Outcome Of Allogeneic Hematopoietic Cell Transplantation Research Articles

Treatment Patterns and Clinical Outcomes of Patients with Moderate to Severe Acute Graft-Versus-Host Disease: A Multicenter Chart Review Study.

Acute graft-versus-host disease (aGVHD) remains a barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT) outcomes. Contemporary comprehensive analyses of real-world clinical outcomes among patients who develop aGVHD post-HSCT are needed to better understand the unmet needs of this patient population. This multicenter, retrospective chart review describes treatment patterns and clinical outcomes among patients (≥18 years old) from Finland, Sweden, and France who developed grades II-IV aGVHD after their first HSCT (January 2016-June 2017). From 13 participating centers, 151 patients were included. The median (Q1, Q3) age at HSCT was 56 (45, 62) years old. One line of aGVHD treatment was received by 47.7%, and the most common first-line treatment was methylprednisolone (alone or in a combination regimen, 74.2%; monotherapy, 25.8%). Among patients treated with methylprednisolone, 79.5% achieved a complete or partial response. The median (Q1, Q3) number of treatment lines was 2.0 (1.0, 3.0). The median (Q1, Q3) time to obtain an aGVHD diagnosis from transplant was 29.5 (21.0, 44.0) days, and 14.5 (7.0, 34.0) days to achieve the best response for 110 evaluable patients. At 6 and 12 months, 53.6% and 49.0%, respectively, achieved a complete response. Chronic GVHD occurred in 37.7% of patients, and aGVHD reoccurred in 26.5%. Following aGVHD diagnosis, mortality rates were 30.0% at 6 months and 37.3% at 12 months. Findings from this study demonstrate a continuing unmet need for new therapies that control aGVHD and improve mortality.

Impact of prior COVID-19 infection on allogeneic hematopoietic stem cell transplantation outcomes.

There are limited data on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in recipients with prior COVID-19 infection. This single-center retrospective study included 54 adult patients who received allo-HSCT from July 2020 to September 2021 after previous COVID-19 infection and 122 control group patients without a history of COVID-19 who underwent HSCT during the same period, with a median follow-up of 17 months. Median time from COVID-19 to allo-HSCT was 211 days. The incidence of main complications in the post-transplant period was not significantly different between the two groups: deep vein thrombosis (p =.85), TMA (p=.8), VOD (p=.25), bloodstream infections (p=.21), pneumonia of any etiology (p=.41), viral infections (p=.85), invasive fungal disease (p=.08). The 2-year non-relapse mortality, relapse incidence, overall survival, and progression-free survival also were comparable in the study and the control groups: 22% (95% CI 10.5-36.2) versus 26.3% (95% CI 18.7-34.6) p =.4; 15.6% (95% CI 7.3-26.9) versus 23.6% (95% CI 16.0-32.3) p =.39; 67.9% (95% CI 50.4-80.3) versus 59.8% (95% CI 50.2-68.1) p =.24 and 62.3% (95% CI 45.5-75.3) versus 49.9% (95% CI 40.0-59.1) p =.18, respectively. The history of previous COVID-19 infection did not affect the results of allo-HSCT.

Pretransplant Blinatumomab Improves Outcomes in B Cell Acute Lymphoblastic Leukemia Patients Who Undergo Allogeneic Hematopoietic Cell Transplantation

