Brazauskas, Ruta

Abstract Introduction: Allogeneic stem cell transplant is an intensive procedure, offered in a limited number of medical centres. We sought to describe how sociodemographic variables impacted access to transplant across the United States, and if disadvantaged populations had inferior access to transplant. Methods: Data from the Surveillance, Epidemiology and End Results Program (SEER) and the Center for International Blood and Marrow Transplant Research (CIBMTR) was integrated to determine the rate of unrelated donor transplantation between 2000 and 2010 in each of the 612 counties included in the SEER registry. Patients under the age of 65 with AML, ALL, and MDS were included, and the analysis was restricted to unrelated donors due to limited availability of ZIP code in CIBMTR data. New incident cases were determined from SEER, and the number of transplants was determined from CIBMTR. The transplant rate was calculated (transplants performed divided by incident cases) for each county. County attributes (percent minority, rural/urban status, percentage below the poverty line, and median family size) were obtained from US Census data. Poisson regression was used to describe how county attributes impacted transplant rates. Transplant rates were calculated separately for AML, White residents, and pediatric ALL. Results: 3147 patients were identified in the CIBMTR dataset that met inclusion criteria. The estimated ZIP code completeness was 75%. There were 30,468 new incident diagnoses of ALL, AML, and MDS. For AML, patients from rural areas (less than 20,000 residents) and patients from areas with higher poverty levels had lower transplant rates (Table 1). Minority status and family size did not impact transplant rate. In regression models, higher levels of poverty remained associated with lower transplant rates, while rurality did not (Table 2). The results were similar among White residents. In contrast, in pediatric ALL, no county attributes (poverty, rurality, percent minority, and family size) were significantly associated with a difference in transplant rate (Table 1). However, numbers of transplants were smaller, limiting power. Discussion: Patients with AML from disadvantaged areas had lower rates of unrelated donor transplant. While patients from disadvantaged areas were also more likely to be non-White, and non-White Americans are less likely to have an available unrelated donor, this difference was also seen in White Americans from disadvantaged areas. This suggests the lower transplant rate is due impaired access to transplant. Poverty rate was the most important predictor of transplant rate. The results of this study suggest that improving access to transplant in disadvantaged populations should be a priority for health care administrators. Based on these results, approximately 2500 Americans do not undergo allogeneic transplant annually due to inferior access associated with higher poverty rates. Table 1 Univariate Analysis Table 1. Univariate Analysis Table 2 Acute Myeloid Leukemia, Regression Model * Metropolitan = county > 50,000 people, micropolitan = county > 20,000, rural county < 20,000. Table 2. Acute Myeloid Leukemia, Regression Model. / * Metropolitan = county > 50,000 people, micropolitan = county > 20,000, rural county < 20,000. Disclosures Hahn: Novartis: Equity Ownership; NIH: Research Funding.

