MRD-negative Rates Research Articles

Real-World Experience with Minimal Residual Disease Testing with Next Generation Flow Cytometry and Functional Imaging in Multiple Myeloma

Background: Minimal residual disease (MRD) diagnostics in multiple myeloma (MM) are gaining increasing importance to determine response depth beyond complete remission (CR) since novel agents have shown to induce high rates of deep clinical responses. Moreover, recent reports indicated combining functional imaging with next generation flow cytometry (NGF) could be beneficial in predicting clinical outcome. This applies in particular to the subset of patients suffering from relapsed/refractory multiple myeloma (RRMM) who tend to show a higher incidence of residual focal lesions despite serological response. Here, we report our institutions experience with implementing both functional imaging and NGF-guided MRD diagnostics in clinical practice. Methods: Our study included patients with newly diagnosed multiple myeloma (NDMM) and RRMM achieving VGPR, CR or sCR. Bone marrow aspirates were obtained for MRD-testing according to IMWG 2016 criteria. Samples were collected between July 2019 and July 2020 and analyzed with NGF (according to EuroFlowTM guidelines) at a sensitivity level of 10-5. Results were compared to functional imaging obtained with positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI). High-risk disease was defined as presence of deletion 17p, translocation (14;16) or (4;14). Results: We included 66 patients with NDMM (n=39) and RRMM (n=27) who achieved VGPR or better. In patients with RRMM the median number of treatment lines was 2 (range 2-11). Fifteen patients suffered from high-risk disease. Median age at NGF diagnostics was 64 years (range 31-83). Among patients achieving VGPR (n=27), CR (n=10) and sCR (n=29) seventeen (26%) were MRD-negative by NGF testing. CR or better was significantly associated NGF MRD-negativity (p=0.04). Notably, rates of NGF MRD-negativity were similar among patients with NDMM (28%) and RRMM (26%). Even some heavily pretreated patients who underwent ≥ 4 lines of therapy achieved MRD-negativity on NGF (2 of 9). Functional imaging was performed in 46 (70%) patients with DW-MRI (n=22) and PET (n=26). Median time between NGF and imaging assessment was 2 days (range 0-147). Combining results from imaging and NGF, 12 out of 46 (26%) patients were MRD-negative with both methods (neg/neg). Three patients displayed disease activity as measured with both, imaging and NGF (pos/pos). Twenty-nine of the remaining patients were MRD-positive only according to NGF (pos/neg), while two patients were positive on imaging only (neg/pos). More patients demonstrated combined MRD-negativity on NGF and imaging (neg/neg) in the NDMM setting than in RRMM (32% versus 19%). We also observed that 30% of the patients with high-risk genetics showed MRD-negativity on both imaging and NGF. Of note, none of the patients with very advanced disease (≥4 previous lines) was MRD-negative on both techniques. Conclusion In the clinical routine, MRD diagnostics could be used to tailor maintenance and consolidation approaches for patients achieving deep responses by traditional IMWG criteria. Our real-world experience highlights that MRD-negativity can be achieved in patients suffering from high-risk disease and also in late treatment lines, supporting its value as endpoint for clinical trials. However, our data also support MRD diagnostics to be combined with functional imaging at least in the RRMM setting to rule out residual focal lesions. Future studies using MRD for clinical decision-making are highly warranted. Disclosures Einsele: Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rasche:Celgene/BMS: Honoraria; GlaxoSmithKline: Honoraria; Oncopeptides: Honoraria; Skyline Dx: Research Funding; Janssen: Honoraria; Sanofi: Honoraria.

A Phase II, Open-Label, Single Arm Trial to Assess the Efficacy and Safety of the Combination of Tisagenlecleucel and Ibrutinib in Mantle Cell Lymphoma (TARMAC)

