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Top 5 Abstracts in CLL
ASCO 2017: My Top 5 Most Interesting CLL Abstracts

Released: June 22, 2017

Expiration: June 21, 2018

John M. Burke
John M. Burke, MD
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The ASCO 2017 annual meeting showcased a number of important studies that I expect will influence the treatment of chronic lymphocytic leukemia (CLL) and may improve outcomes for patients. In this commentary, I discuss the 5 abstracts that I feel have the most potential to be practice changing.

Abstract 7503: A genetic risk-stratified, randomized phase II intergroup study of fludarabine/antibody combinations in symptomatic, untreated CLL: results from Cancer and Leukemia Group B (CALGB) 10404 (Alliance)

Ruppert and colleagues presented results from the randomized phase II CALGB 10404 intergroup study of fludarabine/antibody combinations in symptomatic, untreated patients with CLL. This complex study attempted to answer several questions, including whether consolidation with lenalidomide after chemoimmunotherapy could provide benefit.

In this study, 342 patients were randomized to fludarabine and rituximab (FR) or fludarabine, cyclophosphamide, and rituximab (FCR) for 1 cycle and tested for the presence of genetic abnormalities. Following genetic analysis, patients receiving FR who were found to have del(11q)—a relatively adverse prognostic factor—received 5 cycles of FCR. Patients who did not have del(11q) and had been randomized to FR continued for 5 additional cycles of FR and patients randomized to the FCR arm received 5 additional cycles of FCR. Then, lenalidomide consolidation was given to those patients with del(11q) who received FCR, whereas those patients without del(11q) who had received FR were randomized to lenalidomide or no consolidation (Figure). Lenalidomide was given at 5-10 mg/day, on Days 1-21 of 28-day cycles for up to 6 cycles.

Figure 1. CALGB 10404 trial design.

Although lenalidomide consolidation converted only a few patients from a PR to a CR, the PFS rate at 2 years was longer with lenalidomide vs no consolidation. In addition, PFS was superior with FCR alone vs FR alone. Of importance, in the non-del(11q) group, even though the median PFS with FR followed by lenalidomide was not statistically better than with FCR alone (66 vs 78 months, respectively; P = .25), the OS curve for the patients treated with FR plus lenalidomide unexpectedly separated from the FR and FCR arms after approximately 4 years of follow-up. The authors used statistical analyses accounting for the crossover of the Kaplan-Meier curves by giving more weight to the divergence in the curves to argue that the FR followed by lenalidomide modestly improves OS vs either FCR or FR (P = .045 and .01, respectively).

I do not think these results lend themselves to definitive conclusions but longer follow-up on this trial would be worthwhile to see if the OS improvement with lenalidomide consolidation is maintained over time. Furthermore, there was an unexpected plateau in survival at approximately 4 years in the patients without del(11q) who received lenalidomide consolidation, with more than 80% of patients remaining alive out through 96 months at this time. This is an interesting finding that warrants additional consideration.

I have never used lenalidomide consolidation or maintenance in clinical practice, although consideration of various maintenance approaches has been discussed by some experts. To my knowledge, this is the first study to suggest improved OS with consolidation or maintenance therapy in CLL. I also do not routinely use FR as induction therapy in young, healthy patients. Instead, I usually use FCR; this trial did not answer the question of consolidation lenalidomide after FCR in patients without del(11q). These findings are not immediately practice changing, but they do warrant further study of lenalidomide consolidation in CLL.

Abstract 7504: Ublituximab and ibrutinib for previously treated genetically high-risk CLL: results of the GENUINE phase III study

Sharman and colleagues conducted the phase III GENUINE study of ublituximab and ibrutinib in previously treated patients with high-risk CLL. Ibrutinib alone typically achieves excellent results in relapsed/refractory CLL. However, in high-risk patients, progression through ibrutinib remains a problem, and it was hoped that outcomes could be improved by adding an anti-CD20 antibody. Ublituximab is an investigational, glycoengineered, anti-CD20 monoclonal antibody. In a previous phase II study, the combination of ublituximab and ibrutinib achieved an ORR of 88%, including CRs, which are not usually seen with ibrutinib alone.

