A Review of Selected Presentations From the XVII International Workshop on Chronic Lymphocytic Leukemia
May 12-15, 2017 • New York, New York
Special Reporting on:
• Outcomes of Ibrutinib-Treated Patients With CLL/SLL With High-Risk Prognostic Factors in an Integrated Analysis of 3 Randomized Phase 3 Studies
• Outcomes of Standard-of-Care Regimens in Treatment-Naive Chronic Lymphocytic Leukemia Patients With Unmutated Immunoglobulin Heavy Chain Variable Genes
• The Role of MRD in the Setting of Novel Targeted Therapies
• Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (GA101) for Previously Untreated Patients With Chronic Lymphocytic Leukemia With Mutated IGHV and Non-Del(17p)
• Characteristics of Patients Treated for CLL in a Real-World Registry: Results From informCLL
PLUS Meeting Abstract Summaries
With Expert Commentary by:
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
Outcomes of Ibrutinib-Treated Patients With CLL/SLL With High-Risk Prognostic Factors in an Integrated Analysis of 3 Randomized Phase 3 Studies
Outcomes in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) are heavily influenced by genetic abnormalities.1-3 As described by the Döhner hierarchical classification, the shortest median survival is seen in patients with deletion of chromosome arm 17p (del[17p]), followed by del(11q).1 The unmutated immunoglobulin heavy chain variable (IGHV) gene is a prognostic factor for poor response to chemoimmunotherapy.2 Patients with del(13q) as their sole abnormality fare better than those with normal cytogenetic profiles.
In the phase 2 PCYC-1102 and PCYC-1103 trials, 5-year follow-up of 132 patients who received treatment with ibrutinib showed that median progression-free survival (PFS) was shortest in those with del(17p), followed by del(11q).4 In a multivariate analysis that included IGHV, complex karyotype, clinical stage, age, and del(17p), only del(17p) was independently associated with PFS or overall survival (OS).
Dr Thomas Kipps presented results of an analysis of pooled data from CLL patients treated with ibrutinib in three phase 3 clinical trials.5 Each of the phase 3 clinical studies demonstrated superior outcomes in the ibrutinib arm vs the comparator arm. The RESONATE trial (Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia; PCYC-1112) included 391 patients who had received at least 1 prior therapy (mean, 3 prior therapies) and were ineligible for or refractory to purine analogue therapy.6 Patients were randomly assigned to receive ibrutinib at 420 mg once daily or ofatumumab at an initial dose of 300 mg followed by 11 doses at 2000 mg throughout 24 weeks. In the ofatumumab arm, 131 patients crossed over to ibrutinib following progressive disease. The 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]) included 269 treatment-naive patients ages 65 years or older. Patients with del(17p) were excluded. Study participants were randomly assigned to receive ibrutinib at 420 mg once daily or chlorambucil at 0.5 mg/kg (up to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle. In the extension study, 64 patients in the chlorambucil arm crossed over to ibrutinib.7 The HELIOS study (A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma; CLL3001) included 578 patients who had received at least 1 prior therapy (mean, 2 therapies).8 Patients with del(17p) were excluded. All patients received treatment with bendamustine plus rituximab (BR), and were then randomly assigned to receive ibrutinib (420 mg once daily) or placebo for a maximum of 6 cycles. After disease progression, 142 patients in the placebo arm crossed over to ibrutinib.
The pooled analysis evaluated the impact of the IGHV mutation, del(11q), trisomy 12, and the complex karyotype. (The analysis omitted del[17p] since patients with this mutation were excluded from 2 of the trials.) There were 620 patients treated with ibrutinib and 590 patients in the control arms.
In the cohort of patients who received treatment with ibrutinib, the overall response rates (ORRs) and the complete response (CR) rates were similar regardless of the presence of the IGHV mutation, del(11q), and the complex karyotype (Figure 1). The CR rate was reduced among patients who lacked trisomy 12 (P=.04). OS at 42 months was similar regardless of the presence of mutated IGHV, trisomy 12, complex karyotype, and del(11q).
At a median follow-up of 36.4 months, PFS was similar for patients with mutated or unmutated IGHV (P=.41) in the ibrutinib arm (Figure 2). In the comparator arms, mutated IGHV was associated with a superior PFS (P<.01). Trisomy 12 did not impact PFS in the ibrutinib or comparator arms. In the ibrutinib arm, presence of the complex karyotype and del(11q) did not impact PFS. In the comparator arms, however, an inferior PFS was seen in patients with complex karyotype (P<.01) and del(11q; P<.01).
