How I Treat Chronic Lymphocytic Leukemia: An Expert Perspective on Frontline Management
Richard R. Furman, MD
Director of the CLL Research Center
Weill Cornell Medicine
New York, New York
H&O When is frontline treatment initiated in patients with CLL?
RF The current standard of care for patients with chronic lymphocytic leukemia (CLL) is a strategy of “watch and wait.” The data for this paradigm were generated in the 1970s and 1980s, when far less information on prognosis was available. With a watch-and-wait strategy, treatment is not initiated until patients meet criteria established by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL). The most common indications for treatment are rapid lymphocyte doubling time, bone marrow failure as manifested by worsening anemia and thrombocytopenia, symptomatic lymphadenopathy or splenomegaly, and B symptoms. The idea behind watch and wait is to defer therapy until signs suggest that the CLL is active. Many physicians and patients attempt to delay therapy for as long as possible, with the idea that every day therapy is delayed translates into an additional day of survival. There are no data suggesting an advantage to delaying therapy once disease is active. The idea behind watch and wait is to initiate therapy once the CLL shows signs of becoming active, and that would be once the iwCLL criteria are met.
This strategy may change in the future, with the identification of prognostic markers that might suggest a poor outcome. For example, patients with risk factors for developing Richter’s transformation (eg, the NOTCH1 mutation, stereotyped V genes) or who have a 17p deletion (which can lead to mutations that make ibrutinib less effective), might benefit from early therapy before these secondary changes occur.
H&O What are the treatment goals?
RF The most important goals are progression-free survival (PFS) and overall survival. With many novel agents, PFS translates into an improvement in overall survival primarily because it is possible to induce very deep responses without cumulative toxicities.
An equally important goal of therapy is to avoid long-term toxicities. CLL-related symptoms resolve rapidly with novel therapies. Therefore, there is no benefit from getting patients into a deep remission quickly. What is most important is to ensure that treatment does not cause damage or toxicities that will impact the patient’s long-term survivability. Chemotherapy can impact function of the bone marrow and the immune system, leading to cytopenias, myelodysplastic syndrome or acute leukemia, or recurrent, life-threatening infections.
H&O Does marrow damage or marrow sparing impact your choice of frontline treatment?
RF Very much so. With the array of novel agents for CLL available, we should start to see a significant prolongation of survival. We therefore must keep a very close eye on the toxicities that might emerge much later on, such as bone marrow failure and secondary malignancies. Chemotherapy dramatically increases the risk of these toxicities.
H&O Does your frontline treatment algorithm still include chemoimmunotherapy?
RF I do not use chemoimmunotherapy under any circumstances in any patients. For me, the long-term risks of bone marrow failure and secondary cancers outweigh any benefits with this treatment.
My first choice of frontline therapy for most patients with CLL is ibrutinib as a single agent. For patients with the 11q or 17p deletions, there is currently a clinical trial of ibrutinib plus venetoclax, which should be very promising. My hope is that for patients who are at risk of not doing well long-term with ibrutinib, it will be possible to use this combination.
Patients whose condition is not suitable for treatment with ibrutinib, such as those with bleeding diathesis or at risk of atrial fibrillation, I treat with either obinutuzumab or venetoclax as frontline therapy.
The long-term efficacy of ibrutinib and the risk of bleeding and atrial fibrillation are the most important components of the decision-making algorithm when choosing frontline therapy. Immunoglobulin gene mutational status does not enter into the algorithm at all because it does not impact long-term outcomes with ibrutinib.
H&O What are the trial data supporting the use of ibrutinib in the frontline setting?
RF The pivotal study that led to the approval of ibrutinib in frontline CLL for all patients was the phase 3 RESONATE-2 trial (PCYC-1115; A 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). This study compared ibrutinib vs chlorambucil in patients who were older than 65 years. The results, published in 2015, showed an estimated 24-month PFS of 98% with ibrutinib vs 85% with chlorambucil, and a risk reduction of 84% with ibrutinib compared with chlorambucil. Subsequent analyses of the RESONATE-2 data continue to show improvements in PFS, overall survival, and overall response.