In the GENUINE trial, 117 patients with high-risk, relapsed/refractory CLL were randomized 1:1 to ibrutinib or ibrutinib with ublituximab. High-risk CLL was defined as the presence of del(17p), del(11q), or a TP53 mutation by centralized testing. The combination appears safe: Infusion reactions to ublituximab were seen in 50%, but only 5% of those were grade 3/4. Neutropenia was more frequent in the ublituximab arm (22% vs 12%), but rates of grade 3/4 neutropenia, anemia, and other adverse events were similar between arms.

The ORR (primary endpoint) in the combination arm was 78% vs 45% with ibrutinib alone (P < .001). The CR rate was 7% with ublituximab plus ibrutinib vs 0% with ibrutinib alone. Minimal residual disease (MRD) negativity was achieved in 19% vs 2% of patients, respectively (P < .01). Of note, ublituximab virtually eliminated the transient lymphocytosis that is generally seen with ibrutinib alone. A nonsignificant trend toward improved PFS was seen (HR: 0.559), but due to study modifications early on to allow for reduced target enrollment, the study was not powered to detect a change in PFS.

The GENUINE trial demonstrates that the addition of ublituximab to ibrutinib in high-risk patients with relapsed/refractory CLL improves the ORR. Yet, these interesting results must be interpreted with caution due to the absence of a PFS improvement. In my opinion, it could be appropriate to add ublituximab to ibrutinib for selected patients in whom a rapid response is desirable, but ublituximab is not commercially available or approved.

Abstract 7509: CD19 CAR T-cells combined with ibrutinib to induce CR in CLL

Gill and colleagues conducted a pilot trial of anti-CD19 CAR T-cells combined with ibrutinib in adults with CLL/small lymphocytic lymphoma who were not already in CR despite at least 6 months of ibrutinib. For background, previous observations have suggested that anti-CD19 CAR T-cell therapy in patients with CLL can achieve CR rates of 25% to 45%. The authors hypothesized that continuing ibrutinib with the addition of CAR T-cell therapy would improve the CR rate. Patients (N = 11) had CLL/small lymphocytic lymphoma and had progressed after at least 1 regimen before ibrutinib or had del(17) or a TP53 mutation and were currently receiving ibrutinib but had not achieved CR. The CAR T-cell therapy program consisted of lymphodepleting chemotherapy with either fludarabine/cyclophosphamide or bendamustine, given 1 week prior to anti-CD19 CAR T-cell infusion. At this point, the follow-up remains short; the longest follow-up of any patient to date is 9 months. Of 9 evaluable patients, all with high-risk CLL, 8 achieved a marrow CR and 1 had a PR. In terms of tolerability, all patients experienced cytokine release syndrome, and 2 patients had additional serious adverse events (grade 3 febrile neutropenia, grade 4 tumor lysis syndrome). The high rate of marrow CR suggests that adding CAR T-cell therapy to ongoing ibrutinib improves response rates; the authors plan to treat a total of 25 patients.

Longer follow-up is needed to determine how long these responses are sustained, but these results are promising so far. I personally had suspected that CAR T-cell therapy is toxic enough that it should be reserved for the most refractory patients as a later line of therapy. These results suggest that perhaps using CAR T-cell therapy earlier in the disease, such as in patients who seem to be responding normally to ibrutinib, may turn out to be warranted after further study.

Of note, the nodal responses were less robust than the marrow responses. These are early data, so whether these patients were true CRs and how this may translate into more clinically relevant endpoints like PFS and OS has yet to be determined, but it is certainly an interesting strategy and appears reasonably safe and effective.

