Kurzfassung: Background: Leukemia stem cells (LSCs) play a critical role in AML propagation and relapse. Other investigators have also highlighted unique gene expression profiles for the leukemia stem cell population. Here we compared the results of in vitro drug sensitivity testing against a custom panel of drugs and drug combinations for blast populations vs. leukemia stem cell populations derived from the same patients, as well as mutation analysis for a panel of 194 recurrently mutated genes in AML. Patients and Methods: Patient AML samples were obtained with IRB approval. LSCs were isolated by fluorescence-activated cell sorting (FACS) and the blast population enriched to 〉 90% using immunomagnetic beads from blood samples from 5 patients with AML. A sixth AML patient sample was used for NOD/SCID IL2R γc−/− engraftment, in order to compare characteristics of pre- and post-engraftment subclones. Our CLIA approved custom assay includes 153 drugs and targeted agents, both FDA approved and investigational, with additional drug combinations. High throughput screens (HTS) were conducted with enriched cells adherent to matrix protein in 384 well plates with 8 concentrations of each drug spanning 4 logs. Viability was assessed with CellTiter-Glo (Promega). HTS were performed on LSCs, blasts and pre- as well as post-engraftment AML subclones from the xenograft. Dose-response curves were generated to calibrate drug resistance patterns. Mutation analysis by NGS for a panel of 194 recurrently mutated genes in AML (MyAML®) including 37 translocations was also conducted for the LSC and blast populations. Results: AML blasts and LSCs exhibited divergent drug susceptibility patterns (see volcano plot in Figure). Of 11 drugs commonly used in AML, 8 were typical chemotherapy drugs. Five of these compounds were effective against blasts, but none were effective against LSCs (p-value: 0.0256), suggesting a possible mechanism for post-treatment relapse or primary refractoriness. LSCs were also resistant to mitomycin-C, an agent that induces DNA interstrand crosslinks and DNA breaks, in contrast to blasts that were variably sensitive. Of note, we identified 12 drugs from 8 classes defined by mechanism of action that may target LSCs, in some cases preferentially, when compared with blasts. Drugs effective in preferentially targeting LSCs included tyrosine kinase inhibitors, histone deacetylase inhibitors, 1 cyclin-dependent kinase inhibitor, 1 proteasome inhibitor and 1 microtubule assembly inhibitor. Several of the drugs that efficiently killed LSCs have been studied clinically in AML, while others have theoretical or established efficacy against LSCs by drug class. Only one commonly used drug in AML, sorafenib, a multikinase inhibitor used in FLT3+ disease that may improve survival in younger patients, was effective against LSCs. Blast specific drugs include romidepsin, dinaciclib, alvocidib, ganetespib, selinexor, dorsomorphin, vinblastine, cladribine, dabrafenib, selumetinib, etoposide, torkinib and those in Figure. Blast and LSC drug susceptibility patterns were distinct for each patient. Further, the engrafted xenograft subclone grew very rapidly, was resistant to standard chemotherapy, and possessed three new deleterious mutations in KMT2C (2), SF3B1 and 1 possibly damaging mutation in NUP214, suggesting possible genetic contributions to chemotherapy resistance. We also compared mutation profiles for LSCs vs. blasts in 5 patients, and identified LSC specific mutations in WNK3, WNK4 and BUB1, each in 2 of the 5, and there were also other mutations that were LSC or blast specific. Of note, Bub1 is a mitotic checkpoint serine/threonine kinase that controls mitosis in cancer stem cells (Venere et al Cancer Discov. 2013). WNK3 and WNK4 also both encode serine/threonine protein kinases. Conclusions: The distinct drug susceptibility patterns of patient-specific LSC and blast populations highlight the potential of an individualized approach to treat AML. LSCs are resistant to S-phase agents used in standard-of-care chemotherapy. Genetically distinct minority resistant LSC subclones present at diagnosis may grow rapidly under some conditions, and contribute to drug resistance and relapse. Incorporating the results of functional drug screening focused on LSC subclones may allow more individualized treatment of AML patients and identify patient-specific therapies that lead to improved outcomes. Figure Figure. Disclosures Carson: Invivoscribe Inc.: Employment. Patay:Invivoscribe Inc.: Consultancy, Equity Ownership, Patents & Royalties. Becker:Novartis: Research Funding; Trovagene: Research Funding; CVS Caremark: Consultancy; JW Pharmaceuticals: Research Funding; Rocket Pharmaceuticals: Research Funding; Pfizer: Consultancy; Amgen: Research Funding; BMS: Research Funding; Abbvie: Research Funding; GlycoMimetics: Research Funding.

