Bone Marrow Minimal Residual Disease Research Articles

Maintenance of Long-Term Undetectable Minimal Residual Disease after Combination of Ibrutinib with Abbreviated Chemotherapy in the Icll-07 Filo Trial

Maintenance of Long-Term Undetectable Minimal Residual Disease after Combination of Ibrutinib with Abbreviated Chemotherapy in the Icll-07 Filo Trial

Quantitative Analysis of Minimal Residual Disease (MRD) Shows High Rates of Undetectable MRD after Fixed-Duration Chemotherapy-Free Treatment and Serves As Surrogate Marker for Progression-Free Survival: A Prospective Analysis of the Randomized CLL14 Trial

Fischer: Roche: Other: travel grants; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritgen:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Al-Sawaf:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Tandon:Roche: Equity Ownership; Roche Products Ltd: Employment. Fink:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Other: travel grants. Stübig:Hexal: Speakers Bureau. Brüggemann:Amgen, Celgene, Janssen: Honoraria, Speakers Bureau; Amgen, Janssen: Membership on an entity's Board of Directors or advisory committees; affimed, Amgen, Celgene, Regeneron: Research Funding; Amgen, Incyte, PRMA: Consultancy. Jiang:Genentech: Employment, Equity Ownership; F. Hoffman-La Roche: Equity Ownership. Schary:Abbvie: Employment, Equity Ownership. Eichhorst:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees. Wendtner:MorphoSys: Consultancy, Honoraria, Research Funding; GILEAD Science: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen-CILAG: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Kreuzer:Roche and Abbvie: Honoraria, Other: Expert testimony. Langerak:F. Hoffmann-La Roche Ltd: Research Funding; Gilead: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Genentech, Inc.: Research Funding. Goede:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, speaker fees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, Speakers Bureau; janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, speaker fees, Speakers Bureau. Böttcher:AbbVie: Honoraria, Other: Travel grants, Research Funding; Celgene: Research Funding; Janssen-CILAG: Honoraria, Other: Travel grants, Research Funding; Roche: Honoraria, Research Funding; Genentech: Research Funding; Becton Dickinson: Research Funding; Novartis: Research Funding. Stilgenbauer:AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Other: Travel support; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau.

Dreamm-5: Platform Trial Evaluating Belantamab Mafodotin (a BCMA-directed Immuno-conjugate) in Combination with Novel Agents in Relapsed or Refractory Multiple Myeloma (RRMM)

Background: Patients with RRMM who have relapsed through multiple prior lines of therapy need novel, effective, targeted agents. B-cell maturation antigen (BCMA) is a cell-surface receptor required for plasma cell survival that is ubiquitously expressed on MM cells, but virtually absent on naïve and memory B cells. Belantamab mafodotin (GSK2857916) is a BCMA-directed immuno-conjugate with an afucosylated, humanized anti-BCMA monoclonal antibody (mAb) conjugated by a protease-resistant cysteine linker to a microtubule disrupting agent, monomethyl auristatin F (MMAF). Belantamab mafodotin specifically binds to BCMA, eliminating MM cells by a multimodal mechanism including delivering MMAF to BCMA-expressing malignant cells, enhancing antibody-dependent cellular cytotoxicity, and leveraging immunogenic cell death. In an open-label, phase 1 study (DREAMM-1), belantamab mafodotin monotherapy had a manageable safety profile and demonstrated rapid, deep and durable clinical response (60% overall response rate, 14.3 months duration of response) with significant progression free-survival (PFS; 12 months) in patients with heavily pretreated MM. Belantamab mafodotin is being evaluated in clinical trials in various lines of MM therapy, either as monotherapy or in combination. The DREAMM-5 platform trial is a phase 1/2 study that incorporates an efficient design with 1 master protocol, wherein multiple belantamab mafodotin-containing combinations will be evaluated in separate substudies to identify effective doublet combinations versus a shared belantamab mafodotin monotherapy control arm. Initial substudies will include combinations with the T-cell activating checkpoint mAbs GSK3359609 (an IgG4 inducible T-cell costimulatory [ICOS] agonist antibody that is Fc optimized to selectively enhance T-cell function to enable antitumor responses), GSK3174998 (a humanized wild-type IgG1 anti-OX40 agonistic mAb), and a gamma-secretase inhibitor, Nirogacestat (PF-03084014, SpringWorks Therapeutics). Furthermore, as treatment paradigms evolve, including potential genomic subsets of patients with RRMM and actionable mutations, other control arms may be introduced. The combination agent for evaluation in each substudy will be selected based on scientific rationale and/or results of preclinical experiments with the selected agent in combination with belantamab mafodotin. Methods: Patients with RRMM will be eligible if they have received ≥3 prior lines of therapy (consisting of an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 mAb), have measurable disease (as measured by M-protein and free light chain), and acceptable hematologic and vital organ functions. Participants previously treated with an anti-BCMA targeted therapy are eligible except for prior belantamab mafodotin treatment and chimeric antigen receptor (CAR) T-cell therapy within 3 months of screening. Each substudy will have 2 sequential phases to evaluate safety and efficacy (Figure). The dose exploration (DE) phase will evaluate the safety and tolerability of belantamab mafodotin administered in combination with a partner agent. Each DE phase will consist of multiple dosing cohorts (N≤10 per cohort), 1 cohort per doublet combination. The primary objective is to identify a recommended phase 2 dose for each doublet combination based on safety and preliminary efficacy. Once a substudy is selected for the cohort expansion (CE) phase (N=35 per substudy), the objective is to compare the response rate between the doublet combination and the shared belantamab mafodotin monotherapy control arm. Secondary objectives in CE are to assess AEs, durability of response, PFS, and overall survival. Exploratory objectives include assessment of PK for belantamab mafodotin with each partner agent, bone marrow minimal residual disease status, and plasma soluble BCMA levels as candidate prognostic and predictive biomarkers. DREAMM-5 is designed to efficiently identify novel, highly effective belantamab mafodotin-containing doublet combinations for evaluation in pivotal trials against current standard-of-care MM agents. Acknowledgments: Editorial assistance provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd and funded by GSK. Study funded by GSK (208887); drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure Disclosures Richardson: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Biswas:GSK: Employment, Equity Ownership. Holkova:GlaxoSmithKline: Employment, Equity Ownership. Jackson:GlaxoSmithKline: Employment, Equity Ownership. Netherway:GlaxoSmithKline: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Ferron-Brady:GlaxoSmithKline: Employment, Equity Ownership. Yeakey:GlaxoSmithKline: Employment, Equity Ownership. Shelton:GlaxoSmithKline: Employment, Equity Ownership. Montes De Oca:GlaxoSmithKline: Employment. Ahlers:GlaxoSmithKline: Employment, Equity Ownership. Franco:GlaxoSmithKline: Employment, Equity Ownership. Ballas:GlaxoSmithKline: Employment, Equity Ownership; Bristol-Myers Squibb: Equity Ownership; AstraZeneca: Patents & Royalties: Uncompensated copyrights. Paul:GlaxoSmithKline: Employment, Equity Ownership. Luptakova:GlaxoSmithKline: Employment, Equity Ownership. Gupta:GlaxoSmithKline: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

