Chimeric antigen receptor (CAR) T-cell therapy has proven to be an effective adoptive cellular therapy against relapsed/refractory B-cell lymphoma. Prior to the CAR T era, patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) had dismal outcomes, as seen in participants in the international SCHOLAR-1 study.

 Findings from the study, which pooled data from 2 phase 3 clinical trials and 2 observational cohorts, showed an overall objective response rate (ORR) and complete response (CR) rate of 26% (95% CI, 21%-31%) and 7% (95% CI, 3%-15%), respectively, with salvage chemotherapies in patients with refractory and early relapsed DLBCL (n = 636) and a median overall survival (OS) of 6.3 months (95% CI, 5.9-7.0).

Results of the landmark phase 2 ZUMA-1 trial (NCT02348216) showed the safety and efficacy of the CD19-directed CAR T-cell agent axicabtagene ciloleucel (Yescarta) among patients with relapsed/refractory DLBCL (n = 111). The ORR and CR rates were 82% (95% CI, 73%-89%) and 54%, respectively. The 1-year progression free survival and OS rates were 44% (95% CI, 34%-53%) and 59% (95% CI, 49%-68%), respectively.

 Similarly, other CAR T-cell therapies directed against CD19 for patients with relapsed/refractory large B-cell lymphoma using 4-1bb as the costimulatory domain showed similar efficacy in the phase 2 JULIET (NCT02445248) and phase 1 TRANSCEND-NHL-001 (NCT02631044) trials.

CAR T-cell therapies typically come with unique but manageable adverse events (AEs), specifically cytokine release syndrome (CRS) and neurotoxicity. Incidence of CRS and neurotoxicity ranged from 42% to 93% and 30% to 64%, respectively, in the JULIET and TRANSCEND-NHL-001.

At the Winthrop P. Rockefeller Cancer Institute Transplant Center in Little Rock, Arkansas, we closely monitor for CRS and neurotoxicity after CAR T-cell infusion per Lee scale, and also for increased infection risk from pancytopenia and acquired hypogammaglobulinemia from B-cell aplasia.

 I typically put my patients on appropriate antibiotic prophylaxis, use growth factor support as needed for low blood counts, and use intravenous immunoglobulin replacement of 400 mg/kg to mitigate the risk of infection.

The ZUMA- 2, -3, and -5 studies led to FDA approvals for CAR T-cell therapies in relapsed/refractory mantle cell lymphoma, B-cell acute lymphoblastic leukemia, and follicular lymphoma respectively, with studies showing durable efficacy and manageable AE profiles.

 Another recent FDA approval for a CAR T-cell therapy as a second-line treatment for patients with primary refractory and early relapsed DLBCL who are less than 12 months from frontline chemoimmunotherapy came based on the phase 3 ZUMA-7 (NCT03391466) and TRANSFORM (NCT03575351) studies, whose results showed significantly better ORRs and median event-free survival compared with salvage therapy followed by autologous stem cell transplant.

The advent of CD19-directed CAR T-cell therapy certainly has changed the management landscape of several relapsed refractory B-cell malignancies. However, patients who experience disease progression post CAR T-cell therapy often have a poor prognosis with limited therapeutic options. Approximately one-third of patients post CAR T-cell therapy show CD19 loss or downregulation, offering immune escape as possible etiology for disease progression.

The remainder of CAR T nonresponders could have an immunosuppressive tumor microenvironment, upregulation of PD-L1, CTLA-4, poor T-cell infiltration in the tumor bed, poor T-cell functional avidity, or T-cell immunosenescence as possible etiologies for disease progression. Several clinical trials are underway using CAR T agents targeting 2 separate tumor associated antigens, combining PD-1 inhibitors and CTLA-4 inhibitors with immunomodulators, and using other novel approaches to overcome resistance against CAR T.

Akash Mukherjee, MD, is a hematologist/oncologist at the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences (UAMS) and an assistant professor in the Department of Internal Medicine at UAMS College of Medicine in Little Rock. He specializes in allogeneic and autologous stem cell transplantation and CAR T-cell therapy to treat patients with various malignant hematological disorders.

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Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. 

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Articles

Chimeric antigen receptor T-cell therapy has proven to be an effective adoptive cellular therapy against relapsed/refractory B-cell lymphoma. 

Current Treatment Perspectives for CAR T-Cell Therapy in R/R B-Cell Lymphoma

Up to 10% of of all newly diagnosed non-Hodgkin lymphoma cases are mantle cell lymphoma (MCL). As part of the diagnostic work-up for a a patient with newly diagnosed MCL, it is important to establish prognostic disease biology factors such as classical nodal morphology vs blastoid variant vs leukemic variant, 

 mutation status, and Ki-67 reflective of proliferation.

Approximately 10% to 15% of patients with MCL present with a leukemic variant exhibiting lymphocytosis, mild lymphadenopathy, mild cytopenia, and splenomegaly; they usually have an indolent course. These patients can be safely treated with a close wait-andwatch approach without any active treatment. Duration of observation depends on clinical course.

