International Bone Marrow Transplant Registry Research Articles

Age, Gvhd Prophylaxis, and Timing Matter in Thrombotic Microangiopathy after Hematopoietic Cell Therapy- a Secondary CIBMTR Analysis

Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) is associated with significant morbidity and mortality. Risk factors for developing TA-TMA and impact of TA-TMA on survival were published from a large Center for International Bone Marrow Transplantation Registry (CIBMTR) (Epperla et al, BJH. 2020). We used this published database to investigate whether there were different risk factors for developing TA-TMA in children and adults and identify prognostic factors, including timing of TA-TMA diagnosis. Methods: All first allogenic HCT recipients with malignant or non-malignant diseases between 2008-2016 were included in this retrospective secondary analysis of an existing CIBMTR dataset. Measures of association were generated using sub-distribution cox proportional hazard models, treating death as a competing risk. Significant risk factors for developing TA-TMA in univariable models were then tested in a multivariable model. SAS 9.4 (Cary, NC) was used for analysis, and statistical significance was set at 0.05. Results: The incidence of TA-TMA in children and adults was similar, 2.9% (n=138/4818) and 2.8% (n=514/18249) respectively. Significant adjusted risk factors for developing TA-TMA shared in both children and adults included an unrelated donor, and grade 2-4 acute graft versus host disease (aGVHD) (Table 1a). Female sex, black race, peripheral blood and umbilical cord versus bone marrow, and HLA mismatch were risk factors for developing TA-TMA in adults, but not children in a multivariable analysis (Table 1b). AGVHD prophylaxis withpost-transplant cyclophosphamide (PT-CY) compared to calcineurin inhibitor and mycophenolate mofetil (CNI + MMF) was associated with a decreased risk of developing TA-TMA in children, and an adjusted decreased risk in adults. Compared to black adults, black children had a significantly higher proportion of bone marrow as a stem cell source, non-malignant disease as HCT indication, PFS >90, and lower rates of grade 2-4 acute GVHD (p <0.0001). Among all patients with TA-TMA (n=652), features associated an adjusted increased risk of death included age >18 years old, onset of TA-TMA diagnosis ≤ 6 months post HCT, unrelated donor, peripheral blood stem cell source, grade 3-4 acute GVHD, and a performance score of <90 prior to HCT (Table 1c). The estimated 2-year survival in patients with an early HCT-TMA diagnosis (<6 months post HCT, n= 468) was 34.2 ± 8.8% versus 55.9 ± 15.6% in those with a later diagnosis (n= 171), p<0.0001, Figure 1a). The early HCT-TMA cohort had significantly more black patients, CNI + MTX, performance score <90 (P<0.05), though there were no significant differences in the severity of acute GVHD compared to late HCT-TMA. Children with HCT-TMA had a significantly higher estimated 2-year survival compared to adults (49.85 ±17.5 vs 36.73 ±8.8, p= 0.002, Figure 1b); after adjusting for significant differences in the cohorts, the HR of death remained lower in children than adults (0.73, p=0.045) Discussion: Our data add to the prior publication that showed the association of moderate and severe aGVHD and TA-TMA by demonstrating that the incidence of TA-TMA is similar between children and adults though outcomes are better in children and the time of onset post HCT impacted survival. Acute GVHD prophylaxis with PT-CY versus CNI+ MMF was associated with a decreased risk of developing TA-TMA in unadjusted and adjusted models in adults. As there were no differences in proportions of severe aGVHD in the prophylaxis cohorts, additional studies are needed to understand this association. Female sex was not a risk factor for TA-TMA in children, but was for adults, and may be related to the impact of hormones on vascular endothelium, though additional studies are needed. Black race was a risk factor for disease in adults and not children and may be due to lower rates of aGVHD in this adults or smaller numbers limiting power. Our data highlight that early onset TA-TMA was associated with significantly lower survival than TA-TMA diagnosed >6 months post HCT, and that pediatric recipients had higher 2-year OS compared to adults. While this study is limited by the lack of consistent screening among centers, the large sample size, diversity in age, race, HCT indication and transplant approaches, support that expedited and novel interventions for TA-TMA should be considered for children and adults with early onset TA-TMA.

Developing an Allogeneic Hematopoietic Progenitor Cell Transplant Service in a Resource-Limited Country: Challenges and Outcomes.

Introduction Allogeneic stem cell transplant has curative potential for many hematological disorders. Building an allogeneic hematopoietic progenitor cell transplant (HPCT) unit requires huge investment, infrastructure, equipment, medical supplies, and training of health care professionals. The key objective of this study is to share our experience of developing an allogeneic HPCT service at our tertiary care cancer hospital in a low-middle-income country. In addition, this study presents the outcomes of the first 30 allogeneic HPCTs done at our center. Methods This retrospective observational study included adult patients 18 years old or older with hematological malignancies who underwent allogeneic HPCT between July 2019 and April 2023 at Shaukat Khanum Memorial Cancer Hospital and Research Centre. Result Of the 30 patients, 24 underwent matched sibling donor (MSD) transplants in which a myeloablative-conditioning regimen (MAC) was used in 19, and a reduced conditioning regimen (RIC) was used in one. Of the six haploidentical-related donor transplants, four received MAC, and two received RIC. The median recipient age at HPCT was 23 and 21 years for MSD and Haplo-related donor transplants, respectively. The median follow-up duration was 12 months (Range: 10 days - 33 months). The overall survival rate at one yearwas 71.3% among all allogeneic stem cell transplant patients, whereas the disease-free survival rate at one yearwas 63.7%. In the acute lymphoblastic leukemia group, the disease-free survival rate at one year post allograft was 51.5%, while in the acute myeloid leukemia group, it was 78.7%. Conclusion This study demonstrates the successful development of an allogeneic bone marrow transplant unit at our hospital despite significant financial constraints. This has allowed us to provide a potentially curative and life-saving treatment to a substantial number of cancer patients. The bone marrow transplant outcomes of this study are comparable to those reported by international bone marrow transplant registries.