The earlier phase 1b/2 PCYC-1102 study evaluated ibrutinib in patients with CLL. The study enrolled patients with relapsed/refractory disease and patients with treatment-naive disease who were ages 65 years or older. There are now 5 years of follow-up data for the cohort of treatment-naive patients, and these data are important in that they demonstrate the long-term safety, tolerability, and durability of ibrutinib treatment. Data from the relapsed/refractory population of patients who had deletion 17p and were treated in the RESONATE study provided the impetus for the US Food and Drug Administration to approve ibrutinib in all patients with the 17p deletion, regardless of their line of therapy. Although the data generated did not include treatment-naive patients with the 17p deletion, this population was included in the initial approval.
H&O What are the long-term data with ibrutinib?
RF Among 31 treatment-naive patients who received ibrutinib in the PCYC-1102 trial, only 2 have developed progressive disease. The median PFS for the treatment-naive patients was not reached, with an estimated PFS at 60 months of 92%. Both of the patients who progressed had the 17p deletion. Thus, ibrutinib has been extremely effective and well-tolerated in treatment-naive patients, except for those with the 17p deletion.
In the relapsed/refractory population, which consisted of 101 patients, the median PFS was 52 months overall. The 2 most important predictors of long-term outcome are factors identified during interphase fluorescence in situ hybridization (FISH) and the complex karyotype. The median PFS was 26 months for patients with deletion 17p, 55 months for patients with deletion 11q, and not reached for patients without deletion 17p, deletion 11q, or trisomy 12. Patients with deletion 13q do particularly well, with PFS rates of approximately 90% to 95% at 5 years. Therefore, patients with deletion 17p, deletion 11q, or trisomy 12 might benefit from additional therapies in order to improve their response durability.
H&O What therapies have you used successfully after frontline ibrutinib?
RF A beneficial aspect to ibrutinib is that it does not induce genomic instability. When patients progress on ibrutinib, they tend to still be sensitive to other treatment options. My choice after ibrutinib is venetoclax. Other therapies used successfully include idelalisib, obinutuzumab, and chimeric antigen receptor (CAR) T-cell therapy.
H&O Do data support the use of ibrutinib in combination with other agents?
RF There must be a good reason to use ibrutinib in combination with another agent. Many of the abstracts presented at the recent meetings looked at novel combinations with chemoimmunotherapy plus ibrutinib. A patient with deletion 13q, trisomy 12, or a normal cytogenetic profile has nothing to gain from the addition of chemoimmunotherapy to ibrutinib. On the other hand, patients with the 11q or 17p deletions have the potential to gain from combination therapy, given the need to improve the PFS. For these patients, my first choice would be venetoclax plus ibrutinib. Ibrutinib and venetoclax are synergistic in vitro, making the venetoclax more effective, and a lead-in of single-agent ibrutinib will allow for tumor debulking, which would lessen the risk of tumor lysis from venetoclax. Additionally, the rapid response during induction with venetoclax may help prevent any additional tumor clonal evolution during that time, and ibrutinib can induce a deep response, hopefully avoiding Richter’s transformation and the
development of resistance.
H&O How do you manage the adverse events seen with ibrutinib?
RF The incidence of toxicities with ibrutinib appears to diminish over time. The most common toxicities include bleeding, diarrhea, hypertension, atrial fibrillation, and arthralgias. The bleeding, diarrhea, and arthralgias tend to occur early in the course of treatment. In contrast, atrial fibrillation is seen most often during the first 12 months of therapy, and rarely beyond 2 years. The incidence of hypertension increases over time, reaching approximately 15% at 5 years. Importantly, the incidence of infections diminishes over time, with fewer infections between years 2 and 3, compared with years 1 to 2 and 2 to 3.
The increased bleeding is grade 1 and 2 only, and patients do not require any additional management. For some patients who are small in size and who develop excessive bruising, a dose reduction to 280 mg daily might help. I try to avoid using ibrutinib in combination with anticoagulation, instead opting mostly for venetoclax or obinutuzumab.
