Cell Transplantation-specific Comorbidity Index Research Articles

Non-Myeloablative Allogeneic Stem Cell Transplant in Acute Myeloid Leukemia: Graft-Versus-Host Disease Potentiates Graft-Versus-Leukemia Effect and Improves Overall Survival

Introduction: Non-myeloablative conditioning regimens enable elderly and younger patients with significant comorbidities to undergo allogenic stem cell transplant (allo SCT). These regimens allow for the benefit of graft-versus-leukemia (GVL) effect with reduced toxicity. A retrospective analysis of 94 patients with acute myeloid leukemia (AML) who received a non-myeloablative transplant with fludarabine (25 mg/m2 days -7 through -3)/cyclophosphamide (1000 mg/m2 days -7 and -6) (Flu/Cy) conditioning was conducted to evaluate patient outcomes. Methods: Ninety-four patients with AML underwent non-myeloablative allo SCT with Flu/Cy conditioning at Penn State Cancer Institute between 2007 and 2015 were retrospectively analyzed. The patients were deemed ineligible for myeloablative or reduced intensity conditioning transplants due to advanced age or significant comorbidities. Most unrelated donor patients (n=69) received tacrolimus/sirolimus/methotrexate as graft-versus-host disease (GVHD) prophylaxis. Overall survival (OS) and disease-free survival (DFS) were assessed with Kaplan-Meier survival curves and log rank tests, and non-relapse mortality (NRM) and relapse rates (RR) were assessed with cumulative incidence of competing events and Gray test. Cox proportional hazard regression with stepwise selection was used for multivariate analysis. Results: Patients with AML underwent Flu/Cy conditioning for allo SCT from either a matched related donor (MRD) (n =16), matched unrelated donor (MUD) (n=54), or mismatched unrelated donor (MMUD) (n=24). Evaluation of AML status immediately prior to allo SCT identified 79 patients in complete remission, 10 patients with non-remission, and 5 patients with primary induction failure. There were 11 patients with hematopoietic cell transplantation specific comorbidity index (HCT-CI): 0, 14 patients with HCT-CI: 1-2, and 69 patients with HCT-CI: ≥3. Post-transplant analysis identified: 48 patients with grade 0, 31 patients with grade I, and 15 patients with grade II-IV acute graft-versus-host disease (aGVHD). Furthermore, 52 patients were without chronic GVHD (cGVHD), 15 experienced limited cGVHD, and 13 experienced extensive cGVHD. One-year OS and DFS were 41.3% (95% CI: 31.3-51%) and 27.7% (95% CI: 18.7-37.4%), respectively. One-year NRM and RR were 12.9% (95% CI: 0.68-21%) and 59.5% (95% CI: 48.2-69.1%). There were no statistically significant differences in NRM between patients with varying comorbidity indices. One-year OS for patients in complete remission versus non-remission prior to transplant was 45.3% versus 20.0% (p<0.01), and was significantly greater in patients with grade I versus grade II-IV aGVHD (45.2% versus 17.8%, p<0.05). Patients with cGVHD showed a lower RR compared to patients without cGVHD (1-year RR 20.4% vs 48.5%, p<0.05). Patients who achieve a chimerism ≥90% within 100 days of transplant achieved a better OS and lower RR compared to patients with a chimerism <90% (1-year OS 51.3% versus 21.4%, p<0.01; 1-year RR 44.0% vs 89.3%, p<0.01, respectively). Multivariate analysis identified grade I aGVHD (versus grade II-IV, p<0.01), cGVHD (versus no cGVHD, p<0.05), and chimerism ≥90% (versus <90%, p<0.05) as independent factors for improved OS. Conclusions: The primary endpoint for this retrospective analysis was OS following non-myeloablative allo SCT for AML utilizing Flu/Cy conditioning. Although RR was high (59.5%), this conditioning regimen resulted in rapid stem cell recovery and low NRM. There were no significant differences in NRM between patients with lower (0, or 1-2) and higher (≥3) HCT-CI and patients receiving MRD, MUD or MMUD. This confirms that Flu/Cy conditioning is safe, especially for patients with multiple comorbidities and receiving MMUD. This analysis also identified a significant improvement in OS for patients with grade I as compared to grade II-IV aGVHD. Also, patients with cGVHD showed a significantly reduced RR. Collectively, the improved survival for patients with grade I aGVHD and cGVHD may be associated with a more robust GVL effect. Additionally, patients who achieve a higher chimerism showed a reduced RR. This study highlights the tolerability of Flu/Cy and the importance of balancing GVHD and GVL effects; future studies are needed to evaluate the addition of maintenance therapies to overcome higher RR occurring with this regimen. Disclosures Naik: Celgene: Other: Advisory board. Zheng:Pfizer: Research Funding. Claxton:Daiichi Sankyo Co. and Ambit Biosciences Corp, Astellas Pharma, Novartis Pharmaceuticals, Incyte Corporation, Cyclacel Pharmaceuticals, Inc, Celegene Corporation, Medimmune, Inc, Merck Sharp & Dohme Corp., Gilead Sciences, Inc.: Research Funding.

