Acute Myeloid Leukemia Patients in Complete Remission with Positive Measurable Residual Disease Prior to Allogeneic Transplant Have Worse Outcomes, Similar to Active Disease Regardless of Conditioning Regimen Intensity and Post-Transplant Cyclophosphamide Administration

Introduction Allogenic hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) is a curative option in patients with intermediate/high risk disease who achieve morphologic complete remission (CR) after induction chemotherapy. Patients in CR but with positive measurable residual disease (pMRD) prior to HCT had high relapse risk(RR) (67% vs 65%) and low 3 year overall survival (OS) (26% vs 23%),similar to those with active disease in a single institution study (Araki et.al; Volume 34, Feb 1,2016, JCO). However, this study included only patients who received myeloablative conditioning (MAC) and included both peripheral blood and marrow grafts. A single institution retrospective study showed that use of MAC compared to reduced intensity conditioning (RIC) improved 3 year RR(19% v 67%; P < .001) and OS( 61% v 43%; P = .02) in patients with pMRD/CR(determined by molecular analysis of limited gene mutational panel)(Hourigan et.al. Volume 38, April 20,2020, JCO). We analyzed a cohort of AML patients that underwent either MAC or RIC followed by peripheral blood stem cell grafts and post-transplant cyclophosphamide (PTCy) based GVHD prevention regimen at our institution to determine the effect of pMRD on transplant outcomes. Methods: To evaluate the impact of pMRD on transplant outcomes, we analyzed AML patients who underwent HCT at Levine Cancer Institute between June 2014 and April 2020 with MRD testing performed within 1 month prior to HCT. MRD testing was performed at University of Washington by using multiparametric flow cytometry (MPC). The overall sensitivity of the assay is conservatively estimated as 0.1%. In our institution, all patients received MAC (Bu/Flu) or RIC (Bu/Flu or Flu/Cy/TBI) regimens followed by peripheral blood stem cell grafts and identical PTCy-based GVHD prophylaxis regimens that included tacrolimus and mycophenolate. Patient and transplant related characteristics were presented via descriptive statistics. Corresponding P-values were determined using Fisher's exact test for categorical variables and nonparametric Mann-Whitney U test for continuous variables. Relapse-free survival (RFS) and OS were estimated using the Kaplan Meier method. All statistical tests were two sided, and a P-value < 0.05 was considered statistically significant. Results From June 2014 to April 2020, 105 patients with AML underwent HCT. Eighty-three patients with MRD results were included in the final analysis - 52 (63%) with negative MRD (nMRD)/CR, 16 (19%) with pMRD/ CR and 15 (18%) with active disease (no CR). Baseline characteristics were similar except for presence of significantly greater number of high risk patients, based on ASTCT disease classification in the active disease group compared to pMRD/CR and nMRD/CR cohorts( 87% vs 19% vs 0%, P =< 0.001). Median follow up for the entire cohort was 32.7 months. RFS was superior in patients with nMRD/ CR compared to pMRD/ CR or active disease (56.4% vs 19.4% vs 35%, P= 0.005). In addition, OS was superior in nMRD/ CR compared to pMRD/CR or active disease (56.7% vs 35.2% vs 40%, P= 0.014). The use of MAC compared to RIC did not improve RFS (0% vs 32%, P= 0.018) and OS (0% vs 44%, P= 0.071) in pMRD/CR cohort. The use of MAC or RIC did not significantly impact RFS (69% vs 52%, P=0.729) or OS (61% vs 53%, P=0.739) in nMRD/CR patients. Conclusion: Our study validates the previous data that prognosis of patients with pMRD/CR (determined by MPC) prior to HCT is not significantly better than those having active disease. The outcomes were poor regardless of conditioning regimen intensity and PTCy based GVHD prophylaxis used at our institution. These patients might benefit from additional chemotherapy or targeted treatments to achieve nMRD prior to HCT and/or maintenance therapy post HCT. Patients with nMRD/CR disease had similar outcomes with MAC or RIC. This finding suggests that less aggressive conditioning regimens incorporating PTCy could be considered in a subset of patients with nMRD/CR, thereby sparing them from complications associated with MAC. Prospective trials are needed to further study these findings. Figure 1 Figure 1. Disclosures Copelan: Amgen: Consultancy. Grunwald: Astellas: Consultancy; Karius: Consultancy; PER: Other; Gilead: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy; PRIME: Other; Daiichi Sankyo: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Trovagene: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Janssen: Research Funding; Blueprint Medicines: Consultancy; Sierra Oncology: Consultancy; Med Learning Group: Other; Cardinal Health: Consultancy; MDEdge: Other; Agios: Consultancy.

