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Introduction Measurable residual disease (MRD) is an established component of acute lymphoblastic leukemia (ALL) management in both children and adults. Society guidelines and expert consensus documents include assessment of MRD as the standard of care following induction therapy, consolidation therapy, and at additional time points, depending on the treatment regimen administered.1–3 Further, the approval of blinatumomab for MRD+ B-ALL has advanced the concept of MRD response as a clinical endpoint in ALL. Although the utility of MRD in ALL has been well defined over the last decades, several questions remain. This extended abstract and the associated presentation focus on areas of ongoing controversy and exploration in ALL MRD, including the following.1) Does increasing the depth of MRD assessment add prognostic value? 2) Is there a role for ongoing MRD monitoring once patients achieve MRD– response? 3) Can MRD assessment of the peripheral blood be substituted for bone marrow? 4) Should MRD assays be applied to the analysis of the central nervous system (CNS)?

Background: Minimal/measurable residual disease (MRD) post initial therapy is prognostic of long term outcomes in patients (pts) with newly diagnosed MM (NDMM), but has not been used to modify therapy. We hypothesized that the combination of daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) would be safe and highly active in pts with NDMM. In addition, we employed MRD by next generation sequencing (NGS) to inform the use and duration of Dara-KRd post-autologous transplant (AHCT) and treatment cessation in pts with confirmed MRD negativity. Methods: Eligible pts had NDMM requiring treatment, CrCl ≥40 ml/min, adequate liver and heart function, ECOG performance status 0-2 with no age limit. There was a planned enrichment for pts with high-risk cytogenetic abnormalities (HRCA). Treatment cycles consisted of daratumumab 16 mg/kg IV days 1,8,15,22 (with typical reduction in frequency with subsequent cycles), carfilzomib 56 mg/m 2 IV days 1,8,15, lenalidomide 25 mg PO days 1-21 and dexamethasone 40 mg PO/IV days 1,8,15,22 repeated every 28 days. Pts received 4 cycles of Dara-KRd as induction, AHCT, and received 0, 4 or 8 cycles of Dara-KRd consolidation, according to MRD status. MRD was evaluated by NGS (ClonoSEQ®) in all pts at end of induction, post-AHCT, and during each 4-cycle block of Dara-KRd consolidation. Primary endpoint was achievement of MRD negativity ( Results: The study accrued 123 participants between 03/2018 and 09/2020. Fifty-three patients (43%) had no HRCA, 46 (37%) had 1 and 24 (20%) had 2+ HRCA [gain 1q, t(4;14), t(14;16), t(14;20) or del(17p)]. Median age was 60 y (36-79) and 20% were 70 or older. Twenty-three percent of pts were non-white, 20% had ECOG 2, 21% had high LDH, and 20% R-ISS3. Disease was trackable by NGS-MRD in 118 (95.9%) of pts. Median follow up is 25.1 mo. Four pts remain on protocol treatment, 20 transitioned to lenalidomide maintenance and 84 (71.2%) have reached confirmed MRD negativity and entered MRD-SURE. For those patients, median follow up post treatment cessation is 14.2 mo. Most common severe adverse events were pneumonia (N=8), and venous thromboembolism (N=3) and 3 patients died during treatment. Overall, 80% of pts have achieved MRD negativity and 66 % MRD < 10 -6. Depth of response improved with each phase of therapy and became similar in patients with 0, 1 or 2+ HR abnormalities as assessed post-AHCT and with MRD-guided consolidation (Figure 1). A similar proportion of patients with 0, 1 and 2+ HRCA reached MRD negativity (78. % vs. 82% vs 79 %) and MRD Conclusion: Monoclonal antibody-based quadruplet therapy, AHCT and MRD response-adapted consolidation therapy leads to the highest rate of MRD negativity reported in NDMM. Near all patients with 0 or 1 HRCA and confirmed MRD negativity remain free of IMWG progression or MRD resurgence despite cessation of treatment. While most patients with ultra-high risk MM reach deep responses with this approach, novel consolidative strategies are needed. For most patients with NDMM, this strategy creates the opportunity of MRD surveillance as an experimental alternative to the burden of indefinite maintenance. Figure 1 Figure 1. Disclosures Costa: Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau. Chhabra: GSK: Honoraria. Dholaria: Janssen: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau. Silbermann: Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Giri: CareVive: Honoraria, Research Funding; PackHealth: Research Funding. Hari: GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. OffLabel Disclosure: Carfilzomib for newly diagnosed multiple myeloma

