Non-relapse Related Mortality Research Articles

Chidamide combined with a modified Bu-Cy conditioning regimen improves survival in patients with T-cell acute lymphoblastic leukemia/lymphoma undergoing allogeneic hematopoietic stem cell transplantation

This study aimed to evaluate the efficacy and safety of chidamide (Chi) combined with a modified Busulfan-Cyclophosphamide (mBuCy) conditioning regimen for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only in the same period. The leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse-related mortality (NRM) were evaluated. Patients in the Chi group were associated with lower 2-year CIR (19.0 vs. 41.4%, P = 0.030), better 2-year LFS (76.1 vs. 48.1%, P = 0.014), and had no significant difference in 2-year OS (80.5 vs. 66.4%, P = 0.088). Patients with minimal residual disease (MRD) positive before HSCT in the Chi group exhibited an advantage in 2-year LFS and a trend towards better 2-year OS (75.0 vs. 10.2%, P = 0.048; 75.0 vs. 11.4%, P = 0.060, respectively). Multivariable analysis showed that the chidamide intensified regimen was independently associated with better LFS (HR 0.23; 95%CI, 0.08–0.63; P = 0.004), and showed no significant impact with OS for all patients (HR 0.34, 95%CI, 0.11–1.07; P = 0.064). The cumulative incidence rates of grade II-IV aGVHD were similar (36.4 vs. 38.6%, P = 0.858). 20 patients in Chi group evinced an elevation in γ-glutamyltransferase, as compared to the mBuCy group (90.9 vs. 65.9%, P = 0.029). No transplantation-related mortality was documented within the first 100 days after transplantation. The results demonstrate that the chidamide intensified regimen may be an effective and acceptable safety option for T-ALL/LBL undergoing allo-HSCT, and further validation is needed.

Long-term outcomes after cardiac transplantation in AL amyloidosis.

7572 Background: Systemic AL amyloidosis can lead to progressive multi-organ dysfunction including advanced heart failure which may require orthotopic heart transplantation (OHT). Hematologic outcomes of AL amyloidosis post-OHT are not well described. Methods: We report outcomes for patients with AL amyloidosis with cardiac involvement post-OHT from Nov 2008 - Jun 2023 at Vanderbilt University Medical Center. Hematologic response was graded per the ISA guidelines. Results: Fourteen pts underwent OHT of whom 13 had lambda light chain disease. Three (21%) pts had isolated AL amyloidosis (AL) without myeloma (MM), while 11 (79%) also had MM: 6 with bone marrow plasma cells (BMPCs) 10-19% (AL-PCMM-10) and 5 with BMPC ≥20% (AL-PCMM-20). One each with AL-PCMM-10 and AL-PCMM-20 had lytic lesions (AL-CRAB). Median age at OHT was 55.5 yrs (range 37-74). Median time from diagnosis to OHT was 18 mo (range 3-62). Five (35%) pts had biopsy-proven extracardiac amyloid involvement. Median difference in serum free light chains at first evaluation was 70 mg/dL (range 9-289). Three pts were Mayo 2012 stage II, 4 stage III, and 7 stage IV. Four pts had t(11;14) and 1 had 1q gain. Ten (71%) pts received triplet therapy (VCd or VRd) and 3 (21%) received quadruplet therapy (Dara-VCd or Isa-VCd) pre-OHT. Six (43%) pts had autologous stem cell transplantation (ASCT); 1 pre-OHT and 5 post-OHT. Of ASCT pts, 1 pt achieved CHR, 1 VGPR, 2 PR, and 1 had PD pre-ASCT. Pre-OHT, 4 pts achieved CHR, 6 VGPR, 3 PR, and 1 had PD. Eleven pts (79%) received maintenance therapy post-OHT (5 proteosome inhibitors, 6 anti-CD38). At last follow-up, 8 pts were in CHR, 3 in VGPR, 1 in PR, and 2 had PD. Four (29%) pts died post-OHT: 2 from AL recurrence (1 each with AL and AL-PCMM-10), 1 from cardiac allograft vasculopathy (AL-CRAB), and 1 from renal failure (AL-CRAB). Three (21%) pts had hematologic relapse 5, 21 and 48 mo post-OHT, and of those, 2 had recurrent cardiac amyloid in graft 37 and 71 mo post-OHT. Of those with hematologic relapse, 2 had AL-PCMM-10 and 1 had AL. One pt had post-transplant lymphoproliferative disorder 126 mo post-OHT, requiring treatment. Median follow-up and survival of the cohort post-OHT was 2.25 yrs (range 0.5-13.8). Conclusions: In this single-center analysis of pts undergoing OHT for cardiac AL amyloidosis, we demonstrate feasibility of excellent long-term outcomes, in predominantly high-risk AL pts where majority harbored high-risk disease with MM overlap, either by AL-CRAB or AL-BMPC. Induction alone led to ≥VGPR response in 10 (71%) pts pre-OHT and further therapy deepened this to 11 (79%) pts. Both AL-CRAB pts died during follow-up, highlighting the overall poor prognosis in this specific subgroup. In our cohort, non-relapse related mortality was seen in only 2 (14%) pts, demonstrating acceptable post-OHT risk and overall ability to achieve far improved outcomes in the high-risk cardiac AL amyloidosis patient population that otherwise suffers from rapid and universal mortality.

D-dimer and sinusoidal obstructive syndrome-novel poor prognostic features of thrombotic microangiopathy in children after hematopoietic cellular therapy in a single institution prospective cohort study.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single-institution cohort study serially enrolled all allogeneic HCT recipients from August 2019-August 2022. Patients were universally screened for TA-TMA and intermediate and high-risk patients were immediately treated with eculizumab. Sub-distribution cox-proportional hazards modelswere used to identify sub-distribution hazard ratios (sHR) for multi-organ dysfunction (MOD) and non-relapse-related mortality (NRM). Of 136 patients, 36 (26%) were diagnosed with TA-TMA and 21/36 (58%) developed MOD, significantly more than those without TA-TMA, (p < .0001). Of those with TA-TMA, 18 (50%) had high-risk TA-TMA (HR-TA-TMA), 11 (31%) had intermediate-risk TA-TMA (IR-TA-TMA), and 8 (22%) had standard risk (SR-TA-TMA). Twenty-six were treated with eculizumab (1/8 SR, 7/11 IR, and 18/18 HR). Elevated D-dimer predicted the development of MOD (sHR 7.6, 95% confidence interval [CI] 1.8-32.3). Children with concurrent sinusoidal obstructive syndrome (SOS) and TA-TMA had an excess risk of MOD of 34% and data supported a biologic interaction. The adjusted NRM risk was significantly higher in the TA-TMA patients (sHR 10.54, 95% CI 3.8-29.2, p < .0001), despite prompt treatment with eculizumab. Significant RF for NRM in TA-TMA patients included SOS (HR 2.89, 95% 1.07-7.80) and elevated D-dimer (HR 3.82, 95% CI 1.14-12.84). An unrelated donor source and random urine protein to creatine ratio ≥2 mg/mg were significantly associated with no response to eculizumab (odds ratio 15, 95% CI 2.0-113.6 and OR 6.5, 95% CI 1.1-38.6 respectively). TA-TMA was independently associated with NRM despite early diagnosis and treatment with eculizumab in this large pediatric transplant cohort. Prognostic implications of D-dimer in TA-TMA merit further investigation as this is a readily accessible biomarker. Concurrent SOS is an exclusion criterion of many ongoing clinical trials, but these data highlight these patients could benefit from novel therapeutic approaches. Multi-institutional clinical trials are needed to understand the impact of TA-TMA-targeted therapies.

