Diagnosis Of MCL Research Articles

Evolving patterns of transplant strategies for mantle cell lymphoma in the era of BTK inhibitors and CAR-T therapy.

e19012 Background: Mantle cell lymphoma is an aggressive lymphoma with poor survival after chemotherapy alone. Both autologous (auto) and allogeneic (allo) transplants have improved outcomes over the years, but transplant strategies most beneficial for MCL are not clearly defined. Recently, BTK inhibitors and chimeric antigen therapies (CAR T) therapy approach has changed the landscape of Mantle cell Lymphoma. Methods: Patient Population:A total of 71 patients underwent transplant for diagnosis of MCL at Penn State Cancer Institute, between March 1993 and March 2023. Median follow up was 3.1 years (32 days-9883 days) after transplant. Patient Characteristics: A total of 71 patients (62 M: 9 F) underwent transplants, including autologous (n=30), allogeneic (n=32), and CAR T (n=9). Since 2020, 19 transplants were performed: CAR T (n=9) auto transplants (n=9) and allogeneic transplants (n=1). Relapsed and refractory MCL (n=4) patients received CAR T whereas patients achieving CR 1 (n=8) and PR1 (n=1) received auto transplants. Most patients were Caucasian (n= 68), with few Hispanic (1), African American (1), or Asian (1). Results: Median age at the time of transplant was 61 (37-70) years for autologous, 56 (33-67) years for allogenic and 63 (55 -75) years for CAR T respectively. Disease status at transplant was CR 52.1% (n=37), primary induction failure or relapsed/refractory 36.6% (n=26), PR 11.3% (n=8). High LDH was seen at the time of transplant in 16.9% (n=12) patients and normal in 83.1%(n=59) patients. Blastoid morphology was seen in only 13.8% (n=4) autologous, 37.9% (n=11) allogenic and 33.3% (n=3) CAR T patients. Outcomes: Overall survival (OS) at 1 year and 3 years was 93.3% and 85.9% for autologous (auto) transplants, 62.5% and 52.9% for Allogeneic (allo) transplants, 88.9% and 76.2% for CAR-T therapy respectively (P = 0.007). Progression free survival at 1 year and 3 years was 86.3% and 75.0% for auto transplants; 50.0% and 43.3% for allo Transplants; 66.7% and 66.7% for CART Therapy (P = 0.03). Primary cause of death was Treatment Related Mortality (TRM) (n= 9) (GVHD=4; Pulmonary=3; MOF=2) and disease progression (n=10); unknown (n=4); other (n=1). Primary cause of death for CAR T therapy was grade IV ICANS and disease progression. Conclusions: Recently CAR T therapies have changed the landscape of MCL treatment algorithm in both Blastoid and non-Blastoid histology MCL patients. But in the era of CAR T therapy and BTK inhibitors for MCL, achieving CR at the time of transplant predicts improved long-term outcomes. Randomized studies or larger retrospective CIBMTR data analysis may be important to answer best transplant strategy for MCL patients. [Table: see text]

Optical genomic mapping is a helpful tool for detecting CCND1 rearrangements in CD5-negative small B-cell lymphoma: Two cases of leukemic non-nodal mantle cell lymphoma

Optical genome mapping (OGM) is a new DNA-based technology which provides comprehensive examination of the entire genome. We report two patients who presented with splenomegaly and leukocytosis with lymphocytosis including villous lymphocytes. Neither patient had lymphadenopathy. Bone marrow evaluation showed involvement by small B-cell lymphoma in a sinusoidal and interstitial distribution, and immunophenotypic analysis showed that the neoplastic cells were positive for B-cell markers and cyclin D1 but were negative for SOX11 and CD5. Initially, the clinicopathologic features in both patients were thought to be suspicious for hairy cell leukemia variant or splenic marginal zone lymphoma. However, OGM detected CCND1 rearrangement: t(2;11)/IGK::CCND1 in one case and t(11;14)/IGH::CCND1 in the other case. These cases illustrate the valuable role OGM can play in establishing the diagnosis of MCL. Case 1 also contributes to the paucity of literature on the rare occurrence of IGK::CCND1 in MCL.

Allogeneic Hematopoietic Stem Cell Transplantation in Advanced Systemic Mastocytosis

