A Review of Selected Presentations From the 2017 American Society of Hematology Annual Meeting and Exposition • December 9-12, 2017 • Atlanta, Georgia
Single-Agent Ibrutinib Vs Chemoimmunotherapy Regimens for Treatment-Naive Patients With Chronic Lymphocytic Leukemia: A Cross-Trial Comparison
Chemoimmunotherapy with one or more chemotherapeu-tic agents and an anti-CD20 mono-clonal antibody is the standard of care for the initial treatment of chronic lymphocytic leukemia (CLL). However, there are limitations to chemoimmunotherapy. The responses can be temporary and toxicities can be challenging, particularly in older patients.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved by the US Food and Drug Administration (FDA) for use in patients with CLL and allows for once-daily oral dosing without chemotherapy. In the randomized, phase 3 RESONATE-2 trial (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]), single-agent ibru-tinib was significantly more effective than chlorambucil in older patients (≥65 years) with CLL without a 17p deletion, demonstrating longer median progression-free survival (PFS; hazard ratio [HR], 0.16; P<.001) and longer overall survival (OS; HR, 0.16; P<.001).1 Ibrutinib also had a better hematologic safety profile.1
To further assess the potential role of single-agent ibrutinib in the first-line treatment of CLL, Dr Tadeusz Robak and colleagues2 con-ducted a cross-trial comparison of updated efficacy and safety outcomes with ibrutinib in RESONATE-2 against outcomes reported in phase 3 trials of various chemoimmunotherapy regimens, including fludarabine, cyclo-phosphamide, and rituximab (FCR) from CLL8,3 bendamustine plus rituximab and FCR from CLL10,4 chlorambucil with obinutuzumab or rituximab from CLL11,5 and ofatumumab plus chlorambucil from COMPLEMENT-1 (Chlorambucil Plus Ofatumumab Versus Chlor-am-bucil Alone in Previously Untreated Patients With Chronic Lymphocytic Leukaemia).6 The patient populations differed somewhat across the studies. On average, patients receiving ibru-tinib were older, less likely to have unmutated IGHV, and more likely to have comorbidities than patients receiving chemoimmunotherapy.
In the overall analysis, primary treatment with ibrutinib was asso-ciated with a longer PFS than any chemoimmunotherapy regimen (Figure 1). Investigators noted that the PFS outcomes were better in older, less-fit patients receiving ibrutinib than in younger, fitter patients receiving FCR in the CLL8 trial (Figure 2). PFS outcomes were also better with ibrutinib compared with FCR historical outcomes and with bendamustine/rituximab in CLL10.4 In patients treated with bendamustine/rituximab or FCR, unmutated IGHV remains a poor prognostic factor. In contrast, IGHV mutation status did not impact PFS outcomes with ibrutinib. These findings suggest that in older patients, ibrutinib may overcome the poor prognostic effect of unmutated IGHV.
Ibrutinib also demonstrated a sig-nificant improvement in PFS over historical results with chlorambucil plus rituximab or obinutuzumab in various trials. The benefit of single-agent ibrutinib over chemoimmunotherapy was particularly strong among high-risk subgroups, including patients with advanced disease, unmutated IGHV, or the 11q deletion. OS outcomes in ibrutinib-treated patients were comparable with those observed with chemoimmunotherapy; in particular, ibrutinib appeared to provide an OS benefit over regimens that contained chlorambucil in the comparator arm.
The patients receiving ibrutinib remained on treatment longer than patients receiving chemoimmunotherapy, with median treatment dur-ations of 34 months vs 5 to 6 months, respectively. Despite the longer treatment period and the older patient population, ibrutinib was associated with lower rates of grade 3 or higher cytopenias compared with FCR or bendamustine/rit-uximab. Rates of grade 3 or higher infections were similar.
The investigators concluded that single-agent ibrutinib may provide a chemotherapy-free initial regimen that has comparable efficacy with that observed with standard combination chemoimmunotherapy. These data were drawn from cross-trial comparisons. Ongoing prospective, randomized trials are comparing ibrutinib (alone or in combination with an anti-CD20 agent) vs FCR,7 bendamustine/ritux-imab,8 and chlorambucil/obin-utuzumab.9
1. 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.
2. Robak T, Burger JA, Tedeschi A, et al. Single-agent ibrutinib vs chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia (CLL): a cross-trial comparison [ASH abstract 1750]. Blood. 2017;130(suppl 1).
3. 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.
4. 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.
5. 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.
6. Hillmen P, Robak T, Janssens A, et al; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multi-centre, open-label phase 3 trial. Lancet. 2015;
7. ClinicalTrials.gov. Ibrutinib and rituximab compared with fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. https://clinicaltrials.gov/ct2/show/NCT02048813. Identifier: NCT02048813. Accessed December 28, 2017.
8. 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 December 28, 2017.
9. ClinicalTrials.gov. A multi-center study of ibrutinib in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab in patients with treatment naïve CLL or SLL. https://clinicaltrials.gov/ct2/show/NCT02264574. Identifier: NCT02264574. Accessed December 28, 2017.
Results From the Phase 3 DUO Trial: A Randomized Comparison of Duvelisib Vs Ofatumumab in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
There is an unmet need for effective therapies for patients with relapsed/refractory CLL. Duvelisib is an orally administered inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma. It is thought that the ability to target both the delta and gamma isoforms of PI3K will allow duvelisib to exert activity against tumor cells and the microenvironment. Duvelisib initially showed antitumor activity in a phase 1 study in patients with advanced CLL/small lymphocytic lymphoma (SLL), demonstrating an overall res-ponse rate (ORR) of 56%.1 Based on this initial finding, the randomized, phase 3 DUO trial (A Phase 3 Study of Duvelisib Versus Ofatumumab in Patients With Relapsed or Refractory CLL/SLL) compared duvelisib vs ofatumumab in patients with relapsed/refractory CLL who developed progressive disease or relapsed after at least 1 prior therapy.2 (Patients previously treated with a BTK or PI3K inhibitor were excluded.) Patients had measurable lymph node disease as assessed by computed tomography (CT) and adequate hemoglobin levels and platelet counts. Patients with Richter trans-formation and prolymphocytic leuk-emia were excluded.
A total of 319 patients were assigned to duvelisib 25 mg twice daily continuously (n=160) or intravenous ofatumumab administered at 300 mg on day 1, then 2000 mg weekly for 7 weeks followed by monthly for 4 months (n=159). All patients received prophylaxis for Pneumocystis pneumonia during treatment, and prophylaxis for cytomegalovirus infection/reactivation was recom-mended. In an optional crossover study, patients switched to ofatumu-mab (n=8) or duvelisib (n=89).
During 2014 and 2015, the DUO trial enrolled patients from Europe (74%), the United States (16%), Australia (7%), and New Zealand (4%). The median age of patients was 69 years (range, 39-90 years), and 60% were male. The baseline factors were fairly well-balanced between the arms. Approximately half of patients had bulky disease, and a third of patients had a 17p deletion or TP53 mutation. ZAP70 positivity (defined as ≥20%) was present in approximately 53% of patients. Grade 4 cytopenias were present at baseline in 11% of patients. Patients had received a median of 2 prior therapies (range, 1-10). Approximately two-thirds of patients had been previously treated with a purine analogue, more than 90% had received an alkylating agent, and approximately 80% had received a monoclonal antibody, most often rituximab.
The median duration of treatment was substantially longer with duvelisib than ofatumumab, at 50 weeks vs 23 weeks, respectively. The most common reasons that patients discontinued treatment with duvelisib were adverse events (AEs; 35%) and disease progression (22%). In the ofatumumab arm, 20% of patients discontinued owing to disease progression. At the time of the analysis, 22% of patients in the duvelisib arm remained on treatment. Among the 110 patients in the ofatumumab arm who developed disease progression (69%), 89 crossed over to receive duvelisib.
