Low Treatment-related Mortality Research Articles

A predictive classifier of poor prognosis in transplanted patients with juvenile myelomonocytic leukemia: a study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myeloproliferative neoplasm requiring hematopoietic stem cell transplantation (HSCT) in most cases. We retrospectively analyzed 119 JMML patients who underwent first allogeneic HSCT between 2002 and 2021. The majority (97%) carried a RAS-pathway mutation, and 62% exhibited karyotypic alterations or additional mutations in SETBP1, ASXL1, JAK3 and/or the RAS pathway. Relapse was the primary cause of death, with a 5-year cumulative incidence of 24.6% (95% CI: 17.1-32.9). Toxic deaths occurred in 12 patients, resulting in treatment-related mortality (TRM) of 9.0% (95% CI: 4.6-15.3). The 5-year overall (OS) and event-free survival were 73.6% (95% CI: 65.7-82.4) and 66.4% (95% CI: 58.2-75.8), respectively. Four independent adverse prognostic factors for OS were identified: age at diagnosis >2 years, time from diagnosis to HSCT ≥6 months, monocyte count at diagnosis >7.2x109/L, and the presence of additional genetic alterations. Based on these factors, we proposed a predictive classifier. Patients with 3 or more predictors (21% of the cohort) had a 5-year OS of 34.2%, whereas those with none (7%) had a 5-year OS of 100%. Our study demonstrates improved transplant outcomes compared to prior published data, which can be attributed to the synergistic impacts of a low TRM and a reduced, yet still substantial, relapse incidence. By integrating genetic information with clinical and hematologic features, we have devised a predictive classifier. This classifier effectively identifies a subgroup of patients who are at a heightened risk of unfavorable post-transplant outcomes who would benefit from novel therapeutic agents and post-transplant strategies.

A Propensity Score-Matched Analysis on the Outcomes of Brexucabtagene Autoleucel from Zuma-2 Study and Allogeneic Stem Cell Transplantation from the EBMT Database in Relapsed and Refractory Post-Btki Mantle Cell Lymphoma

Introduction Brexucabtagene autoleucel (brexu-cel), an autologous anti-CD19 CAR T-cell therapy, is approved in the US for the treatment of relapsed/refractory (r/r) mantle cell lymphoma (MCL) and in Europe for r/r MCL after ≥2 prior lines of therapies, including Bruton's tyrosine kinase inhibitor (BTKi). The pivotal ZUMA-2 trial demonstrated very good efficacy of brexu-cel in r/r MCL and tolerable safety including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (Wang et al. J Clin Oncol. 2022). Allogeneic stem cell transplantation (alloSCT) is potentially curative but is associated with high treatment related mortality (TRM) and clinically significant graft-versus-host disease (GvHD). The optimal choice of treatment between brexu-cel and alloHCTs is unclear. We conducted a propensity score matched (PSM) analysis of brexu-cel and alloSCT in patients (pts) with r/r MCL. Methods Pts from ZUMA-2 were matched with alloSCT pts from the EBMT database. Selection criteria to identify pts in the EBMT registry were: r/r MCL diagnosis and receipt of alloSCT from 2010 to 2020, age ≥18 years, prior treatment with anti-CD20, prior anthracycline- or bendamustine containing regimens, and prior BTKi. We performed a 1:1 nearest neighbor matching without replacement, balanced for 5 baseline parameters: age, sex, number of prior treatment lines, time from diagnosis to cellular immunotherapy, and prior autologous stem cell transplantation (autoSCT). The primary endpoint was overall survival (OS) from cellular immunotherapy. The following secondary endpoints were analyzed: progression-free survival (PFS), TRM, defined as incidence of deaths which are related to the treatment and occurred in absence of disease progression, and rate of GvHD. Competing risks were defined as relapse, progression or treatment-unrelated death for TRM, and death for GvHD. The EBMT registry includes pts who actually underwent alloSCT. To characterize the dropout rate prior to cellular therapy, we conducted a multicenter intent-to-treat (ITT) analysis and identified 77 pts with r/r MCL for whom an unrelated donor search was initiated and an alloSCT was intended. Results Sixty-four of 68 pts from the ZUMA-2 cohort were included in the study; 4 pts were excluded because of inability to anonymize. A total of 270 pts who had undergone alloSCT and met eligibility criteria were identified in the EBMT registry. Patient characteristics between the brexu-cel and the alloSCT cohorts were imbalanced. Brexu-cel pts were older (p<0.001), had more prior lines of treatment (median 3 vs 2, p<0.001), had less prior autoSCT (41% vs 71%, p<0.001), and had longer time between diagnosis and treatment (53 vs 40 months, p=0.01). After 1:1 PSM matching, criteria were well balanced between cohorts. Median follow-up time was 36.5 and 46.4 months for the brexu-cel and the matched alloSCT cohort, respectively. PFS and long-term OS were similar between both cohorts (Fig. 1A). However, the risk of death within the first 12 months was significantly lower in the brexu-cel cohort vs the alloSCT cohort (logistic regression with inverse probability of censoring weighting, risk ratio=0.5, 95% confidence interval [CI] 0.3-0.9, p=0.02). This was mainly attributable to the significantly higher TRM rate in the alloSCT cohort (alloSCT vs brexu-cel: cause specific hazard ratio=7.7, 95% CI 1.9-31.6, p=0.005, Fig. 1B). The cumulative incidence of acute GvHD grade ≥3 at 3 months and chronic GvHD at 24 months was 17.9% (95% CI 9.1-29.0%) and 44.3% (95% CI 30.6-57.2%), respectively. In our ITT analysis, the dropout rate was significantly higher in the cohort intended to receive alloHCT (23%, [18/77]) vs the cohort intended to receive brexu-cel (8% [6/74]; Fisher test, p=0.01). For alloSCT, failure to proceed to cellular therapy was related to progression in 13%, change of patient's preference in 5% and ineligibility in 4%; in the brexu-cel cohort this was due to manufacturing failures in 4% and progression in 3%. Conclusion Brexu-cel is an effective treatment in pts with r/r MCL post-BTKi with a superior safety profile compared with alloSCT, as indicated by lower 12-month mortality, lower TRM, and absence of chronic GVHD-related morbidity. Despite efforts to match pts between the cohorts, the inherent limitations of this study, such as incongruent data sources and case selection bias, have to be considered. Additional analyses will be presented.

Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy

Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown. The primary objective of this study was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR-T therapy. The secondary objective was to evaluate the impact of key treatment-, patient-, and disease-related variables on the time to CRS/ICANS resolution and treatment-related mortality (TRM). We retrospectively analyzed the outcomes of 43 patients with B cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause-specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin, and performance status. Indications for anakinra treatment were grade ≥2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n=40) and grade ≥2 CRS with worsening symptoms despite treatment with tocilizumab (n=3). Anakinra treatment was feasible and safe; discontinuation of therapy because of anakinra-related side effects was reported in only 3 patients (7%). The overall response rate (ORR) to CAR-T therapy was 77%. The cumulative incidence of TRM in the whole cohort was 7% (95% confidence interval [CI], 2% to 17%) at 28 days and 23% (95% CI, 11% to 38%) at 60 days after CAR-T infusion. The cumulative incidence of TRM at day 28 after initiation of anakinra therapy was 0% in the high-dose (>200 mg/day i.v.) recipient group and 47% (95% CI, 20% to 70%) in the low-dose (100 to 200 mg/day s.c. or i.v.) recipient group. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in the high-dose group and was not reached in the low-dose group, owing to the high TRM in this group. Univariate Cox modeling suggested a shorter time to CRS/ICANS resolution in the high-dose recipients (hazard ratio [HR], 2.19; 95% CI, .94 to 5.12; P=.069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin level, and pre-LD Karnofsky Performance Status (KPS), higher anakinra dose remained associated with lower TRM (HR, .41 per 1 mg/kg/day increase; 95% CI, .17 to .96; P=.039. The sole factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin and anakinra dose was higher pre-LD KPS (HR, 1.05 per 10% increase; 95% CI, 1.01 to 1.09; P=.02). Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12 mg/kg/day i.v. We observed an ORR of 77% after CAR-T therapy despite anakinra treatment, suggesting a limited impact of anakinra on CAR-T efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings.

Antigen Directed Therapy Pre-Transplant Confers Superior Post-Transplant Survival Outcome Compared to Conventional Chemotherapy in Pediatric Patients with Relapsed and Refractory B-ALL

Background: Hematopoietic stem cell transplant (HCT) represents the most effective mean to achieve cure for children, adolescents and young adults with relapsed or refractory (R/R) B-ALL. Among the several disease-specific and transplant-specific characteristics evaluated so far, achievement of minimal residual disease (MRD) negative complete remission (CR) prior to HCT is the strongest independent prognostic factor of post-HCT outcome. Antigen directed therapies (ADT) such as blinatumomab, inotuzumab ozogamicin and chimeric antigen receptor (CAR) T-cell are very effective at inducing MRD-negative remission and offer an alternative approach for disease control in patients with chemo-resistant disease. We hypothesized that ADT may provide a more durable disease control and lesser morbidity than conventional chemotherapy (CT) and therefore we sought to explore whether the type of treatment (ADT or CT) adopted to achieve MRD negative CR prior to HCT, impacts post-HCT outcomes. Patients and methods: This is a retrospective, multi-institutional cohort study of patients (pts) with R/R B-ALL who received an allogeneic HCT in MRD negative CR between 2010-2021. Patients were eligible if they were ≤30 years at time of diagnosis of R/R B-ALL, had received either CT or ADT (blinatumomab, CAR T-cell, inotuzumab ozogamicin with or without preceding chemotherapy) for the treatment of R/R B-ALL and had achieved MRD negative CR (<0.01% blasts by flow cytometry) prior to HCT. Patients with isolated extramedullary relapse or acute leukemia of ambiguous lineage or history of prior HCT were excluded. Patients were categorized as being in the "CT" or "ADT" group based on whether they received conventional CT or ADT as last cycle that led to MRD negativity prior to HCT. The primary objective of the study was to compare the EFS, OS and treatment related mortality (TRM) from time of transplant according to the therapy (ADT vs. CT) received pre-HCT. Kaplan-Meier or Aalen-Johansen estimates were used to estimate survival rates and curves were compared using logrank or Gray's tests. Results: Seventy-six pts from 7 centers met eligibility criteria; 38 pts (50.0%) received ADT and 38 pts (50.0%) received chemotherapy as last cycle prior to HCT. Demographic, disease and treatment characteristics are summarized in Table 1; notably, more pts in the ADT group had refractory leukemia and more pts had received ≥4 cycles of therapy before achieving MRD negative remission in the ADT group than in the CT group. The 5-yr. EFS and OS for the entire cohort were 53% and 67%, respectively. EFS was superior in the ADT group compared to the CT group (5-yr. EFS 64% vs. 42%, p=0.04; Figure 1). OS was also superior in the ADT group (85% vs. 47%, p=0.0008; Figure 1). In a univariable and multivariable prognostic model for OS that included age, race, having relapsed or refractory disease and CT or ADT as pre-HCT therapy, pre-HCT therapy was the only significant prognostic factor (p<0.001); in a similar model for EFS, pre-HCT therapy was the only significant prognostic factor in the univariable analysis (p=0.04) but not in the multivariable analysis. There was no difference in the incidence of acute GVHD, rate of immune reconstitution at day 100, time to engraftment and cumulative incidence of relapse between the two groups. However, the CT group appeared to have a higher rate of both TRM (33.0% vs. 8%, p=0.01) and relapse related mortality, although not significant for the latter (19% vs. 7% p=0.12). Conclusion: This multicenter study shows that having received ADT prior to HCT may be beneficial when compared to conventional chemotherapy for patients with R/R B-ALL who receive a HCT in MRD negative CR. Patients who received ADT experienced a superior EFS and OS primarily due to a significantly lower TRM, despite having received more cycles of therapy prior to proceeding to HCT. There was no difference in the relapse rate among the two groups further supporting the notion that MRD negative CR is the single most important predictor of post-HCT relapse. Further analysis is ongoing to identify specific factors that could explain the difference in post-HCT mortality among the 2 groups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Utility of theTreatment-Related Mortality (TRM)score to predict outcomes of adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation.