The chance of diarrhea can be minimized if patients take ibrutinib at bedtime. If patients have an empty stomach for the 6 to 8 hours after they dose (eg, while asleep), they should be able to eat with minimal signs of diarrhea. I have found that this strategy reduces the incidence of diarrhea to as low as 5%. The diarrhea, when it occurs, ameliorates over time.
The hypertension that occurs with ibrutinib is primarily grade 1 or 2 and is easily managed with antihypertensive therapy.
Atrial fibrillation is more problematic. I always discontinue ibrutinib in these patients, and, in many cases, the patient reverts to normal sinus rhythm. That makes it easier to anticoagulate a patient, if necessary based on his or her cardiac status. When patients are back in normal sinus rhythm and no longer require anticoagulation, ibrutinib can be reinitiated. The addition of a β-blocker may provide some measure of protection against recurrence of atrial fibrillation.
When patients develop arthralgias, I usually administer a low dose of prednisone for approximately 2 to 4 weeks. Most patients improve by then, and I taper the prednisone.
Dr Furman is a consultant for Pharmacyclics, AbbVie, Verastem, Gilead, Genentech, TG Therapeutics, and Sunesis.
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.
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.
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.
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.
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.
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.
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.
Highlights in Chronic Lymphocytic Leukemia From the 2017 iwCLL and ASCO Meetings
Commentary by Richard R. Furman, MD
ASCO ABSTRACT Long-Term Efficacy and Safety With Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Up to Four Years Follow-Up of the RESONATE Study
The phase 3 RESONATE trial (A Phase 3 Study of Ibrutinib [PCI-32765] Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia) compared ibrutinib vs ofatumumab in 391 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1 The primary analysis, published in 2014, showed that ibrutinib significantly improved survival, reducing the risk of disease progression by 78% and the risk of death by 57%.1
This analysis by Byrd and colleagues provided long-term efficacy and safety from the RESONATE trial, with follow-up extending to 4 years (median, 3.6 years).2 Progression-free survival (PFS) was not reached for ibrutinib vs 8.11 months for ofatumumab (hazard ratio, 0.133; P<.0001). The 3-year PFS was 59% vs 3%, respectively. The overall response rate for ibrutinib was 91% (Figure 1). The rate of complete response (CR) with or without blood count recovery (CRi) was 9%, and increased over time. Most patients in the ofatumumab arm (68%) crossed over to treatment with ibrutinib. Overall survival was longer for ibrutinib vs ofatumumab, but the median overall survival was not reached for either arm (Figure 2). At 3 years, the rate of overall survival was 74% among patients treated with ibrutinib. Among patients with baseline cytopenias, improvements were seen in hemoglobin (85%), platelets (95%), and absolute neutrophil counts (95%) during extended ibrutinib therapy.
Ibrutinib had the strongest PFS benefit among patients with the 11q deletion. However, PFS did not significantly differ in patients with or without the 11q or 17p deletion. Median PFS was longer among patients without the TP53 mutation than in those with the mutation, but the difference was not statistically significant (not reached vs 40.7 months).
The toxicity profile of ibrutinib was consistent with previous reports. Major hemorrhage and grade 3 or higher atrial fibrillation each occurred in 6% of patients. Grade 3 or higher hypertension occurred in 8% of patients. The incidence of most grade 3 or higher adverse events, including neutropenia, pneumonia, and atrial fibrillation, decreased over time. Treatment discontinuation was attributed to progressive disease in 27% of patients and to adverse events in 12%.
1. 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.
2. Byrd JC, Hillmen P, O’Brien SM, et al. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia: up to four years follow-up of the RESONATE study [ASCO abstract 7510]. J Clin Oncol. 2017;35(15 suppl).
Commentary: Data from the RESONATE study led the US Food and Drug Administration to approve ibrutinib in all patients with the 17p deletion, regardless of their line of therapy. The trial did not include treatment-naive patients, but this population was still included in the initial approval.