Haploidentical Peripheral Blood Stem Cell Transplantation (Haplo-PBSCT) with Cyclophosphamide Pos Transplant (CyPost) in High-Risk Hematologic Malignancies. Results of 5 Years in Transplant Center in Northeast of Mexico

Introduction: Haploidentical peripheral blood stem cell transplantation ( Haplo-PBSCT) is a curative option in patient with hematology malignancy. In Mexico is very difficult to find an identical HLA donor , for this reason Haplo PBSCT it is an option in our public Health institution. Materials and methods: we aimed a retrospective study since (2017 -2021) in our Hospital Unidad Médica de alta Especialidad 25, Instituto Mexicano del Seguro Social (IMSS UMAE 25) Monterrey, Mexico. We include patients over 15 years of age who were undergo Haplo PBSCT with hematolgy malignancies . We performed Analysis of Overall and Relapse-free survival with kaplan meier curves and incidence of acute and chronic graft versus host disease (GVHD) and percentage of Transplant-Related Mortality (TRM). Results: we analized a 38 patients, the median age was 35 years (range 15-64). Of the total , 25 were male (65%) and 13 famale (34%). The rest of baseline data is described in table 1. The median time of neutrophil engrafment was days 17 ( 11-26 ) and platelets was 19.5 days ( 12-38 ). The Incidence of Primary Graft failure was 18 % ( seven patients). Patients with graft had 99-100% chimerism at day 100. The Incidence of aGVHD was 26 % and the cGVHD was 16%. DLI was used in four patients to treat passenger lymphocyte syndrome (2 patients) and ( 2 patients) with severe graft rejection. The principal cause of death was sepsis in eleven patients (29%). Two patients with acute leukemia (AML and ALL) died after development of post transplant lymphoproliferative disease. The TRM was 28.2%. There were no relapse-related deaths during follow-up after Haplo-PBSCT. The median of survival was 4.5 months ( range 1-44) with Overall Survival (OS) of 42 % at 3 years ( figure 1). Conclusion: Our analysis shows results that were comparable with those published in first world international transplant centers . Relapse remains the major cause of transplant failure, in our population the antigenic disparity between donor and recipient can strengthen the immune response versus disease. Haplo-PBSCT is a feasible transplantation method in patients with hematological malignancies in developing countries with limited resources. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Endothelial Activation and Stress Index (EASIX) Measured Pre-Transplant Identifies a Subgroup with High Transplant Related Mortality in Patients with Thalassemia Undergoing Stem Cell Transplantation Using Thiotepa-Treosulfan-Fludarabine Conditioning

Allogeneic stem cell transplantation (SCT) is a curative treatment for beta-thalassemia major. The Pesaro risk stratification classifies patients with thalassemia into three groups (class I, II, and III) to predict the transplant-related mortality (TRM) and graft rejection after myeloablative conditioning with busulfan and cyclophosphamide. However, in developing countries, where inadequate chelation therapy prior to transplant is common, most patients would fall under the class III category. There is heterogeneity in the clinical outcomes in this group. Hence, our center introduced a further refinement in this risk stratification, identifying a subset of "class III high risk" as those with age greater than or equal to 7 years and liver size > 5cm (Mathews V et al. BBMT 2007). Subsequently, we showed that the use of a conditioning regimen containing thiotepa, treosulfan, and fludarabine (TTF) along with a peripheral blood stem cell graft led to improved outcomes in this subset with a reduction in early TRM from 46% (with busulfan-cyclophosphamide) to 13% (Mathews V et al. PLoS One 2013). There is still a need to identify predictors of poor clinical outcomes to optimize further the clinical outcomes of these class III high-risk thalassemia patients. Endothelial activation and stress index (EASIX) is a simple biomarker calculated using lactate dehydrogenase, creatinine, and platelet counts. EASIX has been shown to be predictive of overall survival in various settings like GVHD following reduced-intensity transplants for malignancies in adults, veno-occlusive disease, and nonrelapse mortality following SCT (Luft T et al. Lancet Haem 2017; Jiang S et al. Haematologica 2021; Luft T et al. BMT 2020). Here, we evaluated the role of EASIX (measured before conditioning therapy) as a biomarker in predicting early TRM in patients with thalassemia major who have undergone SCT with a uniform conditioning regimen using TTF at our center. During the study period from January 2012 to December 2019, 281 patients with thalassemia major underwent SCT with a uniform TTF protocol at our center. The median age was nine years (range 1 to 25 years). One hundred and nine (38.8%) were females. As per Pesaro classification (with Vellore modification), three (1.1%) were class I, 34 (12.1%) were class II, 134 (47.7%) were class III low risk, and 110 (39.1%) were class III high risk. The stem cell donors were matched sibling (n=218, 77.6%), matched related non-sibling (n=23, 8.2%), or matched unrelated donors (n=40, 14.2%). The stem cell donor was HLA matched in all cases except 21 (7.5%), wherein there was a mismatch at one locus. Five (1.8%) had a bone marrow graft, while others had peripheral blood stem cell grafts. Thirty-eight (13.5%) patients had transplant-related mortality by day 100 (TRM100). The median follow-up of the cohort was 31 months (range 0 to 103 months). EASIX score pre-transplant was available for 184 (65.5%) patients. There was no difference in the rate of TRM100 in patients where EASIX was available compared to those where EASIX was not available (14.7% versus 11.3%, p 0.47). Also, there was no difference in overall mortality rate in patients where EASIX was available compared to those where EASIX was not available (21.2% versus 17.5%, p 0.53). Among patients with TRM100 vis-à-vis those who did not, the median EASIX score was significantly higher (1.09 versus 0.75, p 0.008). We then plotted a receiver operating characteristics (ROC) curve for predicting TRM100 using the EASIX score. The area under the curve was 0.661 (Figure 1a). A cut-off of 0.85 for the EASIX score had a 70.4% sensitivity and 62% specificity for predicting TRM100. The TRM100 for patients with EASIX above 0.85 was significantly higher than those with EASIX less than 0.85 (24.4% versus 7.5%, p 0.003). On multivariable logistic regression analysis, the factors independently predicting TRM100 were pre-transplant EASIX score, pre-transplant ferritin, unrelated donor source, and chimerism at day 60 (Figure 1b). In patients with thalassemia major undergoing SCT using a uniform TTF conditioning, EASIX score measured pre-transplant can identify patients at greater risk for Day100 TRM. Figure 1 Figure 1. Disclosures Mathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.