Kurzfassung: Introduction Imatinib mesylate (IMT) dose escalation has been proposed as a therapeutic option in patients (Pts) with chronic myeloid leukemia (CML) who failed to achieve optimal response with standard dose IMT. We report the results of prospective multi-center single arm phase ¥≥study evaluating efficacy of escalated dose IMT. We intended to identify patterns of molecular change using serial quantitative RT-PCR and its relationship with clinical outcome. We also planned to find predictive markers for outcome with array comparative genomic hybridization (aCGH) and epigenetic study of bcr gene in addition to BCR/ABL mutation. Patient and methods Pts in chronic phase (CP) CML who failed to achieve optimal response by European LeukemiaNET with adequate organ function were enrolled. Pts in accelerated phase (AP) or blast crisis (BC) who failed to achieve complete hematologic response after 3 months of IMT were also eligible. CP Pts received 600mg daily, while Pts in AP or BC received 600 or 800mg IMT daily. Pts received IMT for at least 12 months or until the appearance of a progressive disease, intolerable toxicity. Along with cytogenetic response (CyR), molecular response (MR) was assessed with BCR-ABL/ABL gene ratio of peripheral blood or bone marrow aspirate. Baseline BCR/ABL gene mutation test was performed using Matrix-assisted laser desorption/ionization time of flight mass spectrometry. Genome-wide screening for regions of genetic gains and losses with baseline blood samples was performed for 38 Pts using aCGH. Methylation status of 4 CpG sites in bcr gene promoter region was tested for 40 Pts and average methylation level was used for analysis. Blood samples at baseline and 6 months after dose escalation were tested. 29 optimal responders to standard dose IMT and 38 healthy donors were also tested for bcr methylation status for additional comparison. Results 71 Pts (median age 49.0 years, M:F=50:21) received escalated dose IMT. Median time to treatment failure (TTTFx) was 18.0 months and toxicities were manageable. 44 and 52 Pts were evaluable for FISH at 6 months and 1 year, where 16 and 17 Pts showed complete CyR (CCyR) respectively. For 61 Pts with serial MR data, TTTFx was longer in Pts who achieved molecular reduction of more than 50% within 6 months (Molecular early responder: MER) than who didn’t (p & lt;0.001). MER’s achieved CCyR more frequently at 6 months and 12 months (p=0.010, & lt;0.001 respectively). Of 24 Pts who had mutational status data, 4 had mutation. They experienced TFx within 12 months and all failed to achieve CCyR. aCGH revealed significant copy number (CN) gain in chromosome 16p11.2 in MER’s compared to non-MER’s (p=0.034). Tendency for increased CN in 22q11.23 and decreased CN in 17q12 was observed in MER’s without reaching statistical significance (p=0.072 and 0.070 respectively). 4 candidate genes within the above regions – GSTT1, SULTA1A, PYCARD, TADAZL – were evaluated for CN variation. GSTT1 CN loss was more frequently observed in MER’s (p=0.035). GSTT1 CN loss also predicted the longer TTTFx without reaching statistical significance (p=0.086). In epigenetic study, Pts in PCyR at the time of study enrollment had increased baseline bcr methylation compared to Pts in less than PCyR (p & lt;0.001). Pts who had increased amount of bcr methylation at 6 months compared to baseline had longer TTTFx compared to who did not (p=0.012). Baseline bcr methylation amount of study Pts was lower when compared to that of optimal responders and healthy donors (p=0.001 and p & lt;0.001 respectively). bcr methylation decreased with increased duration of standard dose IMT both in study Pts and optimal responders (p=0.042 and 0.004 respectively), although the pattern of decrease was different between the two groups (p & lt;0.001). In multivariate analysis baseline bcr methylation status was the only variable related to TTTFx (p=0.047). Conclusion Escalated dose IMT is a reasonable option for CML Pts showing less than optimal response to standard IMT. MER after escalated dose IMT is a useful early predictive marker for long term response. Mutational status of BCR-ABL at baseline is possibly important for response. Chromosome 16p11.2, 22q11.23 and 17q12 are potential locations related to IMT response and GSTT1 CN loss may be a genetic change affecting clinical outcome. bcr methylation status is an epigenetic marker associated with IMT response, where decreased bcr methylation status is related to poor IMT response.