There is long-standing interest in estimating non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) for AML, but existing tools have limited discriminative capacity. Using single institution data from 861 adults with AML, we retrospectively examined the treatment-related mortality (TRM) score, originally developed to predict early mortality following induction chemotherapy, as a predictor of post-HCT outcome. NRM risks increased stepwise across the 4 TRM score quartiles (at 3 years: 9% [95% confidence interval: 5–13%] in Q1 vs. 28% [22–34%] in Q4). The 3-year risk of relapse was lower in patients with lower TRM score (26% [20–32%] in Q1 vs. 37% [30–43%] in Q4). Consequently, relapse-free survival (RFS) and overall survival (OS) estimates progressively decreased (RFS at 3 years: 66% [59–72%] in Q1 vs. 36% [29–42%] in Q4; OS at 3 years: 72% [66–78%] in Q1 vs. 39% [33–46%] in Q4). With a C-statistic of 0.661 (continuous variable) or 0.642 (categorized by quartile), the TRM score predicted NRM better than the Pretransplantation Assessment of Mortality (PAM) score (0.603) or the HCT-CI/age composite score (0.576). While post-HCT outcome prediction remains challenging, these findings suggest that the TRM score may be useful for risk stratification for adults with AML undergoing allogeneic HCT.

Age is no barrier for adults undergoing HCT for AML in CR1: contemporary CIBMTR analysis.

Acute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The most common curative therapy remains an allogeneic hematopoietic stem cell transplantation (HCT), yet it is complicated by treatment-related mortality (TRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in 1,321 patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1) from 2007–2017 and reported to the CIBMTR. Outcomes were compared in three age cohorts (60–64; 65–69; 70+). With median follow-up of nearly 3 years, patients aged 60–64 had modestly, though significantly better OS, DFS and lower TRM than those either 65–69 or 70+; cohorts with similar outcomes. Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p=0.026). TRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥ 3. Conditioning intensity was not a significant predictor of OS in the 60–69 cohort with 3-year OS of 46% for RIC and 49% for MAC (p=0.38); MAC was rarely used over age 70. There was no difference in the relapse rate, incidence of Grade III/IV acute GVHD, or moderate-severe chronic GVHD across the age cohorts. After adjusting for other predictors, age had a small effect on OS and TRM. High-risk features including poor cytogenetics and measurable residual disease (MRD) prior to HCT were each significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; while graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection.

First-line high-dose therapy and autologous blood stem cell transplantation in patients with primary central nervous system non-Hodgkin lymphomas\u2014a single-centre experience in 61 patients

Primary central nervous system non-Hodgkin lymphomas (PCNS-NHLs) are extranodal B-cell lymphomas with poor prognosis. The role of high-dose therapy (HDT) followed by autologous blood stem cell transplantation (ASCT) as first-line therapy is still not clear. We retrospectively collected long-term follow up data of 61 consecutive patients with PCNS-NHL at the University Hospital Düsseldorf from January 2004 to December 2016. Thirty-six patients were treated with conventional chemoimmunotherapy (cCIT) only (CT-group). Seventeen patients received an induction cCIT followed by HDT and ASCT. In the CT-group, the overall response rate (ORR) was 61% (CR 47%, PR 14%), and there were 8% treatment-related deaths (TRD). Progression-free survival (PFS) was 31.8 months, and overall survival (OS) was 57.3 months. In the HDT-group, the ORR was 88% (59% CR, 29% PR), and there were 6% TRD. Median PFS and OS were not reached at 5 years. The 5-year PFS and OS were 64.7%. After a median follow up of 71 months, 10 patients (59%) were still alive in CR/PR following HDT and ASCT, one patient was treated for progressive disease (PD), and 7 had died (41%, 6 PD, 1 TRD). All patients achieving CR prior to HDT achieved durable CR. In the CT-group, 8 patients (22%) were alive in CR/PR after a median follow-up of 100 months. Twenty-eight patients died (78%, 24 PD, 2 TRD, 2 deaths in remission). In the univariate analysis, the HDT-group patients had significantly better PFS (not reached vs 31.8 months, p = 0.004) and OS (not reached vs 57.3 months, p = 0.021). The multivariate analysis showed HDT was not predictive for survival. Treatment with HDT + ASCT is feasible and offers the chance for long-term survival with low treatment-related mortality in younger patients. In this analysis, ORR, PFS and OS were better with HDT than with conventional cCIT alone. This result was not confirmed in the multivariate analysis, and further studies need to be done to examine the role of HDT in PCNSL.

Single HLA Class I Mismatches with High Peptide Divergence in the Graft-Versus-Host Direction Are Associated with Inferior Survival after 9/10 HLA-Matched UD-HCT: A Retrospective Study from the CIBMTR

IntroductionUnrelated donor (UD)-recipient disparity for human leukocyte antigen (HLA) class I adversely affects outcome of hematopoietic cell transplantation (UD-HCT). HLA polymorphisms in the peptide antigen binding groove can affect the repertoire of presented peptides. We have recently shown that the degree of peptide divergence between mismatched HLA-DP allotypes is related to T-cell alloreactivity and clinical permissiveness after UD-HCT (Meurer et al Blood 2021). Here, we hypothesized that the clinical tolerability also of HLA class I mismatches in UD-HCT might depend on the divergence of their respective peptide repertoires.MethodsWe studied 2,562 patients after 9/10 HLA-A, -B, -C, -DRB1, -DQB1-matched UD-HCT for acute myeloid or lymphocytic leukemia, or myelodysplastic syndrome, between 2008 and 2018, and 14,426 10/10 HLA-matched UD-HCT with similar characteristics. Peptide divergence of the mismatched HLA allotypes was predicted based on hierarchical clustering of experimentally determined peptide binding motifs (PBM) (Bassani-Sternberg et al Front Immunol 2018), with 21 different PBM groups identified in 122 HLA class I allotypes (44, 63 and 18 for HLA-A, -B and -C, respectively). The mismatched cohort was stratified into PBM-matches or PBM-mismatches, and within the latter into host-versus-graft (HvG), graft-versus-host (GvH) or bidirectional PBM-mismatches (Figure 1A). The primary study endpoint was overall survival (OS); secondary endpoints included treatment-related mortality (TRM), GVHD and relapse. P-value<0.01 was considered statistically significant.ResultsThe available PBM data allowed us to classify 1,629/2,562 (63.6%) of our pairs. Of these, 386 (23.7%) were PBM-matched and 1,243 (76.3%) were PBM-mismatched, and in the latter, 254 (20.5%), 238 (19.1%) and 751 (60.4%) had HvG, GvH or bidirectional PBM-mismatches, respectively. Transplants were performed mainly with peripheral blood stem cells (78%), myeloablative conditioning (65%) and tacrolimus-based graft-versus-host disease (GvHD) prophylaxis (74%). About half of the 9/10 HLA-matched HCT were performed using in vivo T-cell depletion by anti-thymocyte globulin or Campath, and none used post-transplant cyclophosphamide. Multivariable analyses showed that 10/10 HLA-matched transplants had significantly higher OS, lower TRM and aGvHD 3-4 compared to 9/10 HLA-matched transplants but relapse was similar (Figure 1B,C). There were no significant differences between the PBM-matched and aggregate PBM-mismatched group (Figure 1B). In further analysis, pairs with a bidirectional or only GvH PBM-mismatch had significantly worse OS, compared to pairs in the PBM-matched group or with only a unidirectional HvG (hazards ratio [HR] 0.76, 95% confidence interval [CI] 0.63-0.92, P = 0.0036; Figure 1C). The hazards of TRM and aGvHD 3-4 were lower for the HvG or PBM-matched group compared to the reference (HR 0.78, 95% CI 0.65-0.95, P = 0.0135 and HR 0.79, 95% CI 0.65-0.95, P = 0.0126, respectively), although these were not statistically significant (Figure 1C).ConclusionWe show that single HLA class I PBM-mismatches with high peptide divergence in the unidirectional or bidirectional GvH directions are significantly associated with worse survival after 9/10 HLA-matched UD-HCT compared to PBM-matched or unidirectional mismatching in the HvG direction. These data suggest that the mechanistic role of peptide-diversity for T-cell alloreactivity we previously observed for HLA-DPB1 disparity (Meurer et al., Blood 2021), is also a relevant to class I mismatches, providing a new rationale for selecting permissive donors in the setting of 9/10 HLA-matched UD-HCT. Avoiding class I PBM mismatches in the GvH direction is associated with better survival. [Display omitted] DisclosuresPaczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: Amgen: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding.

