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That’s “NICE”: Making Strides in Lymphoid Malignancies

December 11, 2022
Victoria Vardell, MD, and Manni Mohyuddin, MD

Dr. Manni Mohyuddin (@ManniMD1) hails from Peshawar, Pakistan, and attended Aga Khan University in Karachi. He is an assistant professor in the Division of Hematology and Hematologic Malignancies at Huntsman Cancer Institute at the University of Utah in Salt Lake City, and recently served as an abstract reviewer for the Outcome Research category. He specializes in plasma cell dyscrasias and hematopoietic stem cell transplantation. In his downtime, Dr. Mohyuddin is an avid cyclist, a novice skier, and an obsessive book reader. “If I were not a hematologist,” he said, “I would have gone into politics … and actually tried to do good!”

Dr. Victoria A. Vardell is a native of Sandpoint, Idaho. She completed undergrad at the University of Wyoming and medical school at Creighton University in Omaha. She is currently an internal medicine resident at the University of Utah in Salt Lake City, where she will begin her hematology and oncology fellowship at the Huntsman Cancer Institute next year. Her clinical interests include malignant hematologic disorders, especially multiple myeloma. Dr. Vardell’s hobbies include mountain biking, trail running, snowboarding, and skiing.

Each year, the ASH annual meeting brings an abundance of new information on lymphoma and chronic lymphocytic leukemia (CLL), and this year’s meeting is no disappointment. From basic and translational research on disease pathogenesis and drug mechanisms, to new agents in development and groundbreaking clinical trials, there is a wealth of new data to sort through and make sense of. We review here some important updates on CLL, aggressive lymphomas, and chimeric antigen receptor T-cell (CAR-T) therapy.

Updates on CLL at this ASH annual meeting focused particularly on doublet combinations of targeted Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) inhibitors, often with a finite duration of therapy. Saturday’s Oral sessionaddressed these combinations, including gems such as the five-year update of the CAPTIVATE study, reporting outcomes of fixed-duration ibrutinib plus venetoclax therapy in patients with undetectable measurable residual disease (MRD) randomized to either continued ibrutinib or placebo (i.e., observation). Of the 86 patients who achieved undetectable MRD and were randomized, both placebo and ibrutinib groups had a 98% percent or greater four-year overall survival (OS) and an 88 percent or greater progression-free survival (PFS) at median follow up 41 months, strongly supporting the concept of fixed-duration therapy followed by observation in patients with undetectable MRD. Additionally, other studies have evaluated MRD rates with combination therapy, including an interim analysis of the FLAIR study at two years, finding higher rates of MRD negativity in the ibrutinib + venetoclax arm than in the ibrutinib arm in both immunoglobulin heavy-chain gene mutated and unmutated CLL. MRD kinetics were further explored in the GLOW study, in which ibrutinib + venetoclax demonstrate higher rates of  sustained MRD negativity compared to chlorambucil and obinutuzumab. Adding to the focus on time-limited therapies, the Saturday session on targeted triplet regimens reported data from four different trials! There are now several options to choose from as the treatment landscape continues to evolve at a rapid pace.

Potentially practice-changing studies in mantle cell lymphoma were also presented in New Orleans. The Triangle bagged a plenary session spot (to be covered in Monday’s ASH News Daily)! Other updates pertaining to mantle cell lymphoma included data from the TARMAC study combining anti-CD19 CAR-T tisagenlecleucel with ibrutinib, which yielded a 90 percent response rate in relapsed/refractory mantle cell lymphoma and an estimated 12-month PFS of 75 percent. Whether combination therapy is superior to sequential therapy should be explored in future studies. There is also exciting data demonstrating the efficacy of glofitamab, a novel CD20×CD3-targeted bispecific antibody with bivalency for CD20 in mantle cell lymphoma, with an 84 percent response rate and median duration of response of 12.6 months in a mostly BTK inhibitor-exposed population. Bispecific antibodies are showing promise across various B-cell malignancies and are likely to play a key part in future treatment paradigms for many lymphomas

Additionally, data on pirtobrutinib, an oral noncovalent BTK inhibitor, continues to impress with high response rates (58%) and impressive durability (median duration of response, 22 months) observed in a population of 90 post–BTK inhibitor relapsed patients with mantle cell lymphoma.