Background Mantle cell lymphoma (MCL) is a clinically and pathogenetically distinct B-cell non-Hodgkin lymphoma that presents at a median age of 65 years and typically at an advanced stage. High dose chemotherapy and stem cell transplantation can achieve durable responses, but disease eventually relapses in most patients. Allogeneic transplantation can achieve a cure in some but is only suitable for a minority of younger, fitter patients who achieve remission to salvage but carries risks of GVHD. Bruton tyrosine kinase inhibitors (BTKi) are active in relapsed MCL but the median PFS is generally less than 2 years and ibrutinib failure is associated with particularly poor outcomes (Cheah et al., Ann Oncol 2015). Mutations of TP53 are associated with refractoriness to both chemotherapy and novel agents (Eskelund et al., Blood 2017), and patients with disease harboring these mutations are in particular need of more effective therapies. Promising activity has recently been demonstrated with chimeric antigen receptor T-cells (CAR T), albeit with significant rates of cytokine release syndrome (CRS) and neurotoxicity (Wang et al., New England Journal of Medicine 2020), resulting in FDA approval of brexucabtagene autoleucel in MCL. Rationale Tisagenlecleucel (Novartis) is a CAR T-cell product directed against CD19 that is approved in many countries for the treatment of relapsed DLBCL and ALL. MCL consistently expresses CD19 at diagnosis and relapse and is therefore a promising target. Pre-clinical data suggests synergistic effects if tisagenlecleucel is combined with the BTKi ibrutinib. The proposed mechanism includes enhancing T cell activation and expansion (Fraietta et al., Blood 2016), disrupting the MCL nodal environment (Long et al., The Journal of Clinical Investigation 2017) and mitigating CRS (Ruella et al., Clin Cancer Res 2016). Clinical trials in CLL show that the combination is safe and effective, including deep minimal residual disease negative responses (Gill et al., Blood 2018, Gauthier et al., Hematological Oncology 2019). We hypothesise that combination treatment will be tolerable and improve outcomes in a poor risk MCL population. Combination, time-limited therapy would also avoid the burdens of continuous treatment. Study Design and Methods 20 adult patients with MCL that has relapsed following front-line therapy, or those patients with MCL with TP53 aberrations who have achieved less than complete response on PET imaging after 2 cycles of induction will be enrolled (See Fig 1. for inclusion and exclusion criteria). Treatment consists of 560mg oral ibrutinib followed by a single infusion of tisagenlecleucel. Autologous lymphocytes for CAR T manufacture will be collected after a minimum of 7 days of continuous ibrutinib therapy. Ibrutinib will be continued during CAR T manufacture and for 6 months after infusion (see Fig 2.) Patient characteristics will be presented using descriptive statistics, response rates will be calculated as percentages using exact methods from the binomial distribution, and progression-free survival, duration of response and overall survival will be described using the Kaplan-Meier method. The primary objective is to estimate the complete response (CR) rate at month 4 following tisagenlecleucel infusion in combination with ibrutinib with the primary endpoint being CR rates at month 4 post tisagenlecleucel using the Lugano criteria. Secondary objectives include estimating MRD negative response rates, response rates according to TP53 status, and safety of the combination. Exploratory translational studies include studies of T cell repertoire and phenotype during ibrutinib exposure and after tisagenlecleucel infusion. The role of circulating tumour DNA monitoring in the management of MCL is also being evaluated. The trial is investigator led, sponsored by the Peter MacCallum Cancer Centre, with additional sites throughout Australia. The study was initiated in April 2020 and is actively recruiting patients. The trial is registered at ClinicalTrials.gov: NCT04234061. Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. Blombery:Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria; Novartis: Consultancy. Seymour:Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Pharmacyclics LLC, an AbbVie Company: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Dickinson:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy. OffLabel Disclosure: Tisagenlecleucel is not currently approved for use in MCL.

Cytogenetic Subgroups Drive Risk Stratification and Response to Chemotherapy and Blinatumomab in Children and Young Adults with Relapsed B-ALL: A Children's Oncology Group Study

Background At initial diagnosis, sentinel cytogenetic (CG) abnormalities differ based on demographic/clinical features and are predictive of relapse risk in B-lymphoblastic leukemia (B-ALL). The relevance of CG at 1st relapse is not well defined. Children's Oncology Group (COG) AALL1331 enrolled non-BCR-ABL1+, non-Down syndrome 1st relapse B-ALL patients (pts) 1-30 years (yr) old. After a common chemotherapy induction (Block 1), pts were risk assigned as: High risk (HR): Early bone marrow (BM) relapse <36 months from diagnosis or isolated extramedullary (IEM) relapse <18 months; Intermediate risk (IR): Late BM relapse (>36 months) with minimal residual disease (MRD) ≥0.1% at end Block-1 (EB-1); Low risk (LR): Late BM relapse with MRD <0.1% at EB-1; Treatment failure (TF): M3 BM or failure to clear central nervous system at EB-1. The primary objective of the trial for HR/IR pts was to randomly compare post-reinduction therapy with 2 blocks of chemotherapy vs. blinatumomab, followed by allogeneic transplant. We previously reported the superiority of blinatumomab for HR/IR pts (Brown, ASH 2019). We hypothesized that CG would correlate with clinical features at relapse and response to therapy, enhancing relapse risk stratification. Methods CG data (karyotype and FISH) at relapse were centrally reviewed. CG groups were defined as: favorable (fav) (double trisomies (DT) or ETV6-RUNX1), unfavorable (unfav) (hypodiploid, KMT2A-rearranged (KMT2A-R) or iAMP21), and neutral (all others). Of 662 eligible pts, 130 IEM relapses were excluded, since CG data were not available due to lack of BM involvement. Of 532 BM relapses, CG data were available for 394 (74%); this group was used for associations of CG with clinical features and response to Block 1. Of 188 BM relapses risk assigned HR/IR and randomized, CG data were available for 147 (78%; 72 Arm A chemotherapy, 75 Arm B blinatumomab); this group was used for associations of CG with response to randomized post-reinduction therapy. CG distributions at initial diagnosis were based on data from over 16,000 pts enrolled on COG upfront trials from 1996-2014. Statistical comparisons used Pearson's chi-squared, Fisher's exact, Wilcoxon rank sum, or logrank test as appropriate. All p values are two-sided. Results As expected, unfav CG were more common at relapse compared to diagnosis (17% vs 7% p<0.001), and the opposite for fav CG (22% vs 42% p<0.001). Also expected was the younger age at relapse for the fav (median 8 yr) and KMT2A-R (median 2 yr) CG vs. others (median 12 yr, p=0.002). WBC at relapse was higher in the KMT2A-R (median 11k/uL), but similar in all others (median 5k/uL, p=0.041). Time from diagnosis to relapse differed by CG group, with late BM relapses comprising 79% of fav vs. 61% of neutral vs. 48% of unfav (p<0.001). EB-1 MRD-negative rates were highest for fav (53%), intermediate for neutral (38%) and lowest for unfav (25%, p=0.002). Interestingly, in fav CG group, 62% of ETV6-RUNX1 vs. 40% of DT were EB-1 MRD-negative (p=0.043), suggesting that as for newly diagnosed pts, MRD clearance during relapse reinduction may be slower for DT than for ETV6-RUNX1. EB-1 risk assignments differed significantly by CG group, with rates for fav/neutral/unfav CG of 57%/35%/27% for LR, 16%/31%/34% for HR, and 3%/7%/7% for TF (p<0.01). After 1st course of randomized therapy for HR/IR pts, the rate of EB-2 MRD negativity was (as previously reported) much higher for arm B (75%) vs arm A (25%, p<0.001). Interestingly, EB-2 MRD clearance rates did not vary significantly by CG group for either randomized arm. There was, however, an influence of CG group on survival for arm B, but not for arm A. The 2 yr DFS/OS for fav CG on arm B was 77%/93%, vs. 49%/65% for neutral and 49%/49% for unfav (p=0.069 for DFS, p=0.035 for OS, univariate analysis). For arm A, DFS/OS was similar and consistently poor in all three groups (44%/52% fav vs. 49%/61% neutral and 39%/61% unfav, p=0.92 for DFS, p=0.62 for OS) (Table 1). Conclusions Pts with fav CG B-ALL relapse later and are more likely to achieve MRD negativity after reinduction chemotherapy, resulting in higher rates of LR risk assignment. Interestingly, while the superior MRD clearance with blinatumomab vs. chemotherapy is seen in all CG groups, this only translated into higher rates of DFS/OS in the fav CG group. Thus, the influence of CG on outcomes after 1st relapse may differ based on whether chemotherapy or immunotherapy is used as post-reinduction consolidation. Disclosures Gore: Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Hunger:Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Brown:Jazz: Honoraria; Servier: Honoraria; Janssen: Consultancy; Novartis: Consultancy.