Purpose Advanced systemic mastocytosis (AdvSM) is driven by the KIT D816V mutation in >90% of patients (pts.). Depending on subtype, median survival is between 1.5 and 4 years. Despite recent advances on responses and survival due to the availability of effective KIT inhibitors, allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment option. Data on optimal timing, conditioning regimens, and pre- as well as post-alloHSCT treatments for maintenance or relapse are however scarce. Current recommendations mainly refer to a retrospective analysis published almost 10 years ago (Ustun et al., JCO 32, 2014). With the advent of new therapies and improved transplant procedures, more recently collected data on alloHSCT in AdvSM are needed for actual assessment of optimal treatment strategies. Patients & Methods This retrospective analysis identified 71 pts. with AdvSM who underwent alloHSCT at 20 German centers between 1999 and 2021. Data were collected via the 'German Stem Cell Transplantation Registry (DRST)' and the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)'. Additional baseline characteristics and response status prior to, during and post alloHSCT were provided by the participating centers. Results At time of alloHSCT, median age was 59 years (range 21-84); 55/71 (77%) pts. were male. Median time between diagnosis of AdvSM and alloHSCT was 1.2 years (range 0.1-16.7). Pts. were grouped into (i) aggressive systemic mastocytosis (ASM, n=6) and SM with an associated hematological neoplasm (SM-AHN, n=24), totaling 30/71 (42%) ASM/SM-AHN pts., (ii) SM with an associated acute myeloid leukemia (SM-AML; 28/71, 39%) and (iii) mast cell leukemia ± AHN (MCL±AHN; 13/71, 18%). The median follow-up time after alloHSCT was 1.4 years (range 0-20.4). PFS and OS were 52% (SD ± 6.1%) and 62% (SD ± 5.9%) at 1 year, and 39% (SD ± 6.3%) and 50% (SD ± 6.2%) at 3 years. Discrimination between the three cohorts allowed a three-tier risk stratification (median PFS, 4.5 vs. 0.7 vs. 0.3 years, P<0.001; median OS, 9.0 vs. 3.3 vs. 0.9 years, P=0.007, Figure 1). Overall non-relapse mortality rate was 30% (21/71) including infectious complications in 8/21 (38%), GvHD in 1/21 (5%), cardiotoxicity in 1/21 (5%) and ‘combinations/not further specified’ in 11/21 (52%) pts. The 100-day non-relapse mortality was 8% (6/71; ASM/SM-AHN, 0/30; SM-AML, 4/28, 14%; MCL±AHN, 2/13, 15%). OS was associated with response status of SM (17/41, 41%; median OS 4.6 vs. 1.1 years, P=0.029) or AHN (26/43, 60%, median OS not reached vs. 0.4 years, P=0.003) prior to alloHSCT ( Figure 2). Univariable analyses revealed absence of a KIT D816V mutation (HR 2.9 [1.2-6.5], P<0.001) and a complex karyotype (HR 4.2 [1.8-10.0], P=0.016) as adverse prognostic factors regarding OS. PFS was significantly impacted by diagnosis of MCL±AHN (HR 3.5 [1.7-7.5], P<0.001), absence of a KIT D816V mutation (HR 2.5 [1.2-5.4], presence of a complex karyotype (HR 4.2 [1.8-10.0], P=0.016), P=0.021) and absence of the use of tyrosine kinase inhibitors prior to alloHSCT (HR 0.461 [0.249-0.854], P=0.014). In contrast, HLA match (complete vs. incomplete), type of conditioning (myeloablative vs. dose-reduced intensity), use of total body irradiation (≥8 Gy yes vs. no) or the transplantation at high volume centers (≥7 patients yes vs. no) were not associated with significant differences in PFS or OS. During or after alloHSCT, 30/71 (42%) pts. showed either refractory (9/71, 13%) or relapsed (21/71, 29%) disease (R/R), being highest among MCL±AHN pts. (11/13, 85%; ASM/SM-AHN, 9/30, 30%; SM-AML, 10/28, 36%; P=0.002). R/R SM was predominantly observed in MCL±AHN (10/11, 91%) while R/R AHN was higher in SM-AML patients (6/10, 60%) and ASM/SM-AHN (5/9, 56%). The median time to relapse was 0.6 years (range 0.1-4.5). Post alloHSCT, a response to various treatment regimens was achieved in 13/30 (43%) pts. (ASM/SM-AHN, 3/9, 33%; SM-AML, 5/10, 50%; MCL±AHN, 5/11, 45%) with highest response rates in 9 pts. receiving midostaurin and/or avapritinib (7/9, 78%). Conclusions In pts. with AdvSM eligible for alloHSCT, i) baseline characteristics affect outcome of alloHSCT more than specific transplant procedures, ii) alloHSCT should not be performed in pts. without response prior to alloHSCT and iii) post-alloHSCT strategies such as preemptive or residual disease guided maintenance therapy should be considered to improve post-alloHSCT outcome.

Trends in Survival Outcomes for Mantle Cell Lymphoma in the Era of Novel Therapies