Abstract Background: The association of clinical trial participation with outcomes in cancer patients is controversial, with some studies reporting better outcomes for trial participants while others do not. It is possible that the difference in outcomes is due to differences in baseline characteristics of participants and non-participants. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0201 trial was a large randomized, multi-center study comparing peripheral blood (PB) with bone marrow (BM) for hematopoietic cell transplantation (HCT) from HLA-matched or 1 allele mismatched unrelated donors (URD) in patients with acute leukemia, chronic myeloid leukemia and myelodysplastic syndromes. The trial reported no significant survival differences between PB and BM; there was decreased risk of graft failure but increased risk of chronic graft-versus-host disease (GVHD) with PB grafts (Anasetti et al NEJM 2012). Methods: We compared characteristics of BMT CTN 0201 study participants (n=494) with HCT recipients who did not participate on the trial (n=1384) but were potentially eligible by virtue of known characteristics. These patients received similar conditioning and GVHD prophylaxis as trial participants at 38 United States trial centers during the study time-period. Centers that had no eligible non-trial participants were excluded. Outcomes between patients on and off trial were compared using Cox proportional hazards regression models. Data were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) that collects patient data on all trial and non-trial allogeneic HCT recipients through its registry function. Results: Approximately 29% [494/1878] of apparently eligible patients were randomized and analyzed as part of the trial. There were no significant differences between study participants and non-participants in age or sex distribution, disease types, HLA or sex matching, comorbidities, or interval from diagnosis to HCT. Higher proportions of non-participants were Hispanic, had a lower performance status and lower disease risk, and received myeloablative conditioning and antithymocyte globulin (ATG) or Campath than the study participants. PB was used more commonly as the graft source in the non-participants as compared to the study participants (65% vs. 50%, p<0.001). In multivariate models, overall mortality (HR 1.09, 95% CI 0.95-1.25, p=0.22), transplant-related mortality (HR 1.08, 95% CI 0.89-1.32, p=0.42) and risks of acute grade II-IV (HR 0.96, 95% CI 0.82-1.12, p=0.57) and chronic GVHD (HR 1.06, 95% CI 0.92-1.23, p=0.41) were comparable between study non-participants and participants. Non-participants were at higher risk for relapse than participants (HR 1.24, 95%CI 1.04-1.49, p=0.02) in the multivariate analysis adjusted for disease risk and other clinical variables. Center effect was examined and was not found to be significant (p=0.10). There was no significant interaction between graft source and trial participation (P=0.22) and the risk of mortality was comparable for BM (HR 0.99, 95% CI 0.80-1.22, p=0.90) and PB recipients (HR 1.17, 95% CI 0.97-1.41, p=0.09) whether on trial or off trial. (Figure) Conclusion: Approximately 29% of patients who appeared eligible and were treated with conditioning and GVHD prophylaxis regimens allowed on the trial were enrolled. Despite some differences in clinical characteristics, most of the outcomes of non-trial participants were comparable to trial participants, suggesting that there is no definitive evidence that the outcomes of patients in a clinical trial are superior to those of the non-participants treated in a similar fashion. The comparable outcomes also indicate that the results of this trial were not seriously affected by selection bias and are therefore representative of the larger population. Figure 1: Adjusted overall survival in BMT CTN 0201 trial participants and non-participants Figure 1:. Adjusted overall survival in BMT CTN 0201 trial participants and non-participants Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 591 Background: Survival of patients with MM has improved over the past two decades, in part due to the use of AHCT. Increasingly, second primary malignancies (SPMs) are observed in MM survivors. Determining the baseline incidence and risk factors associated with SPMs after AHCT is important to assess risk and to evaluate the risk-benefit ratio of newer therapies. Methods: We analyzed the incidence of SPMs in 3784 MM patients receiving (“upfront”) AHCT for MM within 18 months of diagnosis between 1990 and 2010 and reported to the CIBMTR. Cumulative incidence rates of SPMs were estimated taking into account the competing risk of death. For each transplant recipient, the number of person-years at risk was calculated from the date of transplantation until date of last contact, death, or diagnosis of SPM, whichever occurred first. Incidence rates for all invasive cancers in the general population were obtained from the SEER database. Age-, sex-, and race- specific incidence rates for overall SPMs and particular anatomical sites were applied to the appropriate person-years at risk to compute the expected numbers of cancers. Observed–to –expected (O/E) ratios were calculated, and Poisson distribution 99% confidence intervals (CIs) were generated. Poisson regression model was used to analyze risk factors for overall SPMs and AML/MDS. Results: Pre-transplant therapy included novel agents in 56% including thalidomide (35%), lenalidomide (9%), bortezomib (16%) or their combinations (11%). Majority (80%) received high dose melphalan conditioning. Post-transplant maintenance therapy included thalidomide (16%), lenalidomide (8%), bortezomib (9%) and interferon (6%). Median follow-up of survivors was 52 months (range 3 to 192 months).With 12707 person years of follow up, 153 new malignancies were reported with a crude rate of 1.2 SPM per 100 person years of follow up. Observed/Expected [O/E] ratio for all SPMs was 0.99 (99% CI, 0.80–1.22). Cumulative incidence of SPM overall was 2.48% (95% CI, 1.96–3.05) at 3 years and 6.0% (95% CI, 4.96–7.10) at 7 years [Figure 1]. Individual SPMs observed significantly more frequently than expected are summarized in Table 1. The cumulative incidence of MDS/AML was 0.5% (95% CI, 0.28–0.78) at 3 years and 1.3 (95% CI, 0.85– 1.9%) at 7 years. Majority had MM progression prior to diagnosis of SPM (65 of 102 patients overall and 15 of 23 patients for MDS/AML). In multivariate analysis, significant risk factors for development of SPMs included: obesity [Hazard ratio = HR 1.89(95%CI, 1.21–2.93), p=0.0047 for BMI>30 vs. BMI<25], older age: [HR10.53 (95%CI, 1.46–75.82), p=0.0195] for 60–69 year olds and HR14.4 (95%CI, 1.89–109.75), p=0.01 for 70+ year olds compared to the 18–39 year old group. Specific conditioning regimens did not correlate with the risk of SPM. The low number of MDS/AML (33 events out of 3784 cases) limited the power of multivariate analysis. Increasing age was significantly associated with development of MDS (HR10.77, (95%CI,92.09–55.51), p=0.004 for 70+ year old vs. 40–49 year olds). Conclusion: In this large cohort of AHCT recipients for MM, the incidence of MDS/AML, melanoma and other skin cancers was significantly higher compared to age and sex matched general population. However the overall risk of SPM was similar to that expected for age and sex matched population. It was also similar to the placebo arms of recent reports by McCarthy Pl et al and Attal M et al (N Engl J Med. 10; 366(19):1770–91). Lenalidomide (8%) or thalidomide maintenance (16%) used in a small subset of patients with comparatively short follow up, was not associated with risk of SPM in the analysis of the overall cohort. Disclosures: Gale: Celgene: Employment. Brandenburg:Celgene: Employment, Equity Ownership. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck all Consultancy. Krishnan:Celgene and Millennium: Consultancy, Speakers Bureau. Dispenzieri:Celgene and Millennium: Research Funding. Hari:Celgene: Consultancy, Honoraria.