Multivariate analysis did not identify any clear prognostic factors associated with ibrutinib treatment, with the possible exception of 0 vs 1 prior therapy (P=.06) and 1 vs 2 prior therapies (P=.06). In the comparator arms, a shorter PFS was seen in patients with unmutated IGHV, del(11q), complex karyotype, 2 or more prior therapies, bulky disease, and elevated levels of β2-microglobulin (P<.05 for each). Genomic risk factors did not alter the ibrutinib safety profile. Across the 3 trials, median exposure to ibrutinib ranged from 33 months to 35 months (range, <1-50 months). Serious adverse events (AEs) were observed in 60% to 68% of patients. AEs leading to discontinuation were observed in 14% to 22% of patients, and AEs leading to death occurred in 5% to 16% of patients. The results suggest that genomic risk factors identified in patients treated with older therapies have a reduced impact in the ibrutinib setting.
References
1. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910-1916.
2. Zenz T, Gribben JG, Hallek M, Döhner H, Keating MJ, Stilgenbauer S. Risk categories and refractory CLL in the era of chemoimmunotherapy. Blood. 2012;119(18):4101-4107.
3. Van Dyke DL, Werner L, Rassenti LZ, et al. The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience. Br J Haematol. 2016;173(1):105-113.
4. Coutré SE, Furman RR, Flinn IW, et al. Extended treatment with single-agent ibrutinib at the 420 mg dose leads to durable responses in chronic lymphocytic leukemia/small lymphocytic lymphoma. Clin Cancer Res. 2017;23(5):1149-1155.
5. Kipps TJ, Fraser G, Coutre SE, et al. Outcomes of ibrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) with high-risk prognostic factors in an integrated analysis of 3 randomized phase 3 studies. Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 19.
6. 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.
7. 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.
8. Chanan-Khan A, Cramer P, Demirkan F, et al; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200-211.
Outcomes of Standard-of-Care Regimens in Treatment-Naive Chronic Lymphocytic Leukemia Patients With Unmutated Immunoglobulin Heavy Chain Variable Genes
Chemoimmunotherapy is the standard of care for patients with CLL. Several studies have demonstrated that CLL patients with unmutated IGHV genes have inferior response rates and survival outcomes following treatment with fludarabine, cyclophosphamide, and rituximab (FCR), BR, or rituximab and chlorambucil.1-4 In CLL patients with mutated IGHV but without del(11q) or del(17p), treatment with FCR conferred a life expectancy similar to that seen in an age-matched population.5 In the RESONATE-2 trial, ibrutinib led to an 83% reduction in the risk of disease progression or death compared with chlorambucil in patients with mutated IGHV and a 93% risk reduction in patients with unmutated IGHV.6
Dr Paolo Ghia presented an analysis of published outcomes in CLL patients who received treatment with FCR, BR, or ibrutinib in the CLL8, CLL10, and RESONATE-2 studies.1,3,6,7 Estimated PFS rates were obtained from Kaplan-Meier curves that were digitized from the original publications. In the 3 studies, the proportion of patients with unmutated IGHV ranged from 43% to 68%. Most patients were male (65% to 74%). The median age was 61 to 62 years in CLL8 and CLL10, and 73 years in RESONATE-2. In CLL8, 10% of patients had del(17p). Patients with del(17p) were excluded from CLL10 and RESONATE-2.
In the RESONATE-2 trial, Kaplan-Meier analysis of patients treated with ibrutinib showed similar rates of PFS over time, regardless of IGHV status. In contrast, the Kaplan-Meier curves did not overlap for patients in the chemoimmunotherapy arm stratified by IGHV mutation status. Among the BR-treated patients from CLL10, those with mutated IGHV had a superior PFS vs those with unmutated IGHV. Similarly, among the FCR-treated patients from CLL8 and CLL10, PFS was superior in patients with mutated IGHV genes. Among patients with mutated IGHV in all 3 trials—who were treated with ibrutinib, FCR, or BR—the Kaplan-Meier curves overlapped through 36 months, at which point the data for ibrutinib-treated patients were not available. After 36 months, PFS was superior for FCR compared with BR.
The estimated 30-month PFS rates for patients with mutated IGHV were 81% for ibrutinib-treated patients, 84% for FCR-treated patients from CLL8, 87% for FCR-treated patients from CLL10, and 83% for BR-treated patients from CLL10 (Figure 3). A comparison of Kaplan-Meier curves from patients with unmutated IGHV showed overlapping curves for patients from CLL8 or CLL10 who received treatment with FCR, a superior PFS for ibrutinib-treated patients with unmutated IGHV, and the lowest PFS rate for patients treated with BR (Figure 4). Estimated 30-month PFS rates for patients with unmutated IGHV were 87% for ibrutinib-treated patients, 64% for FCR-treated patients from CLL8, 65% for FCR-treated patients from CLL10, and 59% for BR-treated patients from CLL10. OS was similar regardless of the presence of the IGHV mutation until approximately 15 months, at which point it decreased for patients with unmutated IGHV and remained lower through 96 months. The cross-trial comparisons suggest that patients with mutated or unmutated IGHV can experience a durable PFS with ibrutinib. In contrast, patients with unmutated IGHV experience inferior outcomes after chem-oimmunotherapy vs those with mutated IGHV.