The rest of the patients will need treatment at diagnosis dictated by the patient’s age, performance status, and disease biology. Ki-67 over 30% and blastoid variant exhibit an aggressive clinical course. Younger patients who are transplant eligible usually receive cytarabine-containing intensive chemotherapy followed by autologous stem cell transplant. With this aggressive approach, the median progression-free survival (PFS) is approximately 9 to 11 years; however, late relapses can occur.

Maintenance with rituximab (Rituxan) can be considered for 2 years post transplant to minimize relapse.

For older and transplant-ineligible patients, I recommend treatment with either bendamustine (Bendeka) plus rituximab (BR) for 6 cycles followed by rituximab maintenance for 2 years or BR plus 500 mg/m2 of cytarabine. These treatments showed 2-year PFS and overall survival (OS) rates of 81% and 86%, respectively.

 mutation or high-risk Mantle Cell Lymphoma International Prognostic Index score have an increased relapse rate despite treatment with chemoimmunotherapy that warrants subsequent treatment with Bruton tyrosine kinase (BTK) inhibitors, BCL2 inhibitors or immunomodulators, or CD19-directed cellular therapy. Findings from the phase 3 SHINE (NCT01776840), ACE-LY-308 (NCT02972840), and SYMPATICO (NCT03112174) clinical trials incorporating BTK inhibitors in combination with BR or using BTK inhibitor plus venetoclax (Venclexta) as frontline therapy could potentially change the treatment paradigm for elderly patients with MCL.

For patients with relapsed or refractory MCL treatment options include a BTK inhibitor plus ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) for patients who have received at least 1 prior therapy.

The combination of ibrutinib and venetoclax has also been studied in relapsed or refractory MCL with an 18-month PFS rate of 57% (95% CI, 40%-82%) among 24 patients in the phase 2 AIM trial (NCT02471391).

Patients usually achieve a median PFS of approximately 16 to 22 months with a BTK inhibitor and have a median OS of approximately 6 to 10 months following disease progression with BTK inhibitor treatment. Findings from the phase 2 ZUMA-2 study (NCT02601313) showed promising efficacy and durability of response in this subset of patients using the CD19-directed chimeric antigen receptor T-cell therapy brexucabtagene autoleucel (Tecartus). Patients treated with the agent (n = 60) achieved a 67% (95% CI, 53%-78%) complete response rate and a 12-month PFS and OS rates of 61% and 83%, respectively, along with a manageable safety profile.

 Allogeneic stem cell transplant could be offered to select patients with relapsed or refractory MCL who have a lower probability of transplant-related mortality as another potentially curative option.

Jain P, Wang M. Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol. 2019;94(6):710-725. doi:10.1002/ajh.25487 

Abrisqueta P, Scott DW, Slack GW, et al. Observation as the initial management strategy in patients with mantle cell lymphoma. Ann Oncol. 2017;28(10):24892495. doi:10.1093/annonc/mdx333

Hermine O, Hoster E, Walewski J, et al; European Mantle Cell Lymphoma Network. Addition of highdose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016;388(10044):565-575. doi:10.1016/S0140-6736(16)00739-X 

Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the second Nordic mantle cell lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016;175(3):410-418. doi:10.1111/bjh.14241 

Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2 

Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017;4(1):e15-e23. doi:10.1016/ S2352-3026(16)30185-5 

Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015;126(6):739-745. doi:10.1182/ blood-2015-03-635326 

Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667. doi:10.1016/ S0140-6736(17)33108-2 

Song Y, Zhou K, Zou D, et al. Treatment of patients with relapsed or refractory mantle-cell lymphoma with zanubrutinib, a selective inhibitor of Bruton’s tyrosine kinase. Clin Cancer Res. 2020;26(16):42164224. doi:10.1158/1078-0432.CCR-19-3703 

Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211-1223. doi:10.1056/NEJMoa1715519 

Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

As part of the diagnostic work-up for a patient with newly diagnosed MCL, it is important to establish prognostic disease biology factors such as classical nodal morphology vs blastoid variant vs leukemic variant, TP53 mutation status, and Ki-67 reflective of proliferation. 

Examining the Role of BTK Inhibitors in Mantle Cell Lymphoma

Akash Mukherjee, MD, assistant professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Arkansas for Medical Sciences, discusses the use of post-transplant maintenance rituximab (Rituxan) in patients with mantle cell lymphoma (MCL) who have received autologous stem cell transplant (ASCT) and considerations for using bendamustine/rituximab (BR) or BR plus cytarabine (R-BAC) in elderly patients who are unfit for transplant.

MCL is a subset of non-Hodgkin lymphoma in which maintenance rituximab following ASCT has been shown to improve survival outcomes, Mukherjee says. In the phase 3 LyMa trial (NCT00921414), maintenance rituximab after R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) induction and ASCT led to a 4-year progression-free survival (PFS) rate of 83% and an overall survival rate of 89%, vs 64% and 80%, respectively, in patients who received observation after ASCT. Although the optimal duration of maintenance rituximab treatment is debated, treating patients with rituximab maintenance every 2 months for at least 2 years after transplantation is 1 approach, Mukherjee explains.

