Clinical Advances in Hematology & Oncology
Considerations in the Frontline Treatment of Chronic Lymphocytic Leukemia: A Post-ASH Update
Susan M. O’Brien, MD
Associate Director for Clinical Sciences
Chao Family Comprehensive Cancer Center
Sue and Ralph Stern Center for Clinical Trials & Research
Professor of Medicine
Division of Hematology/Oncology
Department of Medicine
University of California, Irvine
H&O When is frontline therapy initiated in chronic lymphocytic leukemia (CLL)?
SO The standard approach to CLL is still watch-and-wait. If patients are asymptomatic and have minimal disease, we do not intervene. This approach is based on the fact that approximately a third of patients with CLL will never need treatment. The idea behind watch-and-wait is to spare those patients who would never require therapy. We begin frontline treatment when patients develop problematic symptoms related to the disease, such as bulky lymph nodes, anemia, or low platelets.
My first choice for the management of patients with CLL is always to enroll them in a clinical trial. We cannot advance the science without enrolling patients in clinical trials.
H&O What are the approved frontline therapies?
SO The chemoimmunotherapy regimen fludarabine/cyclophosphamide/rituximab (Rituxan, Genentech/Biogen; FCR) is approved for these patients. The anti-CD20 monoclonal antibodies ofatumumab (Arzerra, Novartis) and obinutuzumab (Gazyva, Genentech) are each approved in combination with chlorambucil. Bendamustine (Treanda, Teva) was approved as a single agent for frontline treatment of CLL, based on a randomized trial that compared it with chlorambucil. However, bendamustine is most commonly used in combination with rituximab, which is known to improve the outcome of chemotherapy. The most recent approval in the frontline setting was for ibrutinib (Imbruvica, Pharmacyclics/Janssen).
H&O What data led to the approval of ibrutinib in the frontline setting?
SO Ibrutinib is the only targeted therapy available for frontline treatment. Approval of ibrutinib was based on a randomized trial comparing it with chlorambucil in older patients with CLL. Patients were older than 70 years or between the ages of 65 to 70 years and with a comorbidity that precluded them from receiving more substantive chemotherapy. The trial showed that ibrutinib was significantly better than chlorambucil. In fact, the progression-free survival achieved with ibrutinib was far superior to that seen in trials evaluating chlorambucil plus a monoclonal antibody.
Ibrutinib first received a frontline indication in patients with CLL who have the 17p deletion. This indication was followed by approval for all patients, regardless of 17p status. Interestingly, although the randomized trial was restricted to older patients, the approved indication is not. Theoretically, ibrutinib can be used as frontline treatment in any patient with CLL.
H&O How do the data for ibrutinib compare with those for chemoimmunotherapy?
SO The data for ibrutinib are clearly much more favorable than those for chlorambucil. Studies are now comparing ibrutinib vs FCR or bendamustine/rituximab in a younger, fit population. Two large, randomized trials from the Intergroup reached accrual in the past year. A 2-arm trial is comparing FCR vs ibrutinib and rituximab. A 3-arm trial is evaluating bendamustine and rituximab vs single-agent ibrutinib vs ibrutinib in combination with rituximab.
H&O How does the older treatment algorithm in CLL differ from your new treatment algorithm?
SO The older treatment algorithm from the German CLL study group had 3 categories. The “go-go” patients were fit, not elderly, and could tolerate a regimen like FCR. The “slow-go” patients were somewhat older or less fit, but still well enough to receive a treatment such as bendamustine/rituximab. A chlorambucil-based regimen might be used in patients who were less well. The “no-go” patients were elderly and had a poor performance status. These patients would receive palliative care, which most often consists of a single-agent antibody in the United States.
My new treatment algorithm also divides patients into 3 groups, but based on different criteria. The first group is older or less-fit patients, who I prefer to treat with ibrutinib irrespective of their mutation status. In younger, fit patients with the immunoglobulin variable region heavy chain (IgVH) mutation, I lean toward FCR. The final decision, however, would be made after discussion with the patient. In younger patients without the IgVH mutation, absent a clinical trial, I begin treatment with ibrutinib.
Historically, it made sense to base the selection of treatment on age and comorbidities because all of the treatments involved chemotherapy. Now that we have ibrutinib, which is so well-tolerated, that older algorithm has less relevance. For me, older patients are still grouped together. For younger patients, the biggest deciding factor is IgVH mutation status.
H&O Does ibrutinib improve outcome when added to chemotherapy?