The trial met its primary endpoint, demonstrating a significant improvement in PFS with duvelisib vs ofatumumab per the independent review committee (Figure 3). Median PFS was 13.3 months with duvelisib vs 9.9 months with ofatumumab (HR, 0.52; P<.0001). The PFS benefit with duvelisib was more pronounced among the 77 patients with a 17p deletion, at a median of 12.7 months vs 9.0 months with ofatumumab (HR, 0.41; P=.0011). The PFS advantage was maintained across other key subgroups, including patients with refractory or early relapse, those with grade 4 cytopenias, older patients, younger patients, and those with both longer and shorter relapses.
The ORR was also significantly higher with duvelisib vs ofatumumab, in both the overall population (73.8% vs 45.3%; P<.0001) and in the subset of patients who had the 17p deletion (70% vs 43%; P=.0182). Lymph node responses (defined as ≥50% decrease in the sum of the product of the greatest diameters of the target lymph nodes from baseline) were observed in 85.0% of the duvelisib arm and 15.7% of the ofatumumab arm. The median OS was not reached in either arm, and OS curves were similar between the arms. The investigators noted that many patients went on to receive subsequent anticancer therapies. Among patients in the ofatumumab arm who crossed over, duvelisib was associated with an investigator-assessed ORR of 73% and a median PFS of 15 months.
AE rates were higher with duv-elisib vs ofatumumab, even with the longer observation period for duv-elisib. Grade 3/4 hematologic AEs included neutropenia (reported in 30% of the duvelisib arm vs 17% of the ofatumumab arm), anemia (13% vs 5%), and thrombocytopenia (8% vs 2%). The most common grade 3/4 nonhematologic toxicities associated with duvelisib were diarrhea (15%), pneumonia (14%), and colitis (12%). Other grade 3/4 AEs occurred in less than 5% of patients. Most cases of diarrhea and colitis were manageable, and they did not require treatment discontinuation. Severe opportunistic infections occurred in 6% of patients. No severe herpes zoster infections were reported. Among the 4 deaths attributed to treatment, the causes were infectious complications in 3 patients and general health deterioration in
1. O’Brien S, Patel M, Kahl BS, et al. Duvelisib (IPI-145), a PI3K-δ,γ inhibitor, is clinically active in patients with relapsed/refractory chronic lymphocytic leukemia [ASH abstract 3334]. Blood. 2014;124(suppl 21).
2. Flinn IW, Hillmen P, Montillo M, et al. Results from the phase 3 DUOTM trial: a randomized comparison of duvelisib vs ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma [ASH abstract 493]. Blood. 2017;130(suppl 1).
Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (GA101) for First-Line Treatment of Patients With CLL With Mutated IGHV and Without TP53 Aberration
FCR is a standard frontline chemoimmunotherapy regimen for younger, fit patients with CLL. FCR has demonstrated efficacy as initial therapy in selected patients, with up to 72% of patients attaining a complete remission (CR) and up to 59% attaining negativity for minimal residual disease (MRD).1,2 Outcomes with FCR are particularly favorable in patients with IGHV-mutated CLL. In an analysis of patients receiving initial therapy for CLL, presence of the IGHV mutation was the best pretreatment predictor of which patients would achieve MRD negativity and improved PFS.3
It has been hypothesized that MRD negativity may predict improvement in OS, and MRD status is a component of many recent CLL trials. Several trials have improved MRD rates and clinical outcomes by altering standard chemoimmunotherapy regimens. In the CLL11 trial, the use of obinutuzumab rather than rituximab in combination with chlorambucil was associated with a significant increase in MRD negativity rates and a significant improvement in OS (HR, 0.41; P=.002).4 In 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 Lymphoma; CLL3001), the addition of ibrutinib to chemotherapy in patients with relapsed/refractory CLL was associated with a higher rate of MRD negativity and a significant improvement in PFS.5
At the 2017 ASH meeting, Dr Nitin Jain reported outcomes from an ongoing, investigator-initiated phase 2 trial that is attempting to improve upon the FCR regimen by using obinutuzumab rather than rituximab and adding ibrutinib.6 The ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) regimen is being evaluated in patients ages 18 years or older with previously untreated, IGHV-mutated, CLL/SLL without a 17p deletion or TP53 aberrations. Enrolled patients have adequate organ function, with an absolute neutrophil count exceeding 500/mm3, a platelet count higher than 50,000/mm3, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 × the upper limit of normal, a total bilirubin less than or equal to 1.5 × the upper limit of normal, and a glomerular filtration rate of 30 mL/min or higher.
In addition to evaluating the addition of ibrutinib to chemotherapy, the trial is assessing the feasibility of a shortened chemotherapy regimen of 3 cycles, with the aim of reducing the risk of secondary acute myeloid leukemia and myelodysplastic syndrome, which occur in 5% of FCR-treated patients.7 The trial enrolled its first patient in April 2016, and enrollment continued as of December 2017. An estimated 45 patients are now enrolled. The presentation at the 2017 ASH meeting provided outcomes for the first 36 patients who began treatment.
The iFCG regimen consisted of obinutuzumab administered in cycle 1 as 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15, followed by 1000 mg on day 1 in courses 2 to 3; fludarabine administered at 25 mg/m2 on days 2 to 4 in cycle 1, then on days 1 to 3 in cycles 2 to 3; cyclophosphamide administered at 250 mg/m2 on days 2 to 4 in cycle 1 and on days 1 to 3 in cycles 2 to 3; and ibrutinib at 420 mg once daily continuously. All patients received antiviral prophylaxis with acyclovir or valacyclovir. Prophylaxis for Pneumocystis jiroveci pneumonia was optional. Initially, administration of prophylactic granulocyte colony–stimulating factor was optional, but the trial was later amended to require it.
After 3 cycles of iFCG, patients were assessed for responses and MRD. Patients with a CR or a complete remission with insufficient count recovery (CRi) and MRD negativity received ibrutinib plus obinutuzumab for 3 cycles, then ibrutinib for 6 cycles. Those with a partial response or MRD positivity after 3 cycles of iFCG received 9 cycles of ibrutinib plus obinutuzumab. After 12 cycles, patients with MRD negativity stopped ibrutinib, and those with MRD positivity continued ibrutinib until they developed progressive disease.
Among the 36 enrolled patients, the median age was 60 years (range, 25-71 years), and 78% were male. Nearly half of patients (47%) had Rai stage III/IV disease. Abnormalities identified through fluorescence in situ hybridization (FISH) included a 13q deletion in 72% of patients and trisomy 12 in 17%. Cytogenetic assessments, obtained for 31 patients, included diploid (68%), 13 deletion (19%), and trisomy 12 (13%). The most common mutations (assessed in 35 patients) were MYD88 (11%) and SF3B1 (6%). After a median follow-up of 13.6 months, 32 of the 36 enrolled patients had completed 3 cycles of iFCG. Among the remaining 4 patients, 3 were receiving iFCG at the time of the analysis. One patient discontinued treatment after day 1 of cycle 1, based on a grade 3 infusion-related reaction and grade 4 thrombocytopenia.