BackgroundBlinatumomab, a bispecific monoclonal antibody, effectively controls refractory B cell acute lymphoblastic leukemia (ALL) and promotes measurable residual disease (MRD) negativity. This study investigated the impact of pretransplant blinatumomab on allogeneic hematopoietic cell transplantation (HCT) outcomes in B cell ALL patients. MethodsWe analyzed the effect of pretransplant blinatumomab on transplant outcomes of 117 adults undergoing allogeneic HCT for B cell ALL at Princess Margaret Hospital, Toronto, between 2010 and 2021. Outcomes assessed included overall survival (OS), graft-versus-host disease and relapse-free survival (GRFS), cumulative incidences of relapse (CIR), and nonrelapse mortality (NRM). ResultsThe median follow-up was 36 months. Thirty-one participants (26.5%) received blinatumomab. Blinatumomab group had higher proportions of individuals with high disease risk index, primary induction failure and was more likely to receive dual T cell depletion with antithymocyte globulin and post-transplant cyclophosphamide. Two-year OS, GRFS, NRM, and CIR in the blinatumomab and nonblinatumomab groups were, respectively: 65.4% versus 45.6% (P = .05), 42.2% versus 17.3% (P = .01), 3.2% versus 43.0% (P = .007) and 34.4% versus 14.4% (P = .02). Blinatumomab was associated with a lower incidence of day-100 grade 2 to 4 and grade 3 to 4 acute graft-versus-host disease (aGVHD): 27.5% versus 56.7% (P = .009), and 10.9% versus 34.7% (P = .04), respectively. Multivariate analysis confirmed the association between pretransplant blinatumomab and improved OS and NRM. ConclusionsPretransplant blinatumomab is associated with improved OS and lower risk of NRM in B cell ALL patients undergoing allogeneic HCT, likely reflecting lower burden of treatment-related toxicity in this population. Larger prospective trials are warranted to validate our findings.

Projected Impact of Omidubicel-onlv on Racial/Ethnic Disparities in Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) Outcomes in Hematologic Malignancies.

In a phaseIII clinical trial (NCT02730299), omidubicel-onlv, a nicotinamide-modified allogeneic hematopoietic progenitor cell therapy, showed rapid hematopoietic and immune recovery compared with standard umbilical cord blood (UCB) transplant across all racial/ethnic groups. A decision-tree model was used to project the effect of omidubicel-onlv availability on addressing health disparities in allogeneic hematopoietic cell transplantation (allo-HCT) access and outcomes for patients with hematologic malignancies. The model used a hypothetical population of 10,000 allo-HCT-eligible US adults, for whom matched related donors were not available. Patients received matched or mismatched unrelated donor, haploidentical, UCB transplant, or no transplant. Scenarios with omidubicel-onlv use of 0% (status quo), 10%, 15%, 20%, and 30% were modeled on the basis of proportional reductions in other allo-HCT sources or no transplant by racial/ethnic group. Increased omidubicel-onlv use was associated with a higher proportion of patients undergoing allo-HCT, decreased time to allo-HCT, decreased 1-year non-relapse mortality, and increased 1-year overall survival, particularly among racial minorities. In the scenario modeling 20% omidubicel-onlv use, the proportion of Black patients receiving allo-HCT increased by 129%; increases were also observed in Asian (64%), Hispanic (45%), and other (42%) patient groups. Modeled time to allo-HCT improved among transplanted patients (23%) from 11.4weeks to 8.8weeks. One-year OS in the overall population increased by 3%, with improvements ranging from 3% for White patients to 5% for Black patients. This study demonstrates that broad access to omidubicel-onlv could increase access to allo-HCT and improve outcomes for patients, with the greatest benefits seen among racial/ethnic minority groups.

Hypomagnesemia May Predict Better Survival and Reduced Nonrelapse Mortality in Allogeneic Hematopoietic Stem Cell Transplantation Recipients

Magnesium (Mg) is an essential element that is required as a cofactor for many cellular reactions, including immunologic pathways. The aim of this study was to investigate the potential impact of serum Mg levels on allogeneic hematopoietic stem cell transplantation (alloHSCT) outcomes. Medical records of 340 alloHSCT recipients (median age: 45 [18-71] years; M/F: 210/130) were reviewed for this retrospective study. Serum Mg levels on days -28, -7, 0, +7, +14, +21, +30, +60, and +90 were included in the analysis. Serum Mg+14 levels predicted nonrelapse mortality (NRM) (P = .025) and had a significant impact on the development of mucositis (P = .027), fungal infection (P = .006), engraftment syndrome (P < .001), sinusoidal obstruction syndrome (SOS) (P = .001), cytomegalovirus (CMV) reactivation (P = .039), and acute graft vs host disease (GvHD) (P < .001). Based on the optimal threshold of serum Mg+14 level (1.33 mg/dL; area under the curve: 0.581 [0.515-0.648]; P = .018), the study group was divided into 2 subgroups as low- and high-Mg+14. The incidence of acute GvHD (P = .002), SOS (P = .013), engraftment syndrome (P = .013), CMV reactivation (P = .001), and Epstein Barr virus reactivation (P = .005) was significantly lower in low-Mg+14 group. The probability of overall survival (OS) was significantly better (P = .002), whereas NRM was lower in the low-Mg+14 group (P = .001). Hypomagnesemia seems to provide a considerable advantage for the post-transplant outcome, which may confirm its potential role in the immunologic microenvironment and adaptive immunity.