SO The HELIOS trial (Ibrutinib Combined With Ben-damustine and Rituximab Compared With Placebo, Bendamustine, and Rituximab for Previously Treated Chronic Lymphocytic Leukaemia or Small Lymphocytic Lymphoma) randomly assigned patients with relapsed CLL to receive bendamustine/rituximab chemotherapy alone vs bendamustine/rituximab plus ibrutinib. The addition of ibrutinib clearly improved outcomes. But what was not answered by this trial is whether bendamustine/rituximab plus ibrutinib is better than ibrutinib alone. The early data appeared comparable. The updated data, however, showed a significant rise in the complete response rate among patients who received bendamustine/rituximab and ibrutinib, much higher than what is seen with ibrutinib alone. The more recent data are starting to suggest that the combination may be better than ibrutinib alone. A benefit to ibrutinib, like many targeted therapies, is that it avoids the adverse events associated with chemotherapy, such as myelosuppression. Combining ibrutinib with chemotherapy may increase efficacy, at least in the minority of patients who are achieving a complete response, but at the expense of potentially increasing toxicity for all patients who receive it. The choice to add chemotherapy to ibrutinib in the relapsed setting is not an easy one.
H&O What adverse events are associated with ibrutinib?
SO In general, ibrutinib is very well-tolerated. The most common side effect is diarrhea, which is usually mild and self-limiting. There are some significant side effects. Atrial fibrillation occurs in 7% to 10% of patients. There is also an increased risk of bleeding caused by interference with the glycoprotein-mediated platelet-aggregation pathway. Most of the bleeding is minor, usually in the form of ecchymosis, but it can also be severe. The risk of bleeding is a particular concern in patients who are receiving an anticoagulant.
Arthralgia is another potential adverse event. It is generally not severe, but it can become problematic in the long-term. Ibrutinib is administered indefinitely, and continual pain, even low-grade, can be difficult for patients to bear. On the rare occasions when I have discontinued treatment with ibrutinib, the most common reason was arthralgia rather than diarrhea or any of the serious side effects.
H&O Do patients with lymphocytosis or baseline cytopenias require a reduced dose of ibrutinib?
SO Patients with lymphocytosis do not require a reduced dose of ibrutinib. Most patients with CLL can have lymphocyte counts in the hundreds of thousands and still be completely asymptomatic. Therefore, lymphocytosis is generally not a concern.
For patients with baseline cytopenias, I generally start with the full dose. Although there is some sporadic myelosuppression associated with ibrutinib, for the most part, ibrutinib is very good at reversing cytopenias. In contrast, we often reduce the starting dose of chemotherapy in patients with baseline cytopenias.
H&O What factors impact your choice of frontline treatment?
SO In older or less-fit patients, I use ibrutinib regardless of the 17p deletion status because it is clearly better than chlorambucil and much less toxic. The real question concerns younger, fit patients. Most physicians would not treat a younger, more-fit patient with chlorambucil; they would select a better, somewhat more aggressive regimen. For example, FCR or bendamustine and rituximab are more myelosuppressive, but they also produce significantly longer progression-free survival than a chlorambucil-based regimen. I divide younger, fit patients into 2 groups based on their IgVH mutation status. Those with the IgVH mutation are candidates for FCR. This approach is supported by 3 articles published in the last year in Germany, Italy, and the United States. The American study, by Thompson and colleagues at MD Anderson, clearly showed very consistent results in terms of a significant plateau in the progression-free survival curve associated with FCR in patients with a mutated IgVH gene. The study from MD Anderson has the longest follow-up, because this regimen was developed there. At 12 to 16 years of follow-up, remission persisted in approximately 60% of patients with a mutated IgVH gene. The big question is whether to consider some of these patients cured. I would say yes. After this long-term follow-up, some of the patients remained negative for minimal residual disease. Even if they do ultimately relapse, it can still be considered a great outcome if patients remain in remission for 15 years after receiving 6 months of chemotherapy.
For my younger patients with the IgVH mutation, I discuss in detail the pros and cons of using chemotherapy. Chemotherapy is associated with more toxicity in the short-term, but it is administered for a limited duration. It can potentially lead to a very long remission, but it carries a small, but real, risk of late acute myeloid leukemia. Ibrutinib is easier to take than chemotherapy, but it is continuous therapy. Long-term data are starting to be reported. At the 2016 American Society of Hematology (ASH) meeting, I presented an analysis of 5-year data from a phase 2 trial of ibrutinib in patients with untreated or relapsed/refractory CLL or small lymphocytic leukemia. At 5 years, progression-free survival was 92% in the treatment-naive patients and 43% in the relapsed/refractory patients. Median progression-free survival was not reached in the treatment-naive cohort and 52 months in the relapsed/refractory cohort. Median overall survival was not reached for both cohorts. At 5 years, overall survival was 92% for the treatment-naive patients and 57% for the relapsed/refractory patients. Over time, the rates of complete response increased to 29% in the treatment-naive patients and to 10% in the relapsed/refractory patients.