References
1. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123(21):3247-3254.
2. Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127(3):279-286.
3. Eichhorst B, Fink AM, Bahlo J, et al; international group of investigators; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928-942.
4. Foà R, Del Giudice I, Cuneo A, et al. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014;89(5):480-486.
5. 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.
6. 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.
7. Ghia P, Hillmen P, Moreno C, et al. Outcomes of standard of care regimens in treatment-naïve chronic lymphocytic leukemia (CLL) patients with unmutated immunoglobulin heavy chain variable (IGHV) genes. Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 188.
The Role of MRD in the Setting of Novel Targeted Therapies
Dr Peter Hillmen presented an overview of the expanding role of minimal residual disease (MRD) assessment in the era of targeted treatment.1 MRD is used as a means to evaluate treatment efficacy in patients with CLL and has traditionally been used as a binary marker that indicates a positive or negative result. Patients who are MRD negative following treatment have longer remissions than patients who are MRD positive. With the introduction of newer agents, MRD may be used to guide duration of therapy. Moreover, because MRD reflects the level of disease, it could be used for early detection of relapse.
The multicenter, open-label, phase 2b ARCTIC (Attenuated Dose Rituximab With Chemotherapy in CLL) and ADMIRE (Does the Add-ition of Mitoxantrone Improve Res-ponse to FCR?) trials included 415 treatment-naive CLL patients who received FCR-like therapy at 60 treatment centers across the United Kingdom.2,3 ARCTIC was a noninferiority trial that compared standard FCR vs fludarabine, cyclophosphamide, and mitoxantrone, plus low-dose rituximab. ADMIRE was a superiority trial that evaluated FCR with or without mitoxantrone. In both trials, bone marrow MRD was assessed 3 months after cessation of chemoimmunotherapy and 9 months after randomization. Patients who were MRD negative had a superior PFS and OS compared with those who were MRD positive. Because these trials ended in 2012, the study participants were unlikely to have received targeted therapies.
MRD negativity is associated with a superior PFS. However, MRD negativity does not necessarily reflect disease eradication, given the technological limitations in detecting small numbers of CLL cells after treatment. Patients who are MRD negative at the end of treatment can still relapse. Tumor cells with a shorter doubling time will cause earlier relapse. These parameters and others are being assessed in mathematical models that aim to describe the normal distribution of patients with various tumor types and thus predict the proportion of patients who are likely to achieve cures with a given treatment. Higher cure rates will require larger log reductions in the population of viable cancer cells. Therefore, therapies associated with a higher proportion of MRD negativity will increase the time that patients spend off-treatment, as well as the proportion of patients who achieve true cures. Modeling of MRD data from the ADMIRE and ARCTIC trials predicted that approximately 16% of MRD-negative patients would achieve a cure and that approximately 38% of MRD-negative patients would relapse.
Ibrutinib treatment induces imm-ediate lymphocytosis that persists for several months in most patients. Obin-utuzumab is a second-generation anti-CD20 antibody that rapidly reverses peripheral blood lymphocytosis and eradicates MRD in some patients. The IcICLLe (Assessment of the Mechanism of Action of Ibrutinib [PCI-32765] in B-Cell Receptor Pathway Inhibition in CLL) extension study is evaluating the efficacy and safety of continuous oral therapy with ibrutinib plus 6 cycles of obinutuzumab in patients with relapsed/refractory CLL.4 Among the 40 enrolled patients, 30 will not have received prior treatment with ibrutinib and 10 will have received at least 1 year of ibrutinib while enrolled in the IcICLLe study. The primary outcome of the extension study is the proportion of patients achieving MRD-negative remission based on criteria from the International Workshop on Chronic Lymphocytic Leukemia (iwCLL).