Next Generation Sequencing and Cytogenetics in Acute Myeloid Leukemia - Therapeutic and Prognostic Impact: A Retrospective Cohort from a Private Centre of Reference in Latin America

Introduction: Acute Myeloid Leukemia (AML) is a prevalent and severe hematological disorder. The emergence of Next-Generation Sequencing (NGS) and karyotiping, has demonstrated associations between chromosomal abnormalities and mutations with worse treatment response and mortality in AML. Current classification of AML is based on its cytogenetic and molecular profile, as defined by World Health Organization (WHO) 2022 and European Leukemia Net (ELN) 2022. Despite its evident importance in AML, application of these diagnostic methods poses new challenges. In Latin America, particularly, there is a clear limitation of data and studies regarding molecular and cytogenetic analysis in AML patients, due to the relatively short time these techniques have been employed and the few accredited centers able to perform them. Therefore, this study primarily aims to provide an in-depth evaluation of the application of NGS and cytogenetic analysis in AML, identifying the impact of somatic mutations on AML mortality and progression free-survival based on the experience of a reference center in Latin America. Secondarily, we aim to determine the molecular and cytogenetic profile of these population and analyze the impact of age, sex and comorbidities in AML prognosis. Methods: This is an unicentric, retrospective and non-interventional cohort performed in Brazilian Hospital Albert Einstein. Inclusion criteria were adult patients (aged ≥18 years) diagnosed with AML between May 2017 and August 2022, who underwent myeloid panel testing through NGS and cytogenetic evaluation at diagnosis. Independent variables analyzed were age, gender, prognostic risk according to ELN 2022, indication of bone marrow transplantation and molecular and cytogenetic risk at diagnosis. High cytogenetic risk was defined by the presence of at least one of the high-risk karyotype abnormalities described in ELN 2022 and high-risk NGS was defined by mutation in the genes ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, U2AF1, ZRSR2, TP53 or FLT3. The primary outcomes evaluated were overall survival (OS) and progression-free-survival (PFS), estimated by the Kaplan-Meier method. Secondary outcomes were disease relapse and non-relapse-related mortality (NRM). Results: From a total of 168 selected patients, 64 filled out elegibility criteria and were included in the study. Mean age at diagnosis was 62,7 years old with a equal proportion of both sexes. 7 patients (10,9%) were classified as favourable risk according to ELN 2022, 13 (20,3%) as intermediate risk and 44 (68,8%) as high risk. 42 (65,6%) had a standard-risk karyotype, whereas high-risk karyotype was found in 22 (34,4%) patients. 47 (73,4%) individuals presented high-risk NGS mutations, with a higher prevalence of gene rearrangements in RUNX1 (20,1%), FLT3 (18,7%), TP53 (15,6%) and SRSF2 (15,6%). Only 17 (26,6%) patients reported exclusively standard-risk or no mutations. After a median follow-up was 26 months, estimated OS was 73% in 1 year and 54% in 2 years. 1 and 2 years PFS was 63% and 45%, respectively. 11% relapsed after 1 year and 27% after 2 years. The incidence of NRM was 25% and 28% after 1 and 2 years, respectively. High-risk karyotype was associated with a signficant reduction in overall survival (hazard ratio [HR] 2,27, 95% CI 1,09-4,70; p=0·028) and progression-free-survival (HR 2,15, 95% CI 1,23-4,11; p=0·02). On the other hand, there was no statistically significant association between high molecular risk by NGS and OS (HR 1.45, 95% CI 0.59-3.58; p=0.41) or PFS (HR 1.43, 95% CI 0.65-3.13; p=0.37). Progressive age has discreetly impacted in OS (HR 1,05, 95% CI 1,02-1,08; p=00005), PFS (HR 1,03, 95% CI 1-1,05; p=0,025) and NRM (HR 1,06, 95% CI 1,02-1,11; p=0,002). No differences in outcomes were found between sex, ELN 2022 risk groups, and treatment with bone marrow transplantation. Conclusions: Next-Generation Sequencing, combined with cytogenetic analysis, has improved precision in prognosis prediction of AML patients of each patient, allowing safe implementation of appropriate individualized therapy. This study showed and association between high-risk cytogenetics and worse prognosis in AML, but no association was observed between molecular risk and AML morbimortality. Further studies with a bigger population and longer follow-up should be conducted in Latin America in order to better clarify and delve deeper into the results reported in this cohort.

Haploidentical Donor Vs. Mismatch Unrelated Donor in Reduced Intensity Conditioning Transplant: A Study from the Spanish Group of Hematopoietic Transplant and Cell Therapy (GETH-TC)