Do we have additional data that challenges R-CHOP’s (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) supremacy at this year’s ASH meeting? Replacing vincristine with polatuzumab vedotin did beat R-CHOP (for PFS) in the POLARIX trial, ending the decade-long supremacy of R-CHOP as front-line therapy for diffuse large B-cell lymphoma (DLBCL). We now have 5-year survival results from the REMoDL-B trial that compared R-CHOP + bortezomib to R-CHOP. Initial results from this study showed no improvement in PFS or OS in the bortezomib arm. However with long-term follow-up, it appears that there is now a PFS and substantial OS benefit for the activated B-cell subtype group with the addition of bortezomib. This is sure to generate a robust discussion on statistical noise, subgroup analysis, postprotocol therapies, and multiplicity testing.

There are still several populations for whom new treatment options are desperately needed, such as DLBCL/high-grade B-cell lymphomas with MYC and BCL2 rearrangements (double hit), and those with central nervous system (CNS) disease. Saturday’s session on the Treatment of CNS lymphoma, Neurologic Toxicities, and Relapsed/Refractory DLBCL provided much-anticipated data in this area. One multi-institutional review of CD19-directed CAR T-cell therapy found similar survival outcomes in patients with double hit (DHL) and double expressor (DEL) lymphomas compared to other DLBCL patients. Until now, the efficacy of CD19-directed CAR-T in DHL and DEL has been challenging to evaluate due to limited numbers of these patients being included in many CAR-T trials. This may not only represent a major therapeutic advance, but also serves as a call to liberalize trial requirements to enrich trials for these high-risk patients. Data on the safety and efficacy of CAR-T therapy in CNS lymphoma is also desperately needed, and data that will be presented on Sunday, December 11, on the efficacy and safety of axicabtagene ciloleucel in primary and secondary CNS lymphoma will be especially welcome. While, more robust data are awaited, this is a great start to advancing therapeutic options in the tricky-to-treat CNS disease.

Options for our older/frail DLBCL population are desperately needed as well. At Saturday’s poster session Dr. Christina Cox presented data on an all-oral regimen (R-DEVEC) for upfront treatment of DLBCL in 23 older and frail patients with DLBCL. This easy and affordable option had comparable complete remission rates (65%) compared to traditional IV chemotherapy, such as R-CHOP, with mild to moderate side effect profile and tolerability. This can be seen as a new possibility for older, frail patients with DLBCL, and it is a welcome area of research where the feasibility of treatment is difficult.

In Hodgkin lymphoma, Saturday brought fascinating updates on management of relapsed and refractory disease, including the “NICE” regimen. Patients with high-risk relapsed/refractory Hodgkin lymphoma received nivolumab +/- ICE (ifosfamide, carboplatin, etoposide) at first relapse followed by autologous transplant. Among 34 patients included, the results sure appear “nice,” with one-year PFS and OS of 90 percent and 100 percent, respectively. Talking about a “NICE” PFS/OS curve, the PFS curve for nivolumab plus doxorubicin/vinblastine/dacarbazine (AVD) for early-stage unfavorable Hodgkin lymphoma is stellar: At 40 months of follow-up, the PFS and OS are 100 percent. We wish we saw survival curves like this more often in hematologic malignancies!

This is just the tip of the iceberg when it comes to exciting advances across lymphoid malignancies — so many that we couldn’t get to them all within the scope of this article. We hope you are as excited as we are for all the “NICE” things to come!

Dr. Vardell and Dr. Mohyuddin indicated no relevant conflicts of interest.

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