Subcutaneous Daratumumab (DARA SC) Plus Standard-of-Care (SoC) Regimens in Multiple Myeloma (MM) across Lines of Therapy in the Phase 2 Pleiades Study: Initial Results of the Dara SC Plus Carfilzomib/Dexamethasone (D-Kd) Cohort, and Updated Results for the Dara SC Plus Bortezomib/Melphalan/Prednisone (D-VMP) and Dara SC Plus Lenalidomide/Dexamethasone (D-Rd) Cohorts

Subcutaneous Daratumumab (DARA SC) Plus Standard-of-Care (SoC) Regimens in Multiple Myeloma (MM) across Lines of Therapy in the Phase 2 Pleiades Study: Initial Results of the Dara SC Plus Carfilzomib/Dexamethasone (D-Kd) Cohort, and Updated Results for the Dara SC Plus Bortezomib/Melphalan/Prednisone (D-VMP) and Dara SC Plus Lenalidomide/Dexamethasone (D-Rd) Cohorts

Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX

High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10–5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.

Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia

Administration of pediatric-inspired chemotherapy to adults up to age 60 with acute lymphoblastic leukemia (ALL) is challenging in part due to toxicities of asparaginase as well as myelosuppression. We conducted a multi-center phase II clinical trial (clinicaltrials gov. Identifier: NCT01920737) investigating a pediatric-inspired regimen, based on the augmented arm of the Children’s Cancer Group 1882 protocol, incorporating six doses of pegaspargase 2,000 IU/m2, rationally synchronized to avoid overlapping toxicity with other agents. We treated 39 adults aged 20-60 years (median age 38 years) with newly-diagnosed ALL (n=31) or lymphoblastic lymphoma (n=8). Grade 3-4 hyperbilirubinemia occurred frequently and at higher rates in patients aged 40-60 years (n=18) versus 18-39 years (n=21) (44% vs. 10%, P=0.025). However, eight of nine patients rechallenged with pegaspargase did not experience recurrent grade 3-4 hyperbilirubinemia. Grade 3-4 hypertriglyceridemia and hypofibrinogenemia were common (each 59%). Asparaginase activity at 7 days post-infusion reflected levels associated with adequate asparagine depletion, even among those with antibodies to pegaspargase. Complete response (CR)/CR with incomplete hematologic recovery was observed post-induction in 38 of 39 (97%) patients. Among patients with ALL, rates of minimal residual disease negativity by multi-parameter flow cytometry were 33% and 83% following induction phase I and phase II, respectively. Event-free and overall survival at 3 years (67.8% and 76.4%) compare favorably to outcomes observed in other series. These results demonstrate pegaspargase can be administered in the context of intensive multi-agent chemotherapy to adults aged ≤60 years with manageable toxicity. This regimen may serve as an effective backbone into which novel agents may be incorporated in future frontline studies. Trial registration: https://clinicaltrials. gov/ct2/show/NCT01920737