The iFCG regimen was associated with high remission rates, with 87% of patients attaining MRD negativity in their bone marrow after 3 cycles (Figure 4). The ORR after 3 cycles of iFCG was 100%, with a CR/CRi rate of 44%. Longitudinal analyses showed that responses improved with time and were observed beyond cycle 6. In an analysis of MRD outcomes by pretreatment characteristics, 3 factors were associated with lower rates of MRD negativity in the bone marrow: higher levels of beta-2 microglobulin, CD38, and ZAP-70 (assessed in 30 patients). MRD negativity rates were similar according to age, sex, Rai stage, FISH features, absolute lymphocyte count, and platelet count.
A total of 19 patients received a year of treatment. All of these patients were MRD-negative and discontinued ibrutinib, as per the protocol. All patients remained MRD-negative after a median follow-up of 5.5 months (range, 0.3-8.5 months) after discontinuation of ibrutinib. At the time of the analysis, all 36 enrolled patients were alive and without disease progression or MRD relapse. The most common grade 3/4 hematologic toxicities were neutropenia and thrombocytopenia, reported in 68% and 27% of patients, respectively, in cycles 1 to 3, and in 42% and 10% of patients, respectively, in cycles 4 to 12. Prophylaxis with granulocyte colony–stimulating factor was mandated for the last 4 patients, and none developed neutropenia.
Grade 3/4 nonhematologic toxicities included elevations of ALT/AST in 4 patients (11%), infusion-related reactions in 2 patients (6%), and arthralgia in 1 patient (3%). An additional 12 patients (33%) had infusion-related reactions of grade 2. Neutropenic fever occurred in 5 patients (14%). Half of patients required dose reductions of fludarabine or cyclophosphamide, and 39% required dose reductions of ibrutinib.
Dr Jain concluded that iFCG induced a high rate of MRD-negative remissions, with 87% of patients attaining MRD negativity in the bone marrow after 3 cycles. All 19 patients who reached the 1-year mark were MRD-negative in the bone marrow and discontinued ibrutinib. The researchers identified molecular factors at baseline that could predict a lower likelihood of attaining MRD negativity.
1. 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.
2. 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.
3. Thompson PA, Strati P, Keating M, et al. Early achievement of MRD-negativity in IGHV-mutated (IGHV-M) patients portends highly favorable outcomes after first-line treatment of CLL with fludarabine, cyclophosphamide and rituximab (FCR). Serial monitoring for minimal residual disease (MRD) in blood after achieving MRD-negativity predicts subsequent clinical relapse [ASH abstract 232]. Blood. 2016;128(suppl 22).
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. Fraser G, Cramer P, Demirkan F, et al. Ibrutinib (I) plus bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): a 2-year follow-up of the HELIOS study [ASCO abstract 7525]. J Clin Oncol. 2016;34(suppl).
6. Jain N, Thompson P, Burger J, et al. Ibrutinib, flu-darabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) for first-line treatment of patients with CLL with mutated IGHV and without TP53 mu-tations [ASH abstract 495]. Blood. 2017;130(suppl 1).
7. Benjamini O, Jain P, Trinh L, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy—distribution and clinical outcomes. Leuk Lymphoma. 2015;56(6):1643-1650.
Improving Depth of Response With Continued Ibrutinib Therapy in CLL Patients
The safety and efficacy of single-agent ibrutinib in patients with CLL who have TP53 aberrations was evaluated in a single-arm, phase 2 trial. Previously published efficacy and safety results from the first 47 evaluable patients showed encouraging activity in this high-risk population.1 At the 2017 ASH meeting, Dr Inhye Ahn reported updated findings, with additional patients and longer follow-up.2 Among 86 patients enrolled, the median age was 63 years, 58% were male, 62% were treatment-naive, 67% had Rai stage III to IV disease, and 63% had TP53 aberrations, including a 17p deletion (58%) and TP53 mutations (4.7%). Most patients (66%) had unmutated IGHV.
Throughout a median follow-up of 48 months, the level of MRD declined with continued ibrutinib treatment. Most patients did not attain MRD negativity (defined as <1 monoclonal B-cell per 10,000 leukocytes [10-4]), but MRD levels declined over time. At 2 years, 58 patients tested MRD-high (≥10-2), and 9 patients tested MRD-low (<10-2). CR rates in these groups were 10% vs 22%, respectively. At 3 years, 47 patients tested MRD-high and 16 patients tested MRD-low, with CR rates of 21% vs 38% (Figure 5).
IGHV mutation status was significantly associated with MRD status. The level of MRD present in the peripheral blood was significantly lower among patients with unmutated IGHV than in those with mutated IGHV (P<.05), starting from the first year of treatment with ibrutinib. (The same trend was not observed in the bone marrow, where MRD outcomes were similar regardless of IGHV status.) Researchers noted that the higher levels of MRD in the peripheral blood of patients with mutated IGHV are consistent with previously observed differences in redistribution lymphocytosis between these subgroups. They suggested that the correlation between MRD levels and IGHV status should be considered by investigators of studies using MRD to determine the duration of treatment with ibrutinib.
After the first year of ibrutinib treatment, the amount of residual CLL burden declined by 36% in the peripheral blood and by 28% in the bone marrow with each additional year. Levels of MRD in the peripheral blood correlated strongly with those measured in the bone marrow. The investigators suggested that this finding raises the possibility of using noninvasive blood testing, rather than bone marrow assessment, to measure MRD in patients receiving ibrutinib.
1. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aber-rations: a phase 2, single-arm trial. Lancet Oncol. 2015;16(2):169-176.
2. Ahn IE, Tian X, Lotter J, et al. Improving depth of response with continued ibrutinib therapy in CLL patients [ASH abstract 4302]. Blood. 2017;130(suppl 1).
Prolonged Improvement in Patient-Reported Outcomes and Well-Being in Older Patients With Treatment-Naive Chronic Lymphocytic Leukemia Treated With Ibrutinib: 3-Year Follow-Up of the RESONATE-2 Study
In the RESONATE-2 trial, single-agent ibrutinib was significantly more effective than chlorambucil in older patients (≥65 years) with treatment-naive CLL, providing an 84% reduction in the risk of progres-sion or death (HR, 0.16; P<.001).1 Other reports have shown that ibrutinib is associated with improvements in quality of life and patient well-being, including in the RESONATE study (Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia; PCYC-1112) in relapsed/refractory CLL, in which ibrutinib was associated with more clinically meaningful improvements in fatigue and global health compared with chlorambucil at week 24.2 Patient-reported outcomes from RESONATE-2 have been previously reported, showing greater improvements with ibrutinib vs chlorambucil in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score (P=.0004) and the European Organization for Research and Treatment core quality-of-life questionnaire (QLQ-C30) global health score (P=.0002) after a median follow-up of 18.4 months.3 At the 2017 ASH meeting, Dr Alessandra Tedeschi presented updated results on quality of life and patient well-being in RESONATE-2.4 The investigators noted that treatment with ibrutinib continues until patients develop pro-gressive disease or unacceptable toxicity, and therefore any impact on quality of life is especially important.
Among the 136 patients assigned to ibrutinib and the 133 patients assigned to chlorambucil, the most common reasons for starting treatment for CLL were the development of constitutional symptoms (45%), progressive bone marrow failure (38%), lymphadenopathy (37%), and splenomegaly (30%). Patients in the ibrutinib arm received treatment for a median of 34.1 months, and 73% of patients were still receiving ibrutinib at the time of analysis, after a median follow-up of 35.7 months. In the chlorambucil arm, the median treatment duration was much shorter, at 7.1 months, and 48% of patients crossed over to ibrutinib after developing progressive disease. The median follow-up in the chlorambucil arm was 34.4 months.
