Estrada‐Merly, Noel

PURPOSE Public reporting of health care outcomes can have unintended effects such as inappropriate risk aversion in patient selection. METHODS The center-specific survival analysis annually assigns all hematopoietic cell transplantation (HCT) centers in the United States a +1, −1, or 0 score for observed outcomes that are above, below, or within a center-specific predicted range of outcome. For each index year (2012-2016), centers receiving a −1 score after 0 scores in the preceding 2 years were compared with contemporaneous centers with as-predicted outcomes (0 score). Changes in the patient population characteristics in the 3 years before versus the 3 years after the index years were compared between the newly below-expected centers (NBCs) and the controls. A multivariate model adjusted for baseline patient population characteristics and center volume. RESULTS No differences in patient selection behavior were identified when comparing the NBCs with the controls across eight key patient population characteristics. For the statistically modeled (predicted) 1-year overall survival (OS), reflecting a holistic measure of centers' patient population risk, we observed no statistically significant difference in change (−0.23% [95% CI, −1.4 to 0.9]; P = .70). The observed OS increased in both NBCs and controls by 0.9% and 4.5%, respectively, without statistically significant difference in change. CONCLUSION Centers receiving a −1 score were not observed to deviate significantly from patient selection trends in the HCT field. These findings suggest that public reporting of HCT outcomes in the United States does not result in unintended bias against HCT for high-risk patients.

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.

Introduction Public reporting of outcomes drives healthcare improvement in many fields, including hematopoietic cell transplantation (HCT), although with possible unintended consequences. The Center for International Blood & Marrow Transplant Research (CIBMTR) publishes an annual Center-Specific Survival Analysis (CSA), which compares HCT centers' observed 1-year overall survival (OS) with their statistically modeled expected 1-year OS, with 95% confidence intervals (CI). Centers with OS within their 95% CI receive a 0 score, indicating as expected outcomes. Those with OS below / above their 95% CI receive a -1 / +1 score, indicating below / above expected OS, respectively. After a -1 report, centers may change their patient selection criteria, causing unintentional systematic exclusion of patient populations who could benefit from HCT. We analyzed how the CSA report influences patient selection practices among centers receiving a -1 score. Methods Centers receiving a -1 report between 2012 and 2016 that had ‘as expected’ survival in the preceding 2 years were classified as newly below expected OS centers (NBCs). The year of their -1 report was used as the index year. Centers with ‘as expected’ OS in the 3 years before and after each index year were identified as control centers, reflecting expected evolution of patient selection in the HCT field. The patient population variables analyzed are shown in Table 1. The difference in patient population characteristics in the 3 years before vs the 3 years after the index years defined the change in patient selection behavior at the NBCs and the controls. A multivariate model adjusting for baseline patient population characteristics and center size was used to compare the change in patient population from before and after the index year in the NBCs and that of the controls. The difference in differences (ΔinΔ) were calculated as ΔNBC - ΔControl. A significance threshold of p<0.01 was used to account for multiple testing. Results After adjusting for overall trends, center size, and baseline patient population characteristics, no differences in patient selection behavior meeting the pre-specified threshold for statistical significance were identified when comparing the NBCs (n=24 centers) with the controls (n=195 centers). In the 3 years following the index years, 4,150 and 25,013 patients were transplanted at NBCs and controls, respectively. The proportion of patients receiving reduced intensity or non-myeloablative conditioning regimens decreased 4.1% in NBCs and increased 5.0% in controls, for a net difference of -9.1% (95% CI: -16.7% to -1.6%, p=0.02). All other patient characteristic proportions changed in the same direction at NBCs and controls, albeit to varying degrees (Table 1). In some high-risk characteristics, (e.g. HCT-CI > 3), a greater increase was seen at NBCs vs controls (ΔinΔ 2.1% 95% CI: -2.8% to 6.9%, p=0.40). In others, (e.g. age 60+ years), a greater increase was seen at controls vs NBCs (ΔinΔ -2.6% 95% CI: -5.9% to 0.7%, p=0.12). To capture a holistic measure of centers' patient population risk, the predicted 1-year survival was compared in the NBCs vs controls using the logistic regression model generated for each year's CSA. The predicted OS increased by 3.08% and 3.30% in the NBCs and controls respectively, with no statistically significant difference (-0.23%, 95% CI: -1.4% to 0.9%, p=0.70, Figure 1). The observed overall survival (adjusted for predicted 1 year OS) also increased in both BECs and controls by 0.9% and 4.5% respectively, without statistically significant difference (-3.6%, 95% CI: -6.7% to -0.7%, p=0.02). Discussion For centers receiving a -1 report, no statistically significant changes were seen in patient population characteristics in the following 3 years when compared to centers with OS was as expected. There was variability in the changes in high-risk patient characteristics at the NBCs relative to the controls, and in some cases more patients with high-risk characteristics were selected at these centers compared to those at controls. The change in predicted overall survival at 1 year, a summary indicator of survival risk, was similar between BECs and control centers. Although the number of patients in centers with below expected OS was small, these findings suggest the public reporting of outcomes in HCT in the US does not unintentionally affect access to HCT for high-risk patients at NBCs.