AML-187: The STIMULUS Clinical Trial Program: Evaluating Combination Therapy with MBG453 in Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS) or Acute Myeloid Leukemia

Context TIM-3, an inhibitory receptor with a key role in regulating adaptive and innate immunity, is expressed on multiple immune cell types as well as leukemic stem cells and blasts, but not normal hematopoietic stem cells, making it a promising target in MDS and AML. In a phase 1b study ( NCT03066648 ), the anti–TIM-3 monoclonal antibody, MBG453, plus decitabine showed promising preliminary efficacy with a good safety profile in patients with higher-risk MDS or AML (Borate et al, ASH 2019). Objective The STIMULUS clinical trial program is evaluating the efficacy and safety of MBG453 combination therapy in patients with HR-MDS or AML. Design Two study designs from the STIMULUS clinical trial program are described. STIMULUS-MDS1 (N≈120; NCT03946670 ) is a double-blind study evaluating whether MBG453 plus hypomethylating agents (HMA) improves complete remission (CR) rate and progression-free survival (PFS) vs HMA alone in HR-MDS. Secondary endpoints include overall survival (OS), event-free survival (EFS), leukemia-free survival (LFS), transfusion independence, safety, pharmacokinetics, and immunogenicity. Eligible patients are treatment-naive, aged ≥18 years, with HR-MDS (IPSS-R high-/very high-risk MDS, or intermediate-risk MDS with ≥5% bone marrow blasts). Patients are randomized 1:1 to receive MBG453 400 mg or placebo IV D8, D22, plus decitabine 20 mg/m2 IV D1–D5; or azacitidine (AZA) 75 mg/m2 IV/SC D1–D7, or D1–D5, D8-D9 of each 28-day cycle. This study is currently recruiting patients worldwide. STIMULUS-AML1 (N≈86; NCT04150029 ) is an open-label study evaluating the safety (incidence of dose-limiting toxicities) and efficacy (CR rate) of MBG453+AZA+venetoclax. Secondary endpoints include safety and tolerability, CR/CRi rate, MRD-negative rate, CR durability, relapse-free survival, EFS, OS, pharmacokinetics, transfusion independence, and immunogenicity. Eligible patients are adults with newly diagnosed untreated AML who are not suitable for IC or HSCT based on age (≥75 years old) or comorbidities (including renal impairment, cardiac and pulmonary comorbidities). Part 1 is a safety run-in (n≈18) across 2 MBG453 dose levels (400/800 mg IV D8 of each 28-day cycle) plus AZA (75 mg/m2 IV/SC D1–D7, or D1–D5, D8-D9) and venetoclax 400 mg PO QD. If the triplet is assessed to be safe, Part 2 (expansion; n≈68) will investigate MBG453 at 800 mg Q4W in combination with AZA+venetoclax.

Who Should Receive an Allogeneic Transplant in First Complete Remission?

The decision to incorporate allogeneic hematopoietic stem cell transplant (allo-HSCT) into front-line therapy in adult acute lymphoblastic leukemia (ALL) should be primarily guided by measurable residual disease (MRD) status and the ALL regimen utilized. While there is no doubt that allo-HSCT benefits patients with poor MRD response after induction or consolidation, the indication of allo-HSCT in cases of good MRD clearance is not clear. As targeted immunotherapies result in high MRD-negative CR rates, early incorporation of these therapies may also prove valuable in reducing the need for HCT in the front-line setting. This review discusses the data and controversies related to allo-HSCT in the front-line therapy of Philadelphia chromosome-negative and -positive ALL.

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk

BackgroundMultiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM).MethodsThis subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10−5 sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk.ResultsAfter a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21–0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR.ConclusionThese updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status.Trial registrationClinicalTrials.gov, NCT02136134. Registered 12 May 2014

Daratumumab + bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM): Baseline SLiM-CRAB based subgroup analysis of CASSIOPEIA.

8538 Background: In the phase 3 CASSIOPEIA study, D-VTd significantly improved outcomes vs VTd in TE NDMM pts at an 18.8-mo median follow-up. To allow earlier diagnosis and treatment of MM, the IMWG added 3 validated biomarkers (≥60% clonal bone marrow plasma cells, serum free light chain ratio ≥100, and &gt; 1 focal bone lesion by MRI; “slim”) to the conventional “CRAB” diagnostic criteria. We present a subgroup analysis of CASSIOPEIA based on baseline slimCRAB criteria. Methods: TE NDMM pts were randomized 1:1 to 4 pre-ASCT induction and 2 post-ASCT consolidation cycles of D-VTd or VTd. The “slim-only” subgroup excludes pts with ≥1 conventional CRAB criterion based on data collected at baseline; the remaining pts were included in the “CRAB” subgroup. Results: Of 1085 randomized pts (543 D-VTd; 542 VTd), 81 were included in the slim-only subgroup (36 D-VTd; 45 VTd) and 1004 were included in the CRAB subgroup. In slim-only vs CRAB pts, 22% vs 54% had an ECOG score of ≥1, 4% vs 16% had ISS Stage III disease, and 11% vs 16% had high-risk cytogenetics. For D-VTd vs VTd pts in the slim-only group, these rates were 22% vs 22%, 8% vs 0%, and 6% vs 16%, respectively. Overall response rates (ORR) and rates of sCR, ≥CR, and MRD negativity were similar between slim-only and CRAB pts; for slim-only pts, rates were significantly higher for D-VTd vs VTd (Table). After an 18.8-mo median follow-up, progression-free survival (PFS) was not significantly different in slim-only vs CRAB pts, or in D-VTd vs VTd slim-only pts (Table). For D-VTd vs VTd CRAB pts, 18-mo PFS rates were 92% vs 84%, and 24-mo PFS rates were 89% vs 76%. Conclusions: Baseline characteristics indicate that slim-only pts were slightly fitter and of lower risk status vs CRAB pts; however, response rates, MRD-negativity rates, and PFS did not differ significantly between these groups. Among slim-only pts, significantly higher response and MRD-negativity rates were achieved with D-VTd vs VTd. Among CRAB pts, PFS rates were higher with D-VTd vs VTd. Clinical trial information: NCT02541383 . [Table: see text]