At baseline, CLL disease-related symptoms included fatigue, night sweats, and weight loss. All of these symptoms improved to a greater extent among patients treated with ibrutinib vs chlorambucil (Figure 6). FACIT-F scores improved consistently over time among ibrutinib-treated patients, whereas they declined over time with chlorambucil. Similar trends were seen for the EQ-5D-5L Visual Analog Scale (VAS) scores. A repeated measure analysis showed that the differences between the treatment arms were significant for both of these scores (P=.0021 for FACIT-Fatigue and P=.0004 for EQ-5D-5L VAS). Among patients who crossed over from chlorambucil to ibrutinib upon disease progression, there was a trend toward improvements in both the FACIT-F scores and the EQ-5D-5L VAS scores, which persisted over time.
The investigators also reported updated PFS findings. After a median follow-up lasting approximately 35 months, the median PFS had not been reached in the ibrutinib arm and was 15.0 months in the chlorambucil arm (HR, 0.130; 95% CI, 0.081-0.208; Figure 7). PFS rates at 30 months were 85% with ibrutinib vs 28% with chlorambucil, and improved disease burden was seen in 86% vs 52%. Rates of hematologic improvement were also significantly higher with ibrutinib vs chlorambucil for both hemoglobin (90% vs 45%; P<.0001) and platelet count (83% vs 46%; P=.0032). These differences were associated with a significant reduction in the need for treatment-emergent hematologic sup-port in the ibrutinib arm.
The most common AEs associated with ibrutinib were diarrhea (47%), fatigue (33%), and cough (30%). Throughout a 3-year period, 7% of ibrutinib-treated patients developed grade 3 or higher bleeding. AEs led to treatment discontinuation in 16% of patients in the ibrutinib arm throughout this time. The Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) analysis, which takes into consideration both the benefits of treatment and the toxicities, indicated a significant improvement in the average time spent without symptoms of progressive disease or grade 3/4 AEs with ibrutinib vs chlorambucil (501 vs 351 days; P<.001). Ibrutinib was also associated with a significant extension in the average Q-TWiST duration (386 vs 329 days; P=.001).
1. 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.
2. Barrientos JC, O’Brien S, Brown JR, et al. Hematologic and immunologic function and patient well-being for the phase III RESONATE™ study of ibrutinib vs. ofatumumab in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma [ASH abstract 4696]. Blood. 2014;124(suppl 21).
3. Ghia P, Tedeschi A, Barr PM, et al. Improvement in quality of life and well-being in older patients with treatment-naïve (TN) CLL: results from the randomized phase 3 study of ibrutinib (ibr) versus chlorambucil (clb) (RESONATE-2™) [EHA abstract P217]. Haematologica. 2016;101(s1).
4. Tedeschi A, Owen C, Robak T, et al. Prolonged improvement in patient-reported outcomes (PROs) and well-being in older patients with treatment-naïve (TN) chronic lymphocytic leukemia treated with ibrutinib (ibr): 3-year follow-up of the RESONATE-2 study [ASH abstract 1746]. Blood. 2017;130(suppl 1).
Initial Results of the Phase 2 Treatment-Naive Cohort in a Phase 1b/2 Study of Obinutuzumab, Ibrutinib, and Venetoclax in Chronic Lymphocytic Leukemia
An ongoing phase 1b/2 study is evaluating a novel triplet regimen of obinutuzumab, ibrutinib, and venetoclax in patients with CLL. The phase 1b component enrolled 12 patients with relapsed/refractory CLL to receive a regimen that included dose-escalated venetoclax. The phase 2 trial has enrolled 25 patients with relapsed/refractory CLL and 25 treatment-naive patients. At the 2017 ASH meeting, Dr Kerry Rogers presented initial results from the phase 2 study in treatment-naive patients.1 All enrolled patients had adequate organ function and bone marrow function. Exclusion criteria included uncontrolled autoimmune hemolytic anemia or thrombocytopenia, active Richter syndrome, central nervous system involvement, and use of warfarin or potent CYP3A4 inhibitors or inducers within 7 days before starting the study treatment.
The doses and schedules used in the phase 2 study were established during the 1b phase.2 Treatment was administered in 14 cycles consisting of 28-day periods. Obinutuzumab was initiated in cycle 1 (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15). In cycle 2, obinutuzumab was administered at 1000 mg on day 1, and ibrutinib was added (420 mg/day each day). Starting in cycle 3, venetoclax was introduced, and dose-escalated according to the FDA label. The primary endpoint in the phase 2 study was MRD-negative CR.
Among the 25 treatment-naive patients, the median age was 59 years (range, 24-77 years), 60% were male, 71% had unmutated IGHV, and 24% had a complex karyotype. FISH testing revealed an 11q deletion in 20% of patients, a 13q deletion in 20%, a 17p deletion in 12%, and trisomy 12 in 12%. The risk of tumor lysis syndrome was medium in 72% of patients and high in 28% of patients.
At the data cutoff, no patients had developed progressive disease. Among the 3 patients who discontinued study treatment, the reasons were investigator choice in cycle 7, patient preference in cycle 10, and neutropenia and colitis in cycle 10 (this patient died). The most common AEs were hematologic. Grade 3/4 hematologic events included neutropenia (48%), thrombocytopenia (36%), leukopenia (36%), lymphopenia (32%), and lymphocytosis (4%). No cases of grade 3/4 anemia or neutropenia were reported. The most common nonhematologic grade 1/2 treatment-related AEs were infusion-related reactions (76%), nausea (60%), bruis-ing (56%), oral mucositis (52%), dyspepsia (48%), hypertension (44%), diarrhea (44%), fatigue (40%), and maculopapular rash (40%). The only grade 3/4 nonhematologic AE reported in more than 1 patient was hypertension, which occurred in 9 patients (36%). No events related to clinical or laboratory tumor lysis syndrome were noted.
The responses were evaluated after cycle 8 (during treatment) in 24 patients. The remaining patient discontinued before cycle 8 and was considered to have treatment failure in the intent-to-treat analysis. The regimen was associated with an ORR of 96%, including 5 patients with a CR (20%), 8 patients with a CRi (32%), and 11 patients with a partial response (44%; Figure 8). The cases of CRi were attributed to cytopenias (4 patients; 50%) and cytopenias and hypocellular marrow (4 patients; 50%). Among the 11 patients with a partial response, 6 (55%) would have been considered a CR based on blood counts and bone marrow requirements, but they had lymph nodes larger than 1.5 cm. Moreover, only 1 of the evaluable patients had morphologic evidence of CLL in the bone marrow.
Among the 24 patients evaluable for MRD in both the blood and bone marrow, 14 (58%) attained MRD negativity in both compartments, inclu-ding 8 of 13 patients (61%) with a CR/CRi and 6 of 11 patients (55%) with a partial response. Only 1 patient with detectable CLL had malignant cells comprising at least 1% in either compartment.
The investigators concluded that the combination of obinutuzumab, ibrutinib, and venetoclax appeared to be a safe combination for use as a first-line regimen for CLL, with hematologic AEs accounting for most toxicities, and high-grade AEs occurring rarely. The regimen appeared to be active, with a high ORR and a high rate of MRD negativity. Results for the primary endpoint of MRD-negative CR rates are expected in mid-2018.
1. Rogers KA, Huang Y, Stark A, et al. Initial results of the phase 2 treatment naive cohort in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax in chronic lymphocytic leukemia [ASH abstract 431]. Blood. 2017;130(suppl 1).
2. Jones JA, Woyach J, Awan FT, et al. Phase 1b results of a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax in relapsed/refractory chronic lymphocytic leukemia CLL) [ASH abstract 639]. Blood. 2016;128(suppl 22).
Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia—Results From Pre-Planned Interim Analysis of the Randomized Phase 3 MURANO Study
Venetoclax has been studied in many recent trials of novel therapeutic approaches for CLL. Initially, venetoclax was evaluated as monotherapy. In a phase 1 dose-escalation study that primarily enrolled patients with relapsed/refractory CLL and poor prognostic factors (including 17p deletion), venetoclax was associated with an ORR of 79%.1 In a subsequent phase 1b study, the combination of venetoclax and rituximab among patients with relapsed/refractory CLL demonstrated an ORR of 86%, inclu-ding a CR rate of 51% and an MRD negativity rate of 57% overall.2 In the phase 1b study, 2 patients starting venetoclax at 50 mg developed clinical tumor lysis syndrome (which was fatal for one). No further cases of tumor lysis syndrome occurred after implementation of prophylactic strategies, which included a lower starting dose of 20 mg. Otherwise, the regimen had an acceptable safety profile.
These findings prompted the randomized, phase 3 MURANO trial (A Study of Venetoclax in Combination With Rituximab Compared With Bendamustine in Combination With Rituximab in Participants With Relapsed or Refractory Chronic Lym-phocytic Leukemia), which compared venetoclax/rituximab against a standard regimen, bendamustine and rituximab, in patients with rel-apsed/refractory CLL. Initial findings were presented at the 2017 ASH late-breaking abstract session.3 The MURANO trial enrolled adults with CLL who had received 1 to 3 prior lines of therapy, including at least 1 chemotherapy-containing regimen. Patients could have received bendamustine if the duration of response was at least 24 months. Patients were randomly assigned to venetoclax/rituximab (n=194) or bendamustine/rituximab (n=195). Venetoclax was introduced over a 6-week ramp-up period, and could reach a dose of 400 mg administered orally once daily for 2 years or until progressive disease or unacceptable toxicity. Rituximab was administered at 375 mg/m2 on day 1 of cycle 1, then 500 mg/m2 on day 1 of cycles 2 to 6. Patients in the bendamustine/rituximab arm received bendamustine at 70 mg/m2 on days 1 and 2 of cycles 1 to 6, plus rituximab.
A total of 389 patients enrolled into the trial between March 2014 and September 2015. Patient demographics and disease characteristics were well-balanced between the arms. The median age was approximately 65 years, 73% of patients were male, 27% of patients had a 17p deletion, and 68% of patients had an unmutated IGHV. Approximately 60% of patients had received 1 prior therapy.
After a median follow-up of 23.8 months, the primary endpoint—investigator-assessed PFS—was significantly improved with venetoclax/rituximab vs bendamustine/rituximab. The median PFS was not reached with venetoclax/rituximab vs 17 months with bendamustine/rituximab (HR, 0.17; 95% CI, 0.13-0.28; P<.0001). Superiority of venetoclax/rituximab vs bendamustine/rituximab was confirmed in an independent review (HR, 0.19; P<.0001). Subgroup analyses showed a similar benefit with venetoclax/rituximab regardless of the number of prior therapies, TP53 mutational status, baseline IGHV mutational status, and 17p deletion status. A lesser benefit and a wider confidence interval was seen in a single subgroup: the 59 patients with refractory CLL (HR, 0.32; 95% CI, 0.15-0.70).
Venetoclax/rituximab was associated with a significant imp-rove-ment in response rates over benda-mustine/rituximab, with investigator-assessed ORRs of 93.3% vs 67.7%, respectively (P<.0001; Figure 9). CR/CRi rates were 26.8% and 8.2% (P<.0001). The independently assessed CR/CRi rates were substantially lower than the investigator-assessed rates, at 8.2% and 1.6%, respectively. This discrepancy was attributed to residual CT scan nodes ranging from 16 mm to 30 mm in diameter, of which 88% were MRD-negative in the peripheral blood (defined as <10-4). MRD negativity in the peripheral blood was observed starting at 4 months in 45% of patients receiving venetoclax/rituximab vs 6% of those receiving bendamustine/rituximab. Rates of MRD negativity in the venetoclax/rituximab arm increased to 62% at 9 months, and then were maintained over time, reaching 60% at 18 months. In the bendamustine/rituximab arm, MRD negativity peaked at 13% at 9 months and declined to 5% at 18 months.
Venetoclax/rituximab also pro-vided a significant OS benefit over bendamustine/rituximab. OS rates were 95.9% vs 91.1%, respectively, at 1 year and 91.9% vs 86.6% at 2 years (HR, 0.48; 95% CI, 0.25-0.90; P=.0186).
Dr Seymour noted that the toxicities observed with venetoclax/rituximab were consistent with those expected in patients with relapsed/refractory CLL. The most common grade 3/4 AE associated with venetoclax/rituximab was neu-tropenia, reported in 58% of patients compared with 39% of patients receiving bendamustine/rituximab. The higher incidence of neutropenia among patients treated with venetoclax/rituximab should be considered in conjunction with the longer reporting period for this arm. Other grade 3/4 AEs repor-ted in at least 5% of patients receiv-ing venetoclax/rituximab were anemia (11% vs 14% with benda-mustine/rituximab), thrombocytopenia (6% vs 10%), and pneumonia (5% vs 8%). AEs led to discontinuation in 12% of patients in the venetoclax/rituximab arm compared with 6% in the bendamustine/rituximab arm.
The efficacy benefit observed with venetoclax/rituximab led the investigators to conclude that this treatment should be a standard option for patients with relapsed/refractory CLL.
1. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322.
2. Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18(2):230-240.
3. Seymour JF, Kipps T, Eichhorst B, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia—results from pre-planned interim analysis of the randomized phase 3 MURANO study [ASH abstract LBA-2]. Blood. 2016;128(suppl 22).
Acalabrutinib Monotherapy in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results From the Phase 1/2 ACE-CL-001 Study
Acalabrutinib, an inves-ti-gational BTK inhibitor, has demonstrated substantial potency and greater selectivity than ibrutinib.1 Acalabrutinib does not inhibit off-target kinases, including the epidermal growth factor receptor and the interleukin 2–inducible T-cell kinase. The selectivity and pharmacokinetics of acalabrutinib permit twice-daily dosing. Studies in healthy individuals suggest near-complete occupancy of BTK over a 24-hour period.1
The safety and activity of acalabrutinib are being evaluated in the phase 1/2 ACE-CL-001 study (ACP-196 [Acalabrutinib], a Novel Bruton Tyrosine Kinase [Btk] Inhibitor, for Treatment of Chronic Lymphocytic Leukemia) in a cohort of patients with relapsed or refractory CLL.2 Between February 2014 and November 2015, the study enrolled 134 patients who had received at least 1 prior treatment. Patients had an ECOG performance status of 0 to 1 and an absolute neutrophil count of at least 0.75 × 109/L or a platelet count of at least 50 × 109/L (unless bone marrow involvement was present). Exclusion factors included treatment with vitamin K antagonists or proton pump inhibitors and relapsed/refractory disease after treatment with a prior BTK inhibitor.
A dose-escalation phase evaluated acalabrutinib at 100 mg to 400 mg once daily or 100 mg to 200 mg twice daily. An expansion phase then evaluated acalabrutinib at 100 mg twice daily or 200 mg once daily, continuing treatment until patients developed disease progression or unacceptable toxicity. Subsequently, all patients were switched to the 100-mg twice daily dosing.
Outcomes with the first 61 enrolled patients have previously been published.3 No dose-limiting toxicities were reported in the dose-escalation phase. After a median follow-up of 14.3 months, acalabrutinib was associated with an ORR of 95% in the overall population and 100% in the subset of patients with a 17p deletion. At the 2017 ASH meeting, Dr John Byrd reported updated findings from ACE-CL-001 that included all 134 enrolled patients. The median age was 66 years, 74% were male, and 39% had bulky disease (≥5 cm). Patients had received a median of 2 prior therapies, 23% had a 17p deletion, 18% had an 11q deletion, 73% had unmutated IGHV, and 41% had a complex karyotype.