Development and Application of a Software to Improve the Data Management of a Bone Marrow Transplant Service in a Brazilian Public Hospital

Introduction The Hematopoietic Stem Cell Transplantation Service (HSCT) of the Amaral Carvalho Hospital began its activities in August 1996. At first, an Excell® spreadsheet was applied, in which all the information concerning the HSCT performed in our service were included. The use of this tool had the purpose of organizing the HSCT service information. In 2009, we started to send data to the Center for International Blood and Marrow Transplant Research (CIBMTR). Due to the beginning of this new activity and the large amount of information requested by CIBMTR, an improvement in the previously used platform was felt necessary. Today there are 12 Brazilian active centers in the CIBMTR. According to a recent CIBMTR report (info request #1807-14), our center has reported an average of 43% of all first transplants performed in Brazil and reported to the CIBMTR in the last 4 years. Objective Due the lack of resources for large investments in the technology information area as a public center, and the need to improve the tool in use, another software was proposed to speed up the data collection, to organize the internal database and to report the data to the CIBMTR. Materials and Methods In 2013 a database was developed in Access® (Microsoft® Office), containing all the information requested in the CIBMTR forms and necessary for the analysis and control of the Service results. After entering all the data, the program is able to generate a report containing all information necessary to complete the pre-HSCT forms (Forms 2804, 2814, 2400 and 2402). Within the program there are links to carry out the risk calculation of VOD (hepatic veno-occlusive disease)/SOS (hepatic sinus obstructive syndrome) and DRI (disaster risk index). There is also a calculator for the HCT-CI (Hematopoietic cell transplant specific comorbidity index), using as a template the site http://www.hctci.org/Home. The post-HSCT data can also be inserted, making it possible to use the database to fill up all the CIBMTR follow-up forms. Results and Discussion With the development of this database program a great improvement was achieved in the quality of organization of internal data and in the timely report to the CIBMTR. Between 2011 and 2014 the average percentage of forms submitted within the proposed deadline was 25.5%, while between 2015 and July 2018 this average increased to 80.5%. Currently, approximately 200 HSCT are reported annually and around 900 post-transplant follow-up forms are sent. Conclusion As the new tool was developed by the data manager, we have the possibility to edit the program according to our needs and with the information requested by CIBMTR. Idealized for routine use, this tool allowed the organization of the information, in a large HSCT center with few resources, helping us to report 100% of the HSCT performed to the CIBMTR since 2009.

Promising Outcome of Umbilical Cord Blood Transplantation in Patients with Multiple Comorbidities

The hematopoietic cell transplantation–specific comorbidity index (HCT-CI) has been recently proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) in allogeneic hematopoietic stem cell transplantation (HSCT). However, the usefulness of the HCT-CI in single-unit umbilical cord blood transplantation (UCBT) remains unclear. We investigated the impact of the HCT-CI on the clinical outcomes of allogeneic HSCT in a single-center retrospective study including 53 recipients of UCBT (UCBT group) and 90 recipients of other HSCT (non-UCBT group). In the non-UCBT group 2-year OS rates for HCT-CI score < 3 and ≥3 were 67% (n = 74; 95% confidence interval [CI], 54% to 78%) and 26% (n = 16; 95% CI, 7% to 51%), respectively (P = .001). In the UCBT group these rates were 66% (n = 39; 95% CI, 48% to 79%) and 69% (n = 14; 95% CI, 36% to 87%), respectively (P = .73). In the non-UCBT group 1-year NRM rates for HCT-CI score < 3 and ≥3 were 14% (95% CI, 6.4% to 22%) and 37% (95% CI, 14% to 61%), respectively (P = .02). In the UCBT group these rates were 6.1% (95% CI, 3.4% to 24%) and 7.7% (95% CI, .4% to 29%), respectively (P = .78). Using multivariate analysis we showed that HCT-CI score ≥ 3 was significantly associated with lower OS (hazard ratio, 3.06; 95% CI, 1.47 to 6.38; P = .003) and higher NRM (hazard ratio, 2.87; 95% CI, 1.18 to 6.96; P = .02) for the non-UCBT group. UCBT showed good OS with low incidence of NRM, even in patients with high HCT-CI scores. Altogether, we propose single-unit UCB to be a promising stem cell source for improving survival in patients with multiple comorbidities.

Impact of Toxicity on Survival for Older Adult Patients after CD34+ Selected Allogeneic Hematopoietic Stem Cell Transplantation

Ex vivo CD34+ selection before allogeneic hematopoietic stem cell transplantation (allo-HCT) reduces graft-versus-host disease without increasing relapse but usually requires myeloablative conditioning. We aimed to identify toxicity patterns in older patients and the association with overall survival (OS) and nonrelapse mortality (NRM). We conducted a retrospective analysis of 200 patients who underwent CD34+ selection allo-HCT using the ClinicMACS® system between 2006 and 2012. All grade 3 to 5 toxicities by CTCAE v4.0 were collected. Eighty patients aged ≥ 60 years with a median age of 64 (range, 60 to 73) were compared with 120 patients aged < 60 years. Median follow-up in survivors was 48.2 months. OS and NRM were similar between ages ≥ 60 and <60, with 1-year OS 70% versus 78% (P = .07) and 1-year NRM 23% versus 13% (P = .38), respectively. In patients aged ≥ 60 the most common toxicities by day 100 were metabolic, with a cumulative incidence of 88% (95% CI, 78% to 93%), infectious 84% (95% CI, 73% to 90%), hematologic 80% (95% CI, 69% to 87%), oral/gastrointestinal (GI) 48% (95% CI, 36% to 58%), cardiovascular (CV) 35% (95% CI, 25% to 46%), and hepatic 25% (95% CI, 16% to 35%). Patients aged ≥ 60 had a higher risk of neurologic (HR, 2.63 [95% CI, 1.45 to 4.78]; P = .001) and CV (HR, 1.65 [95% CI, 1.04 to 2.63]; P = .03) toxicities but a lower risk of oral/GI (HR, .58 [95% CI, .41 to .83]; P = .003) compared with those aged < 60. CV, hepatic, neurologic, pulmonary, and renal toxicities remained independent risk factors for the risk of death and NRM in separate multivariate models adjusting for age and hematopoietic cell transplantation–specific comorbidity index. Overall, the toxicity of a more intense regimen is potentially balanced by the absence of toxicity related to methotrexate and calcineurin inhibitors in older patients. Prospective study of toxicities after allo-HCT in older patients is essential.