Data were available for 20 patients who received ibrutinib monotherapy in the IcICLLe trial and 27 patients who received ibrutinib plus obinutuzumab in the IcICLLe extension study. Peripheral CLL counts fell below baseline after 1 week of combination therapy, but remained above baseline for at least 3 months in patients treated with ibrutinib monotherapy. After 6 months of ibrutinib monotherapy, 13 of 19 evaluable patients had a B-cell count of greater than 5 × 109/L, and no patients had a peripheral blood CLL level of less than 0.01%. In contrast, after 6 months of ibrutinib plus obinutuzumab, all 20 evaluable patients (all of whom were ibrutinib-naive at baseline) had a B-cell count of less than 5 × 109/L, and 5 of 20 patients had a peripheral blood CLL level of less than 0.01%. After 1 month of therapy, patients receiving ibrutinib plus obinutuzumab showed a median 32% decrease in the proportion of CLL cells in the bone marrow compared with baseline (P<.001). Among patients treated with ibrutinib monotherapy, there was a 1% increase from baseline (P=.6). There were 8 patients who had received 12 to 18 months of ibrutinib monotherapy followed by 6 months of ibrutinib plus obinutuzumab, and 5 had a bone marrow MRD of less than 0.01% (Figure 5). Among 10 patients who had received 12 to 18 months of ibrutinib monotherapy only, all had a bone marrow MRD of greater than 1%.
The CLARITY trial (Assessment of Venetoclax in Combination With Ibrutinib in Patients With Chronic Lymphocytic Leukaemia) is a feasibility study evaluating the combination of ibrutinib plus venetoclax, an oral inhibitor of BCL-2, in patients with relapsed or refractory CLL.5 Patients receive treatment with daily ibrutinib monotherapy (420 mg) for 2 months, and then daily venetoclax is added. The initial venetoclax dose was 10 mg daily and escalated weekly to 20 mg, 50 mg, 100 mg, 200 mg, and 400 mg. The primary endpoint is MRD at 12 months, with MRD at 6 months and 24 months as secondary endpoints. Forty-five patients were recruited from May 2016 to March 2017. Among the 26 patients who had completed the venetoclax dose escalation, 1 developed laboratory tumor lysis syndrome. CLL in the peripheral blood increased during the 8 weeks of ibrutinib treatment. After 8 weeks of combination treatment, patients showed a median 3-log reduction in CLL levels (Table 1). The initial bone marrow responses are anticipated after 6 months of combination therapy.
The phase 3 FLAIR trial (Front-Line Assessment of Ibrutinib Plus Rituximab) is comparing FCR vs ibrutinib and rituximab as first-line treatment in patients with CLL.6 In this multicenter, open-label, parallel-group study, patients will be assessed every 6 months for peripheral blood MRD. In the ibrutinib-plus-rituximab arm, treatment will be stopped for patients with a negative MRD at 2 consecutive assessments. The primary endpoint is PFS, with secondary endpoints of OS, MRD, iwCLL response rate, safety, quality of life, and cost effectiveness. The trial protocol was amended to include an arm to evaluate ibrutinib monotherapy and another arm to evaluate ibrutinib plus venetoclax, using the same dosing schedule as the CLARITY trial, with treatment lasting up to 6 years based on MRD results. Recruitment will continue until 2020, with more than 1500 patients enrolled into the 4 arms.
References
1. Hillmen P. Role of MRD in the setting of the novel targeted therapies. Presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY.
2. Howard DR, Munir T, McParland L, et al. Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL [published online May 2, 2017]. Leukemia. doi:10.1038/leu.2017.96.
3. Munir T, Howard DR, McParland L, et al. Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL. Leukemia. 2017;23(18):4079-4088.
4. Rawstron A, Munir T, Muñoz-Vicente S, et al. Addition of obinutuzumab to ibrutinib enhances depletion of CLL cells in the peripheral blood and bone marrow after 1 month & 6 months of combination therapy: initial results from the Bloodwise TAP IcICLLe extension study. Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 242.
5. Muñoz-Vicente S, Bishop R, Hillmen P, et al. The initial report of the Bloodwise TAP CLARITY study combining ibrutinib and venetoclax in relapsed, refractory CLL shows acceptable safety and promising early indications of efficacy. Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 249.
6. ISRCTN registry. FLAIR: front-line therapy in CLL: assessment of ibrutinib + rituximab. http://www.isrctn.com/ISRCTN01844152. ISRCTN identifier: 01844152. Accessed June 12, 2017.
Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (GA101) for Previously Untreated Patients With Chronic Lymphocytic Leukemia With Mutated IGHV and Non-Del(17p)
In young patients with CLL, 6 cycles of FCR yielded CR rates of 40% to 72% and rates of bone marrow MRD negativity of 43% to 58%.1-7 These outcomes are associated with a 5% risk of therapy-related myelodysplastic syndrome/acute myeloid leukemia.8 Patients with mutated IGHV experience superior PFS vs patients with unmutated IGHV after treatment with first-line FCR.7,9,10 MRD negativity after first-line FCR is also associated with a favorable outcome in patients with mutated IGHV, with 5-year PFS rates of approximately 80%.