After a median follow-up of 24.5 months, 78% of patients were still receiving treatment. The most common reasons for treatment discontinuation were AEs (9%; most commonly pneumonia [in 3 patients]) and progressive disease (7%). Acalabrutinib was associated with an ORR of 87%. ORR increased to 93% when including patients with a partial response with lymphocytosis. Among the high-risk subgroups, ORR was 89% in patients with a 17p deletion (n=27), 90% in those with an 11q deletion (n=27), 90% in those with unmutated IGHV (n=81), and 79% in those with a complex karyotype (n=29). Acalabrutinib was associated with resolution of cytopenias in most affected patients, including 86% of those with anemia, 97% of those with neutropenia, and 73% of those with thrombocytopenia. Lymphadenopathy improved in 99% of affected patients.
Among the responding patients, the median time to response was 5.3 months. The median PFS was not reached for the overall population or for high-risk subsets, aside from patients with a complex karyotype, in whom the median PFS was 27.9 months (Figure 10). At 18 months, PFS rates were 90% overall, 80% in patients with a 17p deletion, 100% in those with an 11q deletion, and 95% in those with no complex karyotype.
The most common AEs of any grade included diarrhea (48%), head-ache (47%), upper respiratory tract infection (31%), fatigue (28%), nau-sea (26%), arthralgia (25%), cough (24%), pyrexia (23%), contusion (23%), weight increase (21%), petechiae (21%), and constipation (20%). The most common grade 3 or higher AEs were neutropenia (12%) and pneumonia (11%). Hypertension occurred in 13% of patients (4% grade ≥3). Atrial fibrillation/flutter occurred in 3% of patients at any grade (1% grade ≥3). Seven patients developed fatal AEs, including 4 patients with pneumonia and 1 patient each with Candida sepsis, congestive cardiac failure, and plasmablastic lymphoma. Four patients (3%) developed Richter transformation. A pharmacodynamics analysis, performed in approximately half of patients on day 8 and in 20% of patients at the end of day 28 of cycle 6, showed a median BTK occupancy of 99% at 4 hours after administration of acalabrutinib and 97% to 98% before the next dose.
Three ongoing phase 3 trials are evaluating acalabrutinib for the treatment of CLL. The Elevate CLL TN trial (ACE-CL-007)4 is compar-ing acalabrutinib plus obinutuzumab, single-agent acalabrutinib, and obin-utuzumab plus chlorambucil in patients with treatment-naive CLL. The Elevate CLL relapsed/refractory trial (ACE-CL-006)5 is com-paring acalabrutinib vs ibrutinib in patients with high-risk relapsed/refractory CLL, and the ACE-CL-309 trial6 is comparing acalabrutinib vs investigator’s choice of idelalisib plus rituximab or bendamustine plus rit-uximab in patients with relapsed/refractory CLL.
1. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240-252.
2. Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated results from the phase 1/2 ACE-CL-001 study [ASH abstract 498]. Blood. 2017;130(suppl 1).
3. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-332.
4. ClinicalTrials.gov. Elevate CLL TN: study of obinutuzumab + chlorambucil, acalabrutinib (ACP-196) + obinutuzumab, and acalabrutinib in subjects with previously untreated CLL. https://clinicaltrials.gov/ct2/show/NCT02475681. Identifier: NCT02475681. Accessed December 26, 2017.
5. ClinicalTrials.gov. Elevate CLL R/R: study of acalabrutinib (ACP-196) versus ibrutinib in previously treated subjects with high risk chronic lymphocytic eukemia. ttps://clinicaltrials.gov/ct2/show/NCT02477696. Identifier: NCT02477696. Accessed December 26, 2017.
6. ClinicalTrials.gov. A study of acalabrutinib vs investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in R/R CLL. https://clinicaltrials.gov/ct2/show/NCT02970318. Identifier: NCT02970318. Accessed December 26, 2017.
Highlights in Chronic Lymphocytic Leukemia From the 2017 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
Many presentations at the 2017 Amer-ican Society of Hema-tology (ASH) annual meeting provided important new data in the management of patients with chronic lymphocytic leu-kemia (CLL). Several studies focused on the use of ibrutinib, alone and in combination. Data were also presented for newer treatments, such as duvelisib, venetoclax, and acal-a-brutinib.
Ibrutinib vs Chemoimmunotherapy
Dr Tadeusz Robak provided data from a cross-trial comparison of single-agent ibrutinib vs chemo-immunotherapy.1 Importantly, this analysis showed that ibrutinib was associated with longer progression-free survival (PFS) and a more favorable safety profile than chemoimmunotherapy. Many physicians still use chemotherapy for the frontline treatment of older patients who are somewhat unfit, but could possibly tolerate treatments such as bendamustine/rituximab. The use of chemotherapy in this setting is not unreasonable, and it is based on the rationale that although ibrutinib was superior to chlorambucil in the RESONATE-2 trial (which led to the frontline approval of ibrutinib),2 there are currently no data to show that ibrutinib is better than bendamustine/rituximab in the frontline setting. Two large US Intergroup trials are comparing ibrutinib vs more effective chemotherapy in the frontline setting. One randomized trial is compar-ing fludarabine, cyclophosphamide, and rituximab (FCR) vs ibrutinib/rituximab.3 A 3-arm trial is evaluating bendamustine/rituximab vs ibrutinib monotherapy vs ibrutinib/rituximab.4 These trials accrued approximately a year ago, but data are not yet avail-able.
In the interim, the study by Dr Robak overlaid data from several trials: CLL8, which evaluated FCR (vs FC)5; CLL10, which evaluated bendamustine plus rituximab (vs FCR)6; CLL11, which evaluated obin-utuzumab plus chlorambucil and rituximab plus chlorambucil (vs single agent chlorambucil)7; and COMPLEMENT-1, which evaluated ofatumumab plus chlorambucil (vs chlorambucil).8 The analysis showed that ibrutinib appeared to have the best PFS.1 These data are the reason I use ibrutinib for most patients in the frontline setting. An exception is patients with a mutated IGHV gene. Recent studies evaluating the long-term outcome of FCR by IGHV mutation status consistently showed a plateau on the PFS curve for patients with a mutated IGHV,9-11 and I believe there is a cure fraction. For patients without the IGHV mutation, indirect evidence suggests that ibrutinib is better than chemotherapy (although data from randomized trials are lacking). In the studies included in this analysis, patients in the FCR and bendamustine/rituximab arms were younger than patients in the ibrutinib arm, who were older than 65 years. Ibrutinib still appeared favorable, even though older patients are more likely to experience toxicity and interrupt therapy, and thus have a shorter PFS (with chemotherapy). We await confirmation of these data from the randomized trials.
The randomized phase 3 DUO trial evaluated duvelisib, a phosphoinositide 3 (PI3)-kinase-delta/gamma inhibitor.12 Idelalisib is a PI3K-delta inhibitor; duvelisib also targets gamma, which may be particularly important in T-cell lymphoma. The DUO trial was designed to provide data for the potential registration of duvelisib and approval by the US Food and Drug Administration (FDA). The design was based on the original RESONATE trial, which compared ibrutinib vs ofatumumab in patients with relapsed disease.13 Ofatumumab was given at the standard schedule. The overall response rate was significantly higher with duvelisib, at 74%, vs 45% in the ofatumumab arm. The median PFS was also significantly longer, at 17.6 months based on investigator assessment and 13.3 months according to the independent res-ponse committee, compared with approximately 9.9 months for ofatu-mumab. The data from this study may lead to FDA approval, making a second PI3- kinase agent available for the treatment of CLL.
