Brexucabtagene autoleucel therapy induces complete remission in a primary refractory blastoid mantle cell lymphoma with neurolymphomatosis
Authors: Arushi Khurana, Joanna C. Dalland, Jason R. Young, David J. Inwards, Jonas Paludo
Journal: American Journal of Hematology (2021)

To the Editor: The US Food and Drug Administration (FDA) approved brexucabtagene autoleucel (brexu-cel), the first chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory mantle cell lymphoma (MCL) after two prior lines in July, 2020.1 This approval was based on phase II ZUMA-2 trial which showed an overall response rate (ORR) of 93% and complete response (CR) rate of 67%.2 Blastoid morphology and TP53 mutation are aggressive disease variants in MCL typically associated with poor outcomes.3, 4 The ZUMA-2 trial included 17 patients with blastoid MCL morphology. The ORR and CR rates in the 14 evaluable patients were similar to the classical morphology at 93% and 64%, respectively.5 The ZUMA-2 trial, however, excluded patients with a possible requirement for urgent therapy due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome), involvement of the central nervous system and required patients to be exposed to a Bruton tyrosine kinase (BTK) inhibitor. Neurolymphomatosis (NL) is an extremely rare presentation of non-Hodgkin lymphoma which confers a poor prognosis. Even though NL outcomes have overall improved in the rituximab era, the use of CAR-T for this presentation remains limited.6 We herein report a case of primary refractory MCL with blastoid morphology, and rapidly progressive disease presenting as NL before CAR-T. A 61-year old Caucasian male presented with 2 weeks of back pain, fatigue, and enlarging lymph nodes in the inguinal area. An incisional biopsy from the right inguinal lymph node confirmed mantle cell lymphoma, with a very high proliferation rate (Ki67 90%). There was extensive lymphadenopathy both above and below the diaphragm on the imaging (Figure 1(A)), along with 70% involvement of bone marrow. High-risk disease features at diagnosis were stage IVB disease, high-risk biological MIPI score of 9.4, and skeletal involvement. The initial treatment was bendamustine, rituximab, and high dose cytarabine as part of the clinical trial EA4181 (NCT04115631). Interim PET/CT after three cycles of bendamustine and rituximab, showed a significant improvement in lymphadenopathy and skeletal lesions, however, with new lesions in the nasopharynx and right chest wall (Figure 1(B)). A biopsy of the right chest wall mass confirmed mantle cell lymphoma, now with blastoid morphology. No mutations or alterations were found in MYC or TP53. A second treatment of alternating cycles of R-CHOP/R-DHAP chemotherapy with plans for autologous stem cell transplantation consolidation was initiated. The PET/CT obtained after completion of four cycles of chemotherapy noted a new left popliteal mass (Figure 1(C)). This was biopsied and again confirmed MCL, blastoid variant (Figure 1(F-K)). Since the disease was now chemorefractory, CAR-T consultation was obtained for brexu-cel. After successful collection of T cells no bridging treatment was planned, as the popliteal mass was the only measurable site of disease. Within a week of leukapheresis, there was increased swelling in the left calf, increasing size of the popliteal mass, and numbness over the entire calf area. Prednisone 60 mg was started for bridging to control symptoms during the manufacture period for 7 days. Before starting lymphodepletion chemotherapy for brexu-cel, the PET/CT showed FDG avid (8.4–14.0 SUVmax) disease progression throughout the left lower extremity. The left popliteal mass now infiltrated the calf musculature and several nerves throughout the left lower extremity (Figure 1(D)). A nerve biopsy was considered, however, was defered to avoid delay in treatment due to rapid progression, clinical findings of neuropathy with numbness and pain, and imaging which was highly suggestive of secondary NL presentation. As the CAR-T cells were already manufactured, after careful consideration, the decision was made to proceed with lymphodepletion chemotherapy and CAR-T cell infusion. The patient underwent brexu-cel therapy after lymphodepletion chemo but his course was complicated by cytokine release syndrome (CRS) on day +1 with a peak grade of one based on the ASTCT 2019 grading. Tocilizumab was administered on days +4 and +5 and dexamethasone on day +5 for persistent grade one CRS with subsequent resolution. No