The phase 3 CLL11 trial demonstrated that first-line obinutuzumab plus chlorambucil induced a higher rate of MRD negativity compared with rituximab plus chlorambucil in patients with CLL.11 The phase 3 HELIOS trial investigated ibrutinib plus BR vs BR alone in patients with relapsed or refractory CLL/SLL.12 As assessed by an independent review committee, the PFS at 18 months was 79% for ibrutinib plus BR vs 24% for BR alone (HR, 0.203; 95% CI, 0.150-0.276; P<.0001). After a median follow-up of 25.4 months, MRD-negative response rates were 18.0% for ibrutinib plus BR vs 4.8% for BR alone (P<.0001).
Dr Nitin Jain presented findings from a trial testing the hypotheses that inducing higher rates of MRD negativity would improve rates of PFS and OS and that reducing the number of chemotherapy cycles from 6 to 3 would reduce the risk of therapy-related myelodysplastic syndrome/acute myeloid leukemia.13 The investigator-initiated, phase 2 trial enrolled treatment-naive adults with IGHV-mutated CLL/SLL. Patients with del(17q) or TP53 mutations were excluded. The primary endpoint was the rate of CR and CR with incomplete blood recovery (CRi) and the rate of bone marrow MRD negativity after 3 cycles of treatment. All patients received daily ibrutinib (420 mg) plus 3 cycles of fludarabine, cyclophosphamide, and obinutuzumab (FCG). Granulocyte-colony stimulating factor support was allowed. After the primary endpoint assessment, patients who achieved CR/CRi or MRD negativity received 3 more cycles of treatment with ibrutinib and obinutuzumab, followed by 6 cycles of ibrutinib monotherapy. Patients who achieved a partial response (PR) or were MRD positive received 9 cycles of ibrutinib and obinutuzumab. Patients with a negative bone marrow MRD after completion of all 12 treatment cycles stopped ibrutinib monotherapy. Patients who were MRD positive continued ibrutinib monotherapy until disease progression. Responses were assessed by iwCLL 2008 criteria.14 Blood, bone marrow, and computed tomography scans were performed every 3 months during the first year, then every 6 months. A PR was defined as a lymph node exceeding 1.5 cm. MRD in the bone marrow was assessed by 4-color flow cytometry, with a sensitivity of 10-4.
The first patients were enrolled in April 2016. Data were available for 5 patients who had initiated treatment and 24 who had completed 3 cycles of treatment. Median follow-up was 8.3 months (range, 0.9-13.3 months). One patient was removed from the study after 3 cycles of ibrutinib plus FCG owing to infection with pulmonary Mycobacterium avium complex. Another patient was removed from the study after receiving obinutuzumab (100 mg) plus ibrutinib (420 mg) on day 1 of cycle 1 owing to grade 3 infusion-related reaction and grade 4 thrombocytopenia. The 29 patients had a median age of 60 years (range, 60-71 years), and 83% were male. Based on fluorescence in situ hybridization, 69% of patients had del(13q) and 21% had trisomy 12. Cytogenetic analysis was available for 24 patients and showed 58% with diploid karyotype, 25% with (del)13, and 17% with trisomy 12. The most common mutations were MYD88 (11%) and SF3B1 (7%). The median level of β2-microglobulin was 2.6 mg/L (range, 1.4-8.1 mg/L).
After 3 treatment cycles, the ORR in 24 patients was 100%, including 42% with a CR/CRi and 58% with a PR (Table 2). All of the 10 patients who achieved a CR or CRi also achieved MRD-negative bone marrow. Of the 14 patients who achieved a PR, bone marrow was MRD-negative in 10 (71%). After 3 cycles, 83% of patients treated with ibrutinib plus FCG were MRD negative vs 26% of patients treated with FCR for 3 cycles (based on historical data). Responses continued to improve over time, with 100% of patients achieving MRD negativity and 77% achieving a CR or CRi at 9 months. Nine patients had ceased treatment after 12 months of therapy and were being monitored for changes in MRD status or relapse. Bone marrow MRD negativity was reported in 50% of the 6 patients who had a β2-microglobulin level of at least 4 mg/L, compared with 94% of the 18 patients with a level of less than 4 mg/L (P=.035).
Grade 3/4 AEs included neutropenia (72%), thrombocytopenia (44%), transaminase elevation (13%), atrial fibrillation (3%), arthralgia (3%), and infusion-related reaction (3%). Nine patients (31%) also had a grade 2 infusion-related reaction. Transaminase elevation occurred in 4 patients, but reversed in all by 2 to 4 weeks; these patients resumed therapy without further transaminase elevation. Four patients developed neutropenic fever. Pneumocystis pneumonia, Mycobacterium avium complex pulmonary infection, acute cholecystitis, and herpes zoster were observed in 1 patient each. Dose reductions for fludarabine and cyclophosphamide were required in 57% of patients, and ibrutinib dose reductions were required in 18%. Among the 35% of patients with a treatment delay exceeding 2 weeks, the most common reason was thrombocytopenia.