Second Autologous Stem Cell Transplant as Salvage in Multiple Myeloma – The Oregon Health and Science University Experience

Background: Second autologous transplants (SAT) are routinely performed in the setting of myeloma relapse, though data on outcomes are lacking. We conducted a single-center review of all multiple myeloma patients at OHSU who received SAT (excluding tandems) with responses assessed by International Myeloma Working Group (IMWG) criteria. Results: Sixty-eight patients received SAT between 1999 and 2019. Risk by IMWG was available for 50 patients (10 high-risk). Median age at SAT was 61 (45-74). Median time between 1st and 2nd Autologous stem cell transplantation (ASCT) was 5.5 years (1.1 - 15.2). Median progression-free survival (PFS) after 1st ASCT (available for 53 pts) was 2.5 years (0.3 - 10). The average # of lines of therapy prior to SAT was 2.8 (1-14). SAT prep regimens (available for 67 pts) were: Fifty-one (87%) melphalan 200 mg/m2, 6 (9%) melphalan 140 mg/m2, 1 (2%) BEAM, 1 (2%) melphalan 200 mg/m2 and bortezomib. All used PBSC mobilization. Median overall survival (OS) after SAT was 4.68 years, and median PFS was 1.72 years. By treatment era (1999-2009 vs. 2010-2019), median OS was 1.97 vs. 5.52 years (P = .15). When analyzed by IMWG group (standard/low vs. high risk) median PFS and OS were not significantly different (1.87 vs. 1.61 years and 3.58 vs. 5.91 years, respectively). Treatment-Related Mortality (TRM) occurred in 1 patient (2%). Conclusion: Our experience with SAT for multiple myeloma (MM) shows that it has low TRM and is effective, with median OS >4.5 years, though with a shorter PFS than after 1st ASCT.

Long-Term Results and Cost-Effectiveness of the Flagida-Lite Regimen in Elderly Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

▪INTRODUCTIONAcute Myeloid Leukemia (AML) and high risk Myelodisplastic Syndrome (MDS) have a higher incidence in older patients. Due to their age, comorbidity and unfavorable biology of the disease, intensive chemotherapy offers poor results. Hypomethylating agents and other alternative regimens are being tested but the best strategy is currently not well defined.OBJECTIVEUpdating the FLAGIDA-lite intermediate intensity chemotherapy scheme results (Am J Hematol. 2012 Jan;87(1):42-4). Rate of overall response (OR), overall survival (OS) and treatment-related mortality (TRM) were evaluated. An estimated cost approach and a review of the 5-azacytidine cost estimation was made.PATIENTS AND METHODSSeventy patients older than 65 years with AML or high risk MDS treated with the FLAGIDA-lite regimen in three Spanish centers between 2006 and 2016 were analyzed. Median age was 76 years (IQL 73-81) and patients´ characteristics are shown in table 1 . The regimen consisted of: Fludarabine (40mg/m2 daily, days 1-5, P.O), Citarabine (20 mg/m2 daily, days 1-5, sub-Q) and Idarrubicin (15 mg/m2 daily, days 1-3, P.O until 2014, or IV 10 mg/m2 daily, days 1-3 when oral formulation disappeared). G-CSF (300 µg/24h sub-Q, days -1 to 5) was added except when leukocytosis was greater than 100,000/µl. Treatment administration and subsequent follow-up were performed under hospitalization, home care or ambulatory regimen. We calculated the regimen costs.RESULTSToxicity and Treatment Related MortalityA total of 117 chemotherapy cycles were administered (80 as induction and 37 as consolidation).Sixty-one (76.2%) induction and 34 (91.9%) consolidation cycles were administered under ambulatory or home care regimen; in 21 (34.4%) and 8 (21.6%) of them, respectively, hospital admission was necessary, mainly due to infectious complications.Thirteen (18.6%) patients died after induction, 10 due to treatment-related complications and 4 due to disease progression. Early mortality at 8 weeks was 20.9%. Treatment-related mortality was higher in patients older than 80 years (30 vs 10%), as shown in figure 1.Overall Response and Overall SurvivalSixty patients received one induction cycle and 10 received 2. OR rate was 64.9% (49.1% CR, 8.8% CRi; 7% PR) and 35.1% of patients were refractory. Median time to CR was 36 days (26-51). Twenty-six patients who had reached CR/CRi received consolidation with the same regimen (35 cycles) and 6 patients were submitted to a related allogeneic hematopoietic stem-cell transplantation.With a median follow-up of 23.8 months (9-105) in alive patients, estimated OS at 2 years was 22.6 (±5.4%) in the whole series and 41.1% (±9.4%) in patients who reached CR/CRi, as shown in figure 2. Median OS in patients who reached CR/CRi was significantly higher than in non-responder patients (17.4 vs 2.9 months, p< 0,001).Cost estimationThe cost of one cycle of FLAGIDA-lite, in Spain, is 1825.18 euros, as shown in table 2 . The median number of cycles administered in our study was 2, so the global cost of treatment drugs was 3650.36 euros. The estimated cost in Spain of another non-intensive regimen with not higher or similar efficacy (5-azacitidine) according to literature is 3028.14 euros each cycle and a total cost of 18,168.84 euros (median number of 6 cycles) . ( Health Econ Rev. 2013 Dec 5;3(1):28).CONCLUSIONFLAGIDA-lite is an effective alternative regimen in elderly patients with AML and high risk MDS, with low treatment-related mortality in patients younger than 80 years (10%) and with the possibility of an ambulatory management. This treatment offers an overall response rate around 65%, and an estimated overall survival at two years around 41% in responder patients. Its cost is markedly lower than the cost of 5-azacytidine. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

