood with ibrutinib/obinutuzumab vs 17% and 20%, respectively, with chlorambucil/obinutuzumab. An interesting observation from the ibrutinib/rituximab data was that the complete response rates were low and the rates of undetectable MRD were very low. Essentially, undetectable MRD was not seen. The iLLUMINATE trial suggests that there may be a role for the antibody obinutuzumab in combination with ibrutinib. With the rate of MRD negativity being only 20%, however, this regimen will not impact overall outcomes for most patients. In this trial, the rates of overall survival were higher than 80% for both treatment arms at a median follow-up of 2 and a half years. The similarity is not surprising because many patients who relapse on chlorambucil will go on to receive ibrutinib, and the follow-up duration was short.
Regarding the toxicity profile, there was more myelosuppression and fevers with chemotherapy. Atrial fibrillation was more common with ibrutinib. Rates of hypertension were similar in both arms.
The results of this trial may be practice-changing in Europe, where chlorambucil plus obinutuzumab is the standard of care. This regimen is far less common in the United States.
The phase 2 trial of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) from MD Anderson enrolled only patients with the IGHV mutation; patients with the deletion 17p or the TP53 mutation were excluded.16 As I mentioned, FCR appears to provide a plateau on the PFS curve for patients with mutated IGHV.8 The researchers at MD Anderson did not want to give up chemotherapy in this population because of the possibility of a cure fraction. The idea behind the study was to alter the standard chemotherapy regimen to improve outcomes and reduce toxicity. Because obinutuzumab is the better antibody with chlorambucil, the researchers substituted it for rituximab in the standard FCR regimen. An additional consideration was that ibrutinib improves the outcome of chemotherapy. Several years ago, the HELIOS trial (A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lym-phoma; CLL3001) evaluated ben-damustine and rituximab with or with-out ibrutinib, showing that the addition of ibrutinib improved outcomes.17 Ibrutinib was therefore added to this regimen, but chemotherapy was limited to 3 cycles to minimize the associated short-term and late-term toxicity. Treatment continued with ibrutinib and obinutuzumab.
All patients received obinutuzumab with fludarabine/cyclophosphamide for 3 cycles, plus ibrutinib at the standard dose of 420 mg/day. After 3 cycles, all patients were treated with at least 9 more months of ibrutinib, for a total treatment duration of 1 year. After the 3 cycles, patients then received obinutuzumab for 3 more courses if they had a complete response and were MRD-negative after the 3 months of chemotherapy. Patients with only a partial response or who were MRD-positive received obinutuzumab for 9 more courses. After 12 cycles, patients with undetectable MRD would stop ibrutinib, so all therapy would be discontinued. Patients who were MRD-positive would continue to receive ibrutinib.
The trial enrolled 45 patients, and response was evaluable in 44. The median follow-up was nearly 2 years. The patients’ median age was 60 years. This young age is not surprising, as this group of patients can reasonably tolerate FCR, and by extension, the regimen evaluated in the trial.
After 3 cycles of ibrutinib plus chemotherapy, the rate of MRD undetectability was high, at 89%. This rate appeared to improve with time. Among the 32 patients who reached 1 year of follow-up, all had undetectable MRD and were able to stop treatment. These data compare well with that of historical controls. In the CLL10 trial of FCR vs bendamustine/rituximab, MRD was undetectable in 62% of patients with the IGHV mutation after 6 cycles of therapy.10
The trial of iFCG also analyzed serial bone marrow MRD with a very sensitive, next-generation sequencing assay called clonoSEQ. This assay can detect 1 CLL cell in 105 or 106 cells. Interestingly, of the 18 patients with sequencing data available at 12 months, all patients were MRD-negative by the standard assay, and 71% were MRD-negative according to the clonoSEQ assay, suggesting that these remissions were very deep. The median follow-up after stopping ibrutinib was a little more than a year, and no patient had developed progressive disease.
These interesting data suggest that it is possible to administer very limited chemotherapy in combination with ibrutinib to this group of patients with mutated IGHV. This regimen has the potential to produce very high rates of MRD negativity. Importantly, it may allow therapy to be discontinued, which is attractive to patients as well as payers. It will be interesting to learn the long-term outcome among patients who stop therapy at 1 year.
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
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