Kurzfassung: GATA-2 is a zinc finger-containing transcriptional regulator that plays important roles in embryonic and adult hematopoiesis. Mutations in human GATA2 are associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as immunodeficiency disorders that present with a profound loss of monocytes, dendritic cells and other myeloid lineage populations. Recent work reveals crucial roles for GATA-2 in definitive hematopoietic stem/progenitor cell activity, vascular integrity and lymphatic development. However, the molecular mechanisms by which GATA-2 controls adult hematopoiesis via hematopoietic-cell autonomous functions are largely unknown. To address this question, we generated a tamoxifen-inducible Gata2-deficient mouse strain by breeding Gata2flox/flox mice with Cre-ER transgenic animals. Following tamoxifen treatment, Cre-ER Gata2flox/flox mice show a rapid and profound loss of circulating neutrophils, monocytes and lymphocytes, concomitant with development of anemia. These results are consistent with the requirement for GATA-2 in hematopoietic stem/progenitor cells, and may also reflect GATA-2 function in endothelial cells within the vascular niche. To explore hematopoietic-specific GATA-2 activity, we generated bone marrow chimeric mice with hematopoietic-restricted Gata2-deficiency by transplanting Cre-ER Gata2flox/flox hematopoietic cells into wild type recipients. Cre-ER Gata2flox/flox bone marrow chimeras show rapid development of cytopenias upon tamoxifen exposure, suggesting a cell autonomous role for GATA-2 in maintaining adult hematopoiesis. Strikingly, hematopoietic progenitor cells rapidly lose c-Kit expression upon inducible Gata2 deletion. Chromatin immunoprecipitation and reporter assays suggest GATA-2 cooperates with C/EBPa in regulating kit transcription. Our study suggests conditional deletion of Gata2 restricted to the hematopoietic compartment provides a model for bone marrow failure associated with MDS and mutant GATA2 human immunodeficiencies that may enable further insight into the molecular network by which GATA-2 mediates definitive hematopoiesis. Supported by grants from NIH (AI098099) and the MD Anderson Center for Cancer Epigenetics.(SSW) and the MD Anderson Center for Cancer and Inflammation (HSL). Disclosures No relevant conflicts of interest to declare.

Kurzfassung: In the phase 3 POLARIX study (NCT03274492), polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with similar safety in previously untreated diffuse large B-cell lymphoma. Patients were randomized 1:1 to 6 cycles of Pola-R-CHP or R-CHOP plus 2 cycles of rituximab alone. For registration of POLARIX in China, consistency of PFS in an Asia subpopulation (defined as ≥50% of the risk reduction in PFS expected in the global population) was evaluated. Overall, 281 patients were analyzed: 160 patients from Asia in the intent-to-treat (ITT) population of the global study and 121 from an ITT China extension cohort. Of these, 141 were randomized to Pola-R-CHP and 140 to R-CHOP. At data cut-off (June 28, 2021; median follow-up 24.2 months), PFS met the consistency definition with the global population and was superior with Pola-R-CHP versus R-CHOP (hazard ratio 0.64; 95% confidence interval [CI], 0.40-1.03). Two-year PFS was 74.2% (95% CI, 65.7-82.7) and 66.5% (95% CI, 57.3-75.6) with Pola-R-CHP and R-CHOP, respectively. Safety was comparable between Pola-R-CHP and R-CHOP, including rates of grade 3-4 adverse events (AEs; 72.9% vs 66.2%, respectively), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to study treatment discontinuation (5.0% vs 7.2%), and any-grade peripheral neuropathy (44.3% vs 50.4%). These findings demonstrate consistent efficacy and safety of Pola-R-CHP versus R‑CHOP in the Asian and global populations in POLARIX.