ASCO ABSTRACT Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (GA101) for Previously Untreated Patients With Chronic Lymphocytic Leukemia With Mutated IGHV and Non-Del (17p)
Dr Nitin Jain and colleagues presented results of an ongoing phase 2 trial evaluating ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) among treatment-naive patients with CLL and the IGHV mutation.1 The study shortened the duration of treatment with fludarabine and cyclophosphamide by switching to ibrutinib and obinutuzumab. All patients began treatment with 3 courses of iFCG followed by ibrutinib and obinutuzumab for 3 cycles. Patients who achieved a CR/CRi and were negative for minimal residual disease (MRD) were then treated with ibrutinib for 6 cycles. Patients with a partial response or who were positive for MRD received ibrutinib and obinutuzumab for 6 cycles. After 12 cycles of treatment, patients who were MRD-positive continued to receive ibrutinib until they developed progressive disease. Patients who were MRD-negative stopped ibrutinib. The primary endpoint was CR/CRi plus bone marrow MRD negativity after 3 cycles of iFCG.
The patients’ median age was 60 years (range, 25-71 years). Most patients (83%) were male. The deletion 13q mutation was found in 69%, and 21% had trisomy 12. Among 29 patients who initiated treatment, 24 completed 3 cycles of iFCG and underwent assessment for their response. The median follow-up was 8.3 months.
After 3 cycles of iFCG, the rate of bone marrow MRD negativity was 83%. The overall response rate was 100%, with a CR/CRi rate of 42% and a partial response rate of 58% (Table 1). All of the patients who achieved a CR/CRi were negative for MRD. Among patients who had a partial response, MRD negativity was reported in 71%. All of the 9 patients who received 1 year of treatment were MRD-negative and therefore discontinued ibrutinib.
The most common adverse events were neutropenia (grade 3 in 31% and grade 4 in 41%) and thrombocytopenia (grade 3 in 41% and grade 4 in 3%). Neutropenic fever, the most common infection, occurred in 4 patients.
The authors concluded that iFCG achieved high rates of MRD-negative remission after 3 courses. Enrollment of patients continues.
1. Jain N, Thompson PA, 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) [ASCO abstract 7522]. J Clin Oncol. 2017;35(15 suppl).
Commentary: This study represents a nice attempt to limit the amount of chemotherapy that patients are exposed to. However, it does not address the important issue of whether 3 cycles of fludarabine and cyclophosphamide are still necessary, or if ibrutinib plus obinutuzumab alone would have been sufficient. The HELIOS trial (Ibrutinib Combined With Bendamustine and Rituximab Compared With Placebo, Bendamustine, and Rituximab for Previously Treated Chronic Lymphocytic Leukaemia or Small Lymphocytic Lymphoma) compared bendamustine and rituximab with or without ibrutinib. It found that the patients receiving bendamustine, rituximab, and ibrutinib did much better than the placebo group, but that the Kaplan-Meier PFS curve was superimposable to that of ibrutinib as a single agent. Results from the HELIOS trial raised the question of whether bendamustine and rituximab were necessary. The same question may apply to fludarabine and cyclophosphamide.
iwCLL ABSTRACT Outcomes of Ibrutinib-Treated Patients With CLL/SLL With High-Risk Prognostic Factors in an Integrated Analysis of 3 Randomized Phase 3 Studies
At the 2017 iwCLL meeting, Dr Thomas Kipps presented data from a pooled analysis of patients with CLL treated with ibrutinib in three phase 3 clinical trials.1 In each of these trials, the ibrutinib arm was superior to a comparator arm. The RESONATE trial included 391 patients who had received at least 1 prior therapy and were ineligible for or refractory to purine analogue therapy.2 Patients were randomly assigned to receive ibrutinib or ofatumumab. In the ofatumumab arm, 131 patients crossed over to ibrutinib after they developed 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]) randomly assigned 269 treatment-naive patients to ibrutinib or chlorambucil.3 In the extension study, 64 patients in the chlorambucil arm crossed over to ibrutinib. Patients with deletion 17p were excluded from RESONATE-2. The HELIOS study included 578 patients who had received at least 1 prior therapy.4 Patients with deletion 17p were excluded. After treatment with bendamustine plus rituximab, patients were randomly assigned to receive ibrutinib or placebo for a maximum of 6 cycles. After they developed progressive disease, 142 patients in the placebo arm crossed over to the ibrutinib arm.