The most suitable donor for allogeneic stem cell transplant is still a matter for debate when there is no matched related or unrelated donor. In this setting, information comparing MMURD vs. HAPLO remains scarce and do not show differences between both sources (Piemontese, S et al., Hematol Oncol. 2017; Shem-Tov N et al., Leukemia 2020; Battipaglia G et al., BMT 2022). This study analyzes the outcomes of HAPLO vs. MMURD stem cell transplant recipients in reduced intensity conditioning scenarios (allo-RIC) in a retrospective analysis from the GETH-TC study group. Methods: Consecutive patients receiving a first allo-RIC between 1/2012 and 3/2021 at 9 GETH/EBMT centers with HAPLO or MMURD (mismatch at HLA-A, B, C, or DRB1 by molecular techniques) were included. Patients undergoing HAPLO received post-transplant cyclophosphamide (PTCY) based graft vs. host disease (GVHD) prophylaxis associated with rapamycin, tacrolimus, or cyclosporine, +/- mycophenolate. For MMURD, prophylaxis was diverse, including PTCY. Baseline characteristics and outcomes were compared according to the donor type through logistic regression. To balance the two groups, the Propensity Score Weighting method was performed with the variables that were significant in the logistic regression. Survival was calculated using the Kaplan-Meier method and the HR using the Cox model. The primary objective was the comparison of the aGVHD III-IV or severe chronic GVHD-free/relapse-free survival (GRFS). Secondary endpoints were overall survival (OS), relapse/progression-free survival (DFS), non-relapse-related mortality (NRM), relapse, and acute and chronic GVHD. Results: A total of 411 patients were included, 287 HAPLO and 124 MMURD (Table 1), with a median follow-up of 46.1 and 48.2 months, respectively. The GRFS at 24 months was similar in both groups, 48.5% vs. 53.9% in HAPLO and MMURD, respectively [HR 0.9, P=0.79). There were no differences in 2 year-OS 58.9% vs. 60.7% (HR 1.04, P=0.93), or in 2-year DFS 55.1% vs. 55.8% (HR 1.05, P=0.9). Similarly, NRM (32.3% vs. 32.1% (HR 1.09, P=0.85) and relapse (18.6% vs. 17.9% (HR 0.96 [95%CI 0.31;2.96] P=0.94) did not present statistically significant differences between HAPLO and MMURD. In addition, there was no difference between groups in time to neutrophil (19 days [95%CI 18;20] HAPLO vs 18 days [95%CI 15;19] MMURD, P= 0.08) and platelet engraftment (27 days [95%CI 23;29] HAPLO vs 20 days [95%CI 13; 33] MMURD, P= 0.15). Regarding 2-4 acute GVHD, the incidence at 6 months was 51.7% vs. 63.2% in the HAPLO vs. MMURD recipients (HR 1.44 [95%CI 0.8; 2.6], P=0.23), without significant differences in 3-4 acute GVHD grade. Seventy-seven HAPLO patients and 42 MMURD patients developed global chronic GVHD, with no significant differences in incidence between groups. Remarkably, MMURD (1% [95%CI 0; 2.6]) had lower incidence of severe forms of chronic GVHD than HAPLO (6.7% [95%CI 2.5; 10.6]) (HR 0.11 95%CI [0.02;0.57], P=0.01). When the analysis was restricted to PTCY-based prophylaxis patients (48 MMURD vs. 287 HAPLO), the outcomes were similar, with a significantly lower incidence of severe forms of chronic GVHD in the MMURD group. Finally, events defining GRSF were similarly distributed between both groups (Figure 1), except for chronic GVHD. However, the latter had a low incidence in both groups, so this difference did not impact the primary endpoint. Conclusion: In this cohort of patients, no differences in terms of OS, DFS, NRM, relapse, or GRSF were observed between HAPLO and MMURD. Transplantation with MMURD was associated with less severe chronic GVHD, even when considering the group of patients with PTCY prophylaxis exclusively. This advantage of MMURD compared to HAPLO is not translated into an improvement on the GRFS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Late Morbidity and Mortality after Autologous Blood or Marrow Transplantation (BMT) for Lymphoma in Children, Adolescents and Young Adults - a Report from the BMT Survivor Study (BMTSS)

Introduction: Autologous BMT is an integral part of consolidation and/or salvage therapy for children, adolescents and young adults with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). However, there is paucity of information regarding the long-term outcome after autologous BMT for lymphoma performed in this age group. We address this gap by leveraging the BMTSS to determine the magnitude of risk of chronic health conditions as well as cause-specific late mortality in patients undergoing autologous BMT for lymphoma between 1980 and 2014 at City of Hope, University of Minnesota or University of Alabama at Birmingham. Methods: To be included in this analysis, patients had to have received a single or tandem autologous BMT before age 40y and survived ≥2y after transplantation. BMT recipients (n=583 [HL: 59.7%; NHL: 40.3%]) and a sibling comparison group (n=330) completed a 255-item survey, and self-reported sociodemographics and chronic health conditions. A severity score (grade 3 [severe], 4 [life threatening] or 5 [fatal]) was assigned to the conditions using CTCAE v5.0. Vital status and cause of death information was ascertained using the National Death Index (NDI), medical records and Accurint databases. Logistic regression estimated the odds of grade 3-4 conditions in BMT recipients alive at study participation compared to siblings. Fine-Gray regression estimated the hazard of grades 3-5 chronic health conditions among BMT recipients (alive and deceased), treating death as a competing risk. Results: Median age at BMT was 30.0y (range: 2.0-39.0); median length of follow-up was 9.6y (2.0-32.1) and median age at study participation was 41.1y (13.7-67.1). Severe/life-threatening chronic health conditions in BMT survivors compared with siblings: By age 45y, the cumulative incidence of a grade 3-4 chronic health condition was 31.2% (95%CI; 25.5-37.0) among the BMT survivors and 12.9% (95%CI; 8.8-17.7) among the siblings (p<0.0001) (Figure 1). BMT survivors were at a 3.2-fold greater odds of a grade 3-4 condition (aOR=3.2, 95%CI=2.2-4.8) compared to siblings. Greater odds were observed among BMT survivors vs. siblings for the following conditions: joint replacement (OR=4.9, 95%CI=1.7-13.7), cataract (OR=4.2; 95%CI=1.4-13.0), cardiovascular disease (OR=2.2, 95%CI=1.2-4.0), and multiple conditions (OR=4.9; 95%CI=2.6-9.5). Severe/life-threatening/fatal chronic health conditions among BMT recipients: The 20y cumulative incidence of grade 3-5 conditions for the entire cohort was 46.8% (95%CI=41.6-51.7%). The 20y cumulative incidence was 42.1% (95%CI=34.2-49.7%) for patients with NHL and 49.6% (95%CI=42.9-56.0%) for patients with HL, placing HL patients at a 1.4-fold higher adjusted hazard of grade 3-5 conditions (95%CI=1.0-1.8, p=0.0232). Late mortality in BMT survivors: Conditional on surviving the first 2y after BMT, the all-cause mortality rate was 54.3% (95%CI=48.8-59.4%) at 25y from BMT (HL: 62.6%; NHL: 42.3%). The adjusted hazards of all-cause mortality were higher in HL patients (HR=1.8, 95%CI, 1.3-2.4; reference: NHL), and among Black patients (HR=3.0, 95%CI, 1.9-4.6; reference: non-Hispanic white). Causes of death were available for 84% of the cohort, and included primary disease (35%), subsequent neoplasm (16%), infection (13%), cardiac disease (8%), pulmonary disease (3%), and homicide/suicide/accident (3%). As shown in Figure 2, relapse-related mortality (RRM) plateaued after 20y from BMT, whereas the non-relapse-related mortality (NRM) continued to climb, crossing RRM at 20y from BMT. The 25y cumulative incidence of RRM was 28% (95%CI=22-34%), while that for NRM was 37% (95%CI=31-44%). Patients with HL were at increased risk for RRM (HR=2.3, 95%CI=1.3-3.8, p=0.0029; reference: NHL). The hazard of NRM was greater among HL patients (HR=1.7, 95%CI=1.1-2.7), and Black patients (HR=3.1, 1.5-6.4; reference: non-Hispanic white). Conclusions: The burden of severe/life-threatening chronic health conditions was 3-fold higher in autologous BMT recipients for lymphoma when compared with a non-BMT sibling comparison group. Patients with HL were at increased risk of a severe/life-threatening/fatal conditions as well as late mortality, when compared to patients with NHL. Finally, Black patients were at a higher risk for non-relapse-related mortality. These findings suggest a need for long-term surveillance among the vulnerable sub-populations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Role of Corrected Dlco in Predicting Relapse and Mortality Post Autologous Hematopoietic Cell Transplantation in Multiple Myeloma

