PURPOSE The need for an individualized management of indolent clinical forms in mantle cell lymphoma (MCL) is increasingly recognized. We hypothesized that a tailored treatment with ibrutinib in combination with rituximab (IR) could obtain significant responses in these patients. METHODS This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 12 Spanish GELTAMO sites (ClinicalTrials.gov identifier: NCT02682641 ). Previously untreated MCL patients with indolent clinical forms defined by the following criteria were eligible: no disease-related symptoms, nonblastoid variants, Ki-67 < 30%, and largest tumor diameter ≤ 3 cm. Both leukemic non-nodal and nodal subtypes were recruited. Patients received ibrutinib 560 mg once daily and a total of eight doses of rituximab 375 mg/m2. Ibrutinib could be discontinued after 2 years in the case of sustained undetectable minimal residual disease (MRD). The primary end point was the complete response (CR) rate achieved after 12 cycles according to Lugano criteria. RESULTS Fifty patients with MCL (male 66%; median age 65 years) were enrolled. After 12 cycles of treatment, 42 (84%; 95% CI, 74 to 94) patients had an overall response, including 40 (80%; 95% CI, 69 to 91) with CR. Moreover, undetectable MRD in peripheral blood was achieved in 87% (95% CI, 77 to 97) of cases. At 2 years, 24 of 35 evaluable patients (69%) could discontinue ibrutinib because of undetectable MRD. Four patients had disease progression; three were non-nodal MCL and carried high genomic complexity and TP53 mutations at enrollment. No unexpected toxicity was seen except one patient with severe aplastic anemia. CONCLUSION Frontline IR combination achieves a high rate of CRs and undetectable MRD in indolent clinical forms of MCL. Discontinuation seems appropriate in cases with undetectable MRD, except for TP53-mutated cases.

SummaryMantle cell lymphoma (MCL) after relapse is associated with poor prognosis. No standard of care exists and available evidence for treatments is limited, particularly in patients who fail Bruton tyrosine kinase inhibitor (BTKi) therapy. This multicentre retrospective chart review study, SCHOLAR‐2, addresses this knowledge gap and reports on data collected from 240 patients with relapsed/refractory MCL in Europe who were treated with BTKi‐based therapy between July 2012 and July 2018, and had experienced disease progression while on BTKi therapy or discontinued BTKi therapy due to intolerance. The median overall survival (OS) from initiation of first BTKi therapy was 14.6 months (95% confidence interval [CI] 11.6–20.0) in the overall cohort, 5.5 months (95% CI 3.9–8.2) in 91 patients without post‐BTKi therapy, and 23.8 months (95% CI 18.9–30.1) in 149 patients who received post‐BTKi therapy (excluding chimeric antigen receptor T‐cell treatment). In the latter group, patients received a median of one (range, one to seven) line of post‐BTKi therapy, with lenalidomide‐containing regimens and bendamustine plus rituximab being the most frequently administered; the median OS from initiation of first post‐BTKi therapy was 9.7 months (95% CI 6.3–12.7). These results provide a benchmark for survival in patients with R/R MCL receiving salvage therapy after BTKi failure.

This study (ReCORD-FL) sought to construct a historical control cohort to augment single-arm trials in relapsed/refractory follicular lymphoma (r/r FL). A retrospective study in 10 centers across North America and Europe was conducted. Adults with grade 1-3A FL were required to be r/r after ≥2 therapy lines including an anti-CD20 and an alkylator. After first becoming r/r, patients were required to initiate ≥1 additional therapy line, which defined the study index date. Endpoints were observed from start of each therapy line (including index line) until death, last follow-up, or December 31, 2020. Endpoints were complete response (CR) rate, overall response rate (ORR), time to next treatment or death (TNT-D), event-free survival (EFS), and overall survival (OS). One hundred eighty-seven patients were identified. Most patients' (80.2%) index therapy occurred in third line (3L) (range, 3L-6L). Median follow-up from FL diagnosis was 9 years (range, 1-21 years). CR and ORR to the index therapy were 39.0% and 70.6%, respectively. Median (95% confidence interval) EFS from index was 14.6 (11.0-18.0) months; median OS from index was 10.6 years. Outcomes worsened across successive treatment lines and for patients who were double refractory (r/r to both an anti-CD20 monoclonal antibody and an alkylator) or POD24 (progressed ≤24 months after front-line anti-CD20) at index. Findings demonstrate the unmet need of FL patients with multiply relapsed, double refractory, or POD24 disease. Based on robustness of the historical data collected and comparability with a previous study (SCHOLAR-5), ReCORD-FL presents a valuable source of control data for comparative studies in r/r FL.