CULMINATE: A phase II study of cusatuzumab + azacitidine in patients with newly diagnosed AML, ineligible for intensive chemotherapy.

TPS7565 Background: AML, the most common acute leukemia in adults, is a heterogeneous malignancy characterized by uncontrolled clonal expansion of hematopoietic progenitor cells. Median diagnosis age is ~67 yrs. Despite current therapies prognosis is poor with 5-yr OS ~25% for patients (pts) ≥65 yrs. For pts unable to receive intensive chemotherapy, survival rates are worse, indicating a critical need to develop better treatments. CD70 is expressed on &gt;95% of AML blasts harvested from newly diagnosed AML pts but not on normal hematopoietic stem cells nor most normal tissues. Cusatuzumab is a first-in-class, high-affinity anti-CD70 monoclonal antibody with multiple mechanisms of action, including Fc-mediated cytotoxicity with enhanced ADCC and inhibition of CD70/CD27 signaling, resulting in leukemia blast and stem cell cytotoxicity. As cusatuzumab and azacitidine target distinct pathways of myeloblast propagation, a combination may have a synergistic therapeutic effect and overcome treatment resistance. Initial data from a Phase I study (NCT03030612) with cusatuzumab (1–20 mg/kg) + standard dose azacitidine in AML pts ineligible for intensive chemotherapy showed no dose-limiting toxicity and a CR/CRi (CR with partial/incomplete hematologic recovery) in 10 of 12 pts (ASH 2019, Abs #234). This abstract describes a follow-on Phase II study (NCT04023526). Methods: CULMINATE is a 2-part study of cusatuzumab + azacitidine to determine the optimal dose of cusatuzumab (Table). Inclusion criteria: ≥18 yrs with de novo or secondary AML unfit for intensive therapy (≥75 or &lt;75 yrs with a comorbidity [i.e. ≥1 of: ECOG 2, severe cardiac/pulmonary or moderate hepatic impairment]). In Part 1, pts are randomized 1:1 to cusatuzumab 10 or 20 mg/kg (IV, on Days 3 and 17 of each 28-day cycle) + azacitidine (75 mg/m2 SC or IV on Days 1–7). Data will be reviewed after 15, 30 and 50 pts are enrolled into each arm to select the cusatuzumab dose for the Part 2 expansion cohort in which efficacy and safety will be further evaluated. Follow-up continues until death, loss to follow-up or study end. The primary objective is to determine CR rate. Secondary objectives include rate of CRi/CRh, rate of MRD-negativity, ORR, time to and duration of response, pharmacokinetics, immunogenicity, transfusion independence and safety. Enrollment began in Sept 2019 and is currently two-thirds complete. Clinical trial information: NCT04023526 . [Table: see text]

Impact of minimal residual negativity using next generation flow cytometry on outcomes in light chain amyloidosis.

We evaluated bone marrow minimal residual disease (MRD) negativity in 44 patients with light chain (AL) amyloidosis using next generation flow cytometry (sensitivity ≥1 × 10-5 ; median events analyzed: 8.7 million, range: 4.8 to 9.7 million). All patients underwent MRD testing in 2 years from start of therapy (median: 7 months). The overall MRD negative rate was 64% (n = 28). The MRD-negative rate after one-line of therapy was 71% (20/28). And, MRD negative rates were higher with stem-cell transplant as first-line therapy (86%, 18/21) vs chemotherapy alone as first-line treatment (29%, 2/7), P = .005. The MRD negative rate amongst patients in complete response was 75% (15/20), and in very good partial response, 50% (11/22). There were two patients in partial response/rising light chains (with renal dysfunction) who were MRD negative. There were no differences in baseline characteristics of MRD negative vs MRD positive patients, except younger age amongst MRD-negative patients. Patients with MRD negativity were more likely to have achieved cardiac response at the time of MRD assessment, 67% (8/12) vs 22% (2/7), P = .04. Renal response rates were similar in both groups. Progression free survival was assessed in the 42 patients achieving CR or VGPR. After median follow-up of 14 months, the estimated 1-year progression free survival in MRD negative vs MRD positive patients was 100% (26 patients, 0 events) vs 64% (16 patients, five events), P = .006, respectively. MRD assessment should be explored as a surrogate endpoint in clinical trials and MRD risk-adapted trials may help optimize treatment in AL amyloidosis.