T Cell Depletion as an Alternative Approach for Patients 55 Years or Older Undergoing Allogeneic Stem Cell Transplantation as Curative Therapy for Hematologic Malignancies

T cell–depleted (TCD) allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for hematologic malignancies in adults, shown to reduce graft-versus-host disease (GVHD) without increased relapse. We retrospectively reviewed a single-center, 11-year experience of 214 patients aged ≥ 55 years to determine tolerability and efficacy in the older adult. Most patients (70%) had myeloid diseases, and most acute leukemias were in remission. Median age was 61 years, with related and unrelated donors ≥8/10 HLA matched. Hematopoietic cell transplantation–specific comorbidity index scores were intermediate and high for 84%. Conditioning regimens were all myeloablative. Grafts were peripheral blood stem cells (97%) containing CD3 dose ≤103-4/kg body weight, without pharmacologic GVHD prophylaxis. With median follow-up of 70 months among survivors, Kaplan-Meier estimates of overall and relapse-free survival were 44% and 41%, respectively (4 years). Cumulative incidence of nonrelapse mortality at day +100 was only 10%. Incidence of GVHD for acute (grades II to IV) was 9% at day +100 and for chronic was 7% at 2 and 4 years (8 extensive, 1 overlap). Median Karnofsky performance status for patients > 2 years post-transplant was 90%. As 1 of the largest reports for patients ≥2 aged ≥55 years receiving TCD HSCTs, it demonstrates curative therapy with minimal GVHD, similar to that observed in a younger population.

The Impact of Toxicities on First-Year Outcomes after Ex Vivo CD34+–Selected Allogeneic Hematopoietic Cell Transplantation in Adults with Hematologic Malignancies

Factors that impact first-year morbidity and mortality in adults undergoing myeloablative allogeneic hematopoietic cell transplantation with ex vivo CD34+ selection have not been previously reported. We assessed all toxicities ≥ grade 3 from the start of conditioning to date of death, relapse, or last contact in 200 patients during the first year after transplantation, identifying 1885 individual toxicities among 17 organ-based toxicity groups. The most prevalent toxicities in the first year were of infectious, metabolic, hematologic, oral/gastrointestinal, hepatic, cardiac, and pulmonary etiologies. Renal complications were minimal. Grades II to IV and III and IV acute GVHD at day 100 were 11.5% and 3%, respectively. In separate multivariate models, cardiovascular, hematologic, hepatic, neurologic, pulmonary, and renal toxicities negatively impacted nonrelapse mortality (NRM) and overall survival during the first year. A higher-than-targeted busulfan level, patient cytomegalovirus seropositivity, and an Hematopoietic Cell Transplantation–Specific Comorbidity Index of ≥3 were associated with increased risk of NRM and all-cause death. Ex vivo CD34+ selection had a favorable 1-year OS of 75% and NRM of 17% and a low incidence of sinusoidal obstruction syndrome. These data establish a benchmark to focus efforts in reducing toxicity burden while improving patient outcomes.

Hematopoietic Cell Transplantation–Specific Comorbidity Index Predicts Morbidity and Mortality in Autologous Stem Cell Transplantation

The hematopoietic cell transplantation–specific comorbidity index (HCT-CI) score is a useful tool to assess the risk for nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation. Although the HCT-CI has been investigated in autologous stem cell transplantation (ASCT), its use is limited. To improve on the current use of the HCT-CI score on the morbidity and mortality after ASCT, we assessed the 100-day morbidity defined as orotracheal intubation (OTI), dialysis or shock (vasopressors need), 100-day NRM, early composite morbidity–mortality (combined endpoint that included any previous endpoints), and long-term NRM. We retrospectively reviewed a cohort of 1730 records of adult patients who received an ASCT in Argentinean center's between October 2002 and August 2016. Median follow-up was 1.15 years, and median age was 53 years. Diseases were multiple myeloma (48%), non-Hodgkin lymphoma (27%), and Hodgkin lymphoma (17%); 51% were in complete or partial remission; and 13% received ≥ 3 chemotherapy lines before transplant (heavily pretreated). Early NRM (100-day) was 2.7%, 5.4% required OTI, 4.5% required vasopressors, and 2.1% dialysis, with an early composite morbidity–mortality of 6.8%. Long-term (1 and 3 years) NRM was 4% and 5.2% and overall survival 89% and 77%, respectively. High-risk HCT-CI patients had a significant increase in 100-day NRM compared with intermediate and low risk (6.1% versus 3.4% versus 1.8%, respectively; P = .002), OTI (11% versus 6% versus 4%, P = .001), shock (8.7% versus 5.8% versus 3%, P = .001), early composite morbidity–mortality (13% versus 9 % versus 4.7%, P < .001), and long-term NRM (1 year, 7.7% versus 4% versus 3.3%; and 3 years, 10.8% versus 4% versus 4.8%, respectively; P = .002). After multivariate analysis these outcomes remained significant: early composite morbidity–mortality (odds ratio [95% confidence interval] compared with low risk: intermediate risk 2.1 [1.3 to 3.5] and high risk 3.3 [1.9 to 5.9]) and NRM (hazard ratio [95% confidence interval] compared with low risk: intermediate risk .97 [.8 to 2.4] and high risk 3.05 [1.3 to 4.5]). No significant impact was observed in overall survival. Other than comorbidities, significant impact was observed for heavily pretreated patients, age ≥ 55 years, non-Hodgkin lymphoma, and bendamustine-etoposide-citarabine-melphalan conditioning. We confirmed that the HCT-CI had a significant impact on NRM after ASCT, and these findings are mainly due to early toxicity express as 100-day NRM and the 3 main morbidity outcomes as well as the composite endpoint.

