Director of Indolent Lymphoproliferative Disorders
Department of Hematology
Niguarda Cancer Center
Alessandra Tedeschi, MD, has disclosed that she has received consulting fees from AbbVie, AstraZeneca, Janssen, and Sunesis.
At the 2019 EHA and ICML meetings, we heard some exciting findings in B-cell malignancies, particularly how BTK inhibitors and other targeted therapies continue to have an impact on the care of our patients with these diseases. In this commentary, I share some of my key takeaways from these meetings.
CLL12: Ibrutinib in Asymptomatic, Early-Stage CLL
Clinical observation is considered the standard of care for the management of early Binet stage A CLL. However, since outcomes may be extremely heterogeneous among patients with early-stage disease, several studies of chemotherapy-based regimens have addressed the value of an early intervention to prolong PFS and OS in this setting. Chlorambucil or fludarabine monotherapy showed an increase in median PFS but failed to achieve an OS benefit. Similarly, the CLL7 trial that compared early vs deferred treatment with fludarabine/cyclophosphamide/rituximab (FCR) chemoimmunotherapy in treatment-naive Binet stage A patients with high-risk prognostic features showed an improvement in event-free survival but no effect on OS. This lack of an OS benefit might be related to the higher risk induced by chemoimmunotherapy of developing severe cytopenias and severe infections (73.5% and 19.5%, respectively).
At the 2019 EHA and ICML conferences, Langerbeins and colleagues presented results from the randomized CLL12 trial that was designed to assess whether the introduction of a targeted therapy—in this case, ibrutinib—may change our current approach of observation for previously untreated, asymptomatic patients with CLL and an intermediate or higher risk of progression by GCLLSG prognostic criteria; patients who are not in need of therapy according to current iwCLL guidelines. The primary objective of the CLL12 study was met, as median event-free survival was shown to be significantly longer for patients randomized to receive ibrutinib compared with placebo. Patients treated with ibrutinib also showed a significant improvement in time to next treatment. However, this study has not yet shown an OS benefit, and longer follow-up is needed. In the absence of a demonstrated OS benefit, observation will remain the current standard of care for these patients in clinical practice.
Surprisingly, although typical adverse events of ibrutinib were reported in this study, there were not significant differences in the rate of grade 3/4 adverse events and serious adverse events in the patients treated with ibrutinib compared with those who received placebo. In addition, the rates of infections observed were similar between these 2 groups of patients. These results reinforce the need to continue to explore the potential of an early intervention with targeted therapy in asymptomatic patients that could lead to a change of our current criteria to initiate treatment in patients diagnosed with CLL.
ASCEND: Acalabrutinib vs BR or IdR for Relapsed/Refractory CLL
The ASCEND trial presented by Ghia and colleagues is the first randomized trial comparing acalabrutinib to current standard-of-care combination regimens—in this case, bendamustine plus rituximab (BR) or idelalisib plus rituximab (IdR)—that are used for patients with relapsed/refractory CLL. The baseline clinical and disease characteristics of the randomized patients were well balanced between the ibrutinib arm and the BR/IdR arm. The study met its primary objective endpoint as the PFS rate at 12 months was significantly higher for patients treated with acalabrutinib compared with patients who received either of the control regimens. As patients were allowed to cross over to receive acalabrutinib in case of progressive disease, the OS was similar in the 2 arms.
Notably, acalabrutinib showed a more tolerable safety profile compared with BR/IdR, and up to now, only small proportions of patients have discontinued acalabrutinib due to adverse events. This is consistent with the high selectivity of BTK inhibition with acalabrutinib. The study has definitively clarified the role of acalabrutinib as a salvage regimen considering that for the first time a monotherapy with a BTK inhibitor showed benefit in a phase III trial vs chemoimmunotherapy or an alternative BCR pathway inhibitor.
RESONATE-2: 5-Year Follow-up
First-line treatment with ibrutinib-based therapy has shown superior PFS vs standard treatment options in 4 randomized trials (RESONATE-2, E1912, A041202, iLLUMINATE). Because ibrutinib is given continuously until disease progression or intolerance, follow-up of the patients treated with first-line ibrutinib is critical to inform clinical practice of the long-term efficacy and safety of this treatment approach.