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Background: Previous studies showed that MRD- pts after transplant may have detectable monoclonal protein through IFx, creating confusion regarding their prognostication. That said, MRD assessment in these pts was not performed with next generation techniques nor or in later time points. Additional discordances have been identified between multiparameter flow cytometry (MFC) and NGS, which were confirmed in recent analyses comparing NGF vs NGS. Aim: To characterize discordances between flow cytometry vs NGS and IFx through the investigation of immature B cells sharing the same B-cell receptor immunoglobulin (BcR IG) with MM cells. Methods: Progression-free survival (PFS) according to negative vs positive IFx was analyzed in 219 MRD- pts by MFC after transplant, enrolled in the GEM2000 and GEM2005MENOS65 trials. The same comparison was performed in 205 MRD- pts by NGF after consolidation in the GEM2012MENOS65 trial. MRD detection by NGS was compared to MFC or NGF in 140 and 104 cases, respectively. We performed NGS of BcR IG gene rearrangements (mean: 69,975 sequences) and WES (mean depth: 145x) in a total of 68 B cell samples isolated from the bone marrow (BM) of 7 MM MRD- pts by NGF after treatment (GEM2012MENOS65). These were intentionally selected to avoid contamination from MM plasma cells (PCs) during sorting of CD34 progenitors, B cell precursors, mature B cells and normal PCs. We investigated these populations for the presence of clonotypic BcR IG and somatic mutations detected in MM PCs sorted at diagnosis, using T cells as germline control. In another 10 untreated MM pts, we performed scRNA/BcRseq of total BM B cells and PCs (n=52,735), to investigate if the clonotypic BcR IG of MM PCs was detectable in other B cell stages defined by their molecular phenotype. Results: Among 219 MRD- pts by 4 color MFC after transplant, 76 (35%) showed positive IFx and identical PFS to those with negative IFx (medians of 63 vs 66 months, p=0.96). Similarly, 23/205 (11%) MRD- pts by NGF after consolidation showed positive IFx and identical PFS to those with negative IFx (4y rates of 87% vs 78.5%, p=0.35). Thus, albeit the higher sensitivity of NGF and the later time point (consolidation), approximately 1/10 MRD- pts by NGF continued showing positive IFx, and their outcome was as favorable as that of MRD- cases in CR. We then investigated discordances between flow cytometry and NGS. Among 35 MRD- pts by 4 color MFC, 21 (60%) were MRD+ by NGS, whereas 8/44 (18%) MRD- cases by NGF were MRD+ by NGS; only one of the latter 8 pts relapsed so far. Noteworthy, 9/29 MRD- pts by MFC or NGF showed MRD levels ≥10-4 by NGS, suggesting that other factors beyond sensitivity were accounting for the discordances between MRD assessed by MFC/NGF (in the PC compartment) vs NGS (in whole BM samples). NGS of BcR IG gene rearrangements in sorted BM cells from MRD- pts by NGF, uncovered the presence of MM clonotypes in normal PCs (4/7 pts) and in B cells (5/7 pts) at low frequencies (mean of 0.31% in both, range: 0.003% - 9.4%). These findings were confirmed by scRNA/BCRseq, which unveiled in 10/10 pts that clonotypic cells were confined mostly but not entirely within PC clusters. We next performed WES to investigate if genetic abnormalities present in MM PCs at diagnosis were detectable in the same BM cells sorted after treatment in MRD- pts. Surprisingly, 41/201 (20%) somatic mutations present in diagnostic MM PCs were detectable in CD34 progenitors (n=6/7), B-cell precursors (n=4/7), mature B cells (n=5/7) and phenotypically normal PCs (n=4/7). All somatic mutations shared by MM PCs and sorted BM normal cells were non-recurrent, and genes recurrently mutated in MM (ATM, DIS3, KRAS, LTB, MAX,) as well as copy number alterations (CNA) found in MM PCs, were undetectable in normal cells. Conclusions: Albeit more-sensitive NGF, 11% of MRD- pts continue showing positive IFx. This should not be regarded as a false-negative result, since these pts have similar outcome to those in CR and MRD-. Our findings also suggest that, at least in some pts, discordances between NGF and NGS could be attributed to immature clonotypic cells. However, these lack most somatic mutations and CNA found in MM PCs, and therefore cannot drive disease relapse. This would explain the favorable outcome of MRD- pts by NGF despite positive NGS. From a pathogenic standpoint, our study proposes that a mutated and clonally expanded lymphopoiesis precedes secondary driver mutations or CNA leading to the expansion of MM PCs. Disclosures García-Sanz: Janssen: Honoraria, Other: Travel/accommodations/expenses; Novartis: Consultancy; Amgen: Honoraria; Gilead: Other: Research grants, Research Funding; IVS (Biomed 2-Euroclonality): Patents & Royalties: and other intellectual property; Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria. Chatzidimitriou:Janssen: Research Funding. San-Miguel:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees. Paiva:Amgen: Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy; SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Introduction: To discriminate different outcomes among patients in CR, the International Myeloma Working Group (IMWG )introduced more stringent CR (sCR) criteria by adding to the pre-existing CR parameters the requirement of a normal free-light chain ratio (sFLCr) plus the absence of clonal plasma cells (PCs) in bone marrow (BM) by immunohistochemistry (IHC). In 2011,the low-sensitivity cytometrycriteria were included as alternative methodology to IHC to define sCR. Aim: To validate the preliminary data of our previous study (Blood 2015. 