We know that in relapsed patients who have received ibrutinib, absent a 17p deletion (which is uncommon in frontline patients), the median progression-free survival is 53 months. I would certainly think it would be longer in the frontline setting, but whether that will be 5 years or 10 years, or whether there will even be a plateau, are unknowns.
H&O Which agents would you consider for patients who are intolerant to ibrutinib?
SO Chemoimmunotherapy is always a possibility, and as far as small molecules, one approved combination is idelalisib (Zydelig, Gilead) and rituximab. The other option is venetoclax (Venclexta, AbbVie/Genentech), although the current indication is only for patients with the 17p deletion. There are, thus far, limited clinical trial data for patients who require treatment after ibrutinib. Mato and colleagues recently published an analysis of pooled data from several institutions evaluating patients who had failed or were intolerant to one kinase inhibitor, whether idelalisib or ibrutinib, and then went on to receive the other one. The response rate to the second inhibitor was approximately 50%. Among patients who were truly resistant to the first kinase inhibitor (as opposed to intolerant), the median progression-free survival was only 7 months. To me, shifting from one kinase inhibitor to another is not an attractive option. It might buy some time and serve as a bridge to transplant in a younger, fit patient. However, it is not a long-term solution.
Jones and colleagues are evaluating venetoclax in patients who have failed ibrutinib or idelalisib. Preliminary results show that the response rates are a bit higher than those achieved by crossing over to another tyrosine kinase inhibitor. Dr Jones presented updated data at the 2016 ASH meeting. Objective response was 70% among patients refractory to ibrutinib and 62% in patients refractory to idelalisib. After 11.8 months of follow-up, median duration of response, progression-free survival, and overall survival have not been reached. The estimated 12-month progression-free survival was 80%. As mentioned, however, venetoclax is approved only for patients with the 17p deletion.
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.
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.
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.
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 October 28, 2016.
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 October 28, 2016.
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Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemo-immunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215.
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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, multicentre, open-label phase 3 trial. Lancet. 2015;385(9980):1873-1883.
Jones J, Choi MY, Mato AR, et al. Venetoclax monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib [ASH abstract 637]. Blood. 2016;128(suppl 22).
Jones J, Mato AR, Coutre S, et al. Preliminary results of a phase 2, open-label study of venetoclax (ABT-199 / GDC-0199) monotherapy in patients with chronic lymphocytic leukemia relapsed after or refractory to ibrutinib or idelalisib therapy [ASH abstract 715]. Blood. 2015;126(suppl 23).
Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27(26):4378-4384.
Mato AR, Nabhan C, Barr PM, et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience [published online September 6, 2016]. Blood. 2016;128(18):2199-2205.
O’Brien SM, Furman RR, Coutre SE, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia [ASH abstract 233]. Blood. 2016;128(suppl 22).
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.
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.
Highlights in Chronic Lymphocytic Leukemia From the 2016 American Society of Hematology Annual Meeting and Exposition
December 3-6, 2016 • San Diego, California
Commentary by Susan M. O’Brien, MD
Five-Year Experience With Single-Agent Ibrutinib in Patients With Previously Untreated and Relapsed/Refractory CLL/SLL
As a key cytoplasmic component of the B-cell receptor pathway, Bruton tyrosine kinase (BTK) plays a critical role in controlling proliferation, survival, and differentiation of B-lineage lymphoid cells.1 Ibrutinib is an orally available small molecule that selectively binds to the cysteine 481 residue in the ATP binding domain of BTK, halting kinase activity and inhibiting signaling downstream from the B-cell receptor. Ibrutinib is approved by the US Food and Drug Administration (FDA) as a once-daily treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who are treatment-naive or who have relapsed/refractory disease.2 Results from the phase 1b/2 study PCYC-1102 and the extension study PCYC-1103 demonstrated the efficacy and safety of ibrutinib monotherapy in patients with CLL/SLL, with a manageable safety profile that allows patients to continue on treatment for an extended duration.3-6 Three-year follow-up data yielded an objective response rate (ORR) of 90% and a complete response (CR) rate of 7% in the overall study population while demonstrating durable remissions and improved quality of response over time.