References
1. Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9):980-988.
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. 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.
4. Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18):4079-4088.
5. 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.
6. Tam CS, O’Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4):975-980.
7. Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127(3):279-286.
8. 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.
9. 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.
10. 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.
11. 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.
12. Chanan-Khan A, Cramer P, Demirkan F, et al; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200-211.
13. Jain N, Thompson P, Burger JA, et al. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) for previously untreated patients with chronic lymphocytic leukemia (CLL) with mutated IGHV and non-del(17p). Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 164.
14. 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.
Characteristics of Patients Treated for CLL in a Real-World Registry: Results From informCLL
The informCLL registry was created to analyze real-world CLL treatment patterns, with an emphasis on novel therapies.1 The registry is collecting information on baseline demographic and clinical characteristics, treatment sequencing, and outcomes. A prospective, multi-center, observational study of the registry has a planned enrollment of approximately 1000 patients who are starting treatment with novel therapies and 500 patients initiating other approved CLL therapies. Patients from 200 sites in the United States will be enrolled during a 36-month period that began in September 2015. Included patients are at least 18 years old with a clinical diagnosis of CLL/SLL based on iwCLL 2008 diagnostic criteria.2 Patients initiated treatment within 30 days of registry enrollment and had doc-u-mentation of any prior CLL/SLL treatment. Response data were available for all patients. Patients receiving CLL treatment as part of an interventional clinical study and those with a life expectancy of less than 6 months were excluded.
Data from 241 patients were available for an interim analysis. The mean age was 68 years (range, 40-95 years). Most patients were male (66%) and white (92%). The median time from initial diagnosis to treatment at registry enrollment was 41 months. The most common source of health care coverage was Medicare (56%), followed by employer-based coverage (34%), other (19%), and Medicaid (3%). Patients were treatment-naive (n=132) or had received previous treatment (n=109). Among the latter group, the most common prior CLL therapies were BR (23%), rituximab monotherapy (20%), ibrutinib monotherapy (11%), and FCR (10%). The most common therapies initiated at registry enrollment in the treatment-naive group were ibrutinib monotherapy (32%), BR (21%), FCR (11%), and obinutuzumab plus chlorambucil (10%; Table 3). In the previously treated group, the most common therapies were ibrutinib monotherapy (50%), BR (16%), rituximab monotherapy (13%), and FCR (4%).
Among the entire study population, the most common reason for initiating treatment was evidence of progressive marrow failure, followed by the presence of very large nodes or progressive and/or symptomatic lymphadenopathy, progressive lymphocytosis, and constitutional symptoms (Figure 6). The most common disease-related symptoms at enrollment were fatigue (56%), night sweats (26%), and weight loss (17%). Among the 218 patients with comorbidities at enrollment (91%), the most common were hypertension (59%), type 2 diabetes mellitus without end-organ damage (23%), and pulmonary disorders/chronic obstructive pulmonary disease (12%). At the time of enrollment, 27% of patients had concurrent malignancies, including solid and hematologic tumors.
References
1. Mato A, Sharman J, Pagel J, et al. Characteristics of patients treated for CLL in a real-world registry: results from informCLL. Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 54.
2. Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
Highlights From the XVII International Workshop on Chronic Lymphocytic Leukemia: 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
Several presentations at the XVII International Workshop on Chronic Lymphocytic Leukemia provided insight into the management of treatment-naive and relapsed patients. Data from new clinical trials and subanalyses of existing trials were reported.
Dr Nitin Jain presented results from a phase 2 trial of a novel combination of ibrutinib, fludarabine, cyclophosphamide, and the anti-CD20 monoclonal antibody obinutuzumab in previously untreated patients with chronic lymphocytic leukemia (CLL) who required therapy.1 Importantly, all of these patients had a mutated immunoglobulin heavy chain variable (IGHV) gene. As background, 3 recent studies clearly showed that in patients with a mutated IGHV gene, there appeared to be a long-term plateau in the progression-free survival (PFS) curve after treatment with fludarabine, cyclophosphamide, and rituximab (FCR).2-4 The longest follow-up was reported in a study from MD Anderson Cancer Center, where the FCR regimen was developed.2 This study showed that approximately 60% of patients with the IGHV mutation had no evidence of disease 12 to 16 years after treatment. Were these patients cured? I suspect that some were. Even if they were not cured, however, they still had no disease more than a decade after a finite duration of therapy (6 months), which is a very positive outcome. Chemotherapy may provide a cure fraction among patients with a mutated IGHV gene.