Introduction: Autologous Hematopoietic Cell Transplantation (AHCT) remains the standard of care for multiple myeloma (MM) patients who achieve at least a partial response to prior chemotherapy. Survival post AHCT is associated with disease risk and patient comorbidities, including lung diseases indicated by pulmonary function. The corrected diffusing capacity for carbon monoxide (DLCOc) is usually assessed in transplant candidates in order to determine AHCT eligibility, although precise DLCOc cut-offs are yet to be standardized. Recent studies suggested that a DLCOc ≤60% possesses a prognostic value in predicting relapse and mortality post AHCT. Hence, we aimed to validate the role of DLCOc ≤60% in predicting post-AHCT outcomes at our institution. Methods: We did a retrospective review of MM patients who underwent AHCT at Cleveland Clinic between January 1st, 2011 and January 15th 2021. The patients were categorized based on their corrected DLCO into two groups: DLCOc ≤60% and DLCOc >60% of the predicted value. Baseline characteristics, including patient, disease, and transplant factors were compared between the two groups. The collected data were analyzed using SPSS and GraphPad Prim by means of Chi square, ANOVA, and Kaplan Meier survival analysis. Results: A total of 466 patients with available DLCOc data were included in our study, of which 38 patients had a DLCOc ≤60% and 428 had a DLCOc >60% of the predicted value. Our cohort had a median follow up of 31.9 months post-AHCT. Patient and disease characteristics were similar between the 2 groups, including age (median 59.1 vs 60.3 years, P= 0.407), sex (Males 65.8 vs 58.2%, P=0.361), standard risk (81.5 vs 66.4%) and high risk (18.5 vs 33.6%) cytogenetic profiles (P=0.107), as well as history of smoking (23 vs 38.2%, P=0.1). In addition, both groups had a similar distribution across the International Staging System (ISS) stages (37.9, 37.9, 24.2% vs 38.3, 38.9, 22.8% for stages I, II and III, P= 0.987) and received similar preparative regimens (92.1, 7.9, 0% vs 96.3, 3, 0.7% for Melphalan 200 mg/m2, Melphalan 140 mg/m2 and Busulfan + Cyclophosphamide, P=0.25). Kaplan-Meier survival analysis showed that the DLCOc ≤60% group survived for a significantly shorter period with median overall survival (mOS) of 27.3 vs 91.7 months (P<0.0001) (Fig 1A). In addition, the DLCOc ≤60% group had earlier relapses with median progression free survival (mPFS) of 21.2 vs 38.7 months (P=0.0115) (Fig 1B). Subgroup analysis confirmed that mOS was significantly shorter in the DLCOc ≤60% group irrespective of relapse, with mOS of 25.4 vs 79.6 months (P<0.0001) in relapsed MM of DLCOc ≤60% (n=18) and DLCOc >60% (n=193) patients, respectively. Similarly, non-relapse survival was also shorter (medians unreached) in the non-relapsed DLCOc ≤60% group (n=20) compared to the non-relapsed DLCOc >60% group (n=235) (P<0.0001). When selecting patients of standard risk cytogenetics from both groups, the significant difference in mOS and mPFS was retained with mOS 51.7 vs unreached months (P<0.0001) and mPFS 21.2 vs 67.7 months (P=0.0051) for DLCOc ≤60% group (n=22) and DLCOc >60% (n=225), respectively. Likewise, matching for melphalan 200 mg/m2 regimen patients further maintained the remarkable gap in mOS 25.4 vs 91.7 months (P<0.0001) and mPFS 20 vs 40 months (P=0.0013) for DLCOc ≤60% group (n=35) and DLCOc >60% (n=413), respectively. Conclusion: The pre-AHCT DLCOc level possesses a useful prognostic value that can predict disease relapse as well as both relapse- and non-relapse related mortality post AHCT. This was demonstrated when using a cut-off value of ≤60% vs >60%. Our findings were supported by the fact that both groups had similar clinical and cytogenetic characteristics, thus reducing the risk of confounding effects. Our findings were also validated when controlling for cytogenetic risks and melphalan dosage. Large, prospective trials are warranted to determine whether DLCOc ≤60% can serve AHCT eligibility criterion. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Utility and Validity of Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) in Predicting Overall Survival and Non-Relapse Mortality in Adolescent and Young Adult Population

Introduction: Hematopoietic cell transplantation-comorbidity index (HCT-CI) is a scoring tool of pretransplant comorbidities that is widely used to predict posttransplant overall survival (OS) and non-relapse mortality (NRM). It was initially studied and validated on cohorts of patients from two institutions with higher HCT-CI score predicting higher NRM and lower OS. Median age of patients in those cohorts was 44.8 (0.8-72.2). Further studies from multiple centers showed similar results however, most of these studies included patients older than 40 years. One study looked at the usefulness of HCT-CI in adolescent and young adult (AYA) population and found that HCT-CI might be useful in predicting OS but not NRM, although the sample size was only 56 patients. We aim in this study to test the utility and validity of HCT-CI for predicting OS and NRM in a larger cohort of AYA patients undergoing allogenic stem cell transplant in our center. Methods: We conducted a retrospective cohort, single center study. Only patients between the ages of 14 and 40 years were included. Patients were divided into 3 groups according to HCT-CI: 0, 1-2, or more than 2. Causes of death were assigned as either relapse related versus non-relapse related mortality. Patients have to be seen in clinic at least once after discharge to be included. Results: 499 patients were included in the study. Median age was 24 years. 292 (58.5%) male and 207 (41.5%) female (P = 0.4). Among those patients, 184, 162 and 153 were having HCT-CI of 0, 1-2 and more than 2 respectively (P = 0.4). 361 (73%) patients were having malignant disease while 138 (27%) were having non-malignant disease (P = 0.18). 2-year and 4-year NRM were 8.6% and 16.1% for HCT-CI 0, 9.8% and 20.4% for HCT-CI 1-2, 10% and 16.18 for HCT-CI more than 2 (P = 0.9). 2-year and 4-year OS were 75.7% and 62% for HCT-CI 0, 69.7% and 58.5% for HCT-CI 1-2, 63.5% and 53.7 for HCT-CI more than 2 (P = 0.06). There was no statistically significant difference among all 3 groups in terms of OS or NRM. Conclusion: HCI-CI was not predictive of neither OS nor NRM in our cohort of patients aged between 14 and 40 years. Limitations of our study include the retrospective nature of data collection as well as being a single center-based study. Larger prospective studies in this particular age group would help to more accurately risk stratify patients and predict their post-transplant course. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Validation of the Gatmo Score in Predicting Mortality Following Autologous Hematopoietic Cell Transplant in Multiple Myeloma Patients