Validation of the Hematopoietic Cell Transplantation–Specific Comorbidity Index in Nonmyeloablative Allogeneic Stem Cell Transplantation

The Hematopoietic Cell Transplantation (HCT)–Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty-two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score ≥ 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT.

Evaluation of Performance Status and Hematopoietic Cell Transplantation Specific Comorbidity Index on Unplanned Admission Rates in Patients with Multiple Myeloma Undergoing Outpatient Autologous Stem Cell Transplantation

Although outpatient autologous stem cell transplantation (ASCT) is safe and feasible in most instances, some patients undergoing planned outpatient transplantation for multiple myeloma (MM) will need inpatient admission for transplantation-related complications. We aim to evaluate the difference, if any, between outpatient and inpatient ASCT cohorts of MM patients in terms of admission rate, transplantation outcome, and overall survival. We also plan to assess whether the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and Karnofsky Performance Status (KPS) can predict unplanned admissions after adjusting for confounding factors. Patients with MM (n = 448) who underwent transplantation at our institution between 2009 and 2014 were included in this retrospective analysis. Patients were grouped into 3 cohorts: cohort A, planned inpatient ASCT (n = 216); cohort B, unplanned inpatient admissions (n = 57); and cohort C, planned outpatient SCT (n = 175). The statistical approach included descriptive, bivariate, and survival analyses. There were no differences among the 3 cohorts in terms of type of myeloma, stage at diagnosis, time from diagnosis to transplantation, CD34 cell dose, engraftment kinetics, and 100-day response rates. Serum creatinine was higher and patients were relatively older in both the planned inpatient (median age, 62 years; range, 33 to 80 years) and unplanned (median age, 59 years; range, 44 to 69 years) admission cohorts compared with the outpatient-only cohort (median age, 57 years; range, 40 to 70 years) (P < .05). Performance status (cohort A: median, 90%; range, 60% to 100%; cohort B: 80%, 50% to 100%; cohort C: 80%, 60% to 100%) was lower (P < .05) and HCT-CI score (cohort A: median, 1.78; range, 0 to 8; cohort B: 2.67, 0 to 9; cohort C: 2.16, 0 to 7) was higher (P < .004) in both inpatient groups compared with the planned outpatient cohort. With a median follow up of 5 years, poor performance status (KPS <70%) appeared to be associated with worse survival (P < .002). HCT-CI >2 also appeared to be associated with worse outcomes compared with HCT-CI 0 to 1, the the difference did not reach statistical significance (hazard ratio, 1.41l 95% confidence interval, 0.72 to 2.76). Only 1 patient out of 448 died from a transplantation-related cause. Outpatient transplantation for myeloma is safe and feasible. In our experience, one-third of the patients undergoing outpatient transplantation needed to be admitted for transplantation-related toxicities. Patients in this group had lower preexisting KPS and higher HCT-CI scores. Whether planned admission for this group would have prevented unplanned admissions and undue stress on patients and the healthcare system should be tested in a prospective manner.

Long-Term Follow-Up and Impact of Comorbidity before Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory Acute Myeloid Leukemia—Lessons Learned from the Prospective BRIDGE Trial

In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (HSCT) is considered to be the only treatment providing long-term disease control. The BRIDGE trial studied the safety and efficacy of a clofarabine-based salvage therapy before HSCT in patients with r/r AML. Here, we report the long-term follow-up of this phase II multicenter trial and exploratory analyses on the impact of comorbidity on outcome. Eighty-four patients with a median age of 61 years (range, 40 to 75) were enrolled. Patients were scheduled for at least 1 cycle of salvage therapy with CLARA (clofarabine 30 mg/m2; cytarabine 1 g/m2, days 1 to 5). Chemo-responsive patients with a donor received HSCT after first CLARA. The conditioning regimen consisted of clofarabine 30 mg/m2, day −6 to −3, and melphalan 140 mg/m2 day −2. The Eastern Cooperative Oncology Group (ECOG) score, the hematopoietic cell transplantation–specific comorbidity index (HCT-CI), and the Cumulative Illness Rating Scale were obtained at study enrollment as well as before HSCT. Sixty-seven percent of the patients received HSCT within the trial. After a median follow up of 40 months, the estimated 3-year overall survival (OS) for all enrolled patients and those with HSCT within the trial was 40% and 55%, respectively. Relapse-free survival for patients who underwent transplantation with a complete remission afterwards (n = 50) was 48%, calculated from the day of transplantation. In multivariate analysis, both the HCT-CI and ECOG score had a statistically significant impact on OS with a hazard ratio of 1.22 (P = .025)and 1.72 (P = .001), respectively. Using a clofarabine-based salvage therapy combined with early allogeneic HSCT, we were able to achieve good long-term results for patients with r/r AML. In this cohort, both the HCT-CI and the ECOG scores gave prognostic information on OS, showing the feasibility and clinical relevance of comorbidity evaluation at the time of diagnosis of r/r AML patients.