The idea behind the study by Dr Jain was to enhance the results—make that 60% higher—as well as reduce toxicity, both short-term and long-term.1 The study modified standard FCR by replacing rituximab with obinutuzumab, a more potent antibody. Ibrutinib was added since it has very high activity as a single agent. Importantly, chemotherapy was limited to 3 cycles, which would reduce the short-tem complications, as well as the small but real risks of developing late myelodysplastic syndrome or acute myeloid leukemia related to treatment with FCR.
Dr Jain presented preliminary data from the trial.1 All of the patients were older than 18 years, and all had the IGHV mutation. Patients with a 17p deletion were excluded from the trial because they are not treated with chemotherapy in the upfront setting.
Patients received ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab for 3 cycles. Treatment was then modified based on the presence of minimal residual disease (MRD) and overall response. Patients with a complete response who were MRD-negative received 3 more months of ibrutinib and obinutuzumab (so chemotherapy was stopped), and then 6 more months of ibrutinib. That brought them to a year of treatment. If they were MRD-negative after 12 cycles, then all therapy was stopped.
When patients remained MRD positive or had only a partial response after receiving the 3 cycles of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab, treatment consisted of ibrutinib and obinutuzumab for 9 more cycles. Treatment was then discontinued among patients who were MRD-negative. Among MRD-positive patients, treatment with ibrutinib continued until disease progression.
For purposes of comparison, the study used historical data for results after 3 cycles of FCR among patients with the IGHV mutation.5 Historically, most patients were treated with 6 cycles of FCR. After 3 cycles, the bone marrow MRD negativity rate was 26%. The primary endpoint of the study by Dr Jain was to improve on that 3-month response.1 There were 24 patients who completed 3 cycles of treatment. Some were still receiving maintenance treatment with ibrutinib and obinutuzumab. At 3 months, the bone marrow MRD negativity rate was 83%. This is strikingly better than the historical rate of 26% with FCR alone. The best response so far is MRD negativity in the bone marrow, which was reported in all 24 patients. Among the 9 patients who were treated for a year, all were MRD-negative and discontinued therapy. No patient developed progressive disease, but the median follow-up was short, at 8.3 months.
The combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab is a very exciting frontline combination for patients with the IGHV mutation. The early data are encouraging. The trial continues to accrue patients.
Dr William Wierda presented a poster outlining an ongoing trial evaluating the combination of ibrutinib and venetoclax in treatment-naive patients with CLL.6 Ibrutinib and venetoclax are the 2 most potent single-agent small molecules available, and they have different mechanisms of action. The preclinical rationale for the use of these agents in combination is based on ex vivo and in vivo data showing that pretreatment with ibrutinib improves the activity of venetoclax and enhances BCL-2 dependence.7 The study from Dr Wierda is a multicenter, double-blind, placebo-controlled, randomized phase 2 trial. The plan is to enroll 150 treatment-naive patients younger than 70 years who require therapy. The lead-in phase is treatment with ibrutinib at 420 mg once daily for 3 cycles. Then patients are treated with the combination of standard-dose ibrutinib (420 mg once daily) plus standard-dose venetoclax (400 mg once daily) for 12 cycles. Lead-in treatment with ibrutinib is becoming more common in trials combining ibrutinib with venetoclax. This strategy is based on the idea that debulking the patient prior to initiating venetoclax will minimize the risk for tumor lysis. Patients continue treatment with ibrutinib plus venetoclax for at least twelve 4-week cycles, for a year of therapy. Patients are then assigned to treatment based on their MRD status. MRD-negative patients are randomly assigned to treatment with ibrutinib, without venetoclax, or placebo. Neither the patient nor the principle investigator will be aware of which treatment is being used. Patients who are MRD-positive are randomly assigned to receive either ibrutinib alone or ibrutinib plus venetoclax. The primary endpoint for the randomization phase is the 1-year MRD-negative disease-free survival state. The trial began in October, and it is being conducted in the United States, Australia, and Italy. Recruitment and accrual are underway. The study will provide interesting frontline data on a novel small-molecule combination that does not include chemotherapy.
A study by Dr Paolo Ghia evaluated the outcomes of standard-of-care frontline regimens in patients with an unmutated IGHV across 3 trials: CLL8, CLL10, and RESONATE-2 (Randomized, Multicenter, Open-Label, Phase 3 Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Versus Chlorambucil in Patients 65 Years or Older With Treatment-Naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma [PCYC-1115/1116]).8-11 The CLL8 trial randomly assigned patients to treatment with fludarabine plus cyclophosphamide or FCR.9 This trial is the oldest one in the study; it led the US Food and Drug Administration (FDA) to approve FCR for previously untreated patients with CLL. The randomized CLL10 trial built on the results from the CLL8 trial.10 It compared FCR, as the gold standard, to the popular regimen bendamustine plus rituximab. The randomized RESONATE-2 trial compared ibrutinib vs chlorambucil as frontline therapy in CLL, and led to the FDA approval of ibrutinib in this setting.11
There were many patients in these studies. CLL8 had more than 800, and reported the mutational status for more than 600. In the CLL10 trial, there were more than 500 patients, and the mutational status was known for most of them. The RESONATE-2 trial had 269 patients, and most had a known mutational status.