Introduction Mantle Cell Lymphoma (MCL) is a rare malignancy, associated with aggressive features and poor outcomes. Previous treatment paradigms for MCL involved chemoimmunotherapy and stem cell transplant (SCT), though this has evolved in recent years with the introduction of novel treatments, including bruton's tyrosine kinase (BTK) inhibitors, chimeric antigen receptor T-cells (CAR-T) and immunomodulatory agents such as lenalidomide. Additionally, the incorporation of rituximab maintenance therapy following SCT has demonstrated improved progression-free (PFS) and overall survivals (OS) for MCL patients (pts). While the majority of these novel agents and treatments were FDA approved by demonstrating improved PFS, the benefits of these new treatments on OS trends for MCL pts are not well described. Therefore, to determine whether these advances have translated to OS improvement in the real-world setting, we performed a national analysis of OS trends through multiple treatment eras. Methods The National Cancer Database was used to identify pts diagnosed with MCL from 2004-2020. For pts receiving treatment, the use of front-line single or multiagent therapy, and upfront SCT was compared. Kaplan-Meier and Cox regression analysis was used to compare OS for all MCL pts. Survival was compared by year of diagnosis, with diagnosis in 2004-2013 considered to be managed in the era of chemoimmunotherapy, 2014 and later associated with the introduction of BTK inhibitors, and 2017 and later with the adoption of maintenance rituximab following SCT. Results A total of 31,284 pts with MCL were identified. The mean age at diagnosis was 67 years (yrs) [SD ±12], 93% of pts were White, and 70% had stage IV disease at diagnosis. Pts were increasingly more likely to have ≥2 comorbidities at MCL diagnosis (6.2% from 2004-2013, 8.6% from 2014-2016, and 10.8% from 2017-2020) and were increasingly managed at academic centers (40%, 44%, and 46%, respectively). Rates of pts managed with active surveillance significantly increased over time (4.7% from 2004-2013, 6.7% from 2014-2016, and 8.7% from 2017-2020). Regarding treatment, the rate of upfront multi-agent chemotherapy use decreased over time (67.7% from 2004-2013, 45.2% from 2014-2016, and 38.9% from 2017-2020), corresponding with an increase in single agent treatment (7.9%, 28.2%, and 32.4%, respectively). Notably, the rate of pts receiving SCT following front-line treatment remained similar in each time period (13.6%, 15.4%, and 14.1%, respectively). With a median follow-up of 3.5 yrs, the median OS for all pts with MCL from 2004-2020 was 5.9 yrs (95% CI 5.8-6.0 yrs). The median OS was significantly increased when comparing pts who were diagnosed between 2004-2013 (5.5 yrs) to those diagnosed 2014-2016 (6.8 yrs), and median was not reached for pts diagnosed 2017-2020 (all p<0.001). The median 1-, 3-, and 5-year OS significantly increased following the availability of novel agents after 2014 (2004-2013: 1-year 80%, 3-year 63%, 5-year 52% vs. 2014-2016: 1-year 82%, 3-year 67%, 5-year 58%, p<0.001). Whereas, pts diagnosed from 2017-2020 had similar OS trends as pts diagnosed from 2014-2016 with 1-year 82%, 3-year 66%, 5-year 51% OS, respectively. When adjusted for age and comorbidity burden, the most recent time periods were associated with decreased risk of death (2014-2016: HR 0.81 [95% CI 0.78-0.85], and 2017-2020: HR 0.82 [95% CI 0.78-0.86]) when compared to 2004-2013 (all p<0.001). Conclusions: To our knowledge, this is the largest retrospective review evaluating treatment trends and OS outcomes in pts with MCL in recent decades. These data show that OS has significantly improved for pts diagnosed in the most recent time periods. We hypothesize this is due to the introduction of novel agents such as BTK inhibitors, which is supported by the increased rate of single agent treatment over time, which may be related to BTK inhibitors supplanting chemoimmunotherapy in the front-line setting. We also found that no additional OS improvement was observed during the time period following the adoption of rituximab maintenance after transplant, which may be due to the limited number of pts receiving SCT through each time period. With more follow-up data, future studies may determine whether treatments such as CAR-T (FDA approved in 2020 with data not included in this cohort) have further improved OS outcomes for this incurable malignancy.

Molecular and Clinical Characteristics of Different Toxicity Rates in Anti-CD19 Chimeric Antigen Receptor T Cells: Real-World Experience.

Commercially available anti-CD19 chimeric antigen receptor T cells (CARΤ cells) have offered long-term survival to a constantly expanding patient population. Given that novel toxicities including cytokine release syndrome (CRS) and neurotoxicity (ICANS) have been observed, we aimed to document the safety and toxicity of this treatment in a real-world study. We enrolled 31 adult patients referred to our center for CAR T therapy. Tisagenlecleucel was infused in 12 patients, axicabtagene ciloleucel in 14, and brexucabtagene autoleucel in 5. Cytokine release syndrome was noted in 26 patients while neurotoxicity was observed in 7. Tocilizumab was administered for CRS in 18 patients, along with short-term, low-dose steroid administration in one patient who developed grade III CRS and, subsequently, grade I ICANS. High-dose steroids, along with anakinra and siltuximab, were administered in only two MCL patients. With a median follow-up time of 13.4 months, nine patients were then in CR. The progression-free (PFS) and overall survival (OS) rates were 41.2% and 88.1% at one year, respectively. MCL diagnosis, which coincides with the administration of brexucabtagene autoleucel, was the only factor to be independently associated with poor OS (p < 0.001); meanwhile, increased LDH independently predicted PFS (p = 0.027).In addition, CRP at day 14 was associated with a poor OS (p = 0.001). Therefore, our real-world experience confirmed that commercial CAR T therapy can be administered with minimal toxicity.

BRUIN MCL-321: A phase 3, open-label, randomized study of pirtobrutinib versus investigator choice of BTK inhibitor in patients with previously treated, BTK inhibitor naïve mantle cell lymphoma.