Introduction: Autologous Hematopoietic Cell Transplant (AHCT) is incorporated into standard of care management of Hodgkin's lymphoma (HL), Non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) as well as other types of malignancies. However, AHCT is an aggressive treatment modality, relying upon high dose chemotherapy. Treatment places significant stress on the body and may increase the non-relapse mortality risk in patients with comorbidities; thus, only patients that meet pre-specified eligibility criteria are considered for the procedure. Recently, the Grupo Argentino De Transplante De Medula Osea (GATMO) proposed a scoring system that categorizes HL, NHL and MM patients into risk categories to predict their overall survival (OS) and non-relapse mortality (NRM) post-AHCT. Here, we aim to validate the GATMO score in our internal cohort of MM patients. Methods: All MM patients who underwent AHCT at Cleveland Clinic between 2011 and 2021 were screened for our study. Data pertaining to patients’ demographic, cytogenetic, and clinical characteristics were collected via retrospective chart review, including age at AHCT, gender, as well as list of comorbidities as suggested by the hematopoietic cell transplant-comorbidity index (HCT-CI). GATMO risk scores were calculated through the summation of the following: 1 point if male gender; 1 point if age 55 to <65; 2 points if age ≥ 65; 1 point if HCT-CI ≥3. Accordingly, patients were classified as low risk (LR) if their GATMO score was 0-1, intermediate risk (IR) if their score was 2-3, and high risk (HR) if their score was 4. Results: A total of 513 MM patients who underwent AHCT and with appropriate data available for score calculation were included in this study. They had a median age at diagnosis of 59.3 years, a median age at AHCT 61.4 years, were 57.9% male and 83.2% of White ethnicity, and were followed for a median of 32.9 months post-AHCT. Age group 55 to <65 included 230 (44.8%) patients and age group ≥ 65 included 169 (32.9%) patients. Current smokers were 24(4.7%), Ex-smokers 168 (32.9%) and never smokers 318 (62.4%). Time to transplant was ≥12 months in 150 (29.2%), while the ECOG performance status was 0 in 157 (30.7%), 1 in 318 (62.1%), 2 in 36 (7%) and 3 in 1 (0.2%). ISS stages I, II, and III were determined in 160 (37.7%), 165 (38.9%) and 99 (23.4%), respectively. HR cytogenetics were seen in 134 (32.6%). Pre-AHCT, 314 (66.5%) had received 1 line of therapy, 111 (21.6%) had received 2 lines of therapy, and 61 (11.9%) had received ≥3 lines of therapy. Remission status at AHCT was PR in 208 (40.5%), VGPR in 174 (33.9%) and CR in 131 (25.5%). Components of the HCT-CI index included arrhythmia (10.5%), nonvalvular cardiac (10.9%) and valvular cardiac (1.8%) disease, inflammatory bowel disease (IBD) (0.8%), diabetes mellitus (DM) (13.3%), cardiovascular disease (CVD) (2.7%), psychiatric disease (21.6%), mild hepatic (1.2%) and severe hepatic (0.2%) disease, body mass index (BMI) ≥35 (17.7%), infection at AHCT (3.3%), rheumatological disease (1.6%), peptic ulcer disease (PUD) (0.4%), kidney disease requiring dialysis or creatinine ≥2 (7.4%), mild (33.7%) and severe (20.9%) pulmonary disease, and history of solid tumors requiring treatment (6.8%). The median HCT-CI was 2 (range 0 to 12). Per GATMO score calculation, 137 (26.7%) patients were classified as LR, 335 (65.3%) as IR, and 41 (8%) as HR for mortality post-AHCT. Baseline characteristics including the HCT-CI constituents pertaining to the patients of each risk group are presented in Table 1. Kaplan-Meier analysis asserted the significant difference in survival amongst the 3 risk groups, with median OS 48.5 vs 86.6 vs unreached months (P=0.0017) for the HR, IR and LR groups, respectively (Fig 1). This was further corroborated by the lower time to NRM (medians undefined, P=0.02) and higher 5-year mortality rates (34.1 vs 20.3 vs 15.3%, P=0.03) rates for HR as compared to the IR and LR groups, respectively. There was no significant difference noted in mortality at 1-year (4.9 vs 4.8 vs 2.2%, P=0.4) or 3-year (19.5 vs 14.6 vs 10.9%, P=0.3) intervals post-AHCT. Conclusion: The GATMO scoring system reliably identifies MM patients who are pre-selected for ASCT but at a higher risk of non-relapse related mortality following the procedure. Hence, risk stratification per the GATMO score may guide decision making in MM patients undergoing AHCT candidacy while predicting their mortality risk based upon pre-AHCT comorbid conditions. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of risk scores in outcome of patients with myeloid neoplasms after allogeneic stem cell transplant

BackgroundThe main causes of failure of allogeneic hematopoietic stem cell transplantation (allo-transplant) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are relapse and transplant-related mortality. Different scores have been designed to predict the prognosis of these patients. The objective of this study was to assess which score or combination has better outcome predictive capacity. MethodsRetrospective analysis of patients with AML and MDS who received a first peripheral blood allo-transplant in a single center, between December 2001 and October 2019. Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), European Group for Blood and Marrow Transplantation (EBMT) and Disease Risk Index (DRI) scores were calculated. For each score and for the HCT-CI/DRI and HCT-CI/EBMT combinations, overall survival (OS), cumulative incidence of relapse (CIR), non-relapse-related mortality (NRM), and graft versus host disease-free relapse-free survival (GRFS) were analyzed. Results175 patients were evaluated. With a median (range) follow-up of 3.96 (0.32–17.22) years, the 5-year probabilities (95% CI) of OS, CIR, NRM, and GRFS were 36% (28%–44%), 28% (21%–35%), 38% (30%–46%) and 24% (17%–31%), respectively. For OS, only the DRI score selected two groups with statistically significant differences (DRI 0–1: 41% vs. DRI ≥2: 24%; p=0.011). The combination of DRI 0–1 and HCT-CI 0–2 showed OS probabilities of 45% vs. 26% for those with DRI 0–1 and HCT-CI ≥3; p=0.041. ConclusionsIn patients with AML and MDS submitted to allo-transplant, the combination of HCT-CI and DRI scores provided the best stratification for OS.

Second Allogeneic Stem Cell Transplantation: A Mortality Analysis

Second allogeneic stem cell transplantation (SCT) was realized in 48 patients with myeloid and lymphoid neoplasms at Gustave Roussy institute since 1987. Overall survival rate was about 30 % with better outcome in acute myeloid leukemia cases. Non-relapse related mortality is overwhelming, especially in myelodysplasia patients and despite the fact that complete remission was obtained in their majority. Graft versus Host disease (GvHD) is very common after second transplantation with many grade III - IV cases and one death from severe pulmonary GvHD lesions. Reduced intensity conditioning is certainly less toxic and together with optimal GvHD and infectious disease management, Second SCT may be a reasonable therapeutic option and the only curative treatment for many hematological malignancies.