Kurzfassung: Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of the cases, respectively. Immunophenotyping showed the following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6, NUP98, HNRNPc, HNRNPm, PML, and NPM1. WT1- and NRAS/KRAS-mutations were common comutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (∼29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA sequencing data from 201 patients with AML showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2200055810).

Kurzfassung: Although an expanding array of effective treatments has resulted in recent improvement in survival of patients with mantle cell lymphoma (MCL), outcomes remain heterogeneous, and identification of prognostic factors remains a priority. We assessed the prognostic impact of time to progression of disease (POD) after first-line therapy among 455 patients with relapsed MCL. Patients were categorized by duration of first remission as PRF/POD6, defined as progressive disease during induction or POD within 6 months of diagnosis (n = 65; 14%); POD6-24, defined as POD between 6 and 24 months after diagnosis (n = 153; 34%); and POD & gt;24, defined as POD & gt;24 months after diagnosis (n = 237; 53%). The median overall survival from POD (OS2) was 1.3 years (95% confidence interval [CI], 0.9-2.4) for patients with PRF/POD6, 3 years (95% CI, 2-6.8) for those with POD6-24, and 8 years (95% CI, 6.2-NR) for those with POD & gt;24. Median OS2 was inferior in patients with early POD (defined as PRF/POD6 or POD6-24) after both intensive and less intensive frontline treatment. The prognostic performance of time until POD was replicated in an independent cohort of 245 patients with relapsed MCL, with median OS2 of 0.3 years (95% CI, 0.1-0.5) for PRF/POD6, 0.8 years (95% CI, 0.6-0.9) for POD6-24, and 2.4 years (95% CI 2.1-2.7) for POD & gt;24. Early POD is associated with inferior OS2 in patients with relapsed MCL, identifying a high-risk population for future prospective studies.

Kurzfassung: Background: Traditionally, pre-transplant conditioning regimen is given over 4-6 days before hematopoietic cell transplant (HCT). Delivering higher dose chemotherapy preparative regimen over a longer time period has not been tested previously. We hypothesized that the delivery of myeloablative dose of busulfan over a 3-week period may reduce toxicity and non-relapse mortality (NRM), without affecting relapse, and tested this in a prospective phase II study. Methods: Patients between 18 and 70 years of age with hematological malignancies and adequate organ function, with 8/8-HLA matched related or unrelated donor were eligible. They received a fixed dose of busulfan 80mg/m2 as outpatient on days -20 and -13. Then, fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. GVHD prophylaxis was cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Mycophenolate mofetil (MMF) was added to later unrelated donor recipients. All patients received standard supportive care. The primary endpoint was day 100 NRM. Results: We enrolled 52 patients with a median age of 62 (range, 39-69) years. Almost half (n=25, 48%) had AML or MDS and the other half (n=26, 50%) had had CML or MPD; 1 (2%) had multiple myeloma. Low, intermediate, high and very-high disease risk index (DRI) was present in 3 (6%), 34 (65%), 14 (27%) and 1 (2%). HCT-comorbidity index was & gt;3 in 23 (44%) and 1-2 (n=23, 44%). A majority (n=32, 62%) had an unrelated donor. With a median follow up of 14 months (range, 3-23), NRM at day 100 was 1.9% (n=1) and 8% (95% CI, 0-15) at 1 year. Overall survival, progression-free survival and relapse at 1-year were 83% (95% CI, 73-95%), 78% (95% CI, 67-91%), and 14% (95% CI, 4-24%), respectively [Table]. There were no graft failures. The median time to neutrophil engraftment was 17 days (range, 13-33) and that of platelets ( & gt; 20K/µL, n=45) was 24 days (range, 9-266). Day 100 grade II-IV and III-IV acute GVHD rates were 37% (95% CI, 23-50%) and 6% (95% CI, 0-12%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 9% (95% CI, 0-17%) and 7% (95% CI, 0-14%), respectively. Overall survival at 1-year differed significantly among patients with low/intermediate DRI (94%; 87-100%) and those with high/very high DRI (53%; 31-91%), P=0.001. Conclusion: Myeloablative fractionated busulfan regimen with PTCy GVHD prophylaxis is feasible in older patients, has low incidence of severe acute GVHD, chronic GVHD, and NRM and results in promising overall survival. Table Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; StemLine: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Kebriaei:Amgen: Research Funding; Pfizer: Honoraria; Jazz: Consultancy; Kite: Honoraria. Nieto:Astra-Zeneca: Research Funding; Affimed: Research Funding; Affimed: Consultancy; Novartis: Research Funding. Oran:AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Qazilbash:Autolous: Consultancy; Bioclinica: Consultancy; Speaker: Other: Speaker; Amgen: Other: Advisory Board. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. OffLabel Disclosure: Fludarabine & Busulfan as conditioning agent prior to transplant

Kurzfassung: Introduction: Smoking is a potential risk factor for the development of non-Hodgkin lymphoma (NHL), and prior studies have reported inferior survival in tobacco users with certain subtypes of the disease (Taborelli et al, BMC Cancer, 2017; Ollberding et al, Br J Haematol, 2013). For instance, tobacco smokers with NHL had an inferior overall survival (OS) compared to non-smokers in a series of 471 patients who were managed up front with either chemotherapy (68%), radiation (27%), or observation, and this appeared to be most pronounced in patients with follicular lymphoma and in those with a 20+ pack year smoking history (Geyer et al, Cancer, 2010). The impact of tobacco use on survival specifically in patients with mantle cell lymphoma (MCL) has not been well studied. We conducted a multicenter study in MCL and evaluated the prognostic impact of tobacco use. Methods: We included patients with MCL from 12 sites who were ≥18 years old and for whom smoking status was known at the time of diagnosis. Cases were evaluated for reported smoking status at the time of diagnosis (active smoker, prior smoker, or never smoker) and standard baseline clinical prognostic data were obtained for each patient. Descriptive statistics were generated for these characteristics and were then compared across smoking status using chi-squared tests, Fisher's exact tests, or ANOVA, where appropriate. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method, and were compared using log-rank tests. Results: Of 946 included patients, 456 (48.2%) reported never using tobacco, 360 (38.7%) reported prior tobacco use, and 130 (13.7%) reported active tobacco use at the time of diagnosis. Median age was 59 in the active smoker group, 65 in prior smokers, and 61 in never smokers (p 〈 0.001). Any major medical comorbidity (defined as the presence of CAD, CHF, diabetes, CKD, ESRD, COPD, DVT, prior malignancy, or cirrhosis) was present in 59 (45.4%) of the active smokers, 143 (39.7%) of the prior smokers, and 140 (30.7%) of the never smokers (p = 0.002). Intensive induction regimens were used in 58.2% of active smokers, 47.2% of prior smokers, and 58.4% of never smokers (p=0.007). There were no significant differences between groups in regards to sex, race, ECOG performance status, Ann Arbor stage, time to first treatment, and use of auto transplant in first remission. Patients with no prior history of tobacco use were less likely to have a high risk MIPI score at diagnosis (26% high risk) compared to prior smokers (39.5%) and active smokers (32.5%, p=0.019). With a median follow up of 3.5 years after diagnosis, there was no significant difference between the 3 groups with regards to PFS or OS (Figure 1). Five-year OS in the never smoker group was 79.8% (95% CI: 74.8%, 83.9%) vs 75.1% (64.5%, 82.9%) in the active smoker group, and 80.6% (74.6%, 85.3%) in the prior smoker group (log rank p = 0.4079). Five- year progression free survival was 50.4% (44.6%, 56.0%) in the never smoker group, 42.5% (32.2%, 52.5%) in the active smoker group, and 50.2% (43.5%, 56.6%) in the prior smoker group (log rank p= 0.3595). Conclusions: Our data suggest that active or prior smoking does not significantly impact OS or PFS in patients with MCL. This study is