I presented the 5-year extended follow-up results from the RESONATE-2 trial that represents the longest follow-up to date from a phase III trial of first-line BTK-driven therapy. The PFS benefit was sustained for ibrutinib vs chlorambucil and the BTK inhibitor also maintained improved OS despite the crossover of 57% of patients who had received chlorambucil to ibrutinib therapy. I think that it is important to emphasize that only 6% of patients experienced disease progression while receiving ibrutinib treatment. The efficacy of ibrutinib was also clearly evident in patients with high-risk prognostic features including del(11q), TP53 mutant, and/or IgHV unmutated.
Of importance, no new safety signals emerged with continuous ibrutinib treatment. Most adverse events decreased over time; consistent with this observation, discontinuations and dose reductions occurred most frequently in the first year. We, as clinicians, should remember that using dose holds and dose reductions as necessary enables patients to continue to receive the benefits of ibrutinib treatment. Overall, considering that after up to 5.5 years of follow-up 58% of patients are still continuing treatment with ibrutinib, this approach is clearly a very effective treatment option for our patients with previously untreated CLL.
Phase I/II Trial of Zanubrutinib in Waldenström Macroglobulinemia (WM)
Recently, next-generation BTK inhibitors have been broadly tested in controlled studies for the treatment of lymphoproliferative disorders. The next-generation BTK inhibitor zanubrutinib has demonstrated a favorable pharmacokinetic profile with minimal off-target inhibition of TEC- and EGFR-family kinases in in-vitro cell-based assays and has also shown sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes of patients with B-cell malignancies.
Trotman and colleagues presented data from the first in human phase I/II trial of zanubrutinib in a population of patients with WM. In this study, zanubrutinib demonstrated encouraging clinical activity both in patients with untreated WM and in patients with previously treated WM. The ORR was 90% or higher in both previously untreated and previously treated patients. Notably, 42.5% of patients reached a good quality of response defined as a CR or VGPR.
The other important factor relevant to BTK inhibitor treatment in WM is the impact that MYD88 and CXCR4 mutational status may have on patients’ outcomes. It is well known that patients with wild-type MYD88 treated with ibrutinib have an unfavorable outcome. In the current study, zanubrutinib appeared to overcome the adverse prognostic impact of MYD88 mutational status on antitumor response. A similar finding was reported by Dimopoulos and colleagues in separate study presented at the EHA annual meeting with approximately 54% of patients with wild-type MYD88 achieving at least a PR with zanubrutinib.
The favorable toxicity profile of zanubrutinib was shown by the low discontinuation rate of 10% at 2 years and the low rate of grade 3/4 adverse events. Overall, these results are consistent with the highly selective BTK inhibition exerted by zanubrutinib and the reduced off-target effects on other kinases seen in preclinical studies.
Phase II Trial of Vemurafenib Plus Rituximab in Relapsed/Refractory Hairy Cell Leukemia (HCL)
Finally, the last study that I want to highlight reported on a new targeted agent regimen for patients with HCL that is given for a limited period of time. More than 97% of patients diagnosed with HCL have the BRAF V600E mutation. Vemurafenib, a low-molecular-weight, orally available BRAF serine-threonine kinase inhibitor, has demonstrated significant activity in patients with HCL when given continuously.
Tiacci and colleagues presented results from a small phase II trial that evaluated the combination of vemurafenib (960 mg BID for 8 weeks) plus rituximab (375 mg/m2 every 2 weeks for a total of 8 doses) in a population of heavily pretreated, relapsed/refractory patients with HCL including several patients who had relapsed after responding to previous BRAF inhibitor therapy. Among the 27 evaluated patients, the combination of vemurafenib plus rituximab resulted in the achievement of a very high rate of CRs (96%). Notably, in a previous study of vemurafenib monotherapy in relapsed/refractory HCL, none of the patients who achieved a CR reached measurable residual disease (MRD)–negative status. By contrast, in the current study, the addition of rituximab to vemurafenib resulted in MRD-negative status in 63% of patients. The deep quality of response in this current study translated to durable responses as, with 24 months of follow-up, most of the patients remained free of disease progression. Furthermore, this improvement in response was observed in the absence of any reported new safety signals.
How are you using targeted therapies for your patients with B-cell malignancies? What questions do you have about the use of targeted therapies for your patients with B-cell malignancies? Leave a comment or question below for your online colleagues.