Antibody therapy for multiple myeloma: novel approaches and future perspectives

Although multiple myeloma has been defined as incurable, and the treatment outcome has recently improved rapidly. Antibodies against multiple myeloma, elotuzumab, and daratumumab can safely enhance their effects even when added to the combination therapy of proteasome inhibitors and immunomodulators that have been used till date. Initially, triplet therapy combining antibody therapy with doublet therapy was approved in Japan for relapsed or refractory multiple myeloma. In 2019, daratumumab combination therapies were approved for newly diagnosed multiple myeloma patients, and these therapies are the new standard of care. Recently, the results of clinical trials that added daratumumab to the triplet therapies of proteasome inhibitors, immunomodulators, and dexamethasone have been reported. These trials report greater therapeutic effects, with a significant improvement in the MRD negative rate. We hope that quadruplet therapy including these antibodies will be available in clinical practice, leading to further improvements in the treatment outcomes.

Impact of minimal residual disease status in patients with relapsed/refractory acute lymphoblastic leukemia treated with inotuzumab ozogamicin in the phase III INO-VATE trial

Minimal residual disease (MRD) negativity is a key prognostic indicator of outcome in acute lymphocytic leukemia. In the INO-VATE trial (clinicaltrials.gov identifier: NCT01564784), patients with relapsed/refractory acute lymphocytic leukemia who received inotuzumab versus standard chemotherapy achieved greater remission and MRD-negativity rates as well as improved overall survival: hazard ratio 0.75, one-sided P = 0.0105. The current analysis assessed the prognostic value of MRD negativity at the end of inotuzumab treatment. All patients who received inotuzumab (n = 164) were included. Among patients with complete remission/complete remission with incomplete hematologic response (CR/CRi; n = 121), MRD-negative status (by multiparametric flow cytometry) was defined as <1 × 10–4 blasts/nucleated cells. MRD negativity was achieved in 76 patients at the end of treatment. Compared with MRD-positive, MRD-negative status with CR/CRi was associated with significantly improved overall survival and progression-free survival, respectively: hazard ratio (97.5% confidence interval; one-sided P-value) 0.512 (97.5% CI [0.313–0.835]; P = 0.0009) and 0.423 (97.5% CI [0.256–0.699]; P < 0.0001). Median overall survival was 14.1 versus 7.2 months, in the MRD-negative versus MRD-positive groups. Patients in first salvage who achieved MRD negativity at the end of treatment experienced significantly improved survival versus that seen in MRD-positive patients, particularly for those patients who proceeded to stem cell transplant. Among patients with relapsed/refractory acute lymphocytic leukemia who received inotuzumab, those with MRD-negative CR/CRi had the best survival outcomes.

Daratumumab (DARA) Plus Lenalidomide Versus Lenalidomide Alone As Maintenance Treatment in Patients with Newly Diagnosed Multiple Myeloma (NDMM) after Frontline Autologous Stem Cell Transplant (ASCT): Use of Minimal Residual Disease (MRD) As a Novel Primary Endpoint in the Phase 3 Auriga Study

Background: DARA, a human anti-CD38 IgGκ monoclonal antibody, is approved in many countries as monotherapy in relapsed/refractory MM (RRMM), in combination with standard-of-care (SoC) regimens in RRMM and upfront in transplant ineligible NDMM. DARA is also under investigation as part of induction, consolidation, and maintenance treatment in patients with NDMM who are transplant eligible. However, no studies have specifically compared DARA maintenance to current SoC maintenance regimens. Although deep response as measured by MRD negativity has been associated with positive long-term clinical outcomes, and previous studies have demonstrated that DARA increases MRD negativity rates when combined with SoC therapy, MRD as a primary end point has not been examined in the context of frontline DARA treatment in NDMM. The ongoing phase 3 AURIGA (MMY3021) study will evaluate whether the addition of DARA to lenalidomide maintenance therapy increases the conversion rate to MRD negativity after 1 year of maintenance treatment, compared to lenalidomide alone, in patients with NDMM who are MRD positive after ASCT. Study Design and Methods: This ongoing multicenter, open-label, randomized phase 3 study will enroll approximately 214 patients from up to 60 sites in the United States. Patients 18-79 years of age are eligible if they have NDMM, have not been previously treated with an anti-CD38 antibody, have completed 4-8 total cycles of induction therapy (and/or consolidation therapy), have undergone ASCT, have achieved a very good partial response or better by International Myeloma Working Group (IMWG) criteria after ASCT and/or consolidation therapy, are MRD-positive by next-generation flow (NGF) or next-generation sequencing (NGS), at 60-100 days post-ASCT (or ≤60 days post consolidation therapy). Patients will be stratified by cytogenetic risk status (high risk vs standard risk/unknown status) and randomized 1:1 to DARA plus lenalidomide versus lenalidomide alone. Patients in both arms will receive 10 mg lenalidomide orally continuously during each 28-day cycle. After Cycle 3, if lenalidomide is well tolerated, the dose may be increased to 15 mg at the discretion of the investigator. Patients in the DARA plus lenalidomide arm will receive DARA SC (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc.]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. Treatment will continue until disease progression, unacceptable toxicity, withdrawal, or for a maximum of 36 cycles. The primary endpoint is the MRD-negativity conversion rate (assessed at a 10-5 sensitivity threshold) at 12 months of treatment, assessed via NGS. MRD will also be assessed at 6, 18, 24, and 36 months. Importantly, use of the novel primary endpoint of MRD-negativity will allow for earlier assessment of outcomes and evaluation of deeper response than traditional endpoints such as progression-free survival (PFS) and overall survival (OS). Secondary endpoints include overall MRD-negativity rate at any time, duration of MRD negativity, rate of complete response or better (≥CR), duration of ≥CR, PFS, OS, health-related quality of life, and safety. The ClinicalTrials.gov identifier is NCT03901963. Disclosures Shah: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lutska:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Krevvata:Janssen: Employment. Kane:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Lin:Janssen: Employment, Equity Ownership. Hampras:Janssen: Employment. OffLabel Disclosure: This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.

Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant: Updated Analysis of Maia

Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant: Updated Analysis of Maia

A Phase II Study of Daratumumab in Patients with High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma: First Report of Efficacy and Safety

A Phase II Study of Daratumumab in Patients with High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma: First Report of Efficacy and Safety

Pegasperagase Toxicity in Adult Patients with Acute Lymphoblastic Leukemia: A Single Center Experience Comparing Patients Older and Younger Than 35 Years of Age

Background: The treatment paradigm of adult patients with acute lymphoblastic leukemia (ALL) is primarily derived from successful pediatric chemotherapy regimens. Pegasparagase (PEG) is a key component of pediatric therapy and is the backbone of cytotoxic ALL regimens. However, among the adult population the use of PEG has been limited by the difficulty in tolerating prolonged asparagine depletion. Hepatotoxicity is among the most common adverse events reported with the use of PEG, with grade 3/4 hepatotoxicity seen in 20% of young adults compared to 40-60% of older adults. Incorporating PEG into the treatment of ALL patients under 40 remains an accepted practice despite some studies that report up to 75% of patients have grade 3/4 adverse events as a result of asparagine depletion. In a study of 85 patients with ALL, 3-year overall survival (OS) was significantly different between patients older and younger than 35 (52% vs 83% p = 0.003). Whether this difference is due to PEG toxicity or to other factors remains to be determined. At NYU hospitals, PEG-containing protocols are frequently deployed to treat adult ALL. In our study, we sought to look at the difference in PEG toxicity and response rate (RR) in patients older and younger than 35 and whether these toxicities contributed to a delay in subsequent treatments and to a worse outcome. Methods: We conducted a retrospective chart review of patients older than 18 diagnosed with ALL or lymphoblastic lymphoma, who received at least 1 dose of PEG at our institution between 2014 and 2018. All patients received PEG as part of their first line treatment protocol. Our main objective was to compare the tolerability and toxicity profile of intravenous PEG in patients ≥35 years old versus &lt;35. Our secondary objective was to investigate its effects on chemotherapy delay, RR, and relapse rate. Results: Out of a total of 50 patients, 23 were age ≥ 35 (46%). Mean age was 34.4 (Range: 18.9-63.1). The 2 groups shared similar distributions in gender, race, and Philadelphia chromosome (Ph) subtypes (Table 1). The older group received significantly less PEG, 5114.8 vs. 25353.7 units (p=0.0007) and 1.65 vs. 3.59 doses (p&lt;0.0001) compared to the younger group. Grade 1-4 toxicity profiles were similar as both groups had high hepatotoxicity rates: transaminitis 100% vs. 89% (p=0.079) and hyperbilirubinemia 78% vs. 78% (p=0.104) in the older vs younger group, respectively. Grade 3-4 hepatotoxicity was significantly more pronounced in patients ≥35 years old (transaminitis 65% vs. 33% [p=0.0245], hyperbilirubinemia 48 vs. 15% [p=0.0111]). Coagulopathy rates evaluated with hypofibrinogenemia and thrombosis were similar between the older and the younger groups at 52% vs. 44% [p=0.104] and 17% vs. 7%, [p=0.855], respectively, and the frequency of pancreatitis and anaphylaxis were 4% vs. 18.5% (p=0.422) and 0% vs. 14.8% (p=0.115), respectively. In the older group, only 13% completed the planned PEG dosages compared to 59% in the younger group (p=0.0008), and delay in other chemotherapy by more than 30 days due to PEG hepatotoxicity occurred in 55% of older patients compared to 22% of younger patients (p=0.02). MRD negativity rate after induction was similar in the older and younger group (50% vs. 60% [p=0.491], respectively), but the 12-month relapse free survival was significantly lower in the older group (41%, [95% CI: 55.7%-89%] vs. 77%, [95% CI: 21%-61%], p=0.022) (Figure 1). Conclusions: Patients aged ≥ 35 received significantly less PEG during their treatments but were more likely to develop severe grade 3-4 hepatotoxicity compared to their younger counterparts. The response rates were similar with comparable MRD negativity rates after induction regardless of total amount of PEG administered. However, relapse occurred more frequently in the older group, possibly resulting from more frequent delays in administering other chemotherapy agents due to PEG toxicity. Incorporation of PEG is important in the treatment of ALL but should be used with caution in patients ≥35 years old, and will likely require dose and schedule modifications. A larger prospective trial investigating adequate dosing and scheduling of PEG in this age group is warranted, specifically comparing delays in chemotherapy, relapse, and survival rates in regimens with and without PEG. Disclosures No relevant conflicts of interest to declare.