Dr Susan O’Brien presented 5-year follow-up results from the PCYC-1102 and PCYC-1103 trials.7 PCYC-1102 enrolled 31 treatment-naive CLL/SLL patients ages 65 years or older and 101 patients with relapsed or refractory CLL/SLL. The latter group included 24 patients with high-risk disease, defined as disease progression within 24 months of initiating chemoimmunotherapy. The immunoglobulin variable region heavy chain (IgVH) region was unmutated in 48% of the treatment-naive patients vs 78% of the relapsed/refractory patients. In the relapsed/refractory cohort, patients had received a median of 4 lines of prior therapy (range, 1-12).
The ORR in the entire study population of 132 patients was 89%, including a CR rate of 14%, a partial response (PR) rate of 71%, and a 3% rate of PRs with lymphocytosis. ORR was 87% in the treatment-naive patients vs 89% in the relapsed/refractory patients, including CRs of 29% vs 10%. Among the patients with relapsed/refractory disease, the ORR was 97% in patients with del(11q), 90% in patients with unmutated IgVH, 90% in those with complex karyotype, and 79% in those with del(17p), including CR rates of 9%, 9%, 7%, and 6%, respectively.
At 5 years, the PFS rates were 92% in the treatment-naive cohort vs 43% in the relapsed/refractory cohort (Figure 1). Five-year overall survival (OS) rates were 92% vs 57%, respectively. Among the patients with relapsed or refractory disease, patients with mutated IgVH vs unmutated IgVH demonstrated 5-year PFS rates of 53% vs 38% and 5-year OS rates of 66% vs 55%, respectively. However, the Kaplan-Meier curves for both outcomes showed considerable overlap. In the 34 patients with del(17p) at baseline, median PFS was 26 months, and median OS was 57 months. Five-year PFS was 19%, and 5-year OS was 32%. In the 28 patients with del(11q) at baseline, median PFS was 55 months, and median OS was not reached. Five-year PFS was 33%, and 5-year OS was 61%.
Among patients with a complex karyotype, 90% had relapsed or refractory disease. These patients had received a median of 4 prior therapies. PFS and OS were reduced in this group of patients. For patients without the complex karyotype, 5-year PFS was 69% and OS was 84%, vs 36% and 46% in patients with a complex karyotype. Five-year survival decreased with the number of prior therapies. Five-year PFS was 92% in treatment-naive patients vs 38% in those treated with 4 or more prior therapies. Five-year OS was 92% vs 47%, respectively. Multivariate analysis revealed del(17p) as the only significant predictor of PFS and OS.
Ibrutinib therapy was generally well-tolerated. The rate of adverse events (AEs) of grade 3 or higher decreased over time. In the entire study population, onset of treatment-emergent AEs of grade 3 or greater was highest in the first year of treatment and decreased during subsequent years. The most common AEs of grade 3 or higher were hypertension (26%) and pneumonia (22%). The most common nonhematologic AEs were pneumonia and hypertension in previously treated patients vs hypertension and diarrhea in treatment-naive patients.
For the treatment-naive patients vs those with relapsed/refractory disease, the median time on study was 62 months vs 49 months (range, 1-67 months). In the 2 cohorts, 65% vs 30% of patients remained on therapy, respectively. Discontinuation of study treatment occurred in 20% of patients owing to an AE and in 26% of patients owing to disease progression. The predominant reasons for discontinuing therapy differed in the 2 patient groups, with progressive disease accounting for 3% in the treatment-naive cohort vs 33% in the relapsed/refractory cohort. AEs accounted for 19% vs 21% of discontinuations, respectively.
1. Jeyakumar D, O’Brien S. The next generation of targeted molecules for the treatment of chronic lymphocytic leukemia. Oncology (Williston Park). 2016;30(11):219811.
2. Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics, Inc; 2016.
3. Smith DD, Goldstein L, Cheng M, et al. Modeling absolute lymphocyte counts after treatment of chronic lymphocytic leukemia with ibrutinib. Ann Hematol. 2015;94(2):249-256.
4. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506.
5. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.
6. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48-58.
7. O’Brien SM, Furman RR, Coutre SE, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia [ASH abstract 233]. Blood. 2016;128(suppl 22).
Commentary: These data are important because they represent the longest follow-up available for ibrutinib. The analysis was based on data from the original phase 1b/2 study, which included 2 cohorts: 31 previously untreated patients ages 65 years or older, and 101 patients with relapsed/refractory disease, who had received a median of 4 prior therapies. The relapsed/refractory patients were therefore heavily pretreated. The follow-up analysis shows a best response of 89% for both groups together. In the treatment-naive patients, the CR rate was 29%, which reflects a slight improvement from the 26% that was reported for this group in 2015.