Ibrutinib and Venetoclax Target Distinct Subpopulation of CLL Cells: Rationale for Drug Combination and Implication of Minimal Residual Disease Eradication

Ibrutinib (Ibr) is a specific inhibitor of Bruton tyrosine kinase, a component of the B-cell receptor (BCR) signaling. Venetoclax (Veneto) inhibits the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL) (Byrd NEJM, Roberts, NEJM, 2015 and Roberts, Blood, 2019) and clinical trials using the combination therapy are ongoing. An interesting clinical observation is that the tumor cell sensitivity to these two drugs differ between different anatomic compartments. While lymph node-resident CLL cells are more sensitive to ibr, circulating CLL cells in the peripheral blood are more sensitive to the action of veneto. When these two drugs are used in combination to treat relapsed/refractory (Hillman ASH 2018 and Kater EHA 2019) or previously untreated CLL patients (Jain NEJM 2019), rate of complete response significantly increases compared to single drug alone. Moreover, negativity of bone marrow minimal residual disease continues to improve over time. However, the reason behind these observed compartmental responses is largely unknown, and we investigated the differential response using an ex vivo model that promotes CLL proliferation (CLL proliferation model). A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. We established the ex vivo model using fibroblasts derived from the bone marrow of a CLL patient. In this model, CLL cells closely interact with the bone marrow fibroblasts (BMF) (Fig.1) and divide and proliferate for several generations, as measured by CFSE labeling. The culture, in some cases, may continue for 10 weeks before cell death ensues. With this ability to promote long-term cell proliferation, the model recapitulates one of the most salient features observed histologically in the "proliferation centers" of the CLL lymph nodes. With the proliferation model, we first tested the effects of ibrutinib on cell division/proliferation as well as cell viability in samples taken from 30 CLL patients consisting of 22 ibr-naïve (thus sensitive) and 8 ibr-relapsed (thus resistant) patients. We demonstrate that there was lack of a significant inhibition of ibr on cell viability. In comparison, Ibr markedly inhibited cell proliferation in cells from ibr-naïve/sensitive patients (p<0.0001), while such inhibition was much less prominent in cells from ibr-relapsed/resistant patients (p=0.053). Overall, our data demonstrate that only the dividing subpopulation of CLL responds to ibr, and this response is highly correlated with patients' clinical response to the drug while cell viability responses are not. With the CLL proliferation model, we also evaluated how veneto works. Veneto, as expected, markedly decreased cell viability at clinically achievable concentrations. CFSE profiles of the remaining live cells, however, revealed an interesting pattern of distribution, showing that veneto induces cell death but it preferentially kills the resting CLL population (Fig. 2). In other words, the resting subpopulation of CLL, instead of the dividing one, preferentially responds to veneto as compared to ibr. Combination of the two drugs, as expected, worked most effectively, significantly reducing the total number of live cells, both resting and dividing subpopulations, in all cases. Analyses of CFSE profiles became less meaningful in many of these cases due to the small number of live cells remaining after the combination treatment. In conclusion, our study, comparing the actions of ibr and veneto in a clinically relevant CLL proliferation model, demonstrates for the first time that the drugs target distinct subpopulations of CLL cells with different proliferative capacity. The data also suggest that single drug therapy may leave a subpopulation behind that would potentially rise to cause a future relapse. Our study provides a strong laboratory rationale explaining why combining these two drugs has the potential to eradicate CLL disease. The findings are also in line with the clinical observations regarding the compartmental response; ibrutinib works primarily on the lymph nodes where CLL cells divide in the "proliferation centers" and veneto acts preferentially on the circulating CLL cells that are mostly non-dividing and resting. Disclosures Wang: Incyte Reaserch Institute: Employment. Ma:Abbvie: Research Funding; Xeme: Research Funding; Novartis: Research Funding; Bioverativ: Consultancy; Janssen: Consultancy, Speakers Bureau; Beigene: Research Funding; Kite: Consultancy; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy; Incyte: Research Funding; Juno: Research Funding. Larson:Celgene: Consultancy; Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials.