TPS7587 Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of MCL, but these agents are not curative. cBTKi share pharmacologic liabilities (e.g., low oral bioavailability, short half-life), which collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as MCL, which can manifest as acquired resistance to BTKi. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates and was well tolerated in patients (pts) with MCL regardless of prior therapy (including cBTKi), number of prior lines of therapy, or reason for prior cBTKi discontinuation. Pirtobrutinib was approved by the FDA in January 2023 for R/R MCL after 2 prior lines of therapy including a BTKi. The objective of this study is to establish whether pirtobrutinib is superior to investigator’s choice of cBTKi in pts with previously treated, BTKi naïve MCL. Methods: BRUIN MCL-321 (NCT04662255) is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator’s choice of cBTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in pts with previously treated, BTKi naïve MCL. Approximately 500 pts will be randomized 1:1 and stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2). Enrollment for this study is ongoing. Adults with a diagnosis of MCL who have received ≥ 1 prior line of systemic therapy for MCL and are BTKi naïve are eligible. Pts must have measurable disease by imaging per Lugano criteria and have progressed on or relapsed following the most recent line of therapy. A history of current or prior CNS involvement, significant cardiovascular disease, stroke or intracranial hemorrhage within 6 months of randomization, and autologous stem cell transplant (SCT), allogeneic SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization are key exclusion criteria. Progression-free survival (PFS) per Lugano criteria assessed by an independent review committee is the primary endpoint. Overall response rate, duration of response, investigator-assessed PFS per Lugano criteria, overall survival, event-free survival, time to treatment failure, time to next treatment, PFS2 (time from randomization to disease progression on next line of treatment or death from any cause), safety and tolerability, and pt reported outcomes are secondary endpoints. Clinical trial information: NCT04662255 .

Mast cell leukemia: clinical and molecular features and survival outcomes of patients in the ECNM Registry.

Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by ≥20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had "leukemic MCL" (≥10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P= .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P= .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P= .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P= .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.

Abstract A23: Alternative cyclin D1 transcripts in Mantle Cell Lymphoma

Abstract Mantle Cell Lymphoma (MCL) is a rare aggressive subtype of Non-Hodgkin’s Lymphoma. Upon diagnosis, treatments are varied and there is no universal standard of care. MCL is considered clinically incurable upon relapse. Better understanding of the development of MCL at the molecular level is needed. The initiating event is a hallmark (11; 14) translocation event that juxtaposes cyclin D1 (CCND1) downstream of the IgH enhancer element thus activating protein expression. This IgH recombination precedes the MCL diagnosis by several years. By itself, expression of cyclin D1 is insufficient for tumorigenesis. However, increased cyclin D1 expression combined with alterations in one of several DNA repair genes facilitates lymphomagenesis characterized by high genomic instability. Interestingly at the mRNA level, CCND1 transcripts containing the full length 3`untranslated regions (3`UTRs) have a half-life of ~30 minutes. CCND1 transcripts containing truncated 3`UTRs have a longer half-life up to ~8 hours resulting in increased translation. A subset of MCL patients with highly proliferative disease express CCND1 mRNAs with truncated 3`UTRs. Wiestner et al showed that truncated CCND1 3`UTR expression was associated with a reduction in patient survival by almost two years. While CCND1 3`UTR shortening in 20% of patient samples was due to mutations, the mechanisms driving this event in the rest of patients remain unknown. Our goal is to identify the different truncated CCND1 transcripts in MCL and determine how they are expressed. Using 3′Rapid Amplification of cDNA ends (3′RACE) we previously identified a novel fusion transcript where a short CCND1 3′UTR sequence was linked to intronic sequences of the MRCKB/CDC42BPB gene. In order to measure levels of expression of differently sized CCND1 3`UTR transcripts we used specifically designed primers for qRT-PCR. To determine the type of truncated CCND1 3`UTR expressed in other MCL cell lines we used 3′RACE. Iso Sequencing was used to verify the occurrence of the novel CCND1/MRCK fusion transcript. Cell viability assays were used to determine the impact of targeting the CCND1/MRCK fusion or cyclin D1 activated cyclin dependent kinase 4/6 inhibitor. Our qRT-PCR results showed that most of the MCL cell lines predominantly expressed CCND1 transcripts with truncated 3′UTRs with the exception of Mino-1 where the longer 3′UTR was more dominant. The 3′RACE results indicate that different mechanisms may result in the expression of the truncated CCND1 3`UTR transcript in each cell line. Iso Sequencing data identified 1,032 total reads supporting the CCND1/MRCK fusion transcript verifying our 3’RACE results. Our results suggest that there are different molecular mechanisms being used to regulate cyclin D1 expression in MCL. Cell viability assays showed decreased cell proliferation. In conclusion, identifying and understanding the mechanisms of expression of different CCND1 transcripts has potential in understanding MCL pathogenesis and the development of MCL therapeutics. Funding: 1R01-GM135361-01 to C. P. Masamha. Citation Format: Naazneen Khan, Chioniso P Masamha. Alternative cyclin D1 transcripts in Mantle Cell Lymphoma [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A23.

Impact assessment of different DNA extraction methods for non-invasive molecular diagnosis of tegumentary leishmaniasis

The aim of this study was to evaluate two methods of nucleic acid extraction (spin-column-based method – commercial kit and direct boil - DB) from swab sampling compared to biopsy sampling for the diagnosis of tegumentary leishmaniasis (TL), (cutaneous - CL and mucocutaneous - MCL forms). The impact of these nucleic acid extraction protocols on different types of PCR and LAMP techniques were compared regarding nucleic acid quality, molecular assays accuracy, indirect quantitation, and costs. The evaluated patients were 57 TL cases (36 CL and 21 MCL) and 34 non-cases. Swab samples extracted by the DB method showed a higher DNA degradation rate and worse DNA quality in comparison to the commercial kit. Molecular tests performed on biopsy samples showed identical or higher performance in all analysis, as compared to their own performance on swab samples for TL (CL and MCL). However, only the SSU rRNA TaqMan™ RT-PCR test showed a significant difference between the performance of biopsy and swab samples extracted by commercial kit. The kDNA-cPCR coupled with swab extracted by commercial kit showed the highest accuracy (95.6%) for TL diagnosis. The sensitivity of the LAMP-RT 18S method in swab samples extracted with a commercial kit (82.5%) was close to that found in biopsy samples (86%) for TL diagnosis. The DB extraction method presented the lowest cost. The use of swab as a minimally-invasive sampling method, associated with an efficient nucleic acid extraction protocol, may represent a low-cost alternative for the diagnosis of CL and MCL.