149 - Lower Performance Status and Higher Hematopoietic Cell Transplantation Specific Co-Morbidity Index are Associated with Increased Unplanned Admission Rates for Patients with Multiple Myeloma Undergoing Outpatient Autologous Stem Cell Transplantation

149 - Lower Performance Status and Higher Hematopoietic Cell Transplantation Specific Co-Morbidity Index are Associated with Increased Unplanned Admission Rates for Patients with Multiple Myeloma Undergoing Outpatient Autologous Stem Cell Transplantation

A Novel Prognostic Factor for Allogeneic Hematopoietic Stem Cell Transplantation Based on Bone Marrow Assessment on the Day of Stem Cell Transplantation

[Introduction] Many factors predicting the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) recipient have been reported so far and widely used to assess the potential risk of undergoing allogeneic HSCT. Residual disease is considered one of the risk factors in HSCT, and mainly evaluated by bone marrow aspiration before HSCT. However, disease statuses at the point of stem cell infusion potentially differ from that of pre-transplant evaluation depending on the sensitivity for conditioning therapy or proliferation speed of the blast. In this study, we assessed residual disease by bone marrow aspiration on the day of stem cell transplantation (called "day 0" of HSCT) in order to analyze the relationship between day 0 marrow statuses and HSCT outcomes.[Methods] This study was designed as a retrospective observational analysis, and we collected the patients who received first allogeneic HSCT for hematological malignant diseases between 2010 and 2014. Extramedullary diseases were excluded from the analysis. All HSCTs were consecutive and performed in our center. Bone marrow aspirated material was examined histopathologically, and residual blasts were evaluated by specific markers by immunostaining. If it has detected residual blasts even if only a few cells, it was defined non complete remission (CR) on day 0 (abbreviated as "non-day0CR"). We divided the patients into two groups according to the existence of residual blast in bone marrow on day 0 of HSCT.[Results] We analyzed 121 HSCT recipients including 35 with acute lymphoblastic leukemia, 3 with acute undifferentiated leukemia, 65 with acute myeloid leukemia, 17 with refractory anemia with excess blasts and 1 with blast phase of chronic myelogenous leukemia. The median follow-up of survivors was 983 days (range 330 - 2092 days), and overall survival (OS) was 72% (95% confidence interval: 63 - 79%) at 1 year after HSCT. In univariate analyses, age higher than median 44 year-old, non-CR at the time of pre-HSCT assessment, hematopoietic cell transplantation specific comorbidity index (HCT-CI) at least 1 point, reduced intensity conditioning, and non-day0CR were extracted as predictors of poor OS. With multivariate analysis, HCT-CI and day 0 marrow status were significantly associated with OS. Furthermore, when patients were limited to pre-transplant non-CR subgroup, the patients achieving complete malignancies-free state on day 0 showed comparable prognosis with those who maintained CR before conditioning (Figure 1). Relapse after allogeneic HSCT was observed in 31 patients, and cumulative incidence of relapse was 11% (95% confidence interval: 6 - 17%) at 1 year after HSCT. With univariate and multivariate analyses, there were significant differences between the patients with CR marrow and those with residual malignancies on day 0 (P = 0.002). There was no significant difference in non-relapse mortality between the two groups (P = 0.18).[Conclusions] We showed that bone marrow status on day 0 was significantly associated with OS and cumulative incidence of relapse. To our knowledge, this is the first report about the association with day 0 marrow status and post-HSCT prognosis. A malignancies-free state on day 0 could predict favorable prognosis in allogeneic HSCT, and the patient with residual malignancies on day 0 had lower OS and higher relapse rate. For the patients with residual malignancies on day 0, rapid tapering of immunosuppressant or arrangement of scheduled donor lymphocyte infusion may improve the outcomes. [Display omitted] DisclosuresMiyamura:Nippon Shinyaku CO, LT: Honoraria; Pfizer Inc: Honoraria; Novartis Pharmaceutical: Honoraria; Alexion Pharmaceutical Inc: Honoraria.

Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation

Treosulfan has been incorporated in conditioning regimens for sustained remission without substantial toxicity and treatment-related mortality (TRM). We aimed to analyze the safety and efficacy of a fludarabine 150 mg/m2 and treosulfan 42 g/m2 (FluTreo) conditioning regimen in medically infirm patients. Outcomes were compared with those of a similar historical group treated with fludarabine 150 mg/m2 to 180 mg/m2, busulfan 6.4 mg/kg, and antithymocyte globulin (ATG) 5 mg/kg to 7.5 mg/kg (FluBuATG). Thirty-one consecutive patients with acute myeloid leukemia (AML; n = 21), myelodysplastic syndrome (MDS; n = 6), or treatment-related AML (n = 4) received FluTreo conditioning. The historical group consisted of 26 consecutive patients treated with FluBuATG. In the FluTreo group, engraftment was prompt in all patients and 74% achieved >99% donor chimerism by day +30. No grades III or IV organ toxicities were noted. One-year cumulative incidences (CI) of acute and chronic graft-versus-host disease (GVHD) were 19.4% and 58.4%. The groups were similar for age, disease risk, lines of treatment, hematopoietic cell transplantation–specific comorbidity index, and acute or chronic GVHD incidence, except that there were more matched unrelated donor recipients in the FluTreo group (P < .001). With 20 (range, 2 to 36) months follow-up for FluTreo and 14 (range, 2 to 136) for FluBuATG, the 1-year cumulative overall survival (OS) probability was 76% versus 57%, respectively (P = .026); 1-year disease-free survival (DFS) was 79% versus 38% (P < .001). In multivariate analysis, the only significantly favorable factor for OS and DFS was FluTreo (P = .010 and P = .012). The CI of relapse mortality was markedly decreased in FluTreo versus FluBuATG (7.4% versus 42.3%, P < .001). In conclusion, the treosulfan-based regimen resulted in favorable OS and DFS with acceptable toxicity and low relapse rates compared with busulfan-based conditioning.