Qip-Mass Spectrometry in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Qip-Mass Spectrometry in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

First Line Treatment with Venetoclax and Ibrutinib Induction Followed By Obinutuzumab Intensification Exclusively in CLL/SLL Patients Not in Complete Remission and/or with Detectable Bone Marrow Minimal Residual Disease (NEXT STEP trial)

First Line Treatment with Venetoclax and Ibrutinib Induction Followed By Obinutuzumab Intensification Exclusively in CLL/SLL Patients Not in Complete Remission and/or with Detectable Bone Marrow Minimal Residual Disease (NEXT STEP trial)

Heavy and Light Chain Monitoring in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Heavy and Light Chain Monitoring in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Prognostic Implications of Serum Monoclonal Protein Positivity By Mass-Fix in Bone Marrow Minimal Residual Disease Negative (MRD-) Patients with Multiple Myeloma

Prognostic Implications of Serum Monoclonal Protein Positivity By Mass-Fix in Bone Marrow Minimal Residual Disease Negative (MRD-) Patients with Multiple Myeloma

TEM-MM-101: A Phase I/IIa Dose Escalation Study Evaluating the Safety and Activity of Autologous CD34+ Enriched Hematopoietic Progenitor Cells Genetically Modified for Human Interferon-α2 in Multiple Myeloma Patients with Early Relapse after Intensive Front Line Therapy

BACKGROUND Multiple Myeloma (MM) is an incurable malignancy heralded by an immunosuppressive tumor microenvironment (TME). Therapeutic efforts to reprogram the TME and release innate and adaptive immunity may synergize with current anti-MM drugs, deepen responses and ultimately prolong long-term survival. We have developed an ex vivo gene therapy approach that locally delivers interferon-alpha (IFNa) into the TME through the Tie2+ myeloid progeny of transplanted gene-modified hematopoietic stem and progenitor cells (HSPCs). Preclinical studies in the immunocompetent Vk*Myc murine model as well as in the hematochimeric xenotransplantation setting demonstrate that IFNa gene therapy has anti-MM effect and may subvert the immunosuppressive MM TME, acting both on myeloma cells as well as on the immune infiltrate. Additional toxicology data, demonstrates that a mixture of genetically modified and unmodified CD34+ cells can be transplanted safely. We have therefore progressed into the clinic at Ospedale San Raffaele in Milan, Italy, with our gene therapy approach (Temferon). METHODS The TEM-MM-101 study recruits patients with MM in early relapse (within 18 months) after intensive front line therapy defined as triplet induction (at least 3 cycles including a proteasome inhibitor and/or immunomodulatory drug [IMID]) followed by single or double autologous stem cell transplantation, or, triplet or quadruplet induction including at least a proteasome inhibitor and an IMID, followed by consolidation/maintenance treatment. Three cohorts of 3 patients will be included in the study. Patients will be dosed sequentially in each cohort with data review by an independent data monitoring committee before dose escalation to the next cohort. Key eligibility criteria include achieving at least a VGPR after second line salvage therapy, age 18-70 years, ECOG <2 and Karnofsky >70%, adequate cardiac, renal, hepatic and pulmonary function, and willingness to use appropriate contraception if relevant. Important exclusion criteria include the presence of active autoimmune disease or ineligibility for autologous bone marrow transplant. After confirmation of eligibility, patients undergo autologous peripheral blood HSPC mobilization with lenograstim and plerixafor, before undergoing apheresis. After purification, CD34+ cells undergo transduction with a third-generation, vesicular stomatitis virus-G pseudo-typed lentiviral vector driving myeloid-specific IFNa2 expression. Patients will be offered maintenance treatment from successful HSPC collection until Temferon release. A reduced intensity conditioning regimen is administered at Day -2 followed by ASCT and administration of Temferon at Day 0. Following hematological recovery, patients will be discharged from the Transplant Unit with regular outpatient follow up. After Day +100 from Temferon infusion, patients will resume anti-myeloma consolidation/maintenance treatment according to best clinical practice, unless there is Temferon engraftment and absence of disease on Day +100 evaluations, documented by stringent complete response (sCR) according to the IMWG response criteria, imaging (PET, MRI) negativity, and bone marrow minimal residual disease < 10-4 by multi-parameter flow cytometry, to be confirmed by next generation sequencing. If these response criteria are met on Day +100, patients may stay off maintenance treatment, as long as MRD≤10-5 documented on bone marrow aspirates performed every 3 months, starting from the Day +180 visit. The primary endpoints for this study are: Engraftment of Temferon between Day +30 and Day +100The proportion of patients achieving hematologic recovery by Day +30 from ASCTSafety of Temferon (short-term tolerability of Temferon; stable blood counts and absence of cytopenias > grade 2, unless related to myeloma progression or concomitant medications; absence of systemic IFNa toxicity; absence of Replication Competent Lentivirus; absence of hematologic malignancy that is distinct from progression of the primary neoplasm) The study is actively recruiting patients in Italy. In parallel, a study using Temferon in patients with glioblastoma multiforme with a similar study design and approach (TEM-GBM-001) is also in progress with the first cohort fully recruited. Disclosures Gentner: Genenta Science: Consultancy, Equity Ownership, Research Funding. Mazzoleni:Genenta Science: Employment, Equity Ownership. Russo:Genenta Science: Consultancy, Equity Ownership. Naldini:Genenta Science: Consultancy, Equity Ownership; Magenta Therapeutics: Equity Ownership; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), a joint venture between Fondazione Telethon and Ospedale San Raffaele (OSR): Other: Wiskott-Aldrich Syndrome (WAS) gene therapy was licensed to GlaxoSmithKline (GSK) in 2014. It was then licensed to Orchard Therapeutics (OTL) in April 2018. OTL is the current sponsor of the clinical trial..