AML SCT-BFM 2007: Results of the Prospective Hematopoietic Stem Cell Transplantation (HCT) Trial of the Berlin-Frankfurt-Münster (BFM) Study Group for Children with Very High Risk Acute Myeloid Leukemia

BACKGROUNDPediatric AML represents a rare and heterogeneous disease. Within the BFM study group, HCT for this patient cohort was performed with considerable inter-center variability. AML SCT-BFM 2007 was based on a transplantation consensus and aimed to prospectively generate a reliable body of data on which further transplantation technologies could be based. METHODSAML SCT-BFM 2007 was conducted according to current legislation as an international multicenter clinical trial (EudraCT: 2007-004517-34, NCT00606723), data were collected via a specifically developed remote data entry (RDE)-based data bank, and verified against source data by an on-site monitoring program. Children with cytogentic and molecular high-risk features achieving a complete first remission (CR1) and those in CR2 after a first relapse qualified for HCT from a matched donor (MD). A MD was defined to be identical when at least 9/10 alleles on the HLA-A, B, C, DRB1 and DQ loci did match. A myeloablative conditioning regimen consisting of Busulfan (age adjusted i.v. dosing: 3.2 - 4,8 mg/kg BW on days -7 through -4), Cyclophosphamide (60mg/kg iv on days -3 and -2), and Melphalan (140 mg/m2 on day -1) termed BuCyMel was used. For GVHD prophylaxis CSA and short term MTX were given, for unrelated donors anti-thymocyte globulin (ATG Neovii) was added. Children with refractory primary disease or refractory relapse were eligible for early transplantation. A cytoreductive regimen containing Fludarabine (30mg/m2/d i.v.), Amsacrine (100 mg/m2/d i.v.) and Cytarabine (2g/m2/d i.v.) all on days -12 through -9 (FLAMSA) was immediately followed by a reduced intensity conditioning (RIC) consisting of 4 Gy TBI and Cyclophosphamide (60 (unrelated)/40 (related) mg/kg/d i.v.) on days -4 and -3. After early taper of immunosuppression (MMF halted by day 40 and CSA after taper by day 90) increasing doses of prophylactic donor lymphocyte infusions (DLI) were given on days 120, 150, and 180. Standard statistical methods were used for the analysis of event-free survival (EFS, events: relapse, death from any cause), overall survival (OS), cumulative incidence of treatment related mortality (TRM) and relapse (CIR) after HCT. RESULTSRecruitment was conducted between 5/2010 and 2/2016. 97 children underwent HCT after conditioning with BuCyMel. Median neutrophil engraftment was achieved after 21 days (range 9-38). 3-year EFS and OS were 62%, standard error (SE) 5%, and 73%, SE 5%. CIR was 22%, SE 4%. Median time to relapse was 8 months (range 1-66) after HCT. TRM was 15%, SE 4%, with 8/15 patients dying before day 100. TRM correlated with age with a rate of 9% in children younger than 12 years (n = 68) and 31% in older children and adolescents (Fig. A). This resulted in a stop of using BuCyMel for older children and adolescents in 6/2014. The rate of acute graft versus host disease (aGVHD) grade II-IV was 22%, chronic GVHD developed in 11%. Median neutrophil engraftment for children transplanted for refractory disease (n= 35) was 23 days (range 10-34). 3-year EFS and OS were 46%, SE 8%, and 51%, SE 9%. EFS for primarily refractory disease was 53%, SE 11%, whereas EFS for refractory relapses (n = 7) was 29%. Relapse rate was 43%, SE 9%, and TRM reached 11%, SE 5% (Fig. B). Acute and chronic GVHD rates were at 26% and 17%. CONCLUSIONWithin a well-defined trial concept HCT from a matched donor using BuCyMel for conditioning results in an EFS of 60% with a low TRM rate in younger children. The identical approach is associated with a high TRM rate of 31% in older children and adolescents. Whether the use of alternative conditioning strategies in this population can reduce mortality while maintaining the relapse-free survival rates remains to be determined. In high-risk patients with refractory disease, early use of RIC HCT followed by the infusion of prophylactically given DLI can induce long-term remissions in more than 50% of children without increasing the risk for GVHD. [Display omitted] DisclosuresSauer:Neovii: Research Funding. Lang:Miltenyi Biotec GmbH: Patents & Royalties, Research Funding. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding. Handgretinger:Miltenyibiotec GmbH: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding.

G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (GCLAM) in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Grade Myeloid Neoplasms: Final Results from a Phase 1/2 Trial