limited by the fact that amount of current or former tobacco use was not available and it is not known how many current tobacco users ultimately stopped smoking during the course of their treatment. Future studies should incorporate more specific information regarding smoking history including pack-years and time between discontinuation of tobacco use and date of diagnosis. While tobacco use and other modifiable cardiovascular risk factors should be addressed as appropriate for all patients with MCL, current and former tobacco users can still achieve prolonged PFS and OS and may be candidates for intensive treatments after consideration of their other comorbidities and disease-specific risk factors. Disclosures Calzada: Seattle Genetics: Research Funding. Kolla:Amgen: Equity Ownership. Bachanova:Gamida Cell: Research Funding; GT Biopharma: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Gerson:Seattle Genetics: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding. Danilov:Celgene: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; Pharmacyclics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Curis: Consultancy; Takeda Oncology: Research Funding; Seattle Genetics: Consultancy. Grover:Seattle Genetics: Consultancy. Karmali:Astrazeneca: Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau. Hill:Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghosh:Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Genentech: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Forty Seven Inc: Research Funding; Gilead/Kite: Consultancy, Speakers Bureau; Spectrum: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; T G Therapeutics: Consultancy, Research Funding; Astra Zeneca: Speakers Bureau. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Hamadani:Pharmacyclics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy; Janssen: Consultancy; Medimmune: Consultancy, Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Otsuka: Research Funding; Takeda: Research Funding. Kahl:TG Therapeutics: Consultancy; BeiGene: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Martin:Janssen: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy. Flowers:Karyopharm: Consultancy; Denovo Biopharma: Consultancy; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Spectrum: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; BeiGene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding.

Kurzfassung: Introduction: Mantle cell lymphoma (MCL) is a rare form of lymphoma with no current standard of care. As a result, clinical trials are critical to improving our understanding of the disease and its management. However, clinical trial participation is often limited due to lack of access to studies, restrictive eligibility criteria, and decisions by treating physicians or patients not to participate. We evaluated the rate of enrollment and outcomes associated with clinical trial participation of patients with MCL at 12 US Medical Centers. Methods: We included patients from 12 medical centers in the United States with MCL diagnosed between January 1, 2000, and January 1, 2018, who were ≥ 18 years old, received any induction therapy, and for whom it was known whether initial treatment was on a clinical trial (CT) or not. We compared differences between the two groups (CT vs not) using Fisher's Exact and Chi-square tests as appropriate. We defined overall survival (OS) as time from diagnosis to death. Patients not experiencing an event were censored at their last known follow-up. OS was determined using the Kaplan-Meier method, and univariate and multivariable models were developed to identify predictors of OS. Results: Eight hundred twelve patients were included in this analysis, including 164 (20%) patients who participated in a clinical trial during initial therapy. Rate of participation ranged from 4% to 36% across contributing sites. Median age for the entire cohort was 62 years, 572 (74%) of patients were male, and 95% of patients had ECOG 0-1. MCL International Prognostic Index (MIPI) risk score was high in 163 patients (31%), and 84% of patients had stage IV disease. Ki67 was & gt;30% in 169/225 (43%) patients with available data, and 