A Bispecific CAR-T Cell Therapy Targeting Bcma and CD38 for Relapsed/Refractory Multiple Myeloma: Updated Results from a Phase 1 Dose-Climbing Trial

Background: Anti-B cell maturation antigen (BCMA) chimeric antigen receptor(CAR) T cell therapy has shown promising results from a series of clinical trials. But short progression-free survival (PFS) due to BCMA-negative or positive relapse is pretty much the agenda.Here we constructed a dual-target BM38 CAR incorporating the anti-CD38 and anti-BCMA single-chain variable fragment in tandem plus 4-1BB signaling and CD3 zeta domains and conducted the first-in-human clinical trial(ChiCTR1800018143) in patients with RRMM to evaluate the safety, efficacy and duration of BM38 T cells. Methods:Patients with relapsed or refractory multiple myeloma(RRMM), who had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, were enrolled in the phase 1 dose-climbing trial of the bispecific CAR-T cell therapy. Patients were subjected to a lymphodepleting regimen with Cy(250 mg/m2, d-5 to d-3) and Flu(25 mg/m2, d-5 to d-3) daily prior to the CAR-T infusion (d0). The dose gradients of infused CAR-T cells were 0.5, 1.0, 2.0, 3.0 and 4.0×106 cells/kg and at least 2 patients were involved at every dose level. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma (2016), and the toxicity was graded by CTCAE 5.0. Results: As of 31 July 2019, 16 pts consisting of 10(62.5%) with genetic abnormalities and 5(31.25%) with extramedullary lesions,had received BM38 CAR-T cells in the 5 dose-climbing cohorts. At a median follow-up of 36 weeks, no DLTs and no grade ≥ 3 neurotoxicities were observed. Cytokine release syndrome (CRS), mainly grade 1-2, was reported in 10 of 16 (62.5%) pts; 4 pts had grade ≥ 3 CRS that resolved by tocilizumab and supportive treatment. Almost all the pts were observed with hematological toxicities relieved in the first month after infusion.14(87.5%) pts achieved an overall response with 8(50%) sCR, 2(12.5%) VGPR and 4(25.00%) PR and 14(87.5%) reached bone marrow minimal residual disease(MRD)-negative status. The longest duration of sCR was over 51 weeks and 5(62.5%) of 8 patients had still maintained sCR and 2 transformed to VGPR and 1 to PR. The median duration of progression-free survival(PFS) had not been reached; PFS rates at 9 months was 75%. More encouragingly, 5(100%)extramedullary lesions were eliminated.Up to the observed day, the BM38 CAR-T cells still exist in the patients' peripheral blood by flow cytometry(FCM) and quantitative polymerase chain reaction(q-PCR). The peak time of CAR-T cells proliferation of sCR patients was about the 2nd week after infusion, which was earlier than other patients. 4.0 × 106 CAR T cells (pt11, 12 and 15) were selected for the optimal dose with superior response and acceptable toxicities and expansion cohort would be conducted. Conclusions:Our study demonstrates an improved efficacy with the bivalent BM38 CAR-T therapy for RRMM with a high ORR, especially a higher rate and a longer duration of sCR and effective elimination for extramedullary lesions. No neurotoxicity was observed. CRS and other toxicities were manageable. These initial data provide strong evidence to support the further development of the dual-target CAR-T therapy for RRMM. Clinical trial information: ChiCTR1800018143 Disclosures No relevant conflicts of interest to declare.