The effect of center experience on allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia.

This study aimed to address the prognostic impact of center experience based on the data of 7821 adults with acute myeloid leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2019 in Japan, where medical care was provided within a uniform healthcare system. Center experience was defined based on the number of allogeneic HCTs performed for any indication during the study period, by which centers were divided into low-, intermediate-, and high-volume centers. After adjusting for known confounding factors, the risk of overall mortality was lowest for the high-volume centers and highest for the low-volume centers, with the difference between the center categories attributed primarily to the risk of relapse. Patients transplanted at high-volume centers had higher risks of acute and chronic graft-versus-host diseases but without an increased risk of non-relapse mortality (NRM). These findings reveal the presence of a center effect in allogeneic HCT conducted during the past decade in Japan, highlighting the difference in relapse based on center experience. The weaker effect on NRM compared with that on relapse suggests that the transplantation care quality is becoming equalized across the country.

Use of Pre-Transplant Minicog Cognitive Impairment Screening and Validation of Frailty and Functionality Assessment Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Background: We demonstrated that impaired functionality and frailty have a negative impact on survival after allogeneic hematopoietic cell transplantation (HCT) (Salas et al., 2019). This impact is independent of other predictive models including HCT comorbidity index (HCT-CI) and disease risk index (DRI). Cognitive changes are frequently reported among survivors of autologous and allogeneic HCT. However, impact of the presence of cognitive impairment prior to allogeneic HCT has not been studied. We hypothesized that the presence of cognitive impairment before transplantation could have a negative effect on the outcomes of allogeneic HCT. Patients and methods: We evaluated transplant outcomes of 277 patients who underwent our updated frailty assessment including the MiniCog scale, incorporated as standard of care in April 2020. The MiniCog assessment included recalling of three unrelated words, for a total of three points and drawing of a clock with the face, number and hands indicating a specific time, for a total of 2 points. We used the cutoff score of &amp;lt;3 as a marker of cognitive impairment and evaluated the effect of cognitive impairment on: overall survival (OS), relapse free survival (RFS), non-relapse mortality (NRM). We further sought to validate our previously described frailty scale in prediction of transplant outcomes, including OS, RFS, and NRM, in the new cohort and compare its performance in outcome prediction to the MiniCog scale. Our frailty evaluation included the following variables: Clinical Frailty Scale (CFS), Lawton's instrumental activities of daily living (IADL), timed to get up and go test (TUGT), grip strength (GS) using a hydraulic hand dynamometer, self-rated health questionnaire (SRH), a question on number of falls in the last year (F), C-reactive protein (CRP) and serum albumin (Alb) levels at the time of the consult. The frailty scale was calculated according to the following formula: 1.5×CFS + 1×IADL +1×GS + 1.5×TUGT +1×SRH+1×F+ 1.5×Alb+2×CRP. The frailty scale score ranged from 0-10.5. With these results we stablished 3 frailty cohorts for the patients being planned for alloHCT, fit (≤1), pre-frail (&amp;lt;1 to ≤5.5), and frail (&amp;gt;5.5), based on this risk model. Results: Median age at transplantation was 59 years and 85 (31%) patients were ≥ 65 years. Of all the patients, 36 (14%) had a Karnofsky Performance Scale Index (KPS) of &amp;lt;90%, 206 patients had a low-intermediate risk disease risk index (DRI). Median time of follow up was 9 months. Majority of the patients (46%) underwent transplantation for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Of all patients, 246 (88.8%) had a normal MiniCog score (&amp;gt;3). There was no difference in 2-y OS between patients with normal and low MiniCog score: 67% (95% confidence interval (CI): 59%-74%) vs 60% (95% CI: 36-78%), p=0.21. NRM at 24 months was 26% (95% CI 10-46%) for patients with an abnormal MiniCog vs 23% (95% CI 17-30%), p=0.80. There was no difference in 2-year RFS between patients with normal and low MiniCog score: 65% (95% CI 57-72%) vs 43.5% (95% CI 23-63%), p=0.09. Using the frailty scale, 144 (56%) patients were considered fit, 30 (12%) pre-frail and 81 (32%) frail. Using our original frailty scale, the 2-y OS among the fit, pre-frail and frail patients was: 78% (95% CI 65%-87%), 64% (95% CI 53%-74%) and 27% (95% CI 5.6%-55.6%) p=0.005. 2-year NRM was 19.2% (95% CI 9-31%), 23% (16-32%), and 41.6% (95% CI 11-70%) for the fit, pre-frail and frail patients respectively, p=0.12. Relapse free survival at 24 months was 72.5% (95% CI 58-83%), 60.5% (95% CI 50-70%), and 29% (95% CI 6-57%), p=0.003. Conclusions: In our cohort the sole presence of cognitive decline, based on the MiniCog assessment failed to be a predictor of outcomes after allogeneic HCT. However, ability of our preciously established frailty scale to predict transplant outcomes in this new cohort of patients further validates the results of our previous findings. The presence of frailty is an independent predictor of adverse outcomes after allogeneic HCT.