This 5-year analysis provided several new findings concerning PFS. In previous studies of ibrutinib, the median PFS had not been reached for all patients. The only subgroup with a median PFS had been relapsed/refractory patients with del(17p), in whom it was 26 months. A new finding from the 5-year data is a median PFS of 52 months in the overall relapsed/refractory setting. The median PFS for patients with the del(11q) is 55 months. Among patients who do not have either of these high-risk abnormalities—del(17p) or del(11q)—the median PFS has still not been reached, which is quite striking at 5 years, especially given that the median number of prior regimens in these patients was 4. Median overall survival was reached in only one group of patients, relapsed/refractory patients with del(17p), in whom it was
Among treatment-naive patients, the survival curve had been very similar for years. There had been 1 early drop in the curve, which reflected a patient who progressed and died within the first year of the study. The 5-year analysis shows another late drop in the curve just before 5 years, which represents a patient in remission who died of a secondary malignancy. Among the original 31 treatment-naive patients, only one-third have come off study. Only 1 patient has progressed. The 5-year PFS in the treatment-naive cohort is 96%. These data are very striking.
A multivariate analysis of the relapsed/refractory patients showed that the relevant predictor was the del(17p), which shortened both PFS and overall survival.
Updated Efficacy and Safety From the Phase 3 RESONATE-2 Study: Ibrutinib as a First-Line Treatment Option in Patients 65 Years and Older With CLL/SLL
Dr Paul Barr presented updated efficacy and safety data from the phase 3 RESONATE-2 trial, which evaluated first-line ibrutinib vs chlorambucil in elderly patients with CLL/SLL.1,2 The study enrolled 269 patients ages 65 years or older with treatment-naive CLL/SLL who were not candidates for fludarabine-based therapy. Patients with del(17p) were ineligible. After stratification for performance status and disease stage, patients were randomly assigned to receive ibrutinib at 420 mg once daily until disease progression or unacceptable toxicity, or chlorambucil at 0.5 mg/kg up to a maximum of 0.8 mg/kg on days 1 and 15 in 28-day cycles for a maximum of 12 cycles until disease progression, unacceptable toxicity, or lack of efficacy. Patients with progressive disease were enrolled in a separate extension study (PCYC-1116-CA) with treatment based on investigator choice. The updated analysis of data from 269 patients therefore included 55 patients from the chlorambucil arm who experienced disease progression and underwent subsequent treatment with ibrutinib.
After 29 months of follow-up, the PFS was significantly improved in patients treated with ibrutinib (89 months vs 34 months; hazard ratio [HR], 0.121; 95% CI, 0.074-0.198; P<.0001). In the subgroup of patients with del(11q), ibrutinib treatment was associated with a 99% reduction in the risk of progression or death compared with chlorambucil (HR, 0.014; 95% CI, 0.002-0.108; P<.001; Figure 2). In patients without del(11q), ibrutinib conferred an 82% reduction in the risk of progression or death vs chlorambucil (HR, 0.180; 95% CI, 0.106-0.303; P<.0001). Ibrutinib treatment was associated with a 92% risk reduction in patients with unmutated IgVH (P<.0001) and an 83% risk reduction in patients with mutated IgVH (P<.001).
For the entire study population, the 24-month OS rate was 95% with ibrutinib vs 84% with chlorambucil. These results confirmed the original findings that yielded an estimated 24-month PFS of 98% with ibrutinib vs 85% with chlorambucil, and a risk reduction of 84% with ibrutinib compared with chlorambucil (P=.001).1 The 136 patients in the ibrutinib arm had an ORR of 92%, including 18% CRs or CRs with incomplete blood count recovery; 1% nodular PRs, indicating persistent nodules in the bone marrow; 71% PRs; and 1% PRs with lymphocytosis. CR rates improved with continued ibrutinib treatment, increasing from 7% at 12 months of follow-up, to 15% at 24 months, to 18% at 29 months. The ORR was 100% in patients with del(11q) vs 90% in those without, and 95% in patients with unmutated IgVH vs 88% in those without. With ibrutinib treatment, sustained improvement in the hemoglobin level was achieved in 90% of anemic patients vs 45% with chlorambucil (P<.0001). In patients with thrombocytopenia, a sustained improvement in platelet levels was achieved in 80% of those treated with ibrutinib vs 46% of those treated with chlorambucil (P=.0055).
The median duration of ibrutinib treatment was 29 months (range, 1-36 months), and 79% of patients were continuing treatment at the time the study was reported. Among the 21% of patients who discontinued treatment, the reasons included AEs (12%), death (4%), and disease progression (3%). In patients treated with ibrutinib, the most common AEs of any grade included diarrhea (45%) and fatigue (33%). Most treatment-emergent AEs of grade 3 or greater occurred during the first year of treatment. However, atrial fibrillation of grade 3 or greater was reported in 1% of patients during the first year of treatment with ibrutinib and in 4% of patients during the third year of treatment. Rates of dose reduction and discontinuation owing to an AE also decreased over time.