Phase 1 Study of Decitabine and Vorinostat Followed By Fludarabine, Cytarabine and G-CSF (FLAG) in Children, Adolescents and Young Adults with Relapsed/Refractory AML: Report from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium

Introduction: Despite progress in the treatment of acute myeloid leukemia (AML) over the past few decades, long-term survival of children, adolescents and young adults remains poor. Most treatment failure is secondary to the development of chemotherapy resistance resulting in relapsed or refractory disease. Epigenetic changes in leukemia cells, such as DNA methylation and/or histone acetylation, can lead to alterations in gene expression thereby causing resistance to chemotherapeutic agents. These epigenetic changes are potentially reversible with agents that demethylate DNA and/or inhibit histone deacetylation which ultimately leads to restoration of normal gene expression and chemosensitivity. We are reporting an ongoing phase I trial of decitabine and vorinostat, two epigenetic modifying agents, followed by chemotherapy in children, adolescents and young adults with relapsed or refractory AML. Methods: T2016-003 is a phase I study that was developed and activated in the TACL consortium in July 2017 for patients 1 to 25 years of age with relapsed or refractory AML. The study followed a standard 3 + 3 phase I cohort escalation design. Three dose levels of decitabine were investigated: dose level 1 (7.5 mg/m2); dose level 2 (10 mg/m2); and dose level 3 (15 mg/m2). Patients received decitabine (at assigned dose level) and vorinostat (age <18 years, 180 mg/m2 once daily; >18 years, 200 mg twice daily) days 1 to 5 followed by fludarabine (30 mg/m2, days 6 to 10), cytarabine (2000 mg/m2, days 6 to 10) and granulocyte colony stimulating factor (G-CSF) (5 μ/kg/dose, days 5 until neutrophil recovery) (FLAG). Intrathecal therapy was given up to 72 hours prior to the initial doses of decitabine/vorinostat, with additional intrathecal therapy for central nervous system disease. Patients could receive up to two cycles of therapy. End of course evaluation by bone marrow minimal residual disease (MRD) testing using flow cytometry was performed between days 35 and 42 or upon adequate blood count recovery. Results: Twenty-five patients have enrolled to date with 24 evaluable for dose limiting toxicity (DLT) and response. Median age was 7 (range, 1 to 20) years. Fourteen patients (58.3%) had relapsed after a prior bone marrow transplant and 7 (29.2%) had refractory disease at time of enrollment. There were no dose limiting toxicities at dose level 1 (n=3, 7.5 mg/m2) or 2 (n=3, 10 mg/m2) of decitabine. However, at dose level 3 (n=12, 15 mg/m2), 3 subjects reported Grade 4 invasive fungal infection (Aspergillus terreus, Candida parapsilosis and Rhizomucor pusillus) leading to de-escalation of decitabine to dose level 2. The study continued dose expansion at dose level 2 without DLT, enrolling 7 additional patients. Twenty-two subjects have completed the study and are evaluable for response. Responses were noted at all dose levels. Eight subjects (36.4%) achieved a complete response (CR) or complete response with incomplete hematologic recovery (CRi). Five of the 8 subjects who achieved a CR/CRi were also negative for MRD. Eight subjects had known epigenetic lesions (i.e. KMT2Ar, CEBPα, IDH2) with 6 (75%) achieving a CR, 4 of whom (66.7%) were also MRD negative. Conclusion: Overall, we identified decitabine (10 mg/m2) in combination with vorinostat and followed by FLAG chemotherapy to be well-tolerated and an effective regimen in pediatric patients with relapsed AML, particularly in subjects with known epigenetic lesions. The study continues to enroll at dose level 2 of decitabine for a total accrual goal of 33 subjects. Correlative analysis of peripheral blood and bone marrow investigating methylation, histone acetylation and gene expression is ongoing. Disclosures Burke: Amgen, Inc.: Consultancy, Speakers Bureau.

Outcome in Adolescent and Young Adult (AYA) Patients Compared to Younger Patients Treated for High-Risk B-Lymphoblastic Leukemia (HR B-ALL): Report from the Children's Oncology Group Study AALL0232

Introduction: Adolescent and young adult (AYA) patients (>16 years of age) with high-risk B acute lymphoblastic leukemia (HR B-ALL) have inferior outcomes compared to HR B-ALL patients 1-15 years of age, primarily due to relapse and toxicity. In a prior Children's Oncology Group (COG) HR B-ALL study 1961 (1996 - 2002), 12.7% of patients were AYA (ages 16 - 21 years) with 5-year event-free survival (EFS) and overall survival (OS) of 71.5% and 77.5% respectively. Here we report the outcomes of the most recently completed HR B-ALL COG study AALL0232, comparing AYA and younger patients. Methods: COG study AALL0232 was a Phase 3 randomized trial for patients 1-30 years of age with newly diagnosed HR B-ALL utilizing a 2 x 2 factorial design with an augmented intensityBerlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to two weeks of dexamethasone versus four weeks of prednisone during Induction therapy and high dose methotrexate (HD-MTX) versus escalating Capizzi methotrexate plus pegaspargase (C-MTX) during Interim Maintenance I. Between 2004 and 2011, 3,154 patients enrolled, with 3,081 eligible and evaluable for induction. AYA patients comprised 20% (16-21 years, n= 558; 22-30 years, n=47). Results: The study was amended in 2008 due to an excess incidence of osteonecrosis observed in patients older than 10 years of age who were randomized to dexamethasone. Thereafter, they were nonrandomly assigned to prednisone during induction. The dexamethasone delivered during delayed intensification was also rescheduled from continuous (days 1-14) to discontinuous (days 1-8 and 15-22) delivery. 5-year EFS and OS were 65.1% and 76.9% for AYA patients compared to 77.9% and 87.1% for younger patients (p<0.0001) (Figures 1 and 2). 5-year cumulative incidence of relapse was 18.4% for AYA patients and 13.4% for younger patients (p=0.005), largely due to marrow relapse (13.8% versus 9.0%; p<0.0001). Additionally, fewer AYA patients achieved remission (<5% blasts) at end of Induction, (95.7% versus 97.2%; p=0.078). Day 29 bone marrow minimal residual disease (MRD) <0.01% was achieved in 55.9% of AYA patients compared to 73.9% of younger patients and MRD >1.0% to <10% was reported in 14.8% of AYA compared to 7.3% of non-AYA (p<0.001). Although there was no significant difference in induction mortality (2.5% versus 1.7%; p=0.20), post-induction remission deaths due to toxicity were significantly higher in AYA (5.8% versus 2.6%; p=0.0002). Compared to younger patients, AYAs were more likely to have Ph-like features (17.5% versus 12.1%, p=0.032) and less likely to have ETV6-RUNX1 fusions (3.9% versus 16.3%, p<0.0001). Conclusions: The COG trial AALL0232, which enrolled the largest number of AYA patients to date on a pediatric B-ALL study, demonstrated significantly inferior survival and greater rates of treatment related toxicity compared to younger patients. Although treatment intensification strategies have improved outcomes in younger patients, these have not translated into the same survival benefit in those older. The higher incidence of Ph-like genomic lesions in this group of patients potentially offers a therapeutic opportunity to incorporate targeted therapies for AYA. Thus, future trials must identify novel strategies to not only improve outcomes but further reduce toxicity in the AYA cohort. Disclosures Burke: Amgen, Inc.: Consultancy, Speakers Bureau. Raetz:Pfizer: Research Funding. Gastier Foster:Bristol Myers Squibb (BMS): Other: Commercial Research; Incyte Corporation: Other: Commercial Research. Borowitz:Beckman Coulter: Honoraria. Hunger:Novartis: Consultancy; Jazz: Honoraria; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Equity Ownership. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees.