TMI-Based Dose-Escalated Bone Marrow Transplantation Can Help Preserve the Bone Marrow Microenvironment and Reduce Cellular Senescence in Old Mice

Introduction:Senescence is one of the hallmarks of aging and age-related conditions, including but not limited to, inflammaging, frailty, and various age-related diseases. It has been well-established that radiation and chemotherapy can accelerate senescence. While myeloablative conditioning-based allogeneic hematopoietic cell transplant (HCT) is a curative treatment for patients with leukemia. The dose of total body irradiation (TBI) conditioning has to be reduced in older patients to reduce potential high treatment-related mortality, which may still cause accelerated senescence in aged individuals, resulting in poor survival outcomes. We initiated the testing of a novel total marrow irradiation (TMI) based myeloablative conditioning in older patients to enhance the anti-leukemia effect and overall survival. We hypothesize that this new radiation preconditioning strategy may also reduce radiation-induced senescence in aged individuals compared to TBI to reduce treatment-associated side effects and improve the outcomes of allogeneic HCT. We tested this hypothesis in the present study and further investigated the mechanisms of the effects of TMI-based myeloablative and dose-escalated bone marrow transplantation (BMT) on old mice by examining the changes in expression of various senescence markers and senescence-associated secretory phenotype (SASP) in the bone marrow (BM) and selected organs. Method: The radiation treatment regimens were: TMI (12:4), TMI (16:4) and TBI (12:12), and TBI (16:16), were developed as described (Zuro et al., 2021); i.e. (12:4) means the radiation dose to the BM was 12 Gy and the dose to the organs was 4 Gy. The young (8 weeks old) and aged mice (90 weeks old) of host C57BL/6j (JAX000664, CD45.2) were irradiated in 2 fractions 24h apart, and 25 million whole BM cells from donor (JAX002014, CD45.1) were transplanted by i.v. at 24 h after irradiation. For the hematopoietic stem and progenitor cell (HSPC) population study, more mature hematopoietic progenitors (Lin − Sca-1 −c-Kit + or LK cells) and HSPCs (Lin − Sca-1 + c-Kit + or LSK cells) were examined in BM by flow analysis. Cultured bone marrow mesenchymal stem cells (MSCs) were analyzed for the gene expression of the senescence marker CDNK1a (or p21) and SASP factors MMP13 and CXCL12 by qPCR. For senescence study in organs such as the liver, gut, and spleen, senescence-associated beta-galactosidase (SA-β-gal) staining was performed and expression of the CDNK2a (or p16) was analyzed by qPCR. Results: TMI or TBI treatment with young donor BMT repopulated the BM HSPC population without significant bone damage in aged mice (data not shown). While the BM LK and LSK populations significantly reduced in aged mice after TMI or TBI with young donor BMT compared to aged control mice ( Fig 1A), these populations were not different from young mice groups ( Fig 1B). In addition, TMI or TBI treatment with young donor BMT reduced MSC senescence. Cultured MSCs analysis showed the reduction of p21, MMP13, and CXCL12 expression ( Fig 1C-E) after TMI or TBI with young donor BMT in aged compared to aged control without radiation and BMT. However, while TMI treatment and BMT reduced senescence in the organs, mice receiving TBI treatment and BMT showed a higher senescence