19% of patients (65/271) had a complex karyotype with & gt; 3 chromosomal abnormalities. Four hundred sixteen (53%) of patients received an intensive induction regimen (defined as initial treatment with a high-dose cytarabine-containing regimen and/or receipt of autologous hematopoietic cell transplantation as consolidation), including 333 patients (43%) who underwent transplant consolidation. Patients with an increased lactate dehydrogenase (LDH) level (p & lt;0.001) and & gt; 3 cytogenetic abnormalities (p=0.015) were less likely to participate in clinical trials, but there was no significant difference in rates of participation based on MIPI (p=0.49) or ECOG performance status (p=0.22; Table). Patients treated on study were less likely to receive an intensive regimen compared to those treated off study (p=0.002). Median time to treatment from diagnosis was 35 days for patients enrolled on trial and 31 days for patients not enrolled on trial (p=0.83). With a median follow-up of 3.8 years, the median OS was 13.6 years (95% CI: 11.5-21.1) for patients not treated on a trial and not reached (95% CI: 9.9 - Not Reached) for patients treated on trial (Figure; p=0.036). In a multivariable model including clinical trial participation, MIPI, time to initial treatment, and receipt of an intensive induction regimen, only clinical trial participation (HR 0.54, 95%CI: 0.31-0.93; p=0.028) and high risk MIPI score (HR 4.24, 95% CI: 2.37-7.56; p & lt;0.001) were significant predictors of OS while receipt of an intensive regimen and time to initial treatment were not. Conclusions: Participation in a clinical trial is associated with improved OS among patients with untreated MCL, even when accounting for time to initial treatment and MIPI score. This study is unable to account for other factors that may predict trial participation including baseline comorbidities, socioeconomic status, social support, and distance to the treating center that are frequently factors that limit trial participation. However, these findings do suggest that enrollment on a clinical trial frequently leads to a successful outcome for patients in addition to providing answers to key clinical questions and should be considered for all eligible patients. Disclosures Cohen: Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; UNUM: Research Funding; LAM Therapeutics: Research Funding; Hutchison: Research Funding; Genentech, Inc.: Consultancy, Research Funding; ASH: Research Funding; Lymphoma Research Foundation: Research Funding; Astra Zeneca: Research Funding. Calzada:Seattle Genetics: Research Funding. Kolla:Amgen: Equity Ownership. Bachanova:Incyte: Research Funding; Novartis: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Celgene: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Barta:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding. Danilov:MEI: Research Funding; Seattle Genetics: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Curis: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Celgene: Consultancy; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; Bayer Oncology: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy. Grover:Seattle Genetics: Consultancy. Karmali:Astrazeneca: Speakers Bureau; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Ghosh:Spectrum: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Astra Zeneca: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Forty Seven Inc: Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; T G Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Speakers Bureau. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Hamadani:Otsuka: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Janssen: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy; Medimmune: Consultancy, Research Funding; Pharmacyclics: Consultancy. Martin:Karyopharm: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; Teneobio: Consultancy. Flowers:Pharmacyclics/Janssen: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Millenium/Takeda: Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; BeiGene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Kahl:BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy.