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. Barr PM, Robak T, Owen CJ, et al. Updated efficacy and safety from the phase 3 RESONATE-2 study: ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia [ASH abstract 234]. Blood. 2016;128(suppl 22).
Commentary: Dr Paul Barr presented updated efficacy and safety data from the phase 3 RESONATE trial. This randomized trial led to the approval of ibrutinib as frontline therapy in the United States. Patients were randomly assigned to receive the standard dose of ibrutinib, 420 mg daily, or chlorambucil. Patients were older than 70 years, or ages 65 to 70 years with comorbidities; their median age was 72 years. Chlorambucil was a reasonable comparator arm in this older population. The results, as reported in 2015 in the New England Journal of Medicine by Burger and colleagues, showed that PFS was dramatically longer with ibrutinib than with chlorambucil. The updated data presented by Dr Barr continued to show a dramatic difference. Median PFS was not yet reached with ibrutinib vs 15 months with chlorambucil. The 24-month PFS was 89% with ibrutinib. Even though crossover was allowed on this trial, there was still a survival advantage in the ibrutinib arm.
A subset analysis evaluated the impact of del(11q) and mutated vs unmutated IgVH. The relevance of this analysis is not focused on response. It is known that with chemotherapy-based regimens, response rates are similar regardless of whether patients have del(11q) or unmutated IgVH. Progression-free survival, however, is significantly shorter in patients with del(11q) or unmutated IgVH. This difference was seen in the chlorambucil arm in this study. Among patients treated with chlorambucil, those with the del(11q) had a shorter PFS than those without del(11q). Similarly, patients with unmutated IgVH had a shorter PFS than those without the mutation when treated with chlorambucil. These differences were not seen in the ibrutinib cohort. The entire ibrutinib cohort had a high response rate of 92%. In addition, the CR rate increased from 7% at 1 year to 18% at 2 years. Based on the phase 2 data, the CR rate could potentially improve with time.
The AEs reported for ibrutinib were as expected. Even though the population was older, 16 patients (approximately 12%) discontinued treatment owing to AEs. It is good to know that the longer follow-up is showing robust data with ibrutinib in the frontline setting.
When interpreting these results, some physicians might mention that the current standard of care is to use chlorambucil plus an antibody, rather than chlorambucil alone. However, the median PFS was only 26 months in the randomized trial that led the FDA to approve obinutuzumab with chlorambucil as a frontline regimen, which is far shorter than that achieved with ibrutinib. Therefore, the results of RESONATE-2 are not negated by the use of chlorambucil without an antibody.
Twice Daily Dosing With BGB-3111 Achieves Complete and Continuous BTK Occupancy in Lymph Nodes, and Is Associated With Durable Responses in Patients With CLL/SLL
BGB-3111 is an irreversible, highly selective, second-generation inhibitor of BTK, with high oral bioavailability and exposure levels.1 Dr Constantine Tam presented results from the first-in-human clinical trial of BGB-3111.2 The phase 1 trial included a dose-escalation component followed by expansion. Patients with relapsed or refractory B-cell malignancies were enrolled into cohorts for treatment with BGB-3111 dosed once daily at 40 mg, 80 mg, 160 mg, or 320 mg or dosed twice daily at 160 mg, using a modified 3+3 dose escalation design and disease-specific expansion cohorts. Patients with relapsed or refractory B-cell malignancies were assigned to BGB-3111 at 160 mg twice daily or 320 mg once daily for pharmacodynamic assessments. In order to assess BTK occupancy in the lymph nodes at the time of trough drug exposure, paired lymph node biopsies were taken from these patients at baseline and prior to dosing on day 3. BGB-3111 exposure increased in a dose-dependent manner from 40 mg to 320 mg daily. The maximum concentration and area under the curve of BGB-3111 in patients treated with 80 mg daily were similar to those observed in patients treated with ibrutinib dosed at 560 mg daily.3 Free drug exposure from BGB-3111 (40 mg daily) was similar to that observed from ibrutinib (560 mg daily). In cohorts receiving the 2 highest doses of BGB-3111, drug exposure levels were approximately 8-fold higher compared with ibrutinib (560 mg daily). Complete BTK occupancy was observed in peripheral blood mononuclear cells in the lowest dose cohort. Twenty patients with relapsed or refractory B-cell malignancies were enrolled in the pharmacodynamic assessment cohorts. The median trough BTK occupancy in the lymph nodes was 100% in patients receiving BGB-3111 at 160 mg twice daily vs 94% in those receiving 320 mg once daily (P=.002), and the proportion of patients with greater than 90% trough occupancy at all time points was 94% vs 58%.