The Effect of Daratumumab, Lenalidomide, Dexamethasone (DRd) on Peripheral Blood Stem Cell Mobilisation (PBSC)

Peripheral blood stem cell (PBSC) mobilisation in multiple myeloma (MM) patients after exposure to daratumumab (D), a CD38 targeting monoclonal antibody, produces a lower stem cell yield possibly due to an effect on CD34+ stem cells (Hulin et al., 2021). Similarly, the GRIFFIN study reported greater plerixafor usage to facilitate PBSC mobilisation in patients randomised to DARA-Velcade, Lenalidomide and Dexamethasone (D-VRd) when compared to VRd (Voorhees et al., 2020). In addition, R use has previously been shown to impact adversely on PBSC yields (Kumar et al., 2007) with a recommendation to use cyclophosphamide (cyclo) assisted mobilisation for this group of patients (Mazumder et al., 2008). In this context there remains uncertainty about the role of plerixafor, compared to chemotherapy assisted mobilisation. Aim: To investigate the effect of DRd on PBSC mobilisation and to determine the outcomes of G-CSF (G) + cyclo and G +/-plerixafor mobilisation for patients with prior DRd exposure and to compare PBSC yields to patients mobilised after Velcade, Cyclophosphamide, Dexamethasone (VCD) based induction therapy Methods: The ALLG MM21 study (ACTRN12618001490268) is a multicentre study of transplant eligible refractory and/or relapsed MM patients. Patients were eligible if they had progressive disease or less than a partial response to prior VCD induction therapy. D at 16mg/m2 and d at 40mg was administered on Day 1,8,15 and 22 in combination with R 25mg D1-21 for the first 2 induction cycles. From cycle 3, D was administered fortnightly with R 10mg D1-28 and d 40mg weekly. PBSC mobilisation was undertaken after 2-3 cycles of DRd with a minimum of 14 days off R and D prior to proceeding. The PBSC mobilisation approach and the need plerixafor were based on institutional practice. Results: Fifty patients were enrolled on trial. Three patients experienced progressive disease and 3 patients died prior to mobilisation. A total of 44 patients underwent PBSC mobilisation,11 (25%) of these post-VCD but prior to starting DRd received G-only (Group A); 22/44 (50%) post-DRd received G + cyclo (Group B); and 11/44 (25%) post-DRd received G-only (Group C) (Figure 1). Based on low day 1 CD34+ counts 13/33 (33%) patients required plerixafor post-DRd and 2/11 (18%) post-VCD. Post-DRd 7/33 (21%) patients failed to collect more than 2 million cells/kg and 4 then failed a second attempt at mobilisation. All patients post-VCD/pre-DRd were successfully mobilised. Total PBSC yields were comparable between Groups A and B but significantly lower for Group C versus Group A (Table 1). Group B patients were then compared to a contemporaneous group of non-trial VCD treated and G only mobilised patients (n = 32) and found to have significantly inferior day 1 median peripheral blood (PB) CD34+ cell counts (Table 2, Figure 1). Seven patients (21%) who received G + cyclo experienced grade 3/4 infections with 5 of the 7 demonstrating day 1 PB CD34+ cell counts of <5 per/µl. There were more apheresis days with median 2.5 days (1-5) in the G+ cyclo (Group B) compared to the other G-only or G+ plerixafor groups (median 2 days (1-3)). Conclusions: PBSC collection after DRd salvage was characterised by lower CD34+ cell mobilisation and lower overall PB CD34+ yields when compared to patients mobilised after receiving VCD. Cyclo assisted mobilisation but not G + plerixafor abrogated this effect. Further evaluation of strategies to mitigate against the impact of DR containing induction are required. Figure 1 Figure 1. Disclosures Indran: Jansse-Cilag Pty Ltd.: Other: Registration costs , Patents & Royalties. Quach: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Janowski: BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Estell: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Spencer: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. OffLabel Disclosure: The combination of Daratumumab, Lenalidomide and Dexamethasone therapy is not approved on the Pharmaceutical Benefits Scheme in Australia.