▪Background: Outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission (CR) rates often not exceeding 15-20%. Results from a previous 2 study in poor-risk relapsed/refractory acute myeloid leukemia (AML) suggested encouraging activity of a combination of G-CSF, cladribine, cytarabine, and mitoxantrone (GCLAM). Given data suggesting benefit of escalated doses of anthracyclines in AML, we conducted a phase 1/2 study (NCT02044796) of GCLAM using escalated doses of mitoxantrone for patients with relapsed/refractory AML or high-risk myeloid neoplasms (≥10% blasts).Patients and Methods: Patients≥18 years were eligible if they had a treatment-related mortality (TRM) score of ≤6.9 (corresponding to a predicted 28 day mortality of ≤6.9% with standard induction chemotherapy) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤3.25 mg/dL). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in previous trials). Other drugs doses were G-CSF (days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second course of GCLAM was given if CR was not achieved in cycle 1. Up to 4 cycles of consolidation with GCLA (mitoxantrone omitted) were allowed if CR or CR with incomplete blood count recovery (CRi) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the next treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding infection or constitutional symptoms.Results: Among 26 patients treated in phase 1, 2 DLTs occurred at dose level 4 (encephalopathy and cardiogenic shock), establishing GCLAM with mitoxantrone at 16 mg/m2/day as the MTD. Forty patients, median age 63 [range: 33-77] years, median TRM score 2.0 [0.2-6.39], with AML (n=34) or high-grade myelodysplastic syndrome (n=6) received GCLAM at MTD; 28% had secondary disease. Nineteen were primary refractory and 21 had relapsed disease (median duration of CR1: 12 months). Cytogenetics were favorable in 1, intermediate in 21, and adverse in 18; 6 patients had NPM1 and 1 had FLT3 mutations. Ten patients achieved CR (25%, 95% confidence interval [CI]: 13-41%) and 13 a CRi (32%, 95% CI: 19-49%) with 1-2 induction cycles, for an overall response rate (ORR) of 58% (95% CI: 40-73%). Nine of the 10 CR patients (90%) were negative for minimal residual disease by flow cytometry. One further patient had a morphologic leukemia free state, 11 had resistant disease, 2 were not evaluable, and 2 died in aplasia within 28 days of therapy for a TRM rate of 5%. The median overall survival (OS) was 11.5 months. Besides infections/fever, the most common grade ≥3 adverse events were rash and hypoxia (fluid overload/infection-related). Median times to an absolute neutrophil count ≥500/μL and platelet count ≥50,000/μL were 29 days each. In multivariable analysis controlling for baseline prognostic features, compared to 41 patients treated with GCLAM outside this study with mitoxantrone at 10mg/m2/day, GCLAM with mitoxantrone at 16mg/m2 was associated with better OS (hazard ratio [HR]=0.45, 95% CI: 0.24-0.85, p=.01) and a nonsignificantly higher ORR (odds ratio [OR]=1.87; 95% CI: 0.69-5.10, p=.22). Further, compared to patient treated with other salvage regimens used at our institution (GCLAC [G-CSF, clofarabine and high-dose cytarabine], n=61; d/MEC [decitabine priming, mitoxantrone, etoposide, and cytarabine], n=52), GCLAM with mitoxantrone at 16mg/m2 was associated with better ORR and OS than d/MEC (OR=3.33, p=.012; HR for death= 0.50, p=.01) and a similar ORR compared to GCLAC (OR=1.69, p=.25) after multivariable adjustment with a HR for death of 0.68 (95% CI: 0.39-1.18, p=.17).Conclusion GCLAM with mitoxantrone at 16 mg/m2/day is well tolerated with a low TRM rate, and has potent anti-leukemia activity in relapsed/refractory myeloid neoplasms. Survival for this regimen appears better than when the regimen is used with mitoxantrone at 10 mg/m2/day and compared to other salvage regimens such as d/MEC. DisclosuresScott:Alexion: Consultancy, Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Acceleron: Other: Data and Safety Monitoring Board; Agios Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Becker:GlycoMimetics, Inc.: Research Funding. Walter:Aptevo Therapeutics: Research Funding; ADC Therapeutics: Research Funding.

Autologous Bone Marrow Transplantation for Patients With Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia Following MDS

AbstractIntensive chemotherapy followed by autologous bone marrow transplantation (ABMT) may provide an alternative therapy for young patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS (sAML) lacking a suitable donor. We report the results for 79 patients with MDS/sAML transplanted with autologous marrow in first complete remission (CR). Within the total group of 79, a cohort of 55 patients for whom the duration of first CR was known were compared with a matched control group of 110 patients with de novo AML. The 2-year survival, disease-free survival (DFS), and relapse rates for the 79 patients transplanted in first CR were 39%, 34%, and 64%, respectively. The relapse risk was greater than 55% for all stages and all disease categories. Patients younger than 40 years had a significantly (P = .04) better DFS (39%) than patients older than 40 years (25%). The DFS at 2 years was 28% for the cohort of 55 patients transplanted for MDS/sAML and 51% for those transplanted for de novo AML (P = .025). Relapse rates were 69% for patients with MDS/sAML and 40% for those with de novo AML (P = .007). ABMT for MDS or secondary leukemia results in a lower DFS when compared with similarly treated patients with de novo AML due to a higher relapse rate. The DFS of 28% for these patients suggests that autotransplantation may be a valuable therapy for this disease. The low treatment-related mortality rate of less than 10% supports the view that sufficient numbers of hematopoietic stem cells are present in patients with MDS to allow adequate repopulation after autologous stem-cell transplantation.

Second Autologous Stem Cell Transplant As Salvage Therapy in Multiple Myeloma - the Oregon Health and Science University Experience