neurotoxicity symptoms were observed through day +30. The inflammatory markers showed a peak C-reactive protein (CRP) of 93.2 mg/L (normal <= 8.0 mg/L) on day +5, with normalization by day +9. The clinical symptoms of left leg swelling, calf numbness, and visible soft tissue nodules continued to improve and had resolved at day +30 evaluation. A PET/CT performed 1-month post-brexu-cel infusion showed a complete anatomic and metabolic response with a Deauville score of two (Figure 1(E)). The patient continues to have numbness over the calf area at day +60 evaluation without evidence of relapse and is scheduled for repeat imaging at day +90. To our knowledge, this is the first report of successful use of brexu-cel for MCL with blastoid morphology presenting as NL. Even in large B-cell lymphoma, a lack of data exists for patients with active or a history of secondary central or peripheral nervous system involvement undergoing CAR-T therapy on the registration trials due to exclusion. Recent real-world experiences have shown comparable efficacy and toxicity profile, albeit with small patient numbers and limited follow-up.7-9 Our patient also did not develop any neurotoxicity despite multiple sites of NL. Additionally, NL is an extremely rare presentation of lymphoma and is infrequently seen with MCL. In a recent report of 40 biopsy-proven cases with NL over 16 years, only one patient had MCL.6 Forty-eight percent (19/40) of the patients presented with NL that occurred as a site of progression or relapse of a previously diagnosed lymphoma (secondary NL). The overall survival for secondary NL was significantly worse than those with NL presentation at diagnosis (median OS, median OS, 25.4 vs 138.0 months). Note, NL is also most associated with aggressive lymphomas such as diffuse large B-cell lymphoma (DLBCL), and despite an improvement in survival in the rituximab era, recurrences are frequent. Our patient also had a very aggressive MCL type with blastoid morphology, secondary NL presentation and a high proliferation rate with Ki67 of 90%. Only one DLBCL patient with secondary NL in this series had received CAR-T with subsequent relapse and overall survival of 49.6 months from the time of NL diagnosis. Another case report of a DLBCL patient with NL was reported to have undergone CAR-T; however, the details on the presence of NL at the time of CAR-T and its response were limited.10 Blastoid MCL is an aggressive variant with poorer outcomes compared to the classical MCL. A pooled analysis from three open-labeled studies of MCL patients treated with ibrutinib showed that blastoid morphology affected both PFS and OS in multivariate analysis.3 The median PFS (5.1 vs 14.6 months), OS (12.8 vs not reached at 2 years of follow-up), and duration of response (8.5 vs 18.8 months) were significantly shorter in the blastoid morphology, suggesting the need for an earlier consolidative strategy. Multiple studies now support earlier use of BTK inhibitor ibrutinib with significantly longer PFS and OS when used at first relapse vs later lines of therapy.3, 11 The NCCN guidelines for B-cell lymphoma were updated this year to include brexu-cel after exposure to at least one line of chemoimmunotherapy and a BTK inhibitor following the inclusion criteria of the ZUMA-2 trial.12 The FDA label for brexu-cel, however, does not specify the need for prior BTK inhibitor exposure. The results from ZUMA-2 trial showed durable responses with aggressive variants of MCL such as blastoid morphology and TP53 alterations. The responses and the toxicity profile were also noted to be comparable to the classical morphology with 88% any grade CRS (6% ≥ grade 3), and 65% any grade neurotoxicity (18% ≥ grade 3).5 Based on durable responses to CAR-T and shorter duration of response to BTK inhibitor in blastoid histology an argument could be made for earlier use of CAR-T (after two lines) but before BTK inhibitor therapy as done for our patient. This is the first report of a brexu-cel for MCL-associated NL and blastoid variant with complete remission at day +60 without added neurotoxicity. Real-world evidence will shed more light on the efficacy and toxicity of brexu-cel in patients with NL or central nervous system involvement. Longer follow-up is needed to confirm CAR-T's durability in this patient; however, this report provides evidence for feasibility in an aggressive and rare presentation for MCL. The authors declare no conflict of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.