burden. In the liver, the aged control mice showed a significant increase in SA-β-gal staining, which was decreased in TMI (12:4) and TMI (16:4) mice ( Fig 1F). In contrast, this effect was not observed in aged mice after TBI (12:12) or (16:16) ( Fig 1G). Moreover, the senescence marker p16 expression in the liver and gut was reduced only in TMI (12:4) and TMI (16:4), not in TBI (12:12) or (16:16) ( Fig 1H, I), whereas the p16 expression in the hematopoietic tissue, spleen was decreased in all treatment groups TMI vs. TBI ( Fig 1J). Conclusion: TMI-based dose escalates with young donor BMT in aged mice preserved BM microenvironment and reduced senescence of organs while TBI treatment causes senescence of the organs. Young donor BMT, which combined with TMI or TBI treatment, preserved bone structure and reduced senescence of HSPC and MSC. However, TMI treatment decreased the SA-β-gal staining and p16 expression significantly in organs such as the liver and gut, but not by TBI treatment. This study showed the senescence reduction in both bone marrow and organs after young donor BMT and TMI treatment. For further study, we have a plan to study the mechanism and signaling pathway of senescence reduction.

Impact of Donor Age on Allogeneic Hematopoietic Cell Transplantation Outcomes in Older Adults with Acute Myeloid Leukemia

Allogeneic hematopoietic cell transplantation (alloHCT) provides cure for older patients with acute myeloid leukemia (AML); however, disease relapse remains a major concern. Based on recent data suggesting that younger donor age confers the greatest benefit for alloHCT with matched unrelated donors (MUDs), we attempted to answer a practical question: which donor type provides the best outcomes when an older patient with AML has a matched sibling donor (MSD, also older) versus the best MUD? This retrospective cohort registry study accessed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) in patients with AML age ≥ 50 years undergoing alloHCT from older MSDs (age ≥ 50 years) or younger MUDs (age ≤ 35 years) between 2011 and 2018. The study included common allograft types, conditioning regimens, and graft-versus-host disease (GVHD) prophylaxis. The primary outcome was relapse risk. Secondary outcomes included nonrelapse mortality (NRM), GVHD, disease-free survival (DFS), and overall survival. Among 4684 eligible patients, 1736 underwent alloHCT with an older MSD (median donor age, 60 years), and 2948 underwent alloHCT from a younger MUD (median donor age, 25 years). In multivariable analysis, compared to older MSDs, the use of younger MUDs conferred a decreased relapse risk (hazard ratio [HR], .86; P=.005) and a significantly lower adjusted 5-year cumulative incidence of relapse (35% versus 41%; P=.003), but was associated with an increased risk for chronic GVHD (HR, 1.18; 95% confidence interval [CI], 1.08 to 1.29; P=.0002) and greater NRM only in the earlier period of 2011 to 2015 (HR, 1.24; P=.016). The corresponding NRM rates were significantly lower in the more recent period of 2016 to 2018 (HR, .78; P=.017). The adjusted 5-year DFS probability was 44% (95% CI, 42% to 46%) with an alloHCT from younger MUDs compared to 41% (95% CI, 38% to 43%) with older MSDs (P=.04). In summary, for older patients with AML undergoing alloHCT, the use of younger MUDs is associated with decreased relapse risk and improved DFS compared with the use of older MSDs.