Ibrutinib in Combination Regimens
A study from MD Anderson presented by Dr Nitin Jain was based on the excellent long-term outcomes seen with FCR among patients with CLL who have the mutated IGHV gene.14 I was a coauthor of this study, which aimed to determine whether it would be possible to limit the cycles of chemotherapy and improve outcomes with the add-ition of ibrutinib. The standard 6-cycle FCR regimen is associated with short-term toxicity, cumulative myelosuppression, and rare cases of myelodysplastic syndromes and acute myeloid leukemia that occur in the long-term. This study added ibrutinib, changed the antibody from rituximab to obinutuzumab (based on emerging data suggesting that this antibody may be more powerful7) and stopped the chemotherapy after 3 cycles. At this point, patients with a complete remission (CR) or complete remission with insufficient count recovery (CRi) who were negative for minimal residual disease (MRD) continued treatment with ibrutinib plus obinutuzumab for 3 cycles, and then received ibrutinib alone for 6 cycles. Patients with a partial response or who were MRD-positive were treated with ibrutinib plus obinutuzumab for 9 cycles. At 12 months, patients who were MRD-positive continued treatment with ibrutinib until progressive disease. Patients who were MRD-negative discontinued all treatment. Although ibrutinib is usually administered until the patient develops progressive disease, in this study, it was not. The primary endpoint was to compare the MRD negativity rate at 3 months with the rate based on historical data for FCR, which is 26%.15 The study reported an MRD negativity rate of 87%, which is dramatically higher than the historical control rate. All of the patients who reached the 12-month endpoint were MRD-negative and therefore discontinued treatment.
This study explored an attempt to keep using chemotherapy in the mutated setting. Although ibrutinib may be very effective in these patients, there are no long-term data to know if the same type of plateau on the PFS curve will be seen. There is a possibility that ibrutinib is a curative frontline treatment for patients with mutated IGHV, but the follow-up data are currently too limited to know. This study maintained the use of chemotherapy in a subgroup it may cure, but attempted to (A) shorten the duration of chemotherapy to decrease the toxicity, (B) achieve higher MRD negativity rates by adding ibrutinib and changing the monoclonal antibody to obinutuzumab, and (C) increase the 60% plateau seen with standard FCR in that population.
A study from Ohio State evaluated the combination of ibrutinib, venetoclax, and obinutuzumab.16 There is excitement about combining ibrutinib and venetoclax, with or without an antibody, and several presentations at the 2017 ASH meeting explored these regimens. Previously, the only data available for this approach were from an early analysis of this study presented at the 2016 ASH meeting by Dr Jeffrey Jones.17 The early analysis showed data for 10 relapsed patients. After treatment with ibrutinib, venetoclax, and obinutuzumab, 7 patients were MRD-negative in the blood and 4 patients were MRD-negative in the bone marrow, which was promising. The presentation at the 2017 ASH meeting, by Dr Kerry Rogers, provided data for the frontline cohort of patients in the trial.16 This small cohort consisted of 25 treatment-naive patients. The overall response rate was 96%. Interestingly, at the midpoint, the rate of MRD negativity in the blood and marrow was 58%. It was surprising to see that the MRD negativity rate was not higher, given that these patients were treatment-naive. That may be attributable to the small number of patients or the early time of the assessment. More follow-up will be needed to see if the MRD negativity rate increases.
Another important finding from this study, as first presented at the 2016 ASH meeting,17 was that ibrutinib, venetoclax, and obinutuzumab could be given together at full doses. This study had a phase 1 component in which ibrutinib and obinutuzumab were given at the standard doses, but venetoclax was targeted to a final dose of 100 mg/day, 200 mg/day, or 400 mg/day.17 The phase 1 analysis showed that it was possible to use venetoclax at the full dose. The toxicities reported are what would be expected from each of the drugs used alone. The most common side effect with ibrutinib is diarrhea, and in this study, diarrhea occurred in approximately half of patients, but it was usually mild. Rates of neutropenia were somewhat higher than those reported for the single agents, which is not surprising since neutropenia is seen with both venetoclax and obinutuzumab. In the frontline setting, there were no cases of neutropenic fever, most likely because the neutropenia was often transient.
A study from MD Anderson evaluated venetoclax and ibrutinib in patients with CLL who were previously untreated or who had relapsed/refractory disease.18 There is much excitement about the use of these 2 small molecules, and this trial evaluated them without an antibody. Standard doses were used: 420 mg/day for ibrutinib and a target dose of 400 mg/day for venetoclax. There were 37 patients in the relapsed/refractory cohort and 40 patients in the frontline cohort. The trial design included a run-in period with ibrutinib. Nearly all of the combination trials evaluating ibrutinib and venetoclax with or without an antibody initiate treatment with single-agent ibrutinib or an antibody for 1 to 3 months before venetoclax is started. A lead-in period can debulk the patient to some extent, and reduce the risk for tumor lysis associated with venetoclax.
The study evaluated patients at different time points. Among patients in the frontline cohort, 20 were evaluable for response after 6 months of treatment; only 3 were evaluable after 12 months. The overall response rate was 100% at 6 months and 12 months. The CR rate increased with time, from 75% at 6 months to 100% at 12 months (again, only 3 patients were evaluable at 12 months). Bone marrow MRD negativity was reported in 45% of patients at 6 months and in 100% of patients at 12 months. In the relapsed/refractory setting, 16 patients were evaluable for response at 6 months, and 5 were available at 12 months. The overall response was 100% at both 6 and 12 months. The bone marrow MRD negativity was 13% at 6 months, and increased to 40% at 12 months.
These data were impressive, and they raise the question of whether an antibody is needed when 2 small molecules are used. Treatment outcome with venetoclax appears significantly improved when an antibody is added, but the same improvement is not seen when an antibody is added to ibrutinib. Some combination trials are evaluating all 3 drugs, whereas others are omitting the antibody.19,20 It is too early to tell whether an antibody will improve outcome when added to 2 small molecules. More mature data are needed, and comparisons across trials will need to be done carefully.
Venetoclax Plus Rituximab
Data from a late-breaking abstract presented by Dr John Seymour may potentially lead to a new indica-tion for venetoclax, a BCL2 selective inhibitor.21 This trial com-pared venetoclax/rituximab vs bendamustine/rituximab in relapsed CLL. When this trial was designed several years ago, bendamustine/rituximab was a common regimen in the relapsed setting. Currently, ibrutinib is the more common treatment. Nevertheless, bendamustine/ritux-imab is a reasonable control arm. In this large study of nearly 400 patients, the median PFS was not reached for venetoclax/rituximab vs 17 months for bendamustine/rituximab. The hazard ratio was 0.17, one of the lowest I have seen in a randomized trial. The indication for venetoclax is more narrow in the United States than in Europe and Canada. Single-agent venetoclax is approved by the FDA for patients with the 17p deletion who have relapsed disease. The study by Dr Seymour was not restricted to patients with the 17p deletion. The results will likely expand the indication of venetoclax to include use in combination with rituximab among all patients in the relapsed setting.
