Ongoing evaluation of novel, targeted, and immunotherapies has led to exciting advances across the array of hematologic malignancies over the past year. The availability of new treatment options, along with emerging data on novel combinations and sequencing approaches, is rapidly changing management algorithms.
Laurie H. Sehn, MD, MPH
Ciara L. Freeman, MD, PhD
Changing Management Algorithm of DLBCL
For several decades the management algorithm for treating patients with diffuse large B-cell lymphoma (DLBCL) has remained unchanged, with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) being the universal front-line therapy. Numerous trials examining alternative chemotherapy strategies or the incorporation of novel agents have failed to demonstrate improvement. The recently reported POLARIX trial assessed the anti-CD79b antibody-drug conjugate polatuzumab vedotin-piiq as a replacement for vincristine (Pola-R-CHP) compared with R-CHOP in patients with newly diagnosed intermediate- or high-risk DLBCL.1 With a median follow-up time of 28.2 months, the primary endpoint of investigator-assessed progression-free survival was significantly improved in patients receiving Pola-R-CHP vs R-CHOP (2-year progression-free survival 76.7% vs 70.2%; stratified hazard ratio = 0.73, 95% confidence interval = 0.57–0.95, P = .02). While there was no difference in overall survival at the time of this analysis, more patients in the R-CHOP cohort required additional antilymphoma therapy. Importantly, the use of polatuzumab vedotin did not compromise the delivery of chemotherapy, and the safety profile was similar between the two arms. Based on these results, Pola-R-CHP will likely earn regulatory approval, providing a new standard of care option for patients with DLBCL.
Outcomes in patients with relapsed/refractory disease have been historically poor, particularly for those who are primary refractory or develop early relapse. Standard second-line therapy for suitable patients has relied on platinum-based salvage regimens, followed by autologous stem cell transplantation (ASCT) in chemotherapy-sensitive patients, with a minority of patients being cured. Three recently performed randomized phase III trials have challenged this algorithm by comparing CD19-directed chimeric antigen receptor (CAR) T-cell therapy with this standard-of-care approach in patients with refractory or early relapsing (< 1 year) transplant-eligible large B-cell lymphoma: ZUMA-7 (axicabtagene ciloleucel), BELINDA (tisagenlecleucel), and TRANSFORM (lisocabtagene maraleucel).2-4 While asking a similar question, the three trials had numerous design differences including allowance for bridging therapy, plan for crossover, and definition of the primary endpoint of event-free survival. Ultimately, ZUMA-7 and TRANSFORM were positive, demonstrating a significant improvement in event-free survival in the CAR T-cell therapy arms. The BELINDA trial was negative, but limitations in trial design and delayed administration of CAR T-cell therapy may be implicated. In all trials, more patients were treated with CAR T-cell therapy than were able to proceed to ASCT. The U.S. Food and Drug Administration (FDA) has recently approved axicabtagene ciloleucel for second-line therapy of patients with large B-cell lymphoma who are refractory or relapse within 12 months of first-line immunochemotherapy, leading to a change in the management algorithm for these patients.
Evolving Strategies for CLL
Novel targeted therapies, including Bruton’s tyrosine kinase (BTK) inhibitors and the BCL2 inhibitor venetoclax, have transformed the management of chronic lymphocytic leukemia (CLL) and have markedly improved outcomes. With increased specificity for BTK, next-generation inhibitors were designed to potentially reduce toxicities by minimizing off-target effects. This has now been confirmed within two recently reported randomized phase III trials. The ELEVATE-RR trial compared acalabrutinib with ibrutinib in patients with relapsed or refractory CLL and del(17p) or del(11q). Efficacy was comparable between the two agents, but overall toxicity was lower with acalabrutinib, including a reduction in cardiac events such as atrial fibrillation and hypertension.5 Interim results from the ALPINE trial, comparing zanubrutinib to ibrutinib in all-comers with relapsed or refractory CLL/small lymphocytic lymphoma (SLL), similarly demonstrated improved tolerability with zanubrutinib, with fewer cardiac events and lower rates of treatment discontinuation.6 At the time of this early analysis (12-month landmark results), there was a suggestion of improved efficacy with zanubrutinib, including higher response rates and improved progression-free survival, but longer follow-up is required for definitive conclusions.