Efficacy and Safety Outcomes in the Phase 3 INO-Vate Trial By Baseline CD22 Positivity Assessed By Local Laboratories

Efficacy and Safety Outcomes in the Phase 3 INO-Vate Trial By Baseline CD22 Positivity Assessed By Local Laboratories

A Multicenter Nonrandom Clinical Study Using Induction Regimen of FLAG-IDA or Dae in Treatment of 101 Children with Newly Diagnosed CBF-AML in South of China: Clinical Responses and the Midterm Report of Survival

OBJECTIVE: Patients with core binding factor (CBF) AML generally have a favorable prognosis, but the appropriate intensity of chemotherapy and number of courses are still key points for further exploration by the different leukemic group. Our prospective multicenter clinical study was designed to use high intensity, 4-courses of chemotherapy (backbone of MRC AML 15 protocol) to treat childhood CBF-AML and to observe the feasibility and effectiveness in China. METHODS: Total of 101 children with CBF-AML from 9 centers of south of China were enrolled on the C-HUANAN Children AML 2015 protocol from 2015.1 to 2018.11, accounting for 30.6% of total AML (non-APL) cases. There were 59 boys and 42 girls, aged between 2- 14 years old. The diagnosis of CBF-AML was established by PCR-based detection of RUNX1-RUNX1T1 and CBFβ-MYH11 fusion gene transcripts or by FISH based detection of t(8;21) and inv(16) aberration, respectively. Nine cases were combined with FTL3-ITD. Eleven cases were combined with ASXL1 mutation, and 23 cases were combined with c-KIT mutation. The induction regimen were non-randomized to DAE group and FLAG-IDA group. The induction regimen of DAE group including coures 1 (DAE 3+5+10), course 2 (DAE 3+5+8) . The induction regimen of FLAG-IDA including two courses of FLAG-IDA. Consolidation treatment was same and consisted of 2 courses: 1.HAE or MACE; 2.MidAC. Follow-up observation was then started after 4 courses of treatment. All of patients were followed-up to 06/30/2019, median follow-up time was 25 months. RESULTS: The overall complete remission rate was 93.1% after two courses of induction, 93.8% in the DAE group and 92.8% in the FLAG-IDA group. There was no statistical difference between the two groups. The MRD negative rate (&lt;0.1%) detected by the flow cytometry after first course was 57/87 (65.5%) and 67/77 (87.0%) after second course respectively. The RUNX1-RUNX1T1 or CBFβ-MYH11 gene negative rate was 28/60 (46.7%) and 25/43 (58.1%) after first course and second course of treatment respectively .The overall survival rate (OS) was 83.2%, and the leukemia-free survival rate was 81.1%.Among them, the OS and LFS of the DAE group were 76.4% and 73.2%, respectively, and the OS and LFS of the FLAG-IDA group were 86.3% and 84.6%, respectively( P= 0.331 and 0.241).The OS and LFS of the RUNX1-RUNX1T1 group were 81.8% and 79.2%, respectively.The OS and LFS of the CBFβ/MYH11 group were both 88.9%( P= 0.542 and 0.403). The OS and LFS in CBF-AML with FLT3-ITD positive were both 62.2%. The OS and LFS in CBF-AML without FLT3-ITD were 85.3% and 82.9%, respectively (P=0.045 and 0.081),there was significantly inferior OS in CBF-AML with FLT3-ITD subgroup. Among them, the OS was 60.0% and 85.9% in RUNX1-RUNX1T1 with or without FLT3-ITD group respectively( P=0.041), there was significantly inferior OS in RUNX1-RUNX1T1 with FLT3-ITD subgroup. There were no significant differences in OS and LFS between the CBF with or without C-kit and ASXL1 genes. The overall relapse was 10.9%, and treatment related mortality was 6.9%. Conclusion: The childhood CBF-AML accounted for 30.6% of children's newly diagnosed AML in the South China Children's AML Group. The complete remission rate reached to 93.1% by using 2 courses of intensive induction regimen of DAE or FLAG-IDA. Only 2 courses of consolidation chemotherapy were administered. Two years OS and LFS were higher than 80%.There were significant difference in OS of CBF-AML with FLT3-ITD, and RUNX1-RUNX1T1 AML with FLT3-ITD. There were no significant differences in that of LFS. The overall LFS was close to the outcome of the MRC AML 15 protocol, but there was a gap in OS. The main reason was that the most of relapsed patients abandoned treatment. On other hand the treatment related mortality need to be further reduced. Figure Disclosures No relevant conflicts of interest to declare.