Among the 63 enrolled patients with CLL/SLL, 17 had less than 12 weeks of follow-up and were therefore not included in the analysis. One patient discontinued treatment owing to an AE. Sixty-two patients remained on the study with no evidence of progressive disease.
The ORR was 96%, including 67% PRs and 28% PRs with lymphocytosis. In the 17 patients with del(17p) and/or del(11q), the ORR was 100%. The overall study group showed a dramatic reduction in lymph node burden by the first scan, which was administered 3 months after treatment was initiated. The median absolute lymph node count peaked at approximately 8 weeks after initiating treatment and returned to baseline after approximately 3 to 4 months. In anemic patients, median hemoglobin levels increased over time (Figure 3). Similarly, in patients with a platelet count of less than 100,000/µL at baseline, the median platelet count improved over time.
The most common AE of any grade was bleeding (48%), followed by upper respiratory tract infection (33%) and fatigue (28%). Sixteen patients (35%) had at least 1 AE of grade 3 or greater, 10 patients (22%) had at least 1 serious AE, and 1 patient (2%) discontinued treatment owing to an AE. In the current analysis of 46 patients, 9 patients (20%) experienced diarrhea; all episodes were grade 1 or 2 in severity.
1. Wu J, Liu C, Tsui ST, Liu D. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016;9(1):80.
2. Tam CS, Opat S, Cull G, et al. Twice daily dosing with the highly specific BTK inhibitor, BGB-3111, achieves complete and continuous BTK occupancy in lymph nodes, and is associated with durable responses in patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma [ASH abstract 642]. Blood. 2016;128(suppl 22).
3. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.
Commentary: BGB-3111, a new oral agent, is very potent against BTK and has higher IC50 for some of the other kinases that ibrutinib targets. For example, it has a higher IC50 for the epidermal growth factor receptor, which could theoretically translate into less likelihood of rash or diarrhea compared with that seen with other BTK inhibitors. It has a much higher IC50 for IL2-inducible T-cell kinase than ibrutinib, so potentially it will not interfere with the activities of antibodies. The IC50 on TEC, however, appears similar between BGB-3111 and ibrutinib, which is important because TEC may be responsible for the atrial fibrillation and bleeding that can be seen with ibrutinib. It would be ideal to have a BTK inhibitor that does not target TEC, such as the novel agent acalabrutinib.
Dr Constantine Tam presented interim results of an ongoing phase 1 study of BGB-3111. The study evaluated a variety of different doses ranging from 40 mg daily to 160 twice daily. The study showed that higher plasma levels are achieved with higher doses of BGB-3111, and all doses were associated with activity. An interesting aspect of this study is that it looked within the lymph nodes to determine BTK occupancy. The optimal dose of ibrutinib, 420 mg daily, was selected because it resulted in almost complete occupancy of BTK in the peripheral blood mononuclear cells. The lymph nodes, however, were not evaluated when determining this dose. This information might be relevant because there are some data suggesting that patients with bulky adenopathy do not have as sustained a PFS with ibrutinib. In the study of BGB-3111, the lymph nodes had a sustained occupancy above 90% at doses of 160 twice daily or 320 daily.
The most common side effects with BGB-3111 were petechiae, purpura, and contusion, suggesting that the low IC50 for TEC may lead to minor bleeding, similar to that seen with ibrutinib. Diarrhea, however, was much less frequent than with ibrutinib, occurring in only 20% of patients. There was 1 episode of serious hemorrhage, and 1 episode of atrial fibrillation. The response rate was 96%, which is quite good, especially considering that the patients in the study had relapsed/refractory disease. These patients also showed improvements in cytopenias. Among the relapsed/refractory patients, the median number of prior regimens was 2, so they were less heavily pretreated than patients in the ibrutinib trials previously discussed. No patient has yet developed progressive disease, and there have been no reports of Richter’s transformation. These data are encouraging.