Impact of the COVID-19 Pandemic on in-Person Visit Rates Among Patients with Hematologic Malignancies in the United States

Impact of the COVID-19 Pandemic on in-Person Visit Rates Among Patients with Hematologic Malignancies in the United States

Racial Disparities in Telemedicine Uptake during the COVID-19 Pandemic Among Patients with Hematologic Malignancies in the United States

Racial Disparities in Telemedicine Uptake during the COVID-19 Pandemic Among Patients with Hematologic Malignancies in the United States

Outcomes in mantle cell lymphoma with central nervous system involvement.

e19527 Background: While extra nodal involvement by MCL is relatively common, involvement of the central nervous system (CNS) is a rare ( &lt; 5% of cases) complication with limited treatment options. We report the outcomes of a large cohort of patients (pts) with CNS MCL. Methods: MCL pts with CNS involvement seen at Mayo Clinic between 1/1/1995-9/16/2020 were identified. CNS involvement was defined by histologically confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS lymphoma. Medical records were reviewed for baseline characteristics, treatment, and outcome. Kaplan-Meier method was used for time to event analysis. Results: Out of 1,753 pts with MCL, 36 (2%) had CNS involvement by MCL. Median age at MCL diagnosis was 64 years (range 36-83) and 26 were male (72%). At MCL diagnosis, non-CNS extranodal involvement was seen in 30 pts, 24 with 1 site and 6 with ≥ 2 sites; 24 had bone marrow involvement. 11 (31%) pts had blastoid variant. Median Ki-67 was 40% (range 15-100%). MIPI score was available in 17 pts [low risk (n = 5, 29%), intermediate risk (n = 9, 53%), high risk (n = 3, 18%)]. The most common frontline regimen for MCL was R-CHOP and 14 (39%) pts underwent autologous stem cell transplant in CR1. The incidence of CNS involvement was overall similar over the study period. Median time from MCL diagnosis to CNS involvement was 25 months (m) (range 0-167). 4 (11%) pts presented with CNS involvement at initial diagnosis and 32 presented at relapse (12 isolated CNS relapse and 20 concurrent CNS and systemic relapse. Abnormal CSF was noted in 27 (87%) pts [consistent with MCL diagnosis (n = 26), atypical lymphocytes (n = 1)]. Abnormal CNS imaging was reported in 27 (75%) pts [leptomeningeal (n = 18), leptomeningeal and parenchymal (n = 5), parenchymal (n = 2), ocular (n = 2)]. First line CNS-directed therapy data was available in 33 (92%) pts. 12 (34%) received intrathecal (IT) therapy alone, 19 (54%) received systemic +/- IT therapy, 2 (6%) received radiation alone, and 2 (6%) pts received no treatment (hospice). The overall CNS response to therapy was CR in 13 (42%) pts, PR in 3 (10%), SD in 8 (26%), and PD in 7 (22%) pts. Three pts received BTK inhibitors [ibrutinib (n = 2) or acalabrutinib (n = 1)] as the first CNS-directed therapy. One patient achieved a CR with a response lasting 4 m, another patient achieved a PR with response lasting 10 m. CNS response data was not available in the remaining pts. Median follow up from CNS involvement was 72 m (95% CI: 41-NR). Median EFS for the 1st CNS-directed therapy was 3.7 m (95% CI: 1.6-6.1). At last follow up, 30 pts were deceased. The cause of death was CNS lymphoma in 10 (33%) pts and systemic lymphoma in 9 (30%) pts. Median OS from CNS involvement was 4.7 m (95% CI: 2.3-6.7). Conclusions: CNS involvement by MCL has dismal outcomes as evident by a median OS of approximately 5 m. BTK inhibitors may have a role in treatment of this rare complication, but further prospective investigation is needed.