Emerging data suggest that the use of an antibody and venetoclax may be synergistic,22 which is in significant contrast to the use of an antibody with B-cell receptor inhibitors. The data for the combinations of ibrutinib plus rituximab or idelalisib plus rituximab were similar to the data for the single agents alone. An important difference is that the addition of an antibody to a B-cell receptor inhibitor provides a much more rapid response because it abrogates the lymphocytosis typically seen with B-cell receptor inhibitors. A randomized trial presented at the 2017 ASH meeting by Dr Jan Burger was the first to compare ibrutinib alone with ibrutinib plus rituximab.23 This trial enrolled patients with relapsed disease as well as treatment-naive patients with the 17p deletion, a high-risk cohort not suited for chemotherapy. The study randomly assigned patients to standard-dose ibrutinib vs ibrutinib and rituximab. The PFS curves were the same with both regimens. The follow-up was an average of 2 years, and most patients had not developed relapsed disease. It is possible that the rates of PFS will differ over time. These data suggested that the addition of an antibody to a B-cell receptor inhibitor provides a more rapid response, but not much else. These results are in marked contrast to what is seen with venetoclax and an antibody. There are some data with venetoclax and obinutuzumab showing very high rates of MRD negativity in the frontline setting.24 More data combining rituximab with ibrutinib will be provided by a US Intergroup trial that is evaluating 3 arms: bendamustine/rituximab vs ibrutinib/rituximab vs ibrutinib alone.4 This randomized trial enrolled patients for frontline treatment, as opposed to the current study in the relapsed setting.
Dr John Byrd presented updated results with acalabrutinib in CLL.25 Acalabrutinib is a new Bruton tyrosine kinase (BTK) inhibitor that was recently approved by the FDA for the treatment of mantle cell lymphoma. It is not yet approved for CLL. There are 2 randomized registration trials: one in the relapsed, high-risk setting and one in the frontline setting, but data are not yet available.26,27 The original data for the phase 1 trial in relapsed CLL were published in 2016.28 The study enrolled 134 patients, a large number. The median number of prior regimens was 2. The median follow-up was approximately 25 months. The overall response rate, including partial responses with lymphocytosis, was 93%, consisting mostly of partial remissions. The median PFS was not reached, and the 18-month PFS rate was 90%.
The first question is how acalabrutinib compares with ibrutinib. Data for the head-to-head trial are not yet available.29 Comparing across trials, the data for acalabrutinib appear at least as good. A potential advantage to acalabrutinib is that it may not be associated with the side effects seen with ibrutinib, which are thought to be related to inhibition of kinases other than BTK. Atrial fibrillation and platelet dysfunction might be related to inhibition of the Tec kinase, and diarrhea might be related to inhibition of the epidermal growth factor receptor. Preclinical assessment of the half maximal inhibitory con-centration (IC50) for acalabrutinib against these other kinases shows much higher rates—from tenfold to a thousandfold—than that seen with ibrutinib. The original data showed that diarrhea was not very common with acalabrutinib. Headache is the most common side effect, but it tends to be short-lived, and patients develop tachyphylaxis. With ibrutinib, the most concerning adverse events are atrial fibrillation, major bleeding, and hypertension, which can require patients to discontinue treatment when uncontrollable. In the study by Dr Byrd, hypertension occurred in 13% of patients, which is lower than that seen with ibrutinib.25 Atrial fib-rillation occurred in 3%, vs 10% to 12% for ibrutinib. There was no major bleeding. When comparing adverse events, an important caveat is that the median follow-up with acalabrutinib is 25 months, compared with 5 years for ibrutinib. The data for acalabrutinib are exciting because the efficacy appears at least as good as ibrutinib, and there is a suggestion that the toxicity profile may be better. Results from the randomized trials will help to clarify these data.26,27,29
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.
1. Robak T, Burger JA, Tedeschi A, et al. Single-agent ibrutinib vs chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia (CLL): a cross-trial comparison [ASH abstract 1750]. Blood. 2017;130(suppl 1).
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. ClinicalTrials.gov. Ibrutinib and rituximab compared with fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. ttps://clinicaltrials.gov/ct2/show/NCT02048813. Identifier: NCT02048813. Accessed December 28, 2017.
4. 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 December 28, 2017.
5. Hallek M, Fischer K, Fingerle-Rowson G, et al; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-1174.
6. 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.
7. 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.
8. Hillmen P, Robak T, Janssens A, et al; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multi-centre, open-label phase 3 trial. Lancet. 2015;385(9980):
9. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treat-ment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;
10. 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.
11. Rossi D, Terzi-di-Bergamo L, De Paoli L, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood. 2015;126(16):1921-1924.
12. Flinn IW, Hillmen P, Montillo M, et al. Results from the phase 3 DUOTM trial: a randomized comparison of duvelisib vs ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma [ASH abstract 493]. Blood. 2017;130(suppl 1).
13. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
14. Jain N, Thompson P, Burger J, et al. Ibrutinib, flud-arabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) for first-line treatment of patients with CLL with mutated IGHV and without TP53 mut-ations [ASH abstract 495]. Blood. 2017;130(suppl 1).
15. Strati P, Keating MJ, O’Brien SM, et al. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL. Blood. 2014;123(24):3727-3732.
16. Rogers KA, Huang Y, Stark A, et al. Initial results of the phase 2 treatment naive cohort in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax in chronic lymphocytic leukemia [ASH abstract 431]. Blood. 2017;130(suppl 1).
17. Jones JA, Woyach J, Awan FT, et al. Phase 1b results of a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax in relapsed/refractory chronic lymphocytic leukemia (CLL) [ASH abstract 639]. Blood. 2016;128(suppl 22).
18. Jain N, Thompson PA, Ferrajoli A, et al. Combined venetoclax and ibrutinib for patients with previously untreated high-risk CLL, and relapsed/refractory CLL: a phase II trial [ASH abstract 429]. Blood. 2017;130(suppl 1).
19. ClinicalTrials.gov. Venetoclax and ibrutinib in patients with chronic lymphocytic leukemia (CLL). https://clinicaltrials.gov/ct2/show/NCT02756897. Identifier: NCT02756897. Accessed December 28, 2017.
20. Hillmen P, Munir T, Rawstron A, et al. Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY Study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy [ASH abstract 428]. Blood. 2017;130(suppl 1).
21. Seymour JF, Kipps T, Eichhorst B, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia—results from pre-planned interim analysis of the randomized phase 3 MURANO study [ASH abstract LBA-2]. Blood. 2017;130(suppl 1).
22. Freise KJ, Jones AK, Menon RM, et al. Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. Hematol Oncol. 2017;35(4):679-684.
23. Burger JA, Sivina M, Ferrajoli A, et al. Randomized trial of ibrutinib versus ibrutinib plus rituximab in patients with chronic lymphocytic leukemia [ASH abstract 427]. Blood. 2017;130(suppl 1).
24. Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129(19):2702-2705.
25. Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated results from the phase 1/2 ACE-CL-001 study [ASH abstract 498]. Blood. 2017;130(suppl 1).
26. ClinicalTrials.gov. Elevate CLL TN: study of binutuzumab hlorambucil, calabrutinib (ACP-196) binutuzumab, nd calabrutinib in subjects with previously untreated CLL. https://clinicaltrials.gov/ct2/show/NCT02475681. Identifier: NCT02475681. Accessed December 28, 2017.
27. ClinicalTrials.gov. Elevate CLL R/R: study of acalabrutinib (ACP-196) versus ibrutinib in previously treated subjects with high risk chronic lymphocytic eukemia. ttps://clinicaltrials.gov/ct2/show/NCT02477696. Identifier: NCT02477696. Accessed December 28, 2017.
28. Byrd JC, Harrington B, O’Brien S, et al. Acal-abrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-332.
29. ClinicalTrials.gov. A study of acalabrutinib vs investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in R/R CLL. https://clinicaltrials.gov/ct2/show/NCT02970318. Identifier: NCT02970318. Accessed December 28, 2017.