Background: Though the available number and efficacy of novel agents for multiple myeloma (MM) have improved in recent years, it remains an incurable disease with relapse inevitable in nearly all patients. Autologous stem cell transplantation (ASCT) as consolidation after induction remains the standard of care for transplant-eligible patients with randomized studies showing progression-free survival (PFS) greater than 4 years (Atttal et al., N Engl J Med 2017; 376:1311-1320). Relapse outcomes are also improving with PFS now greater than 3 years in some settings (Bahlis, et al., Leukemia 2020 Jul;34(7):1875-1884). For fit patients with good response to a first ASCT, a second autologous transplant (SAT) can be considered. The American Society for Blood and Marrow Transplantation (ASBMT) and the International Myeloma Working Group (IMWG) guidelines suggest SAT should be considered for those whose first ASCT resulted in remission duration &amp;gt;18 months (Giralt et al., Biol Blood Marrow Transplant 2015; 21:2039-2051). CIBMTR data note 600-700 SATs are performed annually. Most data on SAT come from single-center retrospective series, though pooled analyses note median PFS &amp;gt;1 year and median OS &amp;gt;30 months (Hagen and Stiff, Biol Blood Marrow Transplant 2019 Mar;25(3):e98-e107). Here we present our institution's experience with salvage SAT for MM analyzing treatment outcomes and toxicities. Methods: We performed a single-center retrospective review of all MM patients at Oregon Health and Science University who received SAT for myeloma as salvage therapy. Planned tandem transplants were excluded. Demographic and disease characteristic data at time of original diagnosis and at time of SAT were extracted and responses assessed by IMWG criteria. OS and PFS from SAT were calculated by Kaplan Meier method with progression or death from any cause counted as events for PFS and censoring at last known follow-up for live patients. Results: Baseline characteristics: Sixty-eight patients were identified who received SAT between 1999 and 2020. Durie-Salmon staging at diagnosis was available for 30 patients; 16 (24%) 3A, 7 (10%) 2A, 1 1B (1%), 6 (9%) 3b. The median age at time of SAT was 61 (range 45 -74). The median time between first and second ASCT was 5.5 years, (range 1.1 -15.2 years). Median PFS after first ASCT could be calculated for 53 patients and found to be 2.5 years (range 0.3 - 10). First ASCT conditioning regimen and dosing were available for 56 patients; 55 (81%) received melphalan with 53 (78%) receiving 200mg/m2, 2 (3%) receiving 140mg/m2, 1 (2%) received busulfan + TBI. The average number of lines of therapy prior to SAT was 2.8 (range 1-14). SAT preparative regimens were available for 67 patients: 59 (87%) received melphalan 200mg/m2, 6 (9%) received melphalan 140mg/m2, 1 (2%) received BEAM, 1 (2%) received melphalan 200mg/m2 and bortezomib. All SAT patients received peripheral blood stem cell mobilization. Outcomes: 37 (54%) patients have died at time of data collection. Median OS after SAT was 3.09 years while median PFS was 1.65 years. Treatment related mortality (TRM, defined as death not due to progression within 100 days of SAT) occurred in 1 patient (2%). Long term complications included 10 patients found with other malignancies after SAT (5 with basal or squamous cell skin carcinoma, 2 with MDS, 2 GI malignancies, 1 prostate). Conclusion: Our institution's experience with SAT for MM suggests it's an effective salvage treatment with low treatment-related mortality, though with a shorter PFS than after first transplant. Most patients were able to receive and tolerate full dose melphalan 200mg/m2 for SAT. Disclosures Silbermann: Sanofi-Aventis: Consultancy, Research Funding; Janssen: Consultancy; Karyopharm: Consultancy. Maziarz:Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Novartis and Juno: Research Funding; Novartis and Athersys: Other: DSMB participant; Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Athersys: Patents &amp; Royalties.

Prognostication, Survival and Treatment-Related Outcomes in HIV-Associated Burkitt Lymphoma (HIV-BL): A US and UK Collaborative Analysis

Prognostication, Survival and Treatment-Related Outcomes in HIV-Associated Burkitt Lymphoma (HIV-BL): A US and UK Collaborative Analysis

Very long term follow-up of high dose chemotherapy followed by autologous stem cell transplantation in high risk locally advanced triple negative breast cancer.

e13094 Background: The role of High Dose Chemotherapy (HDC) with Autologous Stem Cell Transplantation (ASCT) in treatment of high risk locally advanced breast cancer remains unclear. This modality stopped being used for breast cancer treatment when trials in early 2000s reported Disease Free Survival (DFS) benefit but no Overall survival (OS) benefit. However, subgroup analyses of these studies reported OS benefit in young and Triple Negative Breast Cancer (TNBC). We report very long-term outcomes of high risk locally advanced TNBC treated with HDC-ASCT at our institution between 1995 and 2001. Methods: We reviewed our BMT database for women with stage IIB or III TNBC treated with HDC-ASCT. We excluded women with hormone positive, Her2/Neu positive/Unknown and metastatic disease prior to transplant per updated AJCC 7th edition. The majority of patients underwent surgery followed by adjuvant Anthracycline and Taxane based induction chemotherapy followed by HDC-ASCT for consolidation. The HDC regimen consisted of Carmustine 600 mg/m2, Cyclophosphamide 5.6gm/ m2 and Cisplatin 165mg/ m2 (STAMP 1 regimen). Four patients received induction regimen as neoadjuvant and HDC-ASCT as adjuvant treatment per the same protocol. All patients received loco-regional radiation after ASCT. Results: 29 patients had locally advanced TNBC treated with HDC-ASCT. Median age at diagnosis was 43 years (IQR 40-51). 28 had at least 4 positive lymph nodes. Median time from diagnosis to ASCT was 5 months. Median overall survival was 17 years (95% CI, 3-19 years), and median DFS was 14 years (95% CI, 1-19). There was no treatment related mortality (TRM) at 30- and 100-days post ASCT. 12 patients (41%) were alive at median of 16 years (95% CI, 12-19) post ASCT. Conclusions: This single institution study of locally advanced high risk TNBC patients who received HDC-ASCT as part of treatment demonstrates a high long term OS exceeded historical controls. This supports a potential role for HDC-ASCT in this cohort of high risk TNBC. Considering the low TRM associated with this approach, prospective evaluation of this strategy is warranted.

Bortezomib, lenalidomide, and dexamethasone (VRD) is superior to lenalidomide, adriamycin, and dexamethasone (RAD) prior to risk-adapted transplant in newly diagnosed myeloma.

8521 Background: High-dose chemotherapy (HDT) followed by autologous stem cell transplant (SCT) remains a standard of care in patients (pts) with newly diagnosed (ND) multiple myeloma (MM). While lenalidomide (R) maintenance is acknowledged to improve outcomes, intensified consolidation (such as tandem-SCT) has yielded conflicting results. Allogeneic (allo) SCT holds the promise of curative potential at the cost of higher treatment-related mortality (TRM). In a previous phase 2 study, we showed a very low TRM rate (6.1%) and feasibility of 12 months (mos) of R maintenance (maint), with auto/allo SCT after R/adriamycin/dexamethasone (RAD). This prompted us to compare, on a randomized rather than a “biological assignment” basis, a second auto- versus (vs) an allo-SCT in pts with an unfavorable prognosis. Methods: The current protocol (DSMM XIV, NCT01685814) was set up according to a double 2x2-factorial design. Post-induction (PInd) CR rate was the efficacy endpoint for the comparison of RAD vs bortezomib (V)/RD (VRD; 3 cycles each). If pts had achieved &gt;VGPR to HDT, a second randomization (2ndR) compared immediate R maint (arm A2) with a second auto-SCT (B2). In case of &lt; VGPR, pts were randomized between a second auto- (C2) and allo-SCT (D2). Planned R maint. duration was 36 mos, except after allo (12 mos). Results: Between 05/2012-06/2016, 476 pts were randomized and 469 received at least one dose of study drug. Pts’ median age was 55 (range, 32–65) years. 11.3% of pts had FISH del17p; 11.6% had t(4;14); and 4.4% had t(14;16). PInd CR rate was 11.8% (90% CI, 7.9%-16.3%) with RAD and 13.0% (90% CI, 8.9-18.0) with VRD (P = .697). 382 pts underwent R2 with 279 pts. (73%) in &gt;VGPR and 103 (27%) in &lt; VGPR, respectively. Median duration of R maint (N = 298) was 21.2 mos for A2, 23.1 mos for B2, 27.4 mos for C2, and 11.0 mos. for D2. At a median follow-up of 40.2 (0.5-87.0) months, median PFS from first randomization with RAD was 41.7 (95% CI, 35.4-48.5) mos vs. 53.7 (95% CI, 46.2-63.1) mos with VRD (P = .0439). Median PFS from 2ndR was 38.7 (95% CI, 30.3-47.3) mos for the 181 RAD vs. 50.7 (95% CI, 44.4-64.9) mos for the 201 VRD pts (P = .0126). Median overall survival (OS) cannot be estimated. With 47 deceased RAD vs 36 VRD pts, HR was .671 (95% CI, .435-1.037; P = .0703). Conclusions: In this study, median PFS benefit was 12 mos in favor of VRD vs. RAD despite comparable PInd CR. We show for the first time a len-PI to be superior to a len-chemo triplet, confirmed with positive OS trends. 3-year PFS for all consolidation arms will be presented. Clinical trial information: NCT01685814 .

Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens. This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF < 28% or EF < 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure. A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% v 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; P = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% v 45.1%; P = .534) and OS (65.0% v 61.9%; P = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% v 12.7%; P = .068). Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.

Treatment of Refractory Acute Myeloid Leukemia and High-Grade Myelodysplastic Syndrome: Implications of Further Care at an Academic Center Versus Community Setting

Introduction: Many patients with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with 10-19% blasts (MDS-EB2) do not enter complete remission (CR) following initial induction chemotherapy. At an academic referral center, such patients often stay to receive additional treatment, or return to their home communities for further care. For patients and providers alike, the decision about whether to stay or go after initial treatment failure is often fraught. To better inform such decision-making, in this retrospective single-center analysis, we compared covariate-adjusted survival for patients who elected to stay for further treatment at our center and those who returned to their home communities for subsequent care. Methods: We included adults ≥ age 18 years of age with newly-diagnosed AML or MDS-EB2 treated at our institution between January 2012 and May 2018 who failed to enter CR (&lt; 5% morphologic bone marrow blasts) or CR with incomplete hematologic recovery (CRi) after their first cycle of induction chemotherapy. We excluded patients who died before they could begin re-induction therapy. Patients who stayed at our institution for additional treatment are referred to as the "stay" group (n=86); patients who left are considered the "go" group (n=35). Multivariable Cox regression analysis was used to account for other measured covariates possibly influencing survival. Results: The go group was older and had a higher median treatment-related mortality (TRM) score (Table 1), the latter predictive of the probability of death within the first 28 days of initial induction therapy. Forty-seven percent of stay patients received high-intensity re-induction (containing cytarabine at individual doses ≥1g/m2) while 50% received low-intensity treatment (e.g. azacitidine, decitabine, or low-dose cytarabine). Twenty-nine percent of go patients received treatment (mostly low-intensity) in the community setting, while 63% received supportive care only. The stay patients had a median of 2 subsequent hospitalizations (range 0-12) and spent a median of 27 days hospitalized after initial treatment failure (range 0-124). Survival was longer in the stay group compared to the go group (median 8.3 vs. 1.8 months, p&lt;0.001, Figure 1). After accounting for covariates, the risk of death was 5.6-fold higher (95% CI 2.9-10.8, p&lt;0.001) in go patients (Table 2). Median follow-up of patients alive at last contact was 20 months in the stay group and 1 month in the go group; 31/35 go patients have died (Figure 1). Re-induction treatment produced CR or CRi in 41/86 stay patients (48%). Achievement of CR was the covariate most strongly associated with survival in the stay group, with a time-dependent regression model for CR demonstrating a hazard ratio (HR) of 0.32 (95% CI 0.18-0.56, p&lt;0.001); the deleterious effect of adverse cytogenetics on survival (Table 2) likely reflects its association with the inability to achieve CR. Improved survival was incompletely explained by receipt of allogeneic hematopoietic cell transplant (HCT), though there was a trend toward improved survival among the 30 patients (35%) in the stay group who underwent allogeneic HCT (time-dependent HR 0.73, 95% CI 0.41-1.3, p=0.28). Discussion: Patients with refractory AML or MDS-EB2 who elected to stay at our institution for additional therapy after initial treatment failure were more likely to live longer than those who returned to their communities. Those in the go group mostly received supportive care alone. Although the survival benefit among the stay group was modest (median additional survival of 6.5 months), it was similar to the incremental survival benefits associated with several recently approved drugs and was strongly associated with achievement of CR, which occurred in 48% of stay patients. Although our study is limited by the inability to account for unknown covariates, a definitive randomized study is not feasible. There is also a relative lack of information about the go patients once they left our center, although we do know that these patients were much less likely to receive AML/MDS-directed therapy than their stay counterparts. A principal problem in advising patients to stay for additional treatment is our limited ability to predict CR with re-induction therapy. However, our findings suggest that patients with non-adverse cytogenetics and lower TRM scores might preferentially be so advised (Table 2). Disclosures Othus: Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Gardner:Abbvie: Speakers Bureau. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Scott:Novartis: Consultancy; Agios: Consultancy; Incyte: Consultancy; Celgene: Consultancy. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Percival:Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees.

Outcomes and Cost-Effectiveness of Autologous Hematopoietic Cell Transplant for Multiple Sclerosis.

This review presents a critical appraisal of the use of autologous hematopoietic cell transplant (AHCT) for the treatment of multiple sclerosis. We present the reader with a brief review on the AHCT procedure, its immunomodulatory mechanism of action in MS, the most recent evidence in support of its use in patients with relapsing-remitting multiple sclerosis (RRMS), as well as its cost considerations. The first meta-analysis of clinical trials of AHCT for patients with MS demonstrated durable 5-year progression-free survival rates and low treatment-related mortality. Recently, the first randomized controlled phase III clinical trial demonstrated AHCT to be superior to best available therapy for a subset of patients with RRMS. This led to the American society for transplant and cellular therapies (ASTCT) to recommend AHCT "for patients with relapsing forms of MS who have prognostic factors that indicate a high risk of future disability." AHCT should be considered for patients with RRMS with evidence of clinical activity who have failed 2 lines of therapy or at least one highly active disease-modifying therapy.