Impact of a novel prognostic model on allogeneic hematopoietic stem cell transplantation outcomes in patients with CMML.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.

Abstract A48: Aging-related, Senescence-associated Secretory Phenotype and Allogeneic Hematopoietic Cell Transplantation Outcomes in Older Adults

Abstract Introduction: Older adults with hematologic malignancies such as AML and MDS increasingly undergo allogeneic hematopoietic cell transplantation (alloHCT). The impact of the aging host environment, especially cellular senescence, remains unexplored, however. Objectives: We hypothesize that pre-transplant senescence-associated secretary phenotype (SASP) is associated with alloHCT outcomes among older patients and tested it in this biomarker correlative study. Methods: We measured ten SASP-related cytokines (IFNγ, IL1β, IL2, IL4, IL6, IL8, IL10, IL12, IL13, and TNFα, and C-reactive protein (CRP) from pre-transplant plasma samples of 155 patients (&amp;gt;50 years) who had undergone alloHCT at MSKCC from 2011 to 2019 for acute leukemias and other myeloid malignancies. Expression of aging biomarker p16 was measured on a subset of patients by immunohistochemistry. Results and Discussion: The median age was 64.1 years (IQR 58.3 – 67.8). Diseases included 57% acute leukemias (AML and ALL) and 43% MDS/MPN. KPS was &amp;lt;90 in 43% and HCT-CI was &amp;gt;3 in 53% of patients. With median follow-up of 61 months for survivors, the 5-year OS and PFS is 50% and 46%, respectively. The 2-year cumulative incidence of non-relapse mortality (NRM) and relapse is 18% and 31%, respectively. At the baseline, these SASP-related cytokines have variable degree of association with KPS, chronologic age, and disease risk. IL2 trended toward significant positive association with OS (HR 1.19, 95% CI 1-1.43, p=0.052) and was significantly associated with PFS (HR 1.21, 95% CI 1.02-1.44, p=0025) in univariate analysis, but not in multivariate analysis after adjusting for clinical characteristics. No cytokine was associated with NRM. IL2 and IL4 were associated with relapse in univariate but not multivariate analysis. Several cytokines including IL12 p70, IL13, IL4, and TNFα were associated with 100d grade II-IV acute GVHD in patients who received CNI-based GVHD prophylaxis. In summary, we found potential association of SASP-related cytokines with patient characteristics and transplant outcomes. We aim to validate these findings and examine their therapeutic potential to improve alloHCT outcomes. Citation Format: Richard J Lin, Phillip Wong, Jessica R Flynn, Erika R Ritter, Caleb Ho, Josel D Ruiz, Ann A Jakubowski, Esperanza B Papadopoulos, Brian C Shaffer, Hugo R Castro-Malaspina, Christina J Cho, Doris R Ponce, Juliet N Barker, Roni Tamari, Craig S Sauter, Boglarka Gyurkocza, Marcel van den Brink, James W Young, Miguel-Angel Perales, Sean M Devlin, Sergio A Giralt. Aging-related, Senescence-associated Secretory Phenotype and Allogeneic Hematopoietic Cell Transplantation Outcomes in Older Adults [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A48.

Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan.

Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test dose alone due to changes in BU clearance caused by drug interactions. We conducted a single-arm phase II trial using the combined test dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an external historical cohort receiving a fixed-dose (fixed-dose group). The first eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and first doses, respectively, targeting a total AUC of 82.1mg·h/L. All patients received either BU and cyclophosphamide conditioning (BU/CY) or fludarabine (FLU)-containing conditioning. The BU clearance at the first dose decreased more in patients receiving FLU than in those receiving BU/CY; however, BU clearance also declined over time in patients who received BU/CY. The simulated total AUC (sAUC) with test dose only was significantly higher in patients who received FLU than in those who received BU/CY, but sAUC with the combined strategy was comparable. The 100-day progression-free survival was 85.5% (95% confidence interval [CI]: 71.9-92.8%), and was not inferior to that in the fixed-dose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse (0.0% vs. 26.9%, p = 0.03), and favorable overall survival (75.1% vs. 57.0%, p = 0.07) at 1year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving efficacy, especially in patients receiving the FLU-containing regimen. Clinical evaluation of efficacy of dose-modified intravenous busulfan in allogeneic hematopoietic stem cell transplantation for hematological malignancy (#UMIN000014077, June 15th, 2014).

HLA Class I Genotype Is Associated with Relapse Risk after Allogeneic Stem Cell Transplantation for NPM1-Mutated Acute Myeloid Leukemia

Mutation-bearing peptide ligands from mutated nucleophosmin-1 (NPM1) protein have been empirically found to be presented by HLA class I in acute myeloid leukemia (AML). We hypothesized that HLA genotype may impact allogeneic hematopoietic stem cell transplantation (allo-HCT) outcomes in NPM1-mutated AML owing to differences in antigen presentation. We evaluated the effect of the variable of predicted strong binding to mutated NPM1 peptides using HLA class I genotypes from matched donor-recipient pairs on transplant recipients' overall survival (OS) and disease-free survival (DFS) as part of the primary objectives and cumulative incidence of relapse and nonrelapse mortality (NRM) as part of secondary objectives. Baseline and outcome data reported to the Center for International Blood and Marrow Transplant Research from a study cohort of adult patients (n=1020) with NPM1-mutated de novo AML in first (71%) or second (29%) complete remission undergoing 8/8 matched related (18%) or matched unrelated (82%) allo-HCT were analyzed retrospectively. Class I alleles from donor-recipient pairs were analyzed for predicted strong HLA binding to mutated NPM1 using netMHCpan 4.0. A total of 429 (42%) donor-recipient pairs were classified as having predicted strong-binding HLA alleles (SBHAs) to mutated NPM1. In multivariable analyses adjusting for clinical covariates, the presence of predicted SBHAs was associated with a lower risk of relapse (hazard ratio [HR], .72; 95% confidence interval [CI], .55 to .94; P=.015). OS (HR, .81; 95% CI, .67 to .98; P=.028) and DFS (HR, .84; 95% CI, .69 to 1.01; P=.070) showed a suggestion of better outcomes if predicted SBHAs were present but did not meet the prespecified P value of <.025. NRM did not differ (HR, 1.04; P=.740). These hypothesis-generating data support further exploration of HLA genotype-neoantigen interactions in the allo-HCT context.

Impact of age on hospitalization and outcomes post allogeneic hematopoietic cell transplantation outcome, a single center experience.

The outcomes of allogeneic hematopoietic cell transplantation (HCT) in older patients are not well defined. We retrospectively analyzed the outcomes of 332 patients, with the median age of 65years (range, 60-76), between 2014 and 2019. We categorized them to 3 age groups (G): G1, 60-65years (n = 175); G2, > 65-70years (n = 127); and G3, > 70years (n = 30). The median length of hospitalization during the initial HCT period was 30days, with a significant difference when stratified by age (p = 0.049). Overall, 183 (58.7%) patients were re-hospitalized within the first 6months post HCT, and 60 (21.6%) in the second 6-month period. The 2-year OS was 56% in G1, 53% in G2, and 34% in G3 (p = 0.05). The 2-year event-free survival (EFS) was 54% for G1, 49% for G2, and 31% for G3 (p = 0.04). Non-relapse mortality (NRM) at 2years was 25% in G1, 36% in G2, and 52% in G3 (p = 0.008). In multivariable analysis, patients aged 60-65years had significantly better EFS (p = 0.04) and had a trend toward lower NRM (p = 0.05) than those aged > 70years. Re-admission in the first 6months post HCT had a significant impact on OS, EFS, and NRM. HCT-specific comorbidity index > 3 had significantly affected NRM. Finally, age had a significant influence on length of hospitalization during HCT. In conclusion, patients aged > 70years have an inferior EFS and higher NRM. This likely related to higher rate of re-admissions due to infectious complications (84%).

Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies.

There is increasing recognition that pathogenic germ line variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germ line predisposition variants have different posttransplant outcomes than those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germ line variants and 34% underwent HSCT. Deleterious germ line variants in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germ line DDX41 variants had a higher incidence of severe (stage 3-4) acute graft-versus-host disease (GVHD) (38%) than recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germ line variants (9%) (P= .002). Importantly, the use of posttransplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germ line DDX41-associated myeloid neoplasms (0% vs 53%, P= .03). Based on these results, we advocate the use of posttransplant cyclophosphamide when individuals with deleterious germ line DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.

27 - Comparison of Allogeneic Hematopoietic Cell Transplantation Outcomes from Younger Matched Unrelated Donor Versus Older Sibling Donor for Older Adults with AML

27 - Comparison of Allogeneic Hematopoietic Cell Transplantation Outcomes from Younger Matched Unrelated Donor Versus Older Sibling Donor for Older Adults with AML

139 - Influence of Timing on Allogeneic Hematopoietic Cell Transplant Outcomes in Acute Myeloid Leukemia Patients

139 - Influence of Timing on Allogeneic Hematopoietic Cell Transplant Outcomes in Acute Myeloid Leukemia Patients

140 - Impact of Obesity and Chemotherapy Dosing on Allogeneic Hematopoietic Cell Transplant Outcomes for Myelodysplastic Syndrome (MDS)

140 - Impact of Obesity and Chemotherapy Dosing on Allogeneic Hematopoietic Cell Transplant Outcomes for Myelodysplastic Syndrome (MDS)

130 - Day Zero Endothelial Activation and Stress Index (EASIX) Best Predicts Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Acute Myeloid Leukemia Patients

130 - Day Zero Endothelial Activation and Stress Index (EASIX) Best Predicts Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Acute Myeloid Leukemia Patients

Association Between Human Leukocyte Antigens and Graft-Versus-Host Disease Occurrence in Allogeneic Hematopoietic Stem Cell Transplantation - A 10-Year Experience on Iranian Patients.

Human leukocyte antigen (HLA) molecules mediate critical roles in determining responsiveness or non-responsiveness of the immune system, especially in transplantation. Some studies have shown a possible association between certain HLA alleles and some allogeneic hematopoietic stem cell transplantation (allo-HSCT) outcomes such as acute/chronic graft-versus-host disease (aGVHD/cGVHD) and overall survival (OS). In the current study, we investigated any possible association of HLA subclasses and acute/chronic GVHD occurrence as well as OS in patients receiving HLA-matched sibling allo-HSCT. We retrospectively evaluated the association of various HLA alleles with the incidence of aGVHD, cGVHD, and OS of 162 patients who received allo-HSCT from HLA-matched sibling between 2009-2018 at Taleghani hospital in Tehran. We found that the incidence of aGVHD grades II-IV was higher among patients who had HLA-B*07 (P=0.031) and HLA-DRB1*07 (P=0.052). The presence of HLA-A*01 was associated with 4.5-fold greater odds of incidence in the extensive-type of cGVHD (P=0.009). Furthermore, HLA-A*03 (P=0.089), HLA-B*13(P=0.013), HLA-B*40 (P=0.042), HLA-DRB1*02 (P=0.074), and HLA-DRB1*04 (P=0.039) were associated with a lower rate of OS. This study suggests that certain HLA alleles might influence the incidence and severity of acute or chronic GVHD in the context of HLA-matched sibling allo-HSCT. In addition, some specific HLA alleles help predict OS in allo-HSCT recipients. These results might be helpful in estimating the incidence of aGVHD, cGVHD, and OS as well as designing personalized therapy.