Introduction Rituximab (R) administration results in significant outcome improvement in B cell precursor acute lymphoblastic leukemia (B-ALL) patients (pts), but is usually restricted to pts with ≥20% CD20+ leukemic blasts. Yet, this arbitrary cut-off is not proven biologically sensible. Moreover, CD20 expression might differ between blood (pb) and bone marrow (bm) and varies under prednisone during early treatment. In the present GMALL08/2013 trial R is administered to all BCR-ABL1-negative B-ALL pts irrespective of the initial leukemic CD20 expression. We assessed the initial and post-prephase CD20 expression in GMALL08/2013 pts and correlated the values with MRD response after Induction I (Ind I) and Consolidation I (Cons I). A historical B-ALL GMALL07/2003 cohort without R treatment and with available CD20 expression and MRD data was used to evaluate for R-unrelated effects. Methods Comparative immunophenotypic quantification of CD20 expression in 207 B-ALL pts was performed at diagnosis (pb d0 and/or bm d0) and/or (a/o) after a 5-day dexamethasone- and cyclophosphamide-containing prephase (pb d6) under EuroFlow standardized procedures. CD20 median fluorescence intensities (CD20-MFI) and percentages of CD20+ B-ALL blasts/all blasts (%CD20+ BL) were assessed. Minimal residual disease (MRD) was determined after Ind I (after 1x R) and Cons I (after 4x R) by quantitative PCR for clone-specific immune gene rearrangements to stratify pts as molecular complete response (MolCR, MRD negativity, assay sensitivity at least 1x10 -4), molecular intermediate response (MolIR, MRD positive non-quantifiable or positive Results bm d0/pb d0. In 91 paired bm d0/pb d0 samples %CD20+ BL as well as the CD20-MFI were significantly higher in pb in common/pre-B ALL (c/pre-B ALL) (n=76: paired t-test: p pb d0/pb d6. CD20 expression of circulating blasts significantly increased after a 5-day prephase in c/pre-B ALL but not in pro-B ALL in 106 paired pb d0/pb d6 samples (paired t-test of CD20-MFI and %CD20+ BL; n=20 pro-B ALL, p=.09 and p=.25; n=86 c/pre-B ALL, p Molecular response under R. The values of %CD20+ BL were correlated with MRD response after Ind I and Cons I (Fig. 3). Since the CD20 expression in the present cohort was shown to be significantly modulated in a drug- and compartment-dependent manner, we used the highest measured value of %CD20+ BL out of the three available values per patient (bm d0, pb d0 a/o pb d6). In the historical cohort (n=145) one value per patient for %CD20+ BL was available. Due to low CD20 expression pro-B ALL did not show any differences in the %CD20+ BL among the risk groups in the present (Ind I n=23, Cons I n=20) and the historical (Ind I n=11; Cons I n=11) cohort. The differences in %CD20+ BL in relation to molecular response were significant in c/pre-B ALL between MolCR and MolFAIL after Ind I (n=127) and Cons I (n=120) (Mann-Whitney test: p=.0002 and p=.0028) and of lower significance between MolIR and MolFAIL after Ind I (p=.013) and between MolCR and MolIR after Cons I (p=.029) in the present cohort. Within the historical cohort (Ind I n=145, Cons I n=143) no significant differences were observed. Conclusions Leukemic CD20 expression was modulated between compartments (bm d0/pb d0) and showed a significant increase in a drug-dependent manner in c/pre-B ALL (pb d0/pb d6) probably in response to dexamethasone. The results might challenge the conventional eligibility criteria for CD20 targeted treatment in c/pre-B ALL. MRD persisters showed lower initial CD20 expression compared to MRD responders in the present cohort consistently receiving R, but not in the historical cohort without R treatment. Accordingly, R seems to improve the early MRD response predominantly in pts with higher CD20 expression. Supported by DJCLS Figure 1 Figure 1. Disclosures Szczepanowski: Amgen: Speakers Bureau. Trautmann: Amgen: Speakers Bureau. Ritgen: Roche: Consultancy, Other: Travel support, Research Funding; Abbvie: Consultancy, Other: Travel support, Research Funding; Chugai: Consultancy; MSD: Consultancy, Other: Travel support; Celgene: Other: Travel support. Nachtkamp: Celgene: Other: Travel Support; bsh medical: Speakers Bureau; Jazz: Speakers Bureau. Viardot: Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; University Hospital of Ulm: Current Employment. Baldus: Jazz: Honoraria; Celgene/BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Schwartz: Morphosys: Research Funding; Gilead: Other: Travel grants, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; MSD Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Basilea: Other: Travel grants. Goekbuget: Pfizer: Consultancy, Other: Research funding for institution; Amgen: Consultancy, Other: Invited talks for company sponsored symposia (with honoraria); Research funding for institution; Astra Zeneca: Other: Invited talk for company sponsored symposia (with honor); Gilead/Kite: Consultancy; Novartis: Consultancy, Other: Research funding for Institution; Jazz Pharmaceuticals: Other: Research funding for institution; Incyte: Other: Research funding for Institution; Cellestia: Consultancy; Erytech: Consultancy; Morphosys: Consultancy; Servier: Consultancy, Other; Abbvie: Other. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. OffLabel Disclosure: Rituximab administration to patients with CD20-negative (

On behalf of the GRAALL group. Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2 nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4. Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44. Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C). Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia

Introduction: The open-label, expanded access study (RIALTO) demonstrated that blinatumomab is efficacious with a manageable safety profile in children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates cytotoxic T cells to kill target B cells. Here, findings from the final analysis of RIALTO are presented (NCT02187354). Methods: Enrolled in the study were children >28 days and Results: As of the data cutoff date (January 10, 2020) for the final analysis, demographics and baseline characteristics of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 61% had For best treatment response within the first 2 cycles, results are comparable to that of the primary analysis. Among 110 patients, overall CR rate was 62.7% (n= 69). Of 98 patients with ≥5% blasts at baseline, 59% (n=58) achieved CR; of them, 79% (n=46) achieved an MRD response and 62% (n=39) proceeded to HSCT. The 2 patients with t(17;19) achieved CR with an MRD response. Of the 4 patients with germline trisomy 21 (Down syndrome), 3 achieved CR with an MRD response Among the 12 patients with Of 110 patients treated with blinatumomab, median OS (95% CI) was 14.6 (11-24.5) months with median follow-up time of 18.2 months, which increased by 1.5 months compared with that reported in the primary analysis, with 29.9% of patients still surviving at month 24. Median RFS (95% CI) remains unchanged at 8.5 months (4.7-14.0), with a median follow-up time of 11.5 months in patients who achieved CR; 38% of patients relapsed and 9% died. RFS was more favorable for patients who received HSCT post blinatumomab (70%) than for those who did not (30%) at month 12, respectively, which is consistent with the results from primary analysis. Among patients who had HSCT prior to blinatumomab (n= 45), median OS (95%) was 16.6 (7.1-NE) months vs 14.6 (10.9-24.5) months in patients without HSCT prior to blinatumomab (n= 65). Compared with the primary analysis, 5 additional patients received HSCT after achieving CR in the final analysis. Median OS among patients in CR after HSCT by MRD responders vs MRD non-responders was NE at 15-month analysis (Figure). Safety results in the final analysis were consistent with those reported in the primary analysis. Of 110 patients, 99% experienced TEAEs, with 65% being grade ≥3 (see Table 3 for details). TRAEs were reported in 74% of patients; 26% were grade ≥3 and 19% were deemed serious. Details on grade ≥3 TRAEs are shown in Table 3. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusions: Overall, the safety and efficacy results from the final analysis are consistent with those reported in the primary analysis as no new safety signals were observed. These findings strengthen the observation that blinatumomab demonstrates durable efficacy and is a suitable treatment option in children with R/R BCP-ALL. Table 1. Disclosures Locatelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceeutical: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Current Employment, Other: Personal Fees ; 20190300609: Patents & Royalties: Licensed patient . Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. Bader:Medac: Patents & Royalties, Research Funding; Amgen: Consultancy, Speakers Bureau; Neovii: Research Funding; Celgene: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding. Schlegel:bluebird bio: Honoraria. Bourquin:Servier: Other: Travel Support. Handgretinger:Amgen: Honoraria. Brethon:Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Rössig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Viswagnachar:IQVIA: Current Employment.