Pawarode, Attaphol

Abstract We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)–HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Abstract Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

AbstractTo develop a prognostic model for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for myelofibrosis (MF), we examined the data of 623 patients undergoing allo-HCT between 2000 and 2016 in the United States (the Center for International Blood and Marrow Transplant Research [CIBMTR] cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients who received transplantation in Europe (the European Bone Marrow Transplant [EBMT] cohort; n = 623). Patient age >50 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98-1.96), and HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased hazard of death and were assigned 1 point. Hemoglobin levels <100 g/L at time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points), and high score (5 points) were 69% (95% CI, 61-76), 51% (95% CI, 46-56.4), and 34% (95% CI, 21-49), respectively (P < .001). Increasing score was predictive of increased transplant-related mortality (TRM; P = .0017) but not of relapse (P = .12). The derived score was predictive of OS (P < .001) and TRM (P = .002) but not of relapse (P = .17) in the EBMT cohort as well. The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF about the transplantation outcomes.

Abstract The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post–auto-HSCT.

Abstract We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained ≥1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3α, 0.73; ST2 + REG3α, 0.79; all P < .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints.

Abstract There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Abstract Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.

PURPOSE There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]–bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor. METHODS We report composite end points of graft-versus-host disease (GVHD)–free relapse-free survival (GRFS) and chronic GVHD (cGVHD)–free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, P < .0071 in multivariable analysis and P < .00025 in direct pairwise comparisons were considered statistically significant. RESULTS In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; P = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; P = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group. CONCLUSION Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.

Abstract Graft-versus-host disease (GVHD), the primary cause of non-relapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation, does not always respond to treatment with high dose systemic corticosteroids. We have recently shown that a combination of three biomarkers (TNFR1, ST2, and REG3α) measured at onset of GVHD can predict day 28 response to treatment and 6-month NRM (Levine, Lancet Haem, 2015). Our goal in the current study was to determine if the same biomarker-based Ann Arbor GVHD algorithm can alsopredict treatment response andmortality whenapplied after one week of systemic corticosteroid treatment. The study population consisted of 378 patients (pts) with acute GVHD from 11 centers in the Mount Sinai Acute GVHD International Consortium. All pts were treated with systemic steroids and provided a plasma or serum sample obtained after one week of treatment (±3 days). The median starting dose of systemic steroids for Grade II-IV GVHD was 2.0 mg/kg/day and for Grade I was 1.0 mg/kg/day, after which treatment varied. Patients were divided into test (n=236) and validation (n=142) cohorts. We applied the Ann Arbor GVHD algorithm to concentrations of TNFR1, ST2, and REG3α measured after one week of treatment to generate a predicted probability of 6-month NRM, which we term the treatment score (TS). We employed unsupervised k-medoidclustering to partition TS values from the test cohort into two groups (high and low). This unbiased approach identified a high score group made up of 25% of pts (n=58) in the test cohort. We observed that the day 28 response rate (complete, CR + partial, PR) was significantly lower in pts with high scores compared to low scores in the test cohort (24% vs 65%, p<0.0001) (Fig 1A). Analysis of the validation cohort using the same TS definitions showed similar differences in response rates (22% vs 61%, p<0.0001) (Fig 1B). Further, nearly four times as many pts with high scores in both cohorts died within 6 months from non-relapse causes compared to pts with low scores (test: 57% vs 17%, p<0.0001; validation: 57% vs 14%, p<0.0001) (Fig 1C/D). As expected, the majority of non-relapse deaths in pts treated for GVHD were directly attributable to GVHD (test: 95%; validation: 89%). Relapse rates for high and low score pts were similar (data not shown), and thus pts with a high TS experienced significantly worse overall survival in both cohorts (test: 37% vs 72%, p<0.0001; validation: 38% vs 79%, p<0.0001) (Fig 1E/F). Approximately half of the pts in each cohort (test: 48%; validation: 44%) responded (CR+PR) to the first week of steroids and these ptshad significantly lower 6-month NRM than non-responders (NR) (test: 17% vs 36%, p=0.0002; validation: 13% vs 36%, p=0.0014). Yet the TS continued to stratify mortality risk independently of clinical response. In the test cohort, pts with a high score comprised 16% of all early responders and experienced more than twice the NRM of early responders with a low score (33% vs 13%, p=0.022) (Fig 2A). Conversely, test cohort pts who did not respond by day 7, but had a low score, fared much better than non-responders with a high score (NRM 21% vs 68%, p<0.0001) (Fig 2B). Two thirds of early non-responders comprised this more favorable group. These highly significant results reproduced in the independent validation cohort in similar proportions (CR+PR: 45% vs 6%, p=0.0003; NR: 61% vs 22%, p=0.0001) (Fig 2C/D). Finally, a subset analysis revealed that pts classified as NR after one week of steroids due to isolated, yet persistent, grade I skin GVHD (24/378, 6%) overwhelmingly had low treatment scores (22/24, 92%) and experienced rates of NRM (9%) comparable to responders with low scores, thus forming a distinct, albeit small, subset of pts with non-responsive GVHD that fares particularly well (Fig 3). In conclusion, a treatment score based on three GVHD biomarkers measured after one week of steroids stratifies pts into two groups with distinct risks for treatment failure and 6-month NRM. It is particularly noteworthy that the TS identifies two subsets of pts with steroid refractory (SR) GVHD who have highly different outcomes (Fig 2B/D). The much larger group, approximately two thirds of all SR pts, may not need the same degree of treatment escalation as is traditional for clinical non-response, and thus overtreatment might be avoided. Because the TSis measured at a common decision making time point, it may prove useful to guide risk-adapted therapy. Disclosures Mielke: Novartis: Consultancy; MSD: Consultancy, Other: Travel grants; Celgene: Other: Travel grants, Speakers Bureau; Gilead: Other: Travel grants; JAZZ Pharma: Speakers Bureau. Kroeger:Novartis: Honoraria, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Jagasia:Therakos: Consultancy. Kitko:Therakos: Honoraria, Speakers Bureau. Ferrara:Viracor: Patents & Royalties: GVHD biomarker patent. Levine:Viracor: Patents & Royalties: GVHD biomarker patent.