Among patients treated with ibrutinib, the estimated 30-month PFS rates were 81% in patients with the IGHV mutation and 87% in those without. Among patients treated with chemotherapy, the rates of 30-month PFS ranged from 83% to 87% in those with the IGHV mutation vs 59% to 65% in those without the IGHV mutation.
The analysis suggested that ibrutinib may have a particular benefit over chemotherapy among patients without the IGHV mutation. Among patients treated with chemoimmunotherapy, response rates are similar regardless of the mutational status, but PFS and overall survival are significantly shorter among those with an unmutated IGHV gene. Patients with the unmutated gene have a much poorer prognosis with any chemotherapy-based regimen, including bendamustine plus rituximab, FCR, and chlorambucil-based regimens. In contrast, the analysis by Dr Ghia showed that ibrutinib is not associated with a poorer prognosis among patients with the unmutated gene.8 In the RESONATE-2 trial, thus far, PFS did not differ according to mutation status.11 Why would patients without the mutation do better with ibrutinib than chemotherapy? One reason for the poorer outcome with chemotherapy is that patients without the IGHV mutation have much stronger signaling through the B-cell receptor. Ligation of the B-cell receptor provides a strong proliferative and survival signal to the cell. Ibrutinib works by inhibiting the B-cell receptor. Ibrutinib appears to be a very effective drug, regardless of the patient’s mutational status. It will have even more success over chemotherapy among the high-risk group of patients without the IGHV mutation.
An interesting presentation by Dr Thomas Kipps evaluated the outcomes of ibrutinib-treated patients across three randomized phase 3 trials: RESONATE (Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia; PCYC-1112), RESONATE-2, and HELIOS (A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma; CLL3001).11-14 The RESONATE trial compared ibrutinib vs ofatumumab among previously treated patients, and led to FDA approval of ibrutinib in the relapsed setting.13 The RESONATE-2 trial led to FDA approval of ibrutinib in the frontline setting.11 The HELIOS trial randomly assigned relapsed patients to bendamustine plus rituximab with or without ibrutinib.14 An important similarity among these trials is that they all had a comparator arm consisting of a chemotherapy-based regimen.
The data from these 3 trials were pooled and analyzed based on various factors, such as mutational status and the presence of deletion 11q or a complex karyotype.12 As expected, in the chemotherapy-based comparator arms, a significantly shorter PFS was seen among patients who had an unmutated IGHV gene, a complex karyotype, or an 11q deletion. An important finding is that outcome with ibrutinib was not impacted by the presence of the 11q deletion, the complex karyotype, or an unmutated IGHV. The analysis shows that the genomic factors that have traditionally led to a poor prognosis with chemotherapy no longer do so with ibrutinib.
Disclosure
Dr O’Brien is a consultant for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc, Vaniam Group LLC, AbbVie, Sunesis, and Alexion. She has received research support from ProNAi, Regeneron, and Acerta. She is a consultant and/or has received research support from Gilead, Pharmacyclics, TG Therapeutics, and Pfizer.
References
1. Jain N, Thompson P, Burger JA, et al. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) for previously untreated patients with chronic lymphocytic leukemia (CLL) with mutated IGHV and non-del(17p). Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 164.
2. 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.
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. 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.
5. 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.
6. Wierda WG, Siddiqi T, Stevens DA, et al. Phase 2 study of the combination of ibrutinib plus venetoclax in patients with treatment-naïve CLL/SLL. Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 188.
7. Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia [published online February 4, 2017]. Leukemia. doi:10.1038/leu.2017.32.
8. Ghia P, Hillmen P, Moreno C, et al. Outcomes of standard of care regimens in treatment-naïve chronic lymphocytic leukemia (CLL) patients with unmutated immunoglobulin heavy chain variable (IGHV) genes. Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 188.
9. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123(21):3247-3254.
10. 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.
11. 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.
12. Kipps TJ, Fraser G, Coutre SE, et al. Outcomes of ibrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) with high-risk prognostic factors in an integrated analysis of 3 randomized phase 3 studies. Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 19.
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. Chanan-Khan A, Cramer P, Demirkan F, et al; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200-211.