While BTK inhibitors are intended to be administered indefinitely, time-limited therapy offers patients the potential for treatment-free intervals. Venetoclax combined with rituximab in the relapsed/refractory setting and venetoclax combined with obinutuzumab as front-line therapy offer time-limited options for patients, with high rates of measurable residual disease (MRD) negativity and prolonged progression-free survival following treatment discontinuation. Thus, the strategy of combining the efficacy of both BTK and BCL2 inhibition in a time-limited regimen is an attractive concept, with early results from several trials recently reported.
The phase III GLOW study randomly assigned elderly patients (> 65 years) with untreated CLL (or younger patients with comorbidities) to ibrutinib/venetoclax vs chlorambucil plus obinutuzumab.7 Patients on ibrutinib/venetoclax had a higher progression-free survival at 30 months (80.5% vs 35.8%, P < .0001), with a higher proportion achieving durable undetectable MRD.
The phase III GAIA trial (CLL13) randomly assigned treatment-naive fit patients with CLL (excluding patients with TP53 mutations or del[17p]) to one of three novel time-limited combinations (venetoclax/rituximab, venetoclax/obinutuzumab, venetoclax/obinutuzumab/ibrutinib) or immunochemotherapy (fludarabine/cyclophosphamide/rituximab for patients ≤ 65 years; bendamustine/rituximab for patients > 65 years).8 The 15-month undetectable MRD rate and complete response rate were significantly improved in patients receiving either venetoclax/obinutuzumab or venetoclax/obinutuzumab/ibrutinib compared with immunochemotherapy. Progression-free survival analysis will require longer follow-up. Updated results from these trials are greatly anticipated.
Expanding Options for Follicular Lymphoma
Although the median survival for follicular lymphoma is measured in decades, it remains incurable with most patients requiring sequential therapies. Immunochemotherapy remains standard front-line treatment, with the majority of patients achieving durable benefit. However, approximately 20% will experience early relapse and have poorer outcomes. Novel therapies are greatly needed, and numerous nonchemotherapy approaches are under evaluation. Lenalidomide and rituximab is commonly used in the second-line setting and various PI3 kinase (PI3K) inhibitors have been approved for third-line (or later) use. However, due to changes in the treatment landscape, both idelalisib and duvelisib have recently been withdrawn from the U.S. market for this indication.
The phase III CHRONOS-3 trial recently compared the PI3K inhibitor copanlisib and rituximab vs rituximab alone in patients with relapsed indolent B-cell lymphoma, demonstrating an improved median progression-free survival of 21.5 months vs 13.8 months (P < .0001) with the combination.9 The dual PI3Kδ/CK1ε inhibitor umbralisib was also recently assessed in a multicohort indolent lymphoma trial that included patients with follicular lymphoma who had relapsed/refractory disease after at least two lines of therapy. Patients with follicular lymphoma had an objective response rate of 45.3% (5.1% complete response) and a median progression-free survival of 11.1 months.10 While PI3K inhibitors demonstrate modest activity in follicular lymphoma, concern for immune-related toxicities have limited their use.
Bispecific antibodies are under evaluation in both aggressive and indolent B-cell lymphomas and are demonstrating great promise. Recently, results from a pivotal phase II trial of the CD20 × CD3 bispecific antibody mosunetuzumab in patients with relapsed/refractory follicular lymphoma following at least two lines of prior therapy were reported.11 In 90 evaluable patients, the primary endpoint of complete response rate was 60% (overall response rate 80%), median duration of response was 22.8 months, and median progression-free survival was 17.9 months. Importantly, mosunetuzumab was well tolerated, with primarily low-grade cytokine-release syndrome observed. Based on these excellent results, it is likely that mosunetuzumab will earn regulatory approval, offering a new therapeutic option for patients with follicular lymphoma.