Primary Analysis of Anti-CD19 Tafasitamab (MOR208) Treatment in Combination with Idelalisib or Venetoclax in R/R CLL Patients Who Failed Prior BTK Inhibitor Therapy (COSMOS Trial)

Primary Analysis of Anti-CD19 Tafasitamab (MOR208) Treatment in Combination with Idelalisib or Venetoclax in R/R CLL Patients Who Failed Prior BTK Inhibitor Therapy (COSMOS Trial)

Excellent Outcomes with Reduced Frequency of Vincristine and Dexamethasone Pulses in Children with National Cancer Institute (NCI) Standard-Risk B Acute Lymphoblastic Leukemia (SR B-ALL): A Report from Children's Oncology Group (COG) Study AALL0932

Background: A key component of COG maintenance chemotherapy for pediatric B-ALL has been the inclusion of vincristine/steroid pulses administered every 4 weeks. With the intensification of pre-maintenance therapy and modern risk stratification, there is uncertainty regarding the optimal frequency of these pulses in the context of modern ALL therapy. AALL0932 was designed to optimize maintenance therapy by asking two questions: (1) whether giving vincristine/dexamethasone (VCR/DEX) pulses every 12 weeks was non-inferior to every 4 week pulses; and (2) whether a starting weekly oral methotrexate (MTX dose) of 40 mg/m²/dose would be superior to the standard 20 mg/m2/dose. We previously reported that there was no benefit to intensifying oral methotrexate during maintenance therapy (ASH 2017). We now report on the outcomes of the VCR/DEX pulses. Methods: Average risk (AR) patients participating in the randomization had NCI SR B-ALL without CNS3 or testicular leukemia, unfavorable genetic characteristics or Down syndrome, AND either favorable genetics (trisomies of chromosomes 4 &10 or ETV6/RUNX1 fusion) with Day 8 peripheral blood (PB) minimal residual disease (MRD) ≥ 0.01% or CNS2 status, Day 29 bone marrow (BM) MRD < 0.01%, OR if neutral cytogenetics, had Day 8 PB MRD < 1% and Day 29 BM MRD < 0.01%. AR patients were randomized to 1 of 4 Maintenance regimens using a 2 x 2 factorial design: (A): VCR/DEX pulses every 4 weeks and oral MTX 20 mg/m²/week (standard arm); (B): VCR/DEX pulses every 4 weeks and oral MTX 40 mg/m²/week; (C): VCR/DEX pulses every 12 weeks and oral MTX 20 mg/m²/week; and (D): VCR/DEX pulses every 12 weeks and oral MTX 40 mg/m²/week. Results from the MTX randomization have been previously reported (ASH 2017). Between 2010 and 2016, 2364 patients were randomized at the start of maintenance to VCR/DEX pulses every 4 weeks [Arms A and B (n=1186)] or VCR/DEX pulses every 12 weeks [Arms C & D (n=1178)]. Results: The 5-year disease-free survival (DFS) (±SE) measured from the time of randomization for the AR subset of patients randomized to receive VCR/DEX pulse every 4 weeks vs. every 12 weeks was 94.1% ±1.0% vs. 95.1% ±0.9%, respectively (one-sided p=0.86 indicating no evidence of DFS inferiority for 12 week frequency). The 5-year overall survival (OS) (±SE) for the AR patients randomized to receive VCR/DEX pulse every 4 weeks vs. every 12 weeks was 98.3% ±0.5%, vs. 98.6% ±0.5%, respectively (one sided p=0.69). There was no evidence of significant interaction between the MTX and VCR/DEX pulses randomizations. Conclusions: AALL0932 demonstrated that the AR subset of patients with SR B-ALL who received VCR/DEX pulses every 12 weeks maintained outstanding outcomes similar to those who received pulses every 4 weeks. The decreased frequency of VCR/DEX pulses will be incorporated into frontline B-lineage COG ALL trials thereby dramatically improving patient and family quality of life. Disclosures Angiolillo: Servier Pharmaceuticals: Consultancy. Schore:Janssen Research & Development, LLC: Research Funding; AMGEN INC: Research Funding. Zweidler-McKay:ImmunoGen: Employment. Borowitz:Beckman Coulter: Honoraria. Relling:Servier Pharmaceuticals: Research Funding. Raetz:Pfizer: Research Funding. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. Hunger:Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Equity Ownership; Jazz: Honoraria; Novartis: Consultancy.