The pooled analysis by Dr Kipps and colleagues evaluated whether outcome was impacted by the presence of the IGHV mutation, deletion 11q, trisomy 12, or complex karyotype. (Deletion 17p was not included since patients with this mutation were excluded from 2 of the 3 trials.) Among patients treated with ibrutinib (n=620), the overall response rates and the CR rates were similar regardless of the presence of the IGHV mutation, deletion 11q, or complex karyotype (Figure 3). Patients with trisomy 12 had a higher CR rate. The presence of mutated IGHV, trisomy 12, complex karyotype, and deletion 11q did not impact overall survival, at a median follow-up of 42 months.
The mutation status of IGHV did not impact PFS (median follow-up, 36.4 months) in the ibrutinib arms (Figure 4). In the comparator arms, a superior PFS was seen in patients with mutated IGHV. The presence of trisomy 12 did not impact PFS in either patient group. In the ibrutinib arm, the complex karyotype and deletion 11q did not impact PFS. In the comparator arms, however, an inferior PFS was seen in patients with these mutations.
The median exposure to ibrutinib ranged from 33 months to 35 months (range, <1-50 months). The toxicity profile of ibrutinib was not impacted by genomic risk factors. Serious adverse events occurred in 60% to 68% of patients. Adverse events led to treatment discontinuation in 14% to 22% of patients and to death in 5% to 16%. The authors concluded that the genomic risk factors used to predict response with older therapies have limited utility with ibrutinib.
1. 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.
2. 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.
3. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.
4. 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.
Commentary: This study showed that the mutational status of the 11q deletion, trisomy 12, or complex karyotyping was not associated with poor outcomes. The follow-up was short.
ASCO ABSTRACT Tolerability and Activity of Chemo-Free Triplet Combination of TGR-1202, Ublituximab, and Ibrutinib in Patients With Advanced CLL and NHL
This phase 1 trial evaluated ibrutinib in combination with 2 novel agents in patients with relapsed/refractory non-Hodgkin lymphoma or patients with CLL/SLL (treatment-naive or relapsed/refractory).1 The glycoengineered monoclonal antibody ublituximab targets an epitope on the CD20 antigen. TGR-1202 is a next-generation PI3Kδ inhibitor.
The trial enrolled 20 patients with CLL/SLL and 18 with non-Hodgkin lymphoma. Eight CLL patients had a 17p and/or 11q deletion. The patients’ median age was 65 years (range, 32-85 years). Two patients had received previous treatment with ibrutinib.
The median follow-up was 11.1 months. The maximum tolerated dose was not reached. Among the 19 evaluable patients with CLL/SLL, the overall response rate was 100%. Six patients had a complete response, and 13 had a partial response. More than half of the evaluable CLL patients (53%) had high-risk cytogenetic features.
An overall response rate of 100% was also seen in patients with mantle cell lymphoma and marginal zone lymphoma. The rate was 80% among patients with
follicular lymphoma and 17% among those with diffuse large B-cell lymphoma.
Among all patients, the most common adverse events were diarrhea (47%), fatigue (47%), dizziness (37%), insomnia (34%), nausea (34%), neutropenia (32%), cough (32%), infusion-related reaction (32%), pyrexia (29%), rash (29%), thrombocytopenia (29%), anemia (26%), and sinusitis (24%). The most common grade 3/4 event was neutropenia, occurring in 18% of patients. The authors concluded that the combination of ublituximab, TGR-1202, and ibrutinib was well-tolerated and showed activity across patients with heavily pretreated and high-risk B-cell malignancies.
1. Nastoupil LJ, Lunning MA, Vose J, et al. Tolerability and activity of chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib in patients with advanced CLL and NHL [ASCO abstract 7511]. J Clin Oncol. 2017;35(15 suppl).