Immunotherapy Advances in Multiple Myeloma
Immunotherapies are also influencing the treatment paradigm of multiple myeloma. Although high-dose melphalan continues to have its place for newly diagnosed, transplant-eligible patients, the addition of an anti–CD38-positive monoclonal antibody to established triplet induction regimens has boosted the depth of responses achieved, as demonstrated by updates of the CASSIOPEIA, GRIFFIN, and GMMG-HD7 trials.12-14 Treating physicians can now anticipate the achievement of MRD in as many as 50% of patients at the end of induction with these four-drug regimens, which was a prespecified endpoint of the GMMG-HD7 trial.14
The ongoing randomized phase III PERSEUS trial (also examining the addition of daratumumab to lenalidomide, bortezomib, and dexamethasone pretransplant) will add further to these data, as unlike GRIFFIN, it is powered to show a progression-free survival difference. Interestingly, practice may change prior to these results becoming available, as the latest NCCN Clinical Practice Guidelines in Oncology have endorsed daratumumab plus lenalidomide, bortezomib, and dexamethasone as a valid option for induction.
After a powerful quadruplet induction, whether the addition of anti-CD38 monoclonal antibody is beneficial as maintenance remains in question. Although a benefit was seen in the daratumumab arm when compared with observation alone in the CASSIOPEIA update, this benefit was less pronounced for patients who received daratumumab upfront as induction.12 This question may need to wait for other randomized phase III studies comparing maintenance daratumumab with lenalidomide alone, such as SWOG S1803 and MMY3021 (AURIGA). For newly diagnosed patients who are considered transplant ineligible, the updated results of the MAIA study demonstrated unprecedented efficacy for upfront daratumumab plus lenalidomide and dexamethasone in this population. (60-month progression-free survival of 52.5% vs 28.7% for lenalidomide/dexamethasone).15 Longer follow-up also demonstrated an overall survival benefit (median not reached for the triplet vs 55.7 months for lenalidomide/dexamethasone alone, P = .0013). Thus, it seems inevitable that soon all newly diagnosed patients will receive an immunomodulatory drug plus anti–CD38-positive monoclonal antibody as part of their first-line therapy for myeloma, whether in the transplant-eligible or ineligible setting.
For patients who experience disease progression after exposure to the three major therapeutic classes (immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies, so-called triple-refractory), the most exciting development is the availability of cellular therapy. March 2021 saw the first approval of B-cell maturation antigen (BCMA)-targeting CAR T-cell therapy, idecabtagene vicleucel, followed less than 1 year later by ciltacabtagene autoleucel. Recently, updated results from this latter construct (CARTITUDE-1 trial) demonstrated an impressive overall response rate of 97.9% in a heavily pretreated population, with > 80% achieving stringent complete response.16 The median duration of response reported approached 2 years (21.8 months), and of the 61 patients evaluable, 91.8% were MRD-negative, which was sustained for ≥ 6 months in 44.3%. In addition, it seems imminent that bispecific T-cell engagers also targeting BCMA, and alternative targets such as G-protein coupled receptor family C group 5 member D (GPRC5D) and Fc receptor-homolog 5 (FcRH5), will become available for patients who are triple-refractory, with response rates ranging from 50% to 81% reported. Bispecific T-cell engagers have the advantage over CAR T-cell therapy in their convenience of administration (frequently subcutaneous) and in that they are immediately accessible in the setting of rapidly progressing disease.
Final Thoughts
Although numerous challenges were encountered during the past year by both patients and investigators, it is not evident in the acceleration of practice-changing research coming to the forefront. Novel agents and powerful combinations capable of eradicating MRD and achieving durable benefit are becoming ever more sophisticated and are now a reality in clinical care. One cannot help but feel an optimistic enthusiasm for what lies ahead in 2022!
DISCLOSURE: Dr. Sehn has received research funding from Teva and Roche/Genentech; and has served as a consultant to Novartis, Genmab, Debiopharm, Teva, Roche/Genentech, AbbVie, Acerta, Amgen, Apobiologix, AstraZeneca, Celgene, Gilead, Incyte, Janssen, Kite, Karyopharm Therapeutics, Lundbeck, Merck, MorphoSys, Sandoz, Seattle Genetics, Takeda, TG Therapeutics, and Verastem. Dr. Freeman has served as a consultant or advisor for Bristol Myers Squibb, Seattle Genetics, Celgene, AbbVie, Sanofi, Incyte, Amgen, and Janssen; and has received research funding from Teva, Janssen, and Roche/Genentech.
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