Ofatumumab Plus Hypercvad/MA Induction Leads to High Rates of Minimal Residual Disease (MRD) Negativity in Patients with Newly Diagnosed Mantle Cell Lymphoma, Results of a Phase 2 Study

Background: Minimal residual disease (MRD) status is an independent prognostic marker for response duration in patients with mantle cell lymphoma (MCL). Rituximab-based therapy led to a molecular remission (MR) in 48% young MCL patients treated with intense chemo-immunotherapy. More recently, 4 courses of R-DHAP were reported to yield a 66% MRD negativity rate prior to high dose chemotherapy and autologous stem cell transplant (HDC-ASCT). Ofatumumab is a humanized type 1 anti-CD20 mAb that binds to a unique, more membrane-proximal epitope on the CD20 antigen. Pre-clinical studies have demonstrated that ofatumumab (O) is more active than rituximab in eliciting complement-mediated cytotoxicity (CMC) in MCL cell lines, primary tumor cells and murine lymphoma xenograft models. Hence, we evaluated the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL (NCT01527149). Study design: This was a single-arm, open-label, multi-center (2 centers), prospective, phase 2 clinical trial. Thirty-seven transplant-eligible patients with newly diagnosed MCL were enrolled. Ofatumumab (1000mg) was given every 3 weeks on day 1, followed by standard doses of alternating HyperCVAD and MA starting on day 3. A total of 6 cycles were given at 3-week intervals followed by HDC-ASCT. Maintenance rituximab 375 mg/m2 every 2 months for 3 years post-ASCT was added after protocol amendment following publication of the LyMa study. Primary objectives were to determine the overall response rate (ORR) and CR rate (CRR) at the end of therapy. Secondary objectives included MRD negativity, progression free survival (PFS), overall survival (OS), feasibility of successful mobilization of autologous stem cells and safety assessment. MRD assessment was performed in peripheral blood (PB) and bone marrow (BM) using high sensitivity multiparametric flowcytometry at baseline, after 2 cycles, after 4 cycles, pre-ASCT, post-ASCT and 6 months post-ASCT. Exploratory endpoints included correlation of MRD with survival, correlation of surface CD20 levels with response and to compare differences in ORR according to Cheson and modified Cheson (MC) criteria. Results: Median age was 60yrs; 73% of patients were male, 92% had an ECOG PS 0-1, majority (81%) had stage 4 disease with 86% having bone marrow involvement; 22% had low risk, 43% had intermediate risk and 35% had high risk MIPI score; 11% had blastoid and 11% had pleiomorphic variants of MCL; 25% harbored p53 deletion. MRD was assessed in 28 of 37 patients; 9 patients from partner site were excluded due to time lag in sample delivery for flowcytometry. MRD positivity was noted in 75% patients in PB and 71.4% patients in BM at baseline. Subsequent samples showed an MRD negativity rate of 82.1% and 64.3% after 2 cycles and 76% and 96% pre-ASCT in PB and BM respectively. Post-ASCT, MRD in BM and PB was found negative in 58% and 90%, respectively. Attainment of early MRD negativity (after 2 cycles) was associated with improved PFS (p=0.04) and OS (p=0.03). Since majority of patients were MRD negative pre-ASCT, we could not demonstrate correlation between pre-ASCT MRD and survival outcomes. The ORR and CRR were 95% and 62% by Cheson and 97% and 84% respectively by modified Cheson criteria. At the end of induction therapy, ORR was 86% and CRR was 62% by Cheson criteria. 73% pts underwent HDC-ASCT. Only one patient failed stem cell collection. The median PFS and OS were 45.5 months and 56 months respectively. There were 3 deaths while on therapy- 2 from sepsis and one from acute myeloid leukemia. Grade 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients, most of them were hematological AEs related to the chemotherapy regimen. Correlation of surface CD20 expression using mean fluorescent intensity (MFI) and response rates is currently under analysis and will be reported at the meeting. Conclusion: The addition of ofatumumab to HyperCVAD/MA led to high rates of MRD negativity by flowcytometry in patients with newly diagnosed MCL. Early MRD negativity (after 2 cycles) was associated with better PFS and OS. Despite higher ORR, CR and MRD negativity rates, survival outcomes were similar to historical cohorts using rituximab-HypeCVAD/MA. This may be in part due to increased number of patients with high-risk disease in our study. Disclosures Reddy: KITE Pharma: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding. Sait:Celgene: Consultancy. OffLabel Disclosure: Ofatumumab was investigated in combination with chemotherapy in newly diagnosed mantle cell lymphoma in this clinical trial.