126:858-62) regarding the lack of influence of an abnormal sFLCr in the outcome of MM patients, through the analysis of a more extensiveseries of newly diagnosed multiple myeloma (NDMM) patients in CR or sCR. Patients and Methods: This study is based on 459 NDMM patients who were transplant candidates and enrolled in the GEM2012MENOS65phase 3trial;evaluable patients were enrolled in a subsequent maintenance trial (NCT02406144).CR and sCR was defined according to the IMWG criteria. Agreeing to the protocol, patients with <5% BM PCs and negative serum immunofixation (IF) but with unavailable urine IF should have been classified as VGPR, but after the results of recent analysis conducted by our group showing that these patients had the same outcome of those in CR (unpublish information), these patients were reclassified as CR. SFLCr (FREELITE assay) was stratified as normal (0.26-1.65) or abnormal (<0.26 if the patient was λ; >1.65 if the patient was κ). BM aspirates were assessed for morphological enumeration of PCs and monitoring of minimal residual disease (MRD) using next-generation flow (NGF) according toEuroFlow SOPs. The median limit of detection was of 3x10-6. We classified as sCR all patients in CR with normal sFLCr and absence of clonal PCs by NGF with a reduced threshold of sensitivity to 10-4.The median follow-up was 40 months. Results: After ASCT,392 patients were evaluable for response; 239 (61%) reached ≥CR. Data from sFLCr and MRD was available in 225 and 221 patients, respectively. In 153 out of a total of 203 (74%) patients in CR in which complete information about FLC and MRD was available were categorized as sCR. The remaining 55 patients were consider in CR because of failure to accomplish 1 of the 2 criteria: abnormal sFLCr (n=49) or MRD+veby low sensitivity flow (n=11); 5patientsshared both criteria.In a landmark from ASCT, with a follow up of 27 months, sCRdidn't show significantly differences inPFS (2 years-PFS 90% vs 83%; P=.2) neither in OS (2 years-OS 96% vs 98%; P=.6) as compared to CR patients.Interestingly, patients with abnormal (n=51) vs normal (n=174) sFLCr showed superimposable PFS (2 years-PFS 86% vs 88%; P=.6) and OS (2 years-OS 95% vs 100%; P=.2).By contrast, in the 11 patients (out of the 221, 5%) with persistent MRD (>10-4) the PFS was significantly poorer as compared with MRD-ve cases (2-yearsPFS 91% vs48%; P=.001)but the OS was similar (2 years-OS 98% vs 96%; P=.3).As validation, we reproduced the analysis in the consolidation-2 end-point (figure 1), where375patients were evaluable for response assessment,267 of them (71%) reached ≥CR. Once again, in the landmark analysis, sCR didn't show significantly differences in PFS with respect to CR patients (2 years-PFS 88% vs 84%; P=.2) neither in OS (2 years-PFS 96% vs 90%; P=.3); moreover, patients with abnormal (n=55) vs normal (n=195) sFLCr showed superimposable PFS (2 years-PFS 84% vs 87%; P=.4) and OS (2 years-OS 89% vs 96%; P=.2).In the MRD analysis, patients with persistent MRD, had significantly inferior PFS (2-years PFS 87% vs 72%; P=.04 for >10-4 MRDsensitivity). If we increase the sensitivity of the MRD to 10-6, the differences in PFS at 2 years are more evident (2 years-PFS 94% vs 67%; P<.000001 for >10-6 sensitivity). Conclusion: These results confirm our previous findings based on GEM05menos65/ GEM10mas65 clinical trials, indicating that for MM patients stringent CR criteria does not predict a different outcome as compared to standard CR. Specifically, the sFLCr doesn't identify patients in CR at distinct risk. If this essential criterion in the definition of sCR lacks connotations for the prognosis, is it not justified to maintain a response category whose real significance depends on the combination of the traditional CR criteria with a negative MRD status based on very low (IHC) or low resolution (<10-4) levels, which is outdated. Figure 1. Figure 1. Disclosures Martinez Lopez: Janssen: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Puig:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Oriol:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ocio:Pharmamar: Consultancy; AbbVie: Consultancy; Seattle Genetics: Consultancy; BMS: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. Mateos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Sanofi: Consultancy; Takeda: Consultancy; Novartis: Consultancy; MSD: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Brystol-Myers Squibb: Consultancy; Amgen: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees. Bladé:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Lahuerta:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.