A147 PRIMARY COLONIC MANTLE CELL LYMPHOMA: A RARE ENTITY

Abstract Background Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL), often diagnosed at later stages with secondary gastrointestinal (GI) involvement. Primary GI MCL is rare and is not often discussed in the literature. Aims To increase awareness of a rare condition that is likely to be encountered but can be challenging to diagnose. Methods Case report and review of the literature. Results Case Report A 78-year-old man with multiple untreated vascular risk factors including atrial fibrillation and type 2 diabetes presented with acute onset left hemiplegia, dysarthria, and imaging consistent with a left pontine stroke. As part of his workup he underwent a CT abdomen/pelvis identifying an 11 x 5 cm intraluminal mass in the transverse colon. Previous screening colonoscopies, for family history of colon cancer, were notable for tubular adenomas without high-grade dysplasia at 13, 12, 10, 7, and 2 years prior to admission. The patient had 16 pounds of weight loss without other constitutional symptoms, change in bowel habits or evidence of GI bleeding. Bloodwork was notable for microcytic anemia (Hemoglobin 91 g/L, MCV 75 fL), from a normal baseline one year prior, without other cytopenias. C-reactive protein (44 mg/L) and GGT (164 U/L) were elevated. Other liver enzymes, lactate dehydrogenase, and electrolytes were normal. Colonoscopy revealed numerous polypoid lesions throughout the entire colon and a large non-obstructive mass with submucosal appearance in the transverse colon. Biopsies were taken from the large mass and one of the smaller polypoid lesions. Histology showed a sheet-like infiltrate of small lymphocytes within the lamina propria. Immunohistochemical staining was positive for CD20, BCL2, Cyclin D1, equivocal for CD5, and negative for BCL6 and CD3. Ki67 index approached 30%. A diagnosis of colonic MCL was made. Literature Review Primary MCL of the GI tract is rare, accounting for only 1 to 4% of all GI malignancies. There is a male and Caucasian predominance with a median age of 68 years at diagnosis. Presenting complaints may include abdominal pain, anorexia, and GI bleeding. Typical endoscopic features are small nodular or polypoid tumors, between 2mm and 2 cm in size, along one or more segments of the GI tract referred to as multiple lymphomatous polyposis (MLP). A single colonic mass is infrequently seen, highlighting the importance of endoscopy for diagnosis, as subtle findings may be missed on radiographic evaluation. Biopsies for immunohistochemistry are essential to distinguish MCL from other NHLs, as almost all cases express cyclin D1. Despite aggressive immunochemotherapy, prognosis is often poor due to MCL’s rapid progression and early relapse. Conclusions Primary GI MCL is a rare entity. Awareness is essential as evaluation and management differ from lymphoma at other sites, and other GI malignancies. Funding Agencies None

Bi-allelic amplification of ATM gene in blastoid variant of mantle cell lymphoma: a novel mechanism of inactivation due to chromoanagenesis?

BackgroundMantle cell lymphoma (MCL) is derived from naïve CD5+ B-cells with the cytogenetic hallmark translocation 11;14. The presence of additional abnormalities is associated with blastoid variants in MCL (BMCL) and confers a poor prognosis. Many of these tumors also show deletion or loss of heterozygosity (LOH) of the ATM gene and biallelic ATM inactivation show significantly higher chromosomal imbalances.Case presentationHere we report a 52 year-old male who presented to the clinic with worsening dyspnea, fever, chills, diffuse lymphadenopathy, splenomegaly and leukocytosis with blastoid cells circulating in blood. The bone marrow aspirate showed about 40% abnormal blast-looking cells and biopsy revealed a remarkable lymphoid infiltrate. The patient was diagnosed with blastoid variant mantle cell lymphoma (BMCL). Chromosome analysis on bone marrow showed a complex karyotype. FISH analysis from B-cell lymphoma panel showed bi-allelic amplification of ATM gene. Other abnormalities were present including CCND1/IGH fusion, confirming the MCL diagnosis, in addition to RB1 and p53 deletion. High resolution SNP-microarray studies showed complex copy number changes, especially on chromosomes 7 and 11, consistent with chromoanagenesis. Microarray studies also showed LOH at the ATM locus indicating the amplification seen on FISH is not biallelic.ConclusionTo the best of our knowledge, ATM gene amplification is not previously reported in BMCL and our case suggests a novel mechanism of ATM inactivation caused by chromoanagenesis resulting in mutant allele specific imbalance with copy number gain.

Comprehensive Analysis of Factors Predictive for Time to Transformation and Risk of Transformation in Patients (pts) with Mantle Cell Lymphoma

Comprehensive Analysis of Factors Predictive for Time to Transformation and Risk of Transformation in Patients (pts) with Mantle Cell Lymphoma

Use of Lenalidomide Plus Rituximab in TP53-Mutated Mantle Cell Lymphoma (MCL) Outside of Clinic Trial: The Moffitt Experience

Introduction MCL is an incurable B-cell lymphoma, accounting for 3-8% of Non-Hodgkin Lymphoma (NHL). Efforts to increase frontline treatment intensity with cytarabine (AraC), autologous transplant, and prolonged Rituximab maintenance have improved outcomes for many. However, those with TP53 mutations do not show similar benefit, highlighting a need for novel approaches in this setting. Lenalidomide plus Rituximab (R2) has been shown to have activity in MCL, but little data exist in the context of TP53 alterations. Methods We retrospectively reviewed 145 patients diagnosed with MCL between 2005 and 2019. Cases were selected by diagnosis of MCL and clinical evaluation from July 2018 to June 2019. A total of 145 unique cases were identified, of which 63 had insufficient testing for TP53, 50 were negative, and 32 were mutation positive by cytogenetics, NGS, or FISH. Patients with mutated TP53 were further assessed for the primary outcome of event-free survival (EFS) and a secondary outcome of overall survival (OS). All statistical analyses were performed using SPSS software. Results Of 32 analyzed patients, 72% were male, with median age 67 years (46-87) and median WBC 15 (3-283). All but one patient presented with ECOG PS 0-1. LDH was elevated in 44%, with high MIPI in 56% of patients. Ki67 was available in 8 cases (median 30%), with 2 additional cases noted only as "blastoid." Frontline therapy consisted of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (RCHOP) or Bendamustine plus Rituximab (BR) with maintenance Rituximab (6 patients), AraC, and/or transplant (8), R2 (8), BTK+Rituximab (2), or palliation (XRT 1, Rituximab 2, watchful waiting 5). Seven patients received R2 in the relapsed setting. With median followup of 44 months, the median OS was not reached (83%), and median EFS among all treated patients was 36 months. Among those who received frontline R2, 63% were male, with median age 68 (55-75), median WBC 74 (11-283), with elevated LDH in 50% and high MIPI in 88%. Ki67 was available for 2 patients, and measured 10% and 80%. The Median OS and EFS were 100% with median followup on therapy of 15 months. Conclusions Survival was surprisingly robust across this cohort of high risk MCL. Treatment with Lenalidomide plus Rituximab may provide an alternative regimen for TP53-mutated MCL in the first-line setting. Further analysis of long-term data will be beneficial to monitor durability of remission. Figure Disclosures Chavez: Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Bello:Celgene: Speakers Bureau. Sokol:EUSA: Consultancy. Pinilla Ibarz:Novartis: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy; Bayer: Speakers Bureau; Sanofi: Speakers Bureau; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria.