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.

AbstractBackgroundLenalidomide maintenance after autologous stem cell transplant (ASCT) in multiple myeloma (MM) results in superior progression‐free survival and overall survival. However, patients with high‐risk multiple myeloma (HRMM) do not derive the same survival benefit from lenalidomide maintenance compared with standard‐risk patients. The authors sought to determine the outcomes of bortezomib‐based maintenance compared with lenalidomide maintenance in patients with HRMM undergoing ASCT.MethodsIn total, the authors identified 503 patients with HRMM who were undergoing ASCT within 12 months of diagnosis from January 2013 to December 2018 after receiving triplet novel‐agent induction in the Center for International Blood and Marrow Transplant Research database. HRMM was defined as deletion 17p, t(14;16), t(4;14), t(14;20), or chromosome 1q gain.ResultsThree hundred fifty‐seven patients (67%) received lenalidomide alone, and 146 (33%) received bortezomib‐based maintenance (with bortezomib alone in 58%). Patients in the bortezomib‐based maintenance group were more likely to harbor two or more high‐risk abnormalities and International Staging System stage III disease (30% vs. 22%; p = .01) compared with the lenalidomide group (24% vs. 15%; p < .01). Patients who were receiving lenalidomide maintenance had superior progression‐free survival at 2 years compared with those who were receiving either bortezomib monotherapy or combination therapy (75% vs. 63%; p = .009). Overall survival at 2 years was also superior in the lenalidomide group (93% vs. 84%; p = .001).ConclusionsNo superior outcomes were observed in patients with HRMM who received bortezomib monotherapy or (to a lesser extent) in those who received bortezomib in combination as maintenance compared with lenalidomide alone. Until prospective data from randomized clinical trials are available, post‐transplant therapy should be tailored to each patient with consideration for treating patients in clinical trials that target novel therapeutic strategies for HRMM, and lenalidomide should remain a cornerstone of treatment.

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 &lt; .001 and HR 5.01, P &lt; .001, respectively) and OS (HR 3.85, P &lt; .001 and HR 8.13, P &lt; .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.

8057 Background: Following autologous hematopoietic stem cell transplant (auto HCT), maintenance therapies improve survival, reduce relapse risk in multiple myeloma (MM), and are the de facto standard-of-care. However, clinical trials have shown an increased risk of second primary malignancies (SPM) with maintenance therapy, including second hematological malignancies (SHM). We examined data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to evaluate the impact of SPM on progression-free (PFS) and overall survival (OS) and the utilization of allogeneic HCT in patients with therapy-related myeloid neoplasms (t-MN). Methods: Adult patients (pts) with MM who underwent first auto HCT in the United States with a melphalan conditioning regimen from 2011-2018 and subsequently received maintenance therapy were included (N=3948). The primary endpoint of interest was the impact of SPM and SHM on OS. Multivariate analytic (MVA) modelling was applied, accounting for competing risks while integrating significant covariates to determine the impact of SPM on PFS and OS. Finally, we studied the utilization and survival following allogeneic HCT for SHM. Results: Baseline characteristics were similar between the two groups. Maintenance regimens used were lenalidomide (2836, 72%), bortezomib (370,9 %) or lenalidomide + bortezomib (372, 9%) based combinations. At a median follow up of 37 months, 175 (5%) pts developed SPM, including 112 (64%) solid 36 (21%) myeloid, and 27 (15%) lymphoid cancers. In MVA, the development of SPM and SHM was associated with an inferior PFS (HR 2.62, P<0.001 and HR 5.01, P<0.001, respectively) and OS (HR 3.85, P<0.001 and 8.13, P<0.001, respectively). The two commonest causes of death were MM (42%) and SPM (30%) for those developing SPM. Similarly, MM (53%) and SHM (18%) were the two commonest causes of death for those developing SHM. Nine (14%,5 t-MDS and 4 t-AML) of 63 patients with SHM underwent an allogeneic HCT. Patients undergoing allogeneic HCT were more likely to have Karnofsky score ≥90 (100% vs. 50%, P=0.02) compared to those who did not. One year survival from allo SCT was 66.7% (CI 34.6-92%). Conclusions: The three-year cumulative incidence of SPM was 3.3 (2.6-4)% in this large contemporaneous CIBMTR cohort. Disease relapse remains the primary cause of death in MM patients who develop SPM or SHM. Given the median OS for MM is now > 10 years, longer follow-up is needed to assess the SPM and SHM risks with maintenance therapy post-auto HCT.