Abstract 7522: Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated patients with CLL with mutated IGHV and non-del(17p)

Jain and colleagues are conducting a phase II study of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated patients with IGHV-mutated CLL and no del(17p) abnormalities. The use of FCR chemotherapy in patients with relatively favorable risk produces a CR rate after 6 cycles of 40% to 72%, and marrow MRD negativity is achieved in approximately 50% of patients. The authors hypothesized that replacing rituximab with obinutuzumab and adding ibrutinib would improve the rate of MRD negativity above 50%, leading to improved PFS and OS. Furthermore, the addition of these new agents should allow the number of chemotherapy cycles to be reduced, potentially lowering the risk of treatment-related secondary malignancies such as MDS and AML.

The primary endpoints were rates of CR, incomplete CR (CRi), and bone marrow MRD negativity. Patients received 3 cycles of iFCG. Of note, ibrutinib was continued for 1 year and then stopped in MRD-negative patients. To date, they have treated 29 patients, and 24 completed all 3 cycles.

The ORR was 100%, and 83% of patients achieved bone marrow MRD negativity, which compares favorably with the 25% to 50% rate seen with FCR. The rate of CR/CRi was 42%. Toxicities included significant neutropenia—grade 3 in 31% of patients and grade 4 in 41%. The study protocol did not specify use of growth factor support, which may have contributed to the high rate of neutropenia.

These results are an early suggestion that their hypothesis is correct: The modifications made to the standard-of-care, FCR, can lead to higher rates of bone marrow MRD negativity and reduce the number of chemotherapy cycles needed for a deep response. This is a clinically relevant finding because many patients are not able to complete a full 6 cycles of FCR chemotherapy and the long-term effects of FCR include an increased risk of secondary malignancies. The iFCG modality seems to be advantageous for patients to reduce the number of chemotherapy cycles, and stopping ibrutinib at 1 year is also appealing for relatively young patients with CLL who may be treated with this combination and who may not want to stay on a lifelong oral therapy for their CLL. A remission that lasts for many years could allow more of these patients to experience a prolonged treatment-free interval. This regimen could be applicable to many patients if it can be delivered safely. I think the rate of neutropenia could be reduced if routine growth factor support were started from the initial chemotherapy cycle. Although these are not immediately practice-changing findings, after this phase II study is completed I think a phase III comparison with a standard regimen would be warranted.

Abstract 7523: Results of a phase II multicenter study of obinutuzumab plus bendamustine in patients with previously untreated CLL

Sharman and colleagues conducted the single-arm phase II GIBB study of obinutuzumab plus bendamustine in patients with previously untreated CLL. In the previous CLL11 study, obinutuzumab improved PFS outcomes compared with rituximab (both with chlorambucil). This study was designed to assess the safety and efficacy of the combination of frontline obinutuzumab plus bendamustine in patients with CD20-positive CLL; the primary endpoint was CR/CRi.

Obinutuzumab was given using standard dosing. Bendamustine was given at 90 mg/m2 for 2 days of each of six 28-day cycles. In total, 102 patients were treated, and 79% completed all 6 cycles. The ORR was 89%, and the CR rate was 49%. MRD negativity in the bone marrow was achieved in 61% of patients, which compares favorably with historical rates with FCR. Grade 3/4 neutropenia in this trial was only 26%, likely due to use of routine growth factor support.

The rates of CR and bone marrow MRD negativity appear to be higher than seen with either historical data with bendamustine plus rituximab or FCR, leading to the conclusion that replacement of rituximab with obinutuzumab may be more effective, similar to the data seen in the CLL11 trial with chlorambucil. Although a phase III trial would be needed to prove a benefit over bendamustine/rituximab, this trial suggests that the combination of bendamustine and obinutuzumab is effective and reasonably safe for previously untreated patients with CLL. I have not used this combination in my routine clinical practice for patients with CLL, but this treatment regimen is approved in follicular lymphoma and is a consideration for some experts.

Please share your questions or thoughts on your current management approaches for patients with CLL in the comment box below.

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Which of the different treatment regimens discussed in this commentary are you most enthusiastic about for your patients with CLL?
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