When using maintenance rituximab, it is important to be aware of the potential for acquired hypogammaglobulinemia and check immunoglobulin (IgG) levels, Mukherjee emphasizes. Patients can receive intravenous IgG replacement therapy as needed to maintain IgG levels above 400 mg/dL, Mukherjee notes.

For elderly patients with MCL who are not fit for transplant, 6 cycles of BR followed by maintenance rituximab is a common treatment approach, Mukherjee says. Additionally, the phase 2 FIL-RBAC500 trial (NCT01662050) used R-BAC, with cytarabine at a low dose of 500 mg/m2, which led to a 2-year PFS rate of 81%, Mukherjee explains. Patients who can tolerate cytarabine can receive R-BAC, although they may also need growth factor support and appropriate prophylactic antibiotics to minimize the risk of neutropenic fever, Mukherjee notes. Although the addition of low-dose cytarabine to the BR backbone is a promising approach in transplant-unfit patients, more head-to-head data with BR and R-BAC are needed to determine which regimen is superior, Mukherjee concludes.

Videos

Akash Mukherjee, MD, discusses the use of post-transplant maintenance rituximab in patients with mantle cell lymphoma who have received autologous stem cell transplant and considerations for using bendamustine/rituximab or BR plus cytarabine in elderly patients who are unfit for transplant.

Dr. Mukherjee on Maintenance Rituximab in MCL

Akash Mukherjee, MD, hematologist, oncologist, University of Arkansas for Medical Sciences, (UAMS), assistant professor, Division of Hematology/Oncology, the Winthrop Cancer Institute, the UAMS College of Medicine, discusses the importance of understanding disease biology when attempting to individualize treatment approaches in mantle cell lymphoma (MCL).

Understanding the classification of nodal morphology is critical in assessing a patient’s disease biology, Mukherjee begins. Patients with MCL can exhibit classical or blastoid/pleomorphic MCL morphologies, Mukherjee says. Previous clinical trials have shown that blastoid and pleomorphic morphological variants are characterized by a more aggressive disease course compared with a classical morphology, Mukherjee says.

 mutations and Ki-67 levels greater than 30% are associated with high-risk status and inferior patient prognosis, Mukherjee continues. These contributing factors are assessed in the MCL International Prognostic Index (MIPI). The index uses data from patients treated in previous clinical trials to characterize patients as high, low, or intermediate risk, and accordingly predict survival outcomes. The 4 independent risk factors included in a patient’s MIPI score are age, ECOG performance status, lactate dehydrogenase (LDH), and leukocyte count, he explains.

In addition to disease biology, it is also important to identify patients who exhibit the leukemic variant of MCL (LV-MCL), Mukherjee states. Patients in this subgroup often display slow or absent clinical progression and are asymptomatic and can present similarly to patients with chronic lymphocytic leukemia, he notes. For example, patients with the indolent variant may display mild-moderate lymphocytosis, mild lymphadenopathy, slight pancytopenia, or mild hepatosplenomegaly without demonstrating transfusion dependence or other high-risk factors, Mukherjee details. Correctly identifying this genetically distinct variant could better inform treatment decisions, as patients with LV-MCL may not need immediate treatment, Mukherjee emphasizes. These patients should instead be monitored and repeatedly examined every 3 months until treatment becomes necessary, Mukherjee concludes.

Akash Mukherjee, MD, discusses the importance of understanding disease biology when attempting to individualize treatment approaches in mantle cell lymphoma.

Dr. Mukherjee on the Role of Disease Biology in the Treatment of MCL

Akash Mukherjee, MD, hematologist, oncologist, University of Arkansas for Medical Sciences, (UAMS), assistant professor, Division of Hematology/Oncology, the Winthrop Cancer Institute, the UAMS College of Medicine, discusses the implications of the FDA approval of lisocabtagene maraleucel (liso-cel; Breyanzi) large B-cell lymphoma (LBCL)

FDA approved the use of liso-cel as second-line therapy

 for adult patients with LBCL, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and follicular lymphoma grade 3B.

The CAR T-cell therapy was supported in part by results from the phase 3 TRANSFORM trial (NCT03575351), Mukherjee says. TRANSFORM randomly assigned patients to standard-of-care salvage chemotherapy vs liso-cel, Mukherjee says. Moreover, enrollment included patients who were refractory to frontline chemotherapy or patients who experienced early relapse within 12 months of previous chemotherapy treatment, Mukherjee explains.

Patients in the liso-cel arm experienced an improved overall response rate and event-free survival vs those given chemotherapy, Mukherjee continues. Based on these results, clinicians now utilize liso-cel as a second-line therapy for appropriate patients, Mukherjee concludes.

Akash Mukherjee, MD, discusses the implications of the FDA approval of lisocabtagene maraleucel in large B-cell lymphoma.


Akash Mukherjee, MD

Articles

Current Treatment Perspectives for CAR T-Cell Therapy in R/R B-Cell Lymphoma

Examining the Role of BTK Inhibitors in Mantle Cell Lymphoma

Dr. Mukherjee on Maintenance Rituximab in MCL

Dr. Mukherjee on the Role of Disease Biology in the Treatment of MCL

Dr. Mukherjee on the Implications of the FDA Approval of Second-line Liso-cel in LBCL