Analysis of Factors Predictive of Risk of Transformation and Time to Transformation in Patients (pts) with Mantle Cell Lymphoma - Cohort Study of 369 Patients

Analysis of Factors Predictive of Risk of Transformation and Time to Transformation in Patients (pts) with Mantle Cell Lymphoma - Cohort Study of 369 Patients

P16, c-Myc, SOX11, P53, ki67 and CD71Protein Expression in Aggressive Morphological Variants of Mantle Cell Lymphomas Compared to Classical Morphological Mantle Cell Lymphomas in Multiple Clinical Trials

On behalf of the Lymphoma Study Association (LYSA) Introduction: Aggressive Mantle Cell Lymphoma variant (A-MCL), including blastic and pleomorphic morphological variants, is a rare subtype of MCL whose frequency varies around 10-15% of all newly-diagnosed MCL patients. According to 2017 World Health Organization (WHO) classification, the diagnosis of A-MCL is based on morphology. A high proliferation rate on Ki-67 staining is not sufficient to be classified as a blastoid or pleomorphic subtype. This might induce diagnostic confusion. The aim of the present retrospective study is to investigate whether or not the CD71, c-Myc, SOX11, P53, ki67 and P16 expressions assessed by immunohistochemistry (IHC) can distinguish A-MCL from classical MCL (C-MCL). We also investigate the prognostic value of these markers in A-MCL patients. Methods: We re-investigated all MCL patients presented with A-MCL (n=110) at diagnosis and who have been enrolled in six prospective clinical trials. At time of inclusion, a centralized pathological review was performed to confirm the diagnosis of MCL. Cases were initially classified according to the 2008 WHO classification (LYMA, MCL-SA, MCL-SJ, RIBVD and RIPAD trials) or according to the 2017 WHO classification (MCLR2-ELDERLY trials). For the present study, we performed a supplemental pathology review by a panel of 5 hematopathologists experts from the LYSA group according to 2017 WHO classification. We identified 75 cases (out of 110) of A-MCL (8 blastic and 67 pleomorphic variants) which represent 15% of all MCL enrolled in these six trials. We have compared A-MCL characteristics to C-MCL who had specimens available for TMA (n=412 C-MCL out of 487 patients enrolled). IHC was performed on TMA, using the six selected antibodies and were scored by quantifying the percentage of cells stained on each spot. Patients available for survival analysis (53 A-MCL and 312 C-MCL) were drawn from all studies (except from the MCLR2-Elderly study that is ongoing). Different cut-offs were considered for progression free survival (PFS) and overall survival (OS) for each variable. The proliferation index was evaluated with Ki67 classical determination eyeballing and Ki67 reading by grid counting. Cut-offs for each of these markers were determined using X-tile software, which determines the optimal value for classifying patients into groups based on overall and progression-free survival. Results: At baseline, the aggressive forms were similar to classical forms in terms of demographic characteristics (age at diagnosis, localization and sex). p53 protein expression was significantly higher in A-MCL patients than in C-MCL (p&lt;0.001) like p16 (p=0.002), c-MYC (p&lt;0.001), CD71 (p&lt;0.001) and Ki67 index (both classical and by grid) (p&lt; 0.001). There was no statistically significant difference in SOX11 expression. In univariate analyses, elevated levels of P16 (&gt;10%), c-MYC (&gt;30%) Ki67 (&gt;40%) were associated with poorer OS and PFS in the cohort of A-MCL and C-MCL patients. There was no significant difference in survival both for OS and PFS regarding P53 (&gt;30%). In multivariate analysis stratified by trial, Ki67 by grid&gt;40% (HR=2.303[1.479-3.585] ; p =0.0002) and c-MYC &gt;30% (HR=1.865 [1.060-3.279] p =0.0305) were predictive for OS whereas only Ki67 by grid &gt;40% (HR=2.055 [1.434, 2.944], p&lt;0.0001) was a significant prognostic factor for PFS. Conclusion: CD71, c-Myc, P53 and P16 expression levels assessed by IHC are higher in A-MCL as compared to C-MCL. These markers could therefore be recommended in routine practice to distinguish between A-MCL and C-MCL. We also found that patients with Ki67 count by grid &gt;40% had significantly shorter PFS and OS and patients with high Myc expression &gt;30% had a significantly poorer OS. Thus, MYC expression and Ki67 by IHC is a suitable test for routine diagnostic practice to assess A-MCL prognosis. Disclosures Le Gouill: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Ribrag:argenX: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dreyling:Novartis: Other: scientific advisory board; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Sandoz: Other: scientific advisory board; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau. Hermine:Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding.