Abstract Plerixafor, a direct antagonist of CXCR4/stromal-derived factor 1, can safely and rapidly mobilize allografts without the use of granulocyte colony-stimulating factor (G-CSF). We conducted a phase 2, multicenter, prospective study of plerixafor-mobilized HLA-identical sibling allografts for allogeneic hematopoietic cell transplantation in recipients with hematological malignancies. Donors (n = 64) were treated with subcutaneous plerixafor (240 µg/kg) and started leukapheresis (LP) 4 hours later. The primary objective was to determine the proportion of donors who were successfully mobilized: defined as collection of ≥2.0 × 106 CD34+ cells per kilogram recipient weight in ≤2 LP sessions. Recipients subsequently received reduced intensity (RIC; n = 33) or myeloablative (MAC; n = 30) conditioning. Sixty-three of 64 (98%) donors achieved the primary objective. The median CD34+ cell dose per kilogram recipient weight collected within 2 days was 4.7 (0.9-9.6). Plerixafor was well tolerated with only grade 1 or 2 drug-related adverse events noted. Bone pain was not observed. Plerixafor-mobilized grafts engrafted promptly. One-year progression-free and overall survivals were 53% (95% confidence interval [CI], 36% to 71%) and 63% (95% CI, 46% to 79%) for MAC and 64% (95% CI, 47% to 79%) and 70% (95% CI, 53% to 84%) for RIC recipients, respectively. Donor toxicity was reduced relative to G-CSF mobilized related donors. This is the first multicenter trial to demonstrate that, as an alternative to G-CSF, plerixafor rapidly and safely mobilizes sufficient numbers of CD34+ cells from matched sibling donors for HCT. Engraftment was prompt, and outcomes in recipients were encouraging. This trial was registered at clinicaltrials.gov as #NCT01696461.

Key Points Over the last decade, allogeneic HCT has been increasingly administered in the United States to adults aged 70 and older with hematologic malignancies. Allogeneic transplant outcomes were reasonable; high comorbidity and ablative conditioning regimens were associated with inferior outcomes.

BACKGROUNDTo evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post‐transplantation.METHODSWe analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n = 3786) or allogeneic (n = 7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre‐HCT depression requiring treatment versus those without pre‐HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post‐HCT using Poisson models. We also compared the incidence of grade 2‐4 acute and chronic graft‐versus‐host disease (GVHD) in allogeneic HCT.RESULTSThe study included 1116 (15%) patients with pre‐transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre‐transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04‐1.23; P = 0.004) and a higher incidence of grade 2‐4 acute GVHD (HR, 1.25; 95% CI, 1.14‐1.37; P < 0.0001), but similar incidence of chronic GVHD. Pre‐transplant depression was associated with fewer days‐alive‐and‐out‐of‐the hospital (means ratio [MR] = 0.97; 95% CI, 0.95‐0.99; P = 0.004). There were 512 (13.5%) patients with Pre‐transplant depression and 3274 (86.5%) without depression who underwent autologous HCT. Pre‐transplant depression in autologous HCT was not associated with OS (HR, 1.15; 95% CI, 0.98‐1.34; P = 0.096) but was associated with fewer days alive and out of the hospital (MR, 0.98; 95% CI, 0.97‐0.99; P = 0.002).CONCLUSIONPre‐transplant depression was associated with lower OS and higher risk of acute GVHD among allogeneic HCT recipients and fewer days alive and out of the hospital during the first 100 days after autologous and allogeneic HCT. Patients with pre‐transplant depression represent a population that is at risk for post‐transplant complications. Cancer 2017;123:1828–1838. © 2017 American Cancer Society.