A Novel Reduced-Toxicity Myeloablative Conditioning Regimen Using Full-Dose Busulfan, Fludarabine, and Melphalan for Single Cord Blood Transplantation Provides Durable Engraftment and Remission in Nonremission Myeloid Malignancies

A pilot study of a novel, reduced-toxicity, myeloablative conditioning regimen using intravenous busulfan 12.8 mg/kg, fludarabine 180 mg/m2, and melphalan 80 mg/m2 for single cord blood transplantation (CBT) was conducted at our institution. Fifty-one patients with myeloid malignancies not in remission were included in this study. Their median age was 59 years (range, 19 to 70 years), with a median hematopoietic cell transplantation–specific comorbidity index score of 3. With a median observation period of 39.6 months (range, 24.3 to 90.8 months) among the survivors, overall survival and progression-free survival at 2 years were both 54.9%. Forty-six of 51 achieved neutrophil engraftment at a median of 19.5 days (range, 13 to 38 days) after transplantation, with a cumulative incidence of 90.2%. No patient developed graft rejection in this study. All patients who achieved engraftment showed hematological complete remission with complete donor chimerism. Eleven patients relapsed at a median of 4.9 months (range, .5 to 26.7 months). Cumulative incidences of nonrelapse mortality (NRM) at 100 days and 2 years were 11.8% and 25.5%, respectively. In conclusion, the present results show that the novel conditioning regimen for single CBT provided durable engraftment and remission with acceptable NRM leading to excellent survival, even for a relatively older population with myeloid malignancies not in remission.

Risk Factors for Invasive Mold Infections and Implications for Choice of Prophylaxis after Allogeneic Stem Cell Transplantation

Invasive mold infections (IMIs) are major complications after allogeneic hematopoietic stem cell transplantation (HSCT) with high mortality. We retrospectively investigated incidence and risk factors for IMI after 797 HSCTs in a center with high autopsy frequency, trying to identify patient groups that would potentially benefit from mold-active prophylaxis. The cumulative 1-year incidence of IMI was 2.1% in patients aged 21 to 40, 7.1% in patients aged 41 to 60, and 16.4% in patients > 60 years of age (P < .01 for patients aged 21 to 40 versus 41 to 60, P < .001 for patients aged 21 to 40 versus patients > 60). Risk factors for a new IMI in multivariate analysis were older age, grades II to IV acute graft-versus-host disease (GVHD) (risk hazard, 4.1; 95% CI, 1.9 to 8.8; P < .001), treatment with mesenchymal stromal cells (risk hazard, 4.0; 95% CI, 2.1 to 7.8; P < .001), transplantation with female donor to male recipient (risk hazard, 2.2; 95% CI, 1.1 to 4.3; P = .02), and hematopoietic stem cell transplantation–specific comorbidity index over 5 (risk hazard, 2.8; 95% CI, 1.1 to 6.8; P = .03). In patients with grade II acute GVHD, no IMI was seen after onset of acute GVHD in 109 HSCTs performed in patients < 40 years of age, as compared with 14 IMIs in 97 HSCTs (14%) performed in patients > 40 years of age (P < .001). To conclude, older age is an important risk factor for developing IMIs, and patients < 40 years of age with grade II acute GVHD do not appear to need mold-active prophylaxis unless receiving prolonged treatment with corticosteroids.

Pretransplant β2-Microglobulin Is Associated with the Risk of Acute Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplant

The risk of acute graft-versus-host disease (aGVHD) can be reliably estimated by the hematopoietic cell transplantation–specific comorbidity index (HCT-CI), which can be further refined by the incorporation of pre–hematopoietic cell transplantation (HCT) serum levels of inflammatory biomarkers such as ferritin and albumin. β2-Microglobulin (β2-m) is a key component of the MHC class I complex, which is independently associated with mortality and frailty in the general population. We took advantage of our institutional protocol that includes measurement of pre-HCT β2-m serum levels in the most patients to investigate whether pre-transplant β2-m levels were associated with the risk of aGVHD. One hundred three consecutive patients submitted to allogeneic HCT, of which 26 developed grades II to IV aGVHD, were included in the analysis. β2-m was significantly associated with age and HCT-CI. Higher levels of β2-m were observed in patients who developed aGVHD (P = .008). In the multivariate Cox regression model, β2-m and HCT-CI remained independently associated with the risk of developing aGVHD. In conclusion, the association between β2-m and the occurrence of aGVHD suggests that the measurement of this protein before HCT might represent an additional element for risk stratification of aGVHD.

The Use of Biomarker Ferritin and Albumin As Well As HCT-CI, but Not PAM, Was Predictive of Suvival, Gvhd and, Relapse in Myeloid Malignancies