Commentary: This study was important in that it combined inhibitors of Bruton tyrosine kinase and phosphoinositide 3-kinase, an approach under study in several trials of B-cell malignancies. The study found that the signal transduction inhibitors worked well in patients with low-grade lymphomas, such as CLL, follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma, but not in patients with diffuse large B-cell lymphoma. These results suggest that the large-cell lymphomas need a very different approach from the low-grade lymphomas.
iwCLL ABSTRACT Outcomes of Standard-of-Care Regimens in Treatment-Naive Chronic Lymphocytic Leukemia Patients With Unmutated Immunoglobulin Heavy Chain Variable Genes
Dr Paolo Ghia and colleagues analyzed outcomes in patients with CLL treated with fludarabine, cyclophosphamide, and rituximab (FCR), bendamustine plus rituximab, or ibrutinib in the CLL8, CLL10, and RESONATE-2 studies.1-4 Kaplan-Meier curves that were digitized from the original publications were used to estimate PFS rates. Across the 3 studies, the proportion of patients with unmutated IGHV ranged from 43% to 68%.
In the RESONATE-2 trial, IGHV status did not impact PFS among patients treated with ibrutinib. Among patients treated with traditional chemoimmunotherapy, inferior outcomes were seen in those with unmutated IGHV vs mutated IGHV. In CLL10, bendamustine plus rituximab was associated with a higher PFS in patients who had mutated IGHV rather than unmutated IGHV. Patients with mutated IGHV also had a better PFS when treated with FCR in the CLL8 and CLL10 trials. Among patients with mutated IGHV from all 3 trials, Kaplan-Meier curves for all treatments overlapped through 36 months. (Data were unavailable for ibrutinib thereafter.) After 36 months, PFS was longer for FCR than bendamustine plus rituximab in patients with mutated IGHV. Among patients with mutated IGHV, the estimated rates of PFS at 30 months were 81% for those who received ibrutinib, 84% for those treated with FCR in CLL8, 87% for those treated with FCR in CLL10, and 83% for those treated with bendamustine plus rituximab in CLL10 (Figure 5).
A comparison of Kaplan-Meier curves from patients with unmutated IGHV showed similar rates of PFS 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 bendamustine plus rituximab (Figure 6). Among patients with unmutated IGHV, the estimated 30-month PFS rates were 87% for those treated with ibrutinib, 64% for those who received FCR in CLL8, 65% for those who received FCR in CLL10, and 59% for those treated with bendamustine plus rituximab in CLL10. The IGHV mutation did not impact overall survival until approximately 15 months. At this time, overall survival decreased among patients with unmutated IGHV and remained lower through 96 months.
This analysis suggested that patients with mutated or unmutated IGHV experienced a durable PFS with ibrutinib. After treatment with chemoimmunotherapy, however, patients with unmutated IGHV had worse outcomes than those with mutated IGHV.
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. 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. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.
4. 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.
Commentary: This study showed that unmutated patients do better with ibrutinib than bendamustine/rituximab and fludarabine/cyclophosphamide/rituximab. These data confirm what is already known, as this study was a subgroup analysis of other studies. It appears that immunoglobulin G mutational status is no longer a prognostic marker with the use of ibrutinib.
ASCO ABSTRACT CD19 CAR-T Cells Combined With Ibrutinib to Induce Complete Remission in CLL
This pilot trial evaluated anti-CD19 chimeric antigen receptor (CAR) T cells in adults with CLL/SLL who had not achieved a CR after treatment with ibrutinib for at least 6 months.1 All patients in the study had also developed disease progression after 1 or more regimens before they began treatment with ibrutinib, unless they had deletion 17(p13.1) or the TP53 mutation. The CAR therapy consisted of CD3z, 4-1BB, and humanized anti-CD19 scFv (CTL119). Manufacturing of the CAR T-cell product was successful in all 10 patients who received the infusion. Treatment with ibrutinib continued throughout the study.
Most patients had the 17p deletion, and 2 patients had increasing BTK C481S clones. The median burden of CLL in the marrow was 10% (range, 10%-50%).
At 3 months, bone marrow was MRD-negative in 8 of 9 evaluable patients (89%). All patients remained in a CR at their last follow-up assessment.