R-MACLO-IVAM Is an Effective Regimen to Induce Long Term Remission in Untreated Mantle Cell Lymphoma

R-MACLO-IVAM Is an Effective Regimen to Induce Long Term Remission in Untreated Mantle Cell Lymphoma

A Systematic Review of the Epidemiology and Economic Burden of Mantle Cell Lymphoma (MCL)

Introduction: MCL is a rare, aggressive subtype of B-cell non-Hodgkin lymphoma associated with a poor prognosis. A comprehensive understanding of the global epidemiology and economic and humanistic burden of MCL is needed to quantify the burden of disease in patients with MCL. Objective/Methods: To examine the burden of MCL, a systematic literature review was conducted to identify publications between the years 2010 to 2019 reporting on the epidemiology (incidence, prevalence, mortality, survival), economic (direct [e.g., drug costs] and indirect [e.g., lost productivity, missed days of work] costs and healthcare resource utilization [HRU; e.g., hospitalization, length of stay, emergency room use, outpatient visits]) and humanistic (e.g., quality of life [QOL], patient-reported outcome measures) burden of patients with MCL. Embase and Medline were searched via ProQuest and the Cochrane Controlled Register of Trials (CENTRAL) via the Cochrane Library. Results: A total of 2206 publications were identified, 177 full-text references screened, and 12 studies reporting epidemiology outcomes in MCL identified. Epidemiology data (1995-2016) were identified for the US (n = 5), UK (n = 2), Belgium (n = 1), France (n = 1), Netherlands (n = 1), Sweden/Denmark (n = 1), and Taiwan (n = 1). Incidence (n = 9) was lower in Taiwan (0.12 persons per 100,000) than in the US (0.8-1.15) and Europe (0.7-1.27). Six studies reported incidence over multiple time periods with 4 studies showing an increase in total incidence or incidence in men over time and 2 studies showing no change or a decrease in incidence in women over time. MCL prevalence was 3.0 per 100,000 persons in the UK (year 2011) and 3.6 per 100,000 persons in Belgium (year 2013). Mortality, reported in 1 US study, showed a consistent decrease from 1995-2013. Three-year all-cause mortality was 38% and MCL-related mortality 30%; 5-year all-cause mortality was 51% and MCL-related mortality 38%. Median overall survival (OS, n = 5) ranged from 28.8 (years 2004-2017; Europe) to 52.0 (years 1999-2013; US) months. Three-year OS (n = 2) was reported as 43.9% in the UK (2004-2017) and 61.0% in Sweden/Denmark (2006-2011). Increasing trends in survival over time were reported in 3 studies (US, Danish/Swedish, Netherlands; n = 1 each); increases in survival in the Netherlands were greatest in younger (age &lt; 65 years) vs older patients (age ≥ 65 years). Twelve studies reported on the economic burden of MCL (Table). An increase in all costs and HRU, including outpatient encounters, emergency room visits, and days spent in the hospital, were found following vs pre MCL diagnosis. Length of hospital stays ranged from 3.0 to 8.3 days. All cause mean monthly costs for MCL patients were $5131 to $16,117 per patient month (PPM). Treatment cost varied with costs generally higher with chemoimmunotherapy and lower with targeted therapies. Adverse events (AEs) were associated with increased economic burden. Mean all-cause costs in patients with no AEs were $5131 PPM compared with $13,560 PPM in patients with ≥6 AEs. Patients experiencing 3-4 AEs during first-line therapy were almost 7-times more likely to require an inpatient admission than those experiencing only 1-2 AEs (OR, 6.9; 95% CI, 4.0-11.93). Patients with ≥6 AEs had inpatient stays lasting 2.2 days longer than those with no AEs. Common AE costs ranged from $5751 (atrial fibrillation) to $19,645 (hepatotoxicity). No studies reporting on indirect costs or the QOL impact of MCL or MCL treatment were identified. Conclusions: The increasing incidence and survival of patients with MCL along with the high costs of disease and treatment suggest an increasing economic burden. Though limited data are available on costs and HRU in populations with MCL and outcomes reported differed across studies, available data shows variability of costs among treatments influenced by AE costs. Some evidence suggests lower costs of therapy with targeted compared with chemoimmunotherapy regimens. The economic burden of MCL and MCL treatment on costs, beyond direct medical costs, needs to be quantified. Furthermore, the humanistic burden of MCL and impact on patient QOL warrants investigation. Additional epidemiology data are needed globally for MCL as well as the need for economic analyses that reflect the real-world treatment of patients with MCL. Disclosures Yang: BeiGene, Ltd.: Employment. Lucas:Pharmerit: Employment. Lesher:Pharmerit: Employment. Caver:BeiGene, Ltd.: Employment. Tang:BeiGene, Ltd.: Employment.