Idelalisib in Combination With Bendamustine and Rituximab in Patients With Relapsed/Refractory CLL
Dr Andrew Zelenetz presented updated results from the randomized, placebo-controlled, double-blind, phase 3 GS-US-312-0115 trial, which examined the addition of idelalisib to bendamustine plus rituximab in patients with relapsed/refractory CLL.1,2 After a median of 21 months of follow-up, more patients remained on study in the idelalisib arm (34%) than the placebo arm (11%), and 31% vs 0 patients continued on study treatment, respectively. After the initial prespecified interim analysis, patients in the placebo arm were informed and discontinued treatment. The updated analysis demonstrated a significant improvement in survival with idelalisib, with a median OS of not reached vs 40.6 months for placebo (HR, 0.67; 95% CI, 0.47-0.96; P=.04). PFS based on independent review was also significantly improved with idelalisib (23.0 months vs 11.1 months; HR, 0.31; 95% CI, 0.24-0.41; P<.0001). In the subgroup of patients without del(17p) or TP53 mutation, the median PFS was 27.8 months in the idelalisib arm vs 11.2 months in the placebo arm (HR, 0.25; 95% CI, 0.17-0.35; P<.001).
An AE of grade 3 or greater occurred in 95% of the idelalisib arm vs 78% of the placebo arm, and 71% vs 45% of patients experienced a serious AE. AEs leading to dose reduction occurred in 16% vs 6% of patients, AEs leading to discontinuation occurred in 33% vs 15%, and deaths occurred in 12% vs 9% of patients in the idelalisib vs placebo arms, respectively. Grade 3/4 AEs of interest that occurred more often in the idelalisib arm included neutropenia (60% vs 47%) and febrile neutropenia (24% vs 6%). The most common serious AEs in the idelalisib vs placebo arms were febrile neutropenia (21% vs 5%), pneumonia (17% vs 8%), and pyrexia (12% vs 5%).
Infection with Pneumocystis jirovecii pneumonia (PJP) was observed in 4 patients (2%) in the idelalisib arm vs 0 patients in the placebo arm, and cytomegalovirus (CMV) infection was observed in 13 patients (6%) vs 3 (1%), respectively. The only death from these infections occurred in a patient with CMV infection in the placebo arm. The risk of CMV infection decreased over time in both arms. Grade 3/4 alanine or aspartate transaminase elevations were more common in patients treated with idelalisib (21% vs 3% and 16% vs 3%, respectively).
1. Zelenetz AD, Brown JR, Delgado J, et al. Updated analysis of overall survival in randomized phase III study of idelalisib in combination with bendamustine and rituximab in patients with relapsed/refractory CLL [ASH abstract 231]. Blood. 2016;128(suppl 22).
2. Zelenetz AD, Robak T, Coiffier B, et al. Idelalisib plus bendamustine and rituximab (BR) is superior to BR alone in patients with relapsed/refractory chronic lymphocytic leukemia: results of a phase 3 randomized double-blind placebo-controlled study [ASH abstract LBA-5]. Blood. 2015;126(suppl 23).
Commentary: Dr Andrew Zelenetz presented an updated analysis of overall survival in a randomized, placebo-controlled, phase 3 trial of idelalisib added to bendamustine and rituximab in patients with relapsed/refractory CLL. Previous data for this study were presented at the 2015 ASH meeting (abstract LBA-5). The new analysis is based on a longer median follow-up of 21 months. This study shows a survival benefit when idelalisib is added to bendamustine and rituximab. Median overall survival was 40.6 months in the placebo arm—patients who received bendamustine/rituximab without idelalisib—and was not reached in the idelalisib plus bendamustine/rituximab arm. The difference was statistically significant. This survival advantage is a new finding. The PFS continues to be very different, at a median of 11 months with placebo vs 23 months with idelalisib. This improvement was seen in basically all subgroups. An analysis that removed the patients with 17p or TP53 mutation showed that the median PFS did not change in the placebo arm, but increased to up to 28 months in the idelalisib arm.
More febrile neutropenia was seen with idelalisib than placebo. In the idelalisib group, 24% of patients experienced grade 3 or higher febrile neutropenia vs only 6% in the placebo group. There was more transaminitis in the idelalisib arm, as is seen in single-agent use. There was also more pneumonia among patients who received idelalisib, at 17% vs 8%. Four cases of PJP occurred in the idelalisib plus bendamustine/rituximab arm, vs none in the placebo plus bendamustine/rituximab arm. There were 13 cases of CMV in the idelalisib arm and only 3 in the placebo arm. In March 2016, the FDA closed the frontline trials of idelalisib based on a higher incidence of infection. Most of that patient population received bendamustine/rituximab plus idelalisib as initial therapy. Thus, it was the same regimen in the frontline setting that led to the closing of the frontline studies. Similarly, in the current analysis, there were more cases of PJP and CMV, but the majority of the infections were not atypical. In addition, despite these infections, there was still a significant survival advantage in favor of the idelalisib plus bendamustine/rituximab arm.