Cardiovascular events among recipients of hematopoietic stem cell transplantation

Abstract Background Allogeneic and autologous hematopoietic stem cell transplantation (HSCT) are potential curative treatments for several hematological malignancies (1). Survival after HSCT has improved over the last decade, but survivors remain at risk for health issues after transplantation. Cardiovascular complications after HSCT are increasingly recognized (2). Cardiovascular diseases may be an important cause of mortality and morbidity in patients after HSCT owing to the toxicities of the cancer therapies; however, the incidence of cardiovascular events (CVEs) in this population has not been completely characterized. The objective of this systematic review is to summarize the evidence on the incidence of CVEs in HSCT recipients. Methods Medline and Embase were searched from inception to December 2020 without language restriction. Two authors independently screened the titles and abstracts. Inclusion criteria were: cohort studies and phase 3 randomized controlled trials that reported CVEs (i.e., heart failure, arrythmias, acute coronary syndrome, and stroke) or cardiovascular death among adults who underwent HSCT for a hematological malignancy. All-cause mortality, relapse-related mortality, and non-relapse-related mortality (NRM) were also collected. Studies in which the follow up period was not started immediately after HSCT were excluded due to the risk of immortal bias. Results Of 8151 nonduplicate articles, 30 studies including 14019 individuals post autologous HSCT, and 22 studies including 31049 individuals post allogeneic HSCT met the inclusion criteria. The cumulative incidence of CVEs in the first 100 days post autologous HSCT was 9% and arrhythmia (i.e., atrial fibrillation) was the most common CVE. In recipients of allogeneic HSCT, the 100-day cumulative incidence of CVEs was 3%, and heart failure (HF) was the most common reported CVE. In recipients of autologous and allogeneic HSCT, cardiovascular death was responsible for 43% and 10% of NRM within 100 days, respectively (Table 1). The incidence of CVEs was 4.96 per 1000-person years (95% CI; 4.21–5.80) in long-term survivors (beyond 100-days) of autologous HSCT, and HF was the most common CVE in this population. In long-term survivors of allogeneic HSCT, the incidence of CVEs was 1.90 per 1000-person years (95% CI: 1.59–2.24). Cardiovascular death was the most frequently reported CVE in long-term survivors of allogeneic HSCT (Table 2). Conclusion CVEs remain a major cause of non relapse morbidity and mortality in recipients of HSCT, especially recipients of autologous HSCT within the first 100 days. Future studies are needed to identify the risk factors for CVEs that are specific to HSCT recipients. Funding Acknowledgement Type of funding sources: None.

Impact of risk scores in outcome of patients with myeloid neoplasms after allogeneic stem cell transplant

BackgroundThe main causes of failure of allogeneic hematopoietic stem cell transplantation (allo-transplant) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are relapse and transplant-related mortality. Different scores have been designed to predict the prognosis of these patients. The objective of this study was to assess which score or combination has better outcome predictive capacity. MethodsRetrospective analysis of patients with AML and MDS who received a first peripheral blood allo-transplant in a single center, between December 2001 and October 2019. Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), European Group for Blood and Marrow Transplantation (EBMT) and Disease Risk Index (DRI) scores were calculated. For each score and for the HCT-CI/DRI and HCT-CI/EBMT combinations, overall survival (OS), cumulative incidence of relapse (CIR), non-relapse-related mortality (NRM), and graft versus host disease-free relapse-free survival (GRFS) were analyzed. Results175 patients were evaluated. With a median (range) follow-up of 3.96 (0.32–17.22) years, the 5-year probabilities (95% CI) of OS, CIR, NRM, and GRFS were 36% (28%–44%), 28% (21%–35%), 38% (30%–46%) and 24% (17%–31%), respectively. For OS, only the DRI score selected two groups with statistically significant differences (DRI 0–1: 41% vs. DRI ≥2: 24%; p=0.011). The combination of DRI 0–1 and HCT-CI 0–2 showed OS probabilities of 45% vs. 26% for those with DRI 0–1 and HCT-CI ≥3; p=0.041. ConclusionsIn patients with AML and MDS submitted to allo-transplant, the combination of HCT-CI and DRI scores provided the best stratification for OS.

High-Dose Melphalan-Based Sequential Conditioning Chemotherapy Followed By Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)

Introduction: The majority of patients with newly diagnosed AML fail to achieve long-lasting remission, even after initial complete remission (CR). Response rates to common salvage regimens reach up to 50% in patients with late relapse and decrease to 10-15% in patients with refractory AML or early relapse. Without allogeneic HSCT the long-term overall survival (OS) for patients with refractory AML hardly reaches 5%. Survival rates of AML patients post allogeneic HSCT are significantly higher for patients transplanted in CR as compared to those transplanted with active leukemia. Common conditioning regimens followed by allogeneic HSCT of patients with active AML have shown disappointing results. Therefore, others and we developed the concept of sequential therapy as a preparative regimen for allogeneic HSCT to optimize the balance between treatment-related toxicity and antileukemic efficacy.Methods: From April 2005 to May 2016, 292 patients with R/R-AML received an allogeneic HSCT at the BMT centers of the German university hospitals of Muenster and Essen. The median age was 56 years (range 17 -74). The remission status prior to transplant was primary refractory (144 patients), secondary refractory (97 patients) or relapsed AML (51 patients). All patients were treated with a single infusion of high dose melphalan, followed by dose-adapted conditioning consisting of fludarabine (120 mg/m2) and 8 Gy TBI or followed by fludarabine (150 mg/m2) and treosulfan (42 g/m2). Median time between melphalan and continuation of the therapy was 5 days (range 1-18 days), resulting in an overall duration of conditioning prior to HSCT of 11 days in most patients. Additional pretreatment with antithymocyte globulin (ATG) was applied to 157 of 222 patients with an unrelated donor and in 44 of 70 patients with a HLA-identical sibling donor. Most patients (except 2) received cyclosporine as acute GvHD prophylaxis in combination with methotrexate (89 patients) or mycophenolate mofetil (197 patients) or both (4 patients).Results: Median follow-up after allogeneic HSCT of all patients alive at last follow-up was 4.8 years. OS rates at 3 years were 34% for primary refractory patients, 29% for secondary refractory patients, and 41% for patients with untreated relapsed AML. Factors associated with an inferior OS were older age, a time interval of 5-9 months between first diagnosis and allogeneic HSCT, and transplantation from an HLA-mismatched unrelated donor. Most importantly, leukemic burden was associated inversely with a 3-year OS of 51%, 31%, and 22% for patients with leukemic blast infiltration of <20%, 20-50%, and >50%, respectively (p <.001). Particularly patients transplanted from HLA-mismatched unrelated donors had a significantly higher non-relapse-related mortality (NRM) rate of 55% (95%CI 27 to 56%) at one year, compared to those transplanted from HLA-matched related (34%, 95%CI 24 to 48%) or unrelated donors (28%, 95%CI 22 to 37%). In addition, adverse risk factors for NRM were older age, pre-existing infection prior to start of conditioning therapy and a higher comorbidity index (HCT-CI >3). Multivariate analysis of risk factors revealed that high disease burden before conditioning (p <.001), longer time interval between first diagnosis and transplantation (p .039), and transplantation from an HLA-mismatched unrelated donor (p .049) were independently associated with inferior overall survival. High risk disease according to cytogenetic and molecular genetic aberrations as an adverse risk factor showed a trend in this analysis (p .052).Conclusion: Allogeneic HSCT remains the most potent treatment option for patients with R/R-AML. High-dose melphalan based sequential conditioning chemotherapy followed by an allogeneic HSCT allows for achieving long-term remission in a substantial proportion of patients with active R/R-AML with otherwise detrimental prognosis. Since allogeneic HSCT is superior to other alternative treatment strategies evaluated in the past, direct allogeneic HSCT should be evaluated prospectively against remission induction therapies followed by an allogeneic HSCT in patients with R/R AML. DisclosuresLenz:Celgene, JJ, Hexal, Roche, BMS, Novartis, Bayer: Consultancy; AstraZeneca, Gilead, JJ, Celgene, Novartis, Bayer: Research Funding.