Kurzfassung: INTRODUCTION The optimal frontline treatment for mantle cell lymphoma (MCL) is not clearly defined. Bendamustine + rituximab (BR) is commonly used as initial therapy. The role of maintenance rituximab (MR) after BR is not agreed upon due to limited data supporting this practice, whereas MR improves overall survival (OS) after autologous stem cell transplant (ASCT) and after R-CHOP for elderly patients who do not receive ASCT. Preliminary results from a subgroup analysis of the randomized phase 3 MAINTAIN study revealed neither a progression-free survival (PFS) nor OS benefit for MR as compared to observation for MCL pts (Rummel, ASCO 2016). In follicular lymphoma patients, however, there does appear to be a PFS benefit to rituximab maintenance following BR. Given these disparate results, we sought additional data to evaluate the role of rituximab maintenance following BR in MCL METHODS MCL pts treated at 12 U.S. medical centers with frontline BR who achieved a complete response (CR) or partial response (PR) and who did not receive consolidative ASCT from 2011 - 2017 were included. Use of MR was based on individual physician/patient preferences. Baseline pt characteristics were compared using chi-squared test, Fisher's exact tests, or ANOVA. Descriptive statistics, comparisons, and OS using the Kaplan-Meier method were stratified by response status as determined by the treating site (complete response (CR) only, partial response (PR) only, and CR/PR). RESULTS Among 135 pts responding to frontline BR who did not complete subsequent ASCT, 80% achieved complete remission (CR) and 20% had a partial remission (PR). Median age was 70 (range 45 - 93) years and 66% were male. Baseline MIPI score was low (13%), intermediate (38%), or high (49%) among patients with available data (n = 92) and did not differ between treatment cohorts. Among responding patients, 78 (58%) received MR and 57 (40%) were observed. With a median follow up of 3.1 years, median OS was not reached for pts responding to BR (with CR or PR) who received MR vs. 6 years for those who received no maintenance (Figure Panel A, P = 0.0013). Use of MR vs. observation was associated with a significant improvement in OS for pts in PR at the end of induction therapy (Figure Panel B, median not reached vs. 1.7 years, P = 0.006), but there was no statistically significant OS difference for pts in CR (Figure Panel C, median not reached vs. 9.6 years, P = 0.2575). In multivariable analysis, MIPI score & lt;6.2 was associated with improved OS [Hazard Ratio (HR) 0.35 (95% confidence interval (CI) 0.12 - 1.02], P = 0.055) as was the use of MR [HR 0.28 (95% CI 0.10-0.79), P = 0.016] . CONCLUSIONS Whereas the MAINTAIN trial showed no PFS advantage to MR after BR for MCL pts, in this multi-center outcomes analysis across multiple US centers, the use of MR was associated with an improvement in OS in pts receiving frontline BR without consolidative ASCT. The survival benefit was only observed for pts in PR after induction therapy. Because of the potential for selection bias in the application of MR, further validation cohorts and prospective study are needed to clarify if there is benefit to maintenance therapy after BR-treated patients not undergoing ASCT as well as the potential for differential benefit of maintenance based on remission status Disclosures Hill: Takeda: Research Funding; Amgen: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding. Martin:Janssen: Consultancy; I-MAB: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; Karyopharm: Consultancy; Teneobio: Consultancy. Calzada:Seattle Genetics: Research Funding. Kolla:Amgen: Equity Ownership. Bachanova:Gamida Cell: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; GT Biopharma: Research Funding; Novartis: Research Funding. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Seattle Genetics: Honoraria, Research Funding; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Research Funding. Danilov:Curis: Consultancy; Bristol-Meyers Squibb: Research Funding; TG Therapeutics: Consultancy; Abbvie: Consultancy; Genentech: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; MEI: Research Funding; Pharmacyclics: Consultancy; Aptose Biosciences: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Seattle Genetics: Consultancy; AstraZeneca: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy. Grover:Seattle Genetics: Consultancy. Karmali:Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau. Ghosh:Celgene: Consultancy, Research Funding, Speakers Bureau; T G Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; Spectrum: Consultancy, Speakers Bureau; Astra Zeneca: Speakers Bureau; Forty Seven Inc: Research Funding; Genentech: Research Funding; Gilead/Kite: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Park:G1 Therapeutics: Consultancy; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Hamadani:Otsuka: Research Funding; Merck: Research Funding; Celgene: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Pharmacyclics: Consultancy; Medimmune: Consultancy, Research Funding; Takeda: Research Funding. Kahl:Seattle Genetics: Consultancy; BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Flowers:Optimum Rx: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Millenium/Takeda: Research Funding; V Foundation: Research Funding; Karyopharm: Consultancy; BeiGene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Denovo Biopharma: Consultancy. Cohen:Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Genentech, Inc.: Consultancy, Research Funding.