Developing the optimal models for pretransplant assessment as more reduced intensity conditioning regimens are implemented and the higher median age of transplant. The pre-transplant assessment of mortality (PAM) assesses all cause mortality at 2 years and the Hematopoietic Stem cell Transplantation specific comorbidity index (HCT-CI) which previously used Charlson comorbidity index (CCI) to assessed NRM based on history and organ function. Previous studies have shown that certain biomarkers such as ferritin and albumin may help optimize risk assessment before transplant. We tested the validity of PAM, HCT-CI, serum ferritin and albumin to predict GVHD, relapse and overall survival (OS) in our older patient population. IRB approval was obtained to retrospectively review clinical outcomes in patients undergoing allogeneic stem cell transplantation at our institution between, 2010 - 2013. We examined a total of 94 patients with myeloid malignancies (see Table 1 for patient characteristics). Risk variables assessed included calculated PAM, HCT-CI and KPS scores and pre HCT serum ferritin and albumin levels. We examined the predictive value of these biomarkers with respect to GVHD, relapse, and overall survival. Of the 94 patients 46% are alive and in remission, 20% have relapse and GVHD developed in 56% of patients. To determine the optimal cutoff for classifying into high and low groups for each risk measure, first the association between the measure and clinical outcomes was determined to obtain the logistic regression. Then area under the curve (AUC) of the receiver operating characteristic (ROC) curve for each clinical outcome against the risk measure was calculated. The cutoff that maximized the sum of the ROC-AUC across all measured was selected. Patients with HCT-CI > 4, (cut off 4), had a less likelihood of survival than those with HCT < 4 OR 4.3 (95% CI: 1.6-11.2) (p=.0033). Similarly, patients with low albumin, (cutoff 4.1), were less likely to than those with high albumin survive OR 0.4 (95% CI: 0.2-0.9) (p=0.02). Patients in the high ferritin group, (cut off 2425) were less likely to survive than those with low ferritin OR 4.0 (95% CI:1.3-2.3) (p=0.016). The high HCT-CI group, (cut off 4) was more likely to relapse than lower HCT-CI OR 2.9, (95% CI: 1.1-8.1) (p=0.04) and patients with a high KPS, (cutoff 81), were less likely to relapse than lower KPS OR 0.3 (95% CI: 0.1-0.8) (p=0.22). In the high ferritin group, (cutoff 2020) patients were more likely to have GVHD than low ferritin group OR 0.2 (95% CI: 0.1-0.7) (p=0.005). (Table 2) We conclude that HCT-CI was more predictive of mortality than the PAM score in our cohort or patients with median age 65 years old. Our results are concordant with previously reported data showing serum ferritin and albumin is useful biomarkers to predict GVHD, relapse and survival. We are now incorporating objective markers such as ferritin, albumin, and other functional assessments to objectively quantify risk in our current patients presenting for allogeneic HSCT.Table 1Patient CharacteristicsAll Patients (N = 94)N (%)Patient Age< 5033 (35)50-5935 (37)60-7026 (28)RaceCaucasian76 (81)African American14 (15)Other4 (4)DonorRelated40 (43)Unrelated54 (57)HLA MismatchNo71 (76)Yes10 (11)Missing13Stem Cell SourceBM5 (5)PBSC89 (95)ConditioningMyeloablative47 (50)Reduced Intensity47 (50)ATGNo13 (14)Yes81 (86)Patient CMV Sero statusNegative41 (44)Positive48 (51)Missing5KPS< 9017 (18)90-10077 (82)BM indicates bone marrow; PBSC, peripheral blood stem cells; CMV, cytomegalovirus.Table 2Biomarkers and Clinical OutcomesBiomarkersGVHDRelapseSurvivalCut-offp-valueCut-offp-valueCut-offp-valuePAM240.1222240.4911210.2077HCT-CCI20330840.049540.0033Ferritin20200.005410700.381824250.0164KPS810.1679810.0226910.1289Albumin4.20.11034.20.27504.10.0220 DisclosuresNo relevant conflicts of interest to declare.

HCT-CI Has Prognostic Value in Acute, but Not Chronic Gvhd Specific Survival

Introduction: Graft-versus-host disease (GVHD) is a major cause of treatment failure in allogeneic hematopoietic cell transplantation (HCT). The hematopoietic cell transplant-specific comorbidity index (HCT-CI) predicts transplant-related mortality (Sorror, et al: Blood, 2005; Raimondi, et al: Blood, 2012), but its prognostic value has not been well explored in the setting of GVHD. It is hypothesized that patients with a high HCT-CI score would have worse outcomes after developing GVHD compared to those with a low HCT-CI score. In this retrospective study we calculated the pre-transplant HCT-CI and analysed its relationship with GVHD specific survival (GSS).Methods: A total of 541 patients who received allogeneic HCT at Princess Margaret Cancer Centre between 2000 and 2012 were included in this retrospective cohort study. The GSS was defined as the time from diagnosis of GVHD (for acute and chronic GVHD separately) until death from a GVHD-related cause, including organ dysfunction directly related to GVHD and infection in the setting of GVHD and immunosuppressive treatment. The GSS in relation to the HCT-CI was analysed using the Cox proportional hazard regression model. The GSS was plotted using the Kaplan-Meier method and the Log-rank test was used for comparison.Results: The incidence of all grades of acute GVHD and grade 2-4 acute GVHD was 68.7±2.1% and 54.9±2.3%, respectively. The incidence of chronic GVHD by the NIH consensus criteria was 72.9±2.8%. With a median follow-up duration of 24 months among survivors after a diagnosis of GVHD, the 2-year rates of acute GSS (aGSS) and chronic GSS (cGSS) were 60.7±2.9 and 74.6±2.7%, respectively.Univariate analysis demonstrated that the HCT-CI score as a continuous variable was prognostic for aGSS (p=0.001, HR 1.198, 95% CI [1.082-1.325]), showing that an increase in the HCT-CI score by 1 resulted in an increase in mortality by 20%. However, for cGSS, there was only borderline statistical significance with a p-value of 0.068 (HR 1.130 95% CI [0.991-1.289]).Patients were divided into 3 groups according to their HCT-CI score: 0-1(n=232, 42.9%), 2-4 (n=267, 49.4%) and ≥5 (n=42, 7.8%). The HCT-CI was able to stratify patients in relation to aGSS (p=0.001): The 2 year aGSS rate was 72.0±3.9% in those with an HCT-CI of 0-1 (n=148), 53.6±4.4% with an HCT-CI of 2-4 (n=173), and 35.6±11.5% with an HCT-CI of ≥5 (n=25). In contrast, no correlation was found with cGSS among the 3 groups (p=0.355). The 2 year cGSS rate was 79.5±3.6% in patients with an HCT-CI of 0-1 (n=141), 70.5±4.3% with an HCT-CI of 2-4 (n=149), and 63.2±14.0% with an HCT-CI of ≥5 (n=24).A multivariable analysis was performed to confirm the HCT-CI score as an independent prognostic factor for GSS, accounting for the following covariates: age, donor type, source of stem cells, and severity of acute GVHD (grade 3-4 vs others) and chronic GVHD (NIH global score mild, moderate and severe). The HCT-CI was found to be an independent risk factor for aGSS (p=0.016, HR 1.15, 95% CI [1.03-1.3]), but not for cGSS (p=0.80, HR 1.02, 95% CI [0.84-1.2]).Conclusion: Patients undergoing allogeneic HCT with significant comorbidities prior to transplant demonstrated by a higher HCT-CI have a shorter GSS. This finding is only significant for survival following acute GVHD (i.e. acute GSS), but not for chronic GVHD. This study suggests that the HCT-CI score may provide additional prognostic information in the assessment of the risk of acute GVHD related outcomes but not chronic GVHD outcomes, and that the assessment of HCT-CI score prior to HCT may be useful in risk adaptive preventive and treatment strategies for GVHD. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Double Umbilical Cord Blood Transplantation after Novel Myeloablative Conditioning Using a Regimen of Fludarabine, Busulfan, and Total Lymphoid Irradiation