Impact of access to care on 1-year mortality following allogeneic blood or marrow transplantation.

Mortality is highest in the first year following an allogeneic hematopoietic stem cell transplant. With recent advancements, we have expanded the pool of patients to whom we are able to offer transplant as a treatment option. In this context, we analyzed socioeconomic, patient, disease and transplant-related variables that predicted for 1-year all-cause, relapse-related (RRM) and non-relapse related mortality (NRM) in 304 patients at the University of Alabama at Birmingham. The 1-year overall survival, RRM and NRM rates were 60.5%, 13.5% and 22.7% respectively. A KPS score < 80, pre-transplant infection and hypertension and non-complete remission disease status adversely effected all-cause mortality. For NRM, increasing age, pre-transplant infection and diabetes, and poor access to care were associated with higher mortality whereas haploidentical donor type was associated with improved survival. For RRM, a KPS score <80, high/very high disease risk index and the presence of comorbidities were risk factors for higher mortality. Poor access to care, in addition to individual comorbidities, performance status and high-risk disease characteristics, is associated with adverse outcomes following transplant. We propose the incorporation of socioeconomic variables with patient, disease, and transplant-related variables to predict 1-year NRM.

Second Allogeneic Stem Cell Transplantation: A Mortality Analysis

Second allogeneic stem cell transplantation (SCT) was realized in 48 patients with myeloid and lymphoid neoplasms at Gustave Roussy institute since 1987. Overall survival rate was about 30 % with better outcome in acute myeloid leukemia cases. Non-relapse related mortality is overwhelming, especially in myelodysplasia patients and despite the fact that complete remission was obtained in their majority. Graft versus Host disease (GvHD) is very common after second transplantation with many grade III - IV cases and one death from severe pulmonary GvHD lesions. Reduced intensity conditioning is certainly less toxic and together with optimal GvHD and infectious disease management, Second SCT may be a reasonable therapeutic option and the only curative treatment for many hematological malignancies.

Single Center Experience with the Use of Hypomethylating Agents in Combination with Donor Lymphocyte Infusions As Initial Salvage Therapy Post Allogeneic Stem Cell Transplant in Relapsed AML/MDS/MPN

Topic Significance & Study Purpose/Background/Rationale Relapsed acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) following an allogeneic stem cell transplant has a bleak prognosis with no standard for treatment identified. Current literature suggests combining hypomethylating agents (HMA) with a donor lymphocyte infusion (DLI) as salvage therapy to reduce disease burden and induce a graft versus leukemia (GVL) effect. At our institution, this salvage therapy option is being used for this population, peaking interest in our experience to date. Methods, Intervention, & Analysis We retrospectively analyzed this salvage regimen with a data cutoff of May 21, 2019. We looked at the patient's treated with HMA and DLI as first line for relapsed AML, MDS, or MPN following an allogeneic stem cell transplant. The planned treatment algorithm was 2 cycles of HMA followed by DLI and repeat for up to one year. This schedule varied depending on physician preference, availability of donor cells, and presence of GVHD (Graft versus host disease). Overall response rate and progression free survival (PFS) at two years were the primary objectives. Secondary objectives were the incidence and severity of GVHD and the toxicity profile of this treatment. Findings & Interpretation Our review identified eighteen evaluable patients with AML, MDS, and MPN with relapsed disease after an allogeneic transplant. Patients received a mean of seven cycles of HMA and an average of two DLIs. PFS at two years with this therapy was 28%. Of those who experienced GVHD, three were severe, four moderate, and five mild. Toxicities most commonly reported included fatigue, pancytopenia, and infection. Discussion & Implications The patients analyzed received HMA and DLI as their initial salvage therapy after failing allogenic transplant. Our analysis noted a Complete Response (CR) rate of 61% (several patients had additional therapies added to help them achieve a CR). Three patients relapsed prior to two years and three patients experienced non-relapse related mortality, leaving the PFS at 28%, suggesting the treatment induces remission, but the durability is in question. GVHD was mostly mild which supports the lower toxicity profile and provides an effective treatment option as initial salvage therapy, specifically for patients not considered medically fit to undergo intensive re-induction.

Classical Monocyte Deficiency Calculated By the Mono-Index Can Predict Mortality in Allogeneic Hematopoietic Stem Cell Transplantation Patients