Encouraging Results with ALL IC-BFM 2009 Protocol Therapy in Pediatric Acute Lymphoblastic Leukemia/Lymphoma in Resource-Limited Setting: A Single-Center Study from India

Background: Acute lymphoblastic leukemia (ALL) is the commonest cancer in children. The survival rates in pediatric ALL have improved to 80-90% in high-income countries, where the goal of current risk-adapted treatment protocols is to minimize treatment-related mortality. In contrast, cure/survival rates are still lower in low-income countries, due to combined effect of disease-related factors, high incidence of treatment abandonment, higher rates of relapse, & higher treatment-related mortality. The Berlin-Frankfurt-Münster (BFM) protocol versions are commonly used for treatment of pediatric ALL in many centers. There is no published data on treatment outcomes with ALL IC-BFM 2009 protocol in pediatric ALL in India. Objective: The study aims to evaluate the treatment outcomes in Indian pediatric ALL/LBL patients treated with ALL IC-BFM 2009 protocol under severe resource-limited settings, in terms of morphological complete remission (CR), minimal residual disease (MRD) status, and disease-free survival. Methods: Our study enrolled 25 newly diagnosed pediatric ALL/LBL patients (age ≤18 years) between February 2018 & June 2019. Induction chemotherapy was initiated as per ALL IC-BFM 2009 protocol after obtaining informed consent. Risk stratification was done as per protocol into standard risk (SR), intermediate risk (IR), and high risk (HR) groups, based on age, baseline leukocyte count, cytogenetics & molecular study findings, day 8 steroid response (peripheral blood absolute blast count), bone marrow MRD by flowcytometry on day 15, and bone marrow morphological response on days 15 & 33 of induction phase. Additional imaging was done to assess response in LBL patients. Central nervous system (CNS)-directed therapy with intrathecal chemotherapy was administered as per protocol. Post-induction therapy consisted of an augmented early intensification phase, risk-adapted consolidation therapy phase, a delayed intensification (reinduction) phase, & maintenance phase. Therapeutic cranial radiation (18 Gy) was administered only to patients with documented CNS leukemia. Results: Of the total 25 patients, 17 had B-ALL, six had T-ALL & two had T-LBL. Median age of patients was 9 years (2-18 years), with 11 boys & 14 girls. All the patients had BCR-ABL negative disease; three patients had t(12;21)(p13;q22)/ETV6-RUNX1. Seven patients (28%) had hyperleukocytosis (leukocyte count >1,00,000/µL) and two patients had CNS leukemia at presentation. Nine out of the 25 patients (36%) were in high risk group as per criteria. Eight patients (32%) had poor steroid response on day 8 of induction (PB blasts ≥ 1000/µL). Six patients had M3 marrow on day 15 (>25% blasts in marrow). Day 15 bone marrow MRD was <0.1% in 13 patients (52%), >0.1% in 7 patients (28%) and could not be done in 5 patients (including the two T-LBL patients). Twenty-three out of 25 patients (92%) achieved morphological CR (marrow blasts <5%) on day 33. There were two deaths in induction; both patients were not in CR as per day 33 bone marrow morphology criteria. One B-ALL patient in HR group died of early medullary relapse. The remaining 22 patients are in CR & doing well on follow up, and four of them have started maintenance phase therapy. The results are summarized in Table 1. Conclusion: Our preliminary results with ALL IC-BFM 2009 treatment protocol in Indian pediatric ALL/LBL patients are encouraging, with 92% complete remission rate, 88% disease-free survival and manageable treatment-related toxicity in spite of severe resource constraints. Long-term follow up & enrollment of higher number of patients is planned. Disclosures No relevant conflicts of interest to declare.

High Sensitivity NGS Analysis of MRD in CLL Patients Prospectively Treated with Ibrutinib Plus FCR (iFCR)

High Sensitivity NGS Analysis of MRD in CLL Patients Prospectively Treated with Ibrutinib Plus FCR (iFCR)

A Phase 1/2 Study of Umbralisib Ublituximab and Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

A Phase 1/2 Study of Umbralisib Ublituximab and Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

MRD Evaluation By PET/CT According to Deauville Criteria Combined with Multiparameter Flow Cytometry in Newly Diagnosed Transplant Eligible Multiple Myeloma (MM) Patients Enrolled in the Phase II Randomized Forte Trial

MRD Evaluation By PET/CT According to Deauville Criteria Combined with Multiparameter Flow Cytometry in Newly Diagnosed Transplant Eligible Multiple Myeloma (MM) Patients Enrolled in the Phase II Randomized Forte Trial

Minimal residual disease and quality sample evaluation by Next Generation Flow cytometry in multiple myeloma patients: a Brazilian experience

Increasing evidence suggests that of minimal residual disease (MRD) in bone marrow (BM) is one of the most relevant independent prognostic factors in multiple myeloma (MM). Recently, EuroFlow consortium developed and validates the Next Generation Flow cytometry (NGF) approach to evaluate BM MRD in MM patients, at very low levels and, simultaneously is able to estimate the sample hemodilution. Here, we evaluated flow-MRD by NGF in MM patients after autologous stem cell transplantation (ASCT) and compared with conventional techniques for response criteria in serum.