We conducted a pilot study evaluating double umbilical cord blood transplantation (dCBT) after myeloablative conditioning with fludarabine and busulfan 3.2 mg/kg i.v. × 4, followed by total lymphoid irradiation at 400 cGy (FluBu4/TLI) for any indicated hematological disorder for patients without a suitable donor. Twenty patients with predominantly high-risk disease underwent dCBT according to protocol. The regimen was well tolerated, with mucositis as the primary observed toxicity (n = 19). The cumulative incidence of neutrophil engraftment was 89% (95% confidence interval [CI], 64% to 97%), with a median time to recovery of 16 days (range, 12 to 31 days). All evaluable patients with neutrophil engraftment achieved complete donor chimerism by day 40. The cumulative incidence of grades III and IV acute graft-versus-host disease (GVHD) at day 100 was 10% (95% CI, 2% to 27%), and the cumulative incidence of chronic GVHD was 35% (95% CI, 16% to 55%) by the end of the study. At 1 year, the cumulative incidence of treatment-related mortality (TRM) was 35% (95% CI, 16% to 55%). The leading cause of nonrelapse mortality was acute GVHD (n = 4), followed by graft failure (n = 2) and chronic GVHD (n = 1). TRM was significantly associated with a pretransplantation hematopoietic cell transplantation–specific comorbidity index score ≥ 3 (P = .005). At 1 year, disease relapse occurred in 6 patients and overall survival was 40% (95% CI, 19% to 60%). We conclude that FluBu4/TLI is an adequate preparative regiment before dCBT, providing high engraftment rates and relatively early neutrophil recovery. The best survival outcomes were seen in patients without significant comorbidities before transplantation, and outcomes are comparable to previously published dCBT studies.

Does the Hematopoietic Cell Transplantation Specific Comorbidity Index (HCT-CI) Predict Transplantation Outcomes? A Prospective Multicenter Validation Study of the Kanto Study Group for Cell Therapy

Recent advances in allogeneic hematopoietic stem cell transplantation have led to increasing use of this modality in older patients who tend to have been more heavily pretreated and have more comorbidities. Thus, the evaluation of comorbidity is of increasing importance to more precisely assess the benefits and risks of the transplantation procedure. Researchers from Seattle developed the hematopoietic cell transplantation–specific comorbidity index (HCT-CI), which was associated with the risk of mortality in several retrospective studies. However, its clinical utility has not been extensively documented in prospective studies. The aim of the present study was to evaluate the utility of the HCT-CI prospectively in a multicenter setting. Overall survival (OS) and nonrelapse mortality (NRM) at 2 years were 59% and 20%, respectively (n = 243). We found that the HCT-CI in its original scale failed to predict OS and NRM in this set of patients. Thus, we applied a flexible HCT-CI risk scoring system (restratifying scores from 0 to 3 to indicate low risk, and scores of 4 or higher as high-risk). The flexible HCT-CI was found to predict 2-year NRM and OS better than the original HCT-CI (NRM: P = .01, OS: P = .003). In subgroup analysis, we evaluated the usefulness of the original HCT-CI for patients excluding those who received cord blood transplantation (n = 186). Both 2-year OS and 2-year NRM were not significantly different according to the original HCT-CI (P = .304, P = .996), but with the flexible HCT-CI, there were significant differences in 2-year OS and 2-year NRM (P = .005 and P = .005, respectively). Multivariate analysis identified age >50, performance status (PS) <90, donor type (HLA-mismatched/unrelated donor), and the flexible HCT-CI ≥4 as significant predictors for worse OS at 2 years. However, the flexible HCT-CI did not remain a significant predictor for NRM at 2 years in multivariate analysis, whereas age, PS, and donor type did. The HCT-CI did not consistently predict both NRM and OS, but it still can be a useful tool in combination with other factors, such as PS and age. Furthermore, the HCT-CI, although potentially useful for capturing pretransplantation comorbidity and risk assessment, may need further validation before its adoption for routine clinical use.