Background: Most studies in immune reconstitution after allogeneic hematologic stem cell transplantation (alloHSCT) focus on adaptive immunity, particularly in lymphocyte recovery. Classical monocytes (cMo) are part of the innate immunity, playing an important role in the defense against fungal and bacterial infections. The innate and adaptive immunity are closely related, and non-classical monocytes (ncMo) participate in this connection, regulating T cell response. However, the role of these cells in the graft versus tumor effect and graft versus host disease (GVHD) is still unclear. Objectives: The aim of the study was to investigate cMo and ncMo reconstitution after alloHSCT and a possible impact of these cells subsets on acute and chronic GVHD, relapse, non-relapse related mortality (NRM) and overall survival (OS). Patients and Methods: This is a retrospective analysis of 77 patients who underwent alloHSCT in 4 different transplant centers in Brazil. Peripheral blood samples were collected from patients at neutrophil engraftment (NE) and 3, 7, 14, 21, and 42 days after NE. The cMo (DR+, CD11c+, CD14+, CD16-) and ncMo (DR+, CD11c+, CD14-, CD16+) were classified and analyzed by 8-color multiparametric flow cytometry (FACSCanto II). In order to analyze the possible impact of duration and severity of monocytopenia after transplant, we calculated then the 'mono-index' and the 'ncMo-index', based on the area over the curve (AOC) of absolute cMO counts (AMC) and absolute ncMo counts, respectively, considering a horizontal line of AMC 0.5x10e9/L as cut-off value for both subpopulations. Results: The medium follow up was 82 months. Out of 77 patients, 46 (60%) were male, and the median age was 17 years (range: 1-74). The stem cell source was bone marrow in 36 (47%), cord blood in 23 (30%), and peripheral blood in 18 (23%); and donors were matched unrelated in 61 (79%), and matched related in 16 (21%) cases. Most patients received myeloablative conditioning (n=47, 61%); and acute leukemia was the most common diagnosis (72%). A total of 40 (52%) patients received total body irradiation (TBI), and 27 (35%) patients received antithymocyte globulin (ATG). We calculated the possible impact of cMo at all timepoints and found no differences in the main outcomes between patients with lower or higher counts. We then analyzed the AOC of all cMo counts (the mono-index). A higher index represents a more severe deficiency of cMo. We then used the receiver operating characteristic (ROC) curve to define the cut-off value of 14234.4 cells/days x mm3 to discriminate patients as cMo deficient (n=31, 40%) or non-deficient (n=46, 60%). Non relapse mortality (NRM) at 6 years was higher in cMo deficient patients calculated by the mono-index (40% vs. 16% for non-deficient, p=0.02, Figure 1). Deficient patients also had worse OS at 6 years (58% vs. 37% for non-deficient, p=0.03, Figure 2). In multivariate analyses, cMo deficiency calculated by the mono-index remained significantly associated with NRM (hazard ratio 3.07, 95% confidence interval) and OS (HR 2.05, 95%CI 1.20-7.85). We observed no impact of mono-index on acute or chronic GVHD or relapse. We observed no impact of the ncMo counts at all timepoints or the ncMo-index in any of the analyzed outcomes. Conclusion: cMo deficiency calculated by the mono-index can predict mortality in alloHSCT. Mono-Index is an inexpensive, accessible and easy to perform tool that might help clinicians in predicting unfavorable outcomes. Further studies are needed to confirm these findings and to test how different transplant strategies or therapeutic changes might interfere with monocytes recovery in alloHSCT. Disclosures No relevant conflicts of interest to declare.

NK CD56brightCD16neg reconstitution over Time (NK56-index) Significantly Impacts Long Term Outcome in Allogeneic Hematopoietic Stem Cell Transplantation

Background:Natural Killer Cells are innate immune system cells important in host defenses against viruses and tumor cells. Two subpopulations are well described: NK CD56bright CD16neg (NK56++16-) which is less frequent in peripheral blood (PB) and associated with high cytokine production, and NK56dim16pos (NK56+16+), more frequent in PB and associated with high cytotoxic activity. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), NK cells are important for infection control, and also for the disease control. The mismatch between donor NK cell receptors and host HLA may lead to a stronger graft versus leukemia (GVL), possibly modulating graft versus host disease (GVHD). However, only a few studies evaluated NK subpopulations recovery after HSCT and the impact on transplant outcomes. Objectives: The aim of the study was to analyze NK cells subpopulations reconstitution after HSCT and their possible impact on HSCT endpoints: relapse, GVHD (acute and chronic), transplantation related mortality and overall survival. Patients and Methods: Overall, 77 patients from 4 HSCT centers (60 % male, median age 17 years, range 1-74), receiving bone marrow (BM, 47%), umbilical cord (UCB, 30%) or peripheral blood (PB, 23%) from unrelated (80%) or related donors (20%) were studied. The most common diagnosis was acute leukemia (AML 38%, ALL 34%). Most patients received myeloablative conditioning (MAC) regimens (61%). Antithymocyte globulin (ATG) was used in 27 patients (35%) and total body irradiation (TBI) in 40 (52%). Median follow up time was 82 months (22-107). NK subpopulations were quantified by multiparametric flow cytometry at engraftment and days 3, 7, 14, 21 and 60 after engraftment. We have then elaborated graphs plotting cells counts over time (until 60 days) and calculated the area over the curve (AOC) for each subpopulation [NK56++16- (NK56-index) and NK56+16+ cells (NK16-index)], considering 0.5x10e9/L as cut-off value for both subpopulations. A higher AOC represents a more profound NK deficiency. Using receiver operating characteristic (ROC) curves we determined cut offs for the AOC that could provide the best correlation with survival. Results:The overall survival (OS) in 80 months was significantly worse in patients with NK56 deficiency, defined by a NK56-index &gt; 14592.31 cells/mm3.days (29% x 73% for non- deficient, p=0.0001, Figure 1). NK56 deficient patients also had a higher cumulative incidence (CI) of non-relapse related mortality (NRM: 35% x 15%, p=0.03, Figure 2). GVHD (acute or chronic) was similar between low NK56-index and high NK-56 index patients. In multivariate analysis, high NK56index remained significantly associated with worse OS [hazard ratio (HR) 3.5; 95% confidence interval (95%CI) 1.6-7.6], and higher NRM (HR 2.9; 95%CI 1.0-8.0). There were no significant correlations between NK16-index with any of the analyzed HSCT outcomes. Conclusion: A higher NK56-index is significantly associated with worse outcome in long term survival and non relapse related mortality in patients submitted to allogeneic hematopoietic stem cell transplantation. This strategy might be helpful in identifying risk groups and possible earlier therapeutic interventions. Disclosures No relevant conflicts of interest to declare.

Obesity is associated with an impaired survival in lymphoma patients undergoing autologous stem cell transplantation.

Autologous hematopoietic stem cell transplantation (auto-HSCT) provides a potentially curative treatment option for relapsed and refractory lymphomas. Obesity displays an emerging epidemic risk factor for global mortality and is associated with an increased mortality in cancer patients. To date, the impact of obesity on the outcome of lymphoma patients undergoing auto-HSCT is understudied. We conducted a retrospective single-center study assessing 119 lymphoma patients who underwent auto-HSCT. Overall survival (OS) served as the primary endpoint whereas progression free survival (PFS), cumulative incidence of non-relapse related mortality (NRM) and cumulative incidence of relapse were analyzed as secondary endpoints. Obese patients (Body mass index, BMI≥30) had significantly lower OS (45.3% vs. 77.9%; p = 0.005) and PFS (29.8% vs. 67.2%; p<0.001) compared to non-obese patients at 48 months post-transplantation. The cumulative incidence of NRM displayed no significant differences while the cumulative incidence of relapse was significantly increased in patients with BMI≥30 (66.2% vs. 21.5%; p<0.001). Patients with a BMI<25 and overweight patients (BMI 25–30; 76.1% vs. 80.9%; p = 0.585), showed no significant difference in OS, whereas patients with BMI≥30 exhibited significant lower OS when compared to either of both groups (76.1% vs. 45.3%; p = .0.021 and 80.9% vs. 45.3%; p = 0.010). Furthermore, in a multivariate analysis, obesity was identified as an independent risk factor for death (Hazard ratio 2.231; 95% CI 1.024 to 4.860; p = 0.043). Further studies are needed to evaluate the reasons for the higher relapse rate causing higher mortality in obese patients.