Cytokine release syndrome occurred in 9 patients. It was grade 1 in 2 patients, grade 2 in 6 patients, and grade 3 in 1 patient. No patient required treatment with the interleukin 6 receptor antagonist tocilizumab. Grade 4 tumor lysis syndrome was reported in 1 patient.
1. Gill S, Frey NV, Hexner EO, et al. CD19 CAR-T cells combined with ibrutinib to induce complete remission in CLL [ASCO abstract 7509]. J Clin Oncol. 2017;35(15 suppl).
Commentary: In this study, patients who did not achieve a CR after 6 months of ibrutinib—which is all patients—were treated with CAR T-cell therapy. An interesting finding was that CAR T-cell therapy may be better tolerated in patients with a lower burden of disease. CAR T cells are associated with significant toxicities, however. Given that the patients enrolled in this study might have had a PFS exceeding 5 years with ibrutinib, I do not believe it was justifiable to expose them to the additional risks of CAR T-cell therapy.
iwCLL ABSTRACT Evaluation of the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI) in Previously Untreated CLL Patients Receiving Chemo-Immunotherapy as First-Line Approach: Analysis of 529 Cases
Dr Massimo Gentile and colleagues evaluated whether the CLL International Prognostic Index can predict overall survival among CLL patients treated with FCR or bendamustine plus rituximab as first-line therapy.1 The CLL International Prognostic Index consists of IGHV status, TP53 status, clinical stage, age, and β2-microglobulin level. The 529 patients in this analysis had these data available at the time of progression.
The median follow-up was 3.4 years (range, 3 months-15.7 years). The 3-year overall survival probability was 98.5% for patients at low risk, 93.7% for those at intermediate risk, 87.8% for those at high risk, and 65.6% for those at very high risk. The Harrell C-statistic for predicting survival was 0.70 (P<.0001). The 3-year PFS probability was 86.5% for patients at low risk, 70.6% for those at intermediate risk, 58.3% for those at high risk, and 29.8% for those at very high risk. The Harrell C-statistic for PFS was 0.63 (P<.0001). FCR had a significantly better outcome than bendamustine plus rituximab among patients in the high-risk and very high-risk groups.
1. Gentile M, Mauro FM, Reda G, et al. Evaluation of the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI) in previously untreated CLL patients receiving chemo-immunotherapy as first-line approach: analysis of 529 cases. Abstract presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY. Abstract 143.
Commentary: This study evaluated a prognostic model using TP53, IGHV, β2-microglobulin, clinical stage, and age. The model was validated among patients treated with chemoimmunotherapy. In the era of novel agents, in which I hope to see the use of chemoimmunotherapy eliminated, this prognostic model has little utility.
iwCLL ABSTRACT Phase 2 Study of the Combination of Ibrutinib Plus Venetoclax in Patients With Treatment-Naïve CLL/SLL
Dr William Wierda presented the design of an ongoing phase 2 trial evaluating the combination of ibrutinib and venetoclax as first-line therapy in patients with CLL or SLL.1 PCYC-1142 is a multicenter, double-blind, placebo-controlled, randomized trial. The primary objectives are to identify the MRD-negative response rate and to determine whether discontinuation of ibrutinib in patients who achieve MRD negativity impacts disease-free survival. Patients will first receive at least 12 cycles of ibrutinib plus venetoclax. Those without MRD at the end of treatment will be randomly assigned to maintenance therapy with either ibrutinib or placebo. Patients who are MRD-positive will be randomly assigned to open-label treatment with ibrutinib plus venetoclax or ibrutinib alone. The primary endpoint for the initial treatment phase of ibrutinib plus venetoclax is the MRD-negative response rate. For the randomized phase of the study, the primary endpoint is the rate of MRD-negative disease-free survival at 1 year. The trial aims to enroll approximately 150 patients.
1. Wierda W, Siddiqi T, Stevens D, 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 95.
Commentary: This trial in progress is evaluating ibrutinib plus venetoclax. This combination appears to be the best approach for patients with high-risk FISH abnormalities, the NOTCH1 mutation, or the VH 4-39 gene.