U-Statistics for left truncated and right censored data

The analysis of left truncated and right censored data is very common in survival and reliability analysis. In lifetime studies patients are often subject to left truncation in addition to right censoring. For example, in bone marrow transplant studies based on International Bone Marrow Transplant Registry (IBMTR), the patients who die while waiting for the transplants will not be reported to the IBMTR. In this paper, we develop novel U-statistics under left truncation and right censoring. We prove the n -consistency of the proposed U-statistics. We derive the asymptotic distribution of the U-statistics using the counting process technique. As an application of the U-statistics, we develop a simple non-parametric test for testing the independence between time to failure and cause of failure in competing risks when the observations are subject to left truncation and right censoring. The finite sample performance of the proposed test is evaluated through a Monte Carlo simulation study. Finally, we illustrate our test procedure using the lifetime data of transformers.

Utility of eGVHD App for bedside GVHD assessment in a high-volume BMT center.

Assessing acute and chronic graft-versus-host disease (GVHD) is challenging because there are several classification systems. The European Society for Blood and Marrow Transplantation and the Center for International Bone Marrow Transplantation Registry task force recommends using the eGVHD application (App) to score acute GVHD according to the Mount Sinai Acute GvHD International Consortium (MAGIC) criteria and chronic GVHD according to the National Institutes of Health 2014 criteria. We prospectively used the eGVHD App at each follow-up visit in a large-volume bone-marrow transplant center in India from 2017 to 2021. We retrospectively evaluated the discrepancy in scoring GVHD severity by physicians not using the App from the same patient charts. The App user satisfaction and experience were recorded using the technology acceptance model (TAM) and the Post-Study System Usability Questionnaire (PSSUQ). In 100 consecutive allogeneic hematopoietic cell transplantation recipients, there was more discrepancy in scoring the severity of chronic GVHD (38%) than acute GVHD (9%) without using the App. The median TAM and PSSUQ scores were six (IQR:1) and two (IQR:1), respectively, indicating high perceived usefulness and user satisfaction. The eGVHD App is an excellent learning tool for hematology/BMT fellows and helps manage GVHD in high-volume BMT centers.

Oxidative stress indicators during the course of acute graft versus host disease

Aim: This prospective study aimed to observe the changes in oxidative stress indicators, including total anti-oxidant status (TAS), total oxidant status (TOS), paraoxanase-1 (PON1), total thiol (TT), native thiol (NT), disulphide (DS) and nitric oxide (NO) levels from sequential blood samples obtained during a de-novo episode of acute graft versus host disease (aGvHD) and evaluate their association with disease severity and the risk of steroid resistant disease.
 Material and Method: Sequential patients who underwent an allogeneic stem cell transplantation (ASCT) in our unit and subsequently developed a de-novo episode of aGvHD between January 2022 and May 2022 were included in case they gave informed consent. All patients were started high dose (2 mg/kg/day) methylprednisolone as institutional standard first-line treatment of aGvHD as soon as the clinical diagnosis is evident. All episodes were confirmed simultaneously with gastrointestinal (GI) endoscopy and/or skin biopsies. TAS, TOS, PON1, TT, NT, DS and NO were studied from blood samples collected on days 0, +3 and +7 of steroid treatment. Demographic characteristics, diagnoses, donor type, GvHD prophylaxis, stage and grade of aGvHD, performance status (PS), the presence of cytomegalovirus (CMV) reactivation and response to steroid therapy were also noted.
 Results: A total of 15 cases was included. The median age was 49 (23-77). Males constituted 60.0% (n=9). The most frequent diagnosis and donor type were acute leukemia (53.3%, n=8) and matched related donor (46.7%, n=7), respectively. High grade aGvHD with Glucksberg grading and International Bone Marrow Transplant Registry severity index (IBMTR-SI) included 53,3% (n=8) and 86.7% (n=10) of cases, respectively. Non-responders (20.0%, n=3) significantly had advanced stage GI involvement, higher grade of aGvHD with Glucksberg grading and IBMTR-SI, and lower PS (p=0.005, p=0.04, p=0.006, and p=0.02, respectively). The changes in TAS, TOS, PON1, TT, NT, DS and NO levels on days 0, +3 and +7 of steroid treatment were not significant. Median PON1 levels on days 0, +3 and +7 of steroid treatment were significantly lower among non-responders (p

Chronic gvhd dictionary—eurograft cost action initiative consensus report

Chronic graft versus host disease (cGVHD) affects patients after allogeneic hematopoietic stem cell transplantation (alloHSCT). This orphan disease poses a challenge for clinicians and researchers. The purpose of the cGVHD Dictionary is to provide a standardized structure for cGVHD databases on an international level, reconciling differences in data retrieval and facilitate database merging. It is derived from several consensus meetings of the EUROGRAFT consortium (European Cooperation in Science and Technology—COST Action CA17138) followed by a consensus process involving European Society for Blood and Marrow Transplantation (EBMT), US GvHD consortium and Center for International Bone Marrow Transplant Registry (CIBMTR). Databases used for the dictionary were: the National Institutes of Health (NIH) database, the Center for International Blood and Marrow Transplant Research, Applying Biomarkers to Minimize Long Term Effects of Childhood/Adolescent Cancer Treatment - Pediatric Blood and Marrow Transplant Consortium database, EBMT registry, the German-Austrian-Swiss GvHD registry, Italian Blood and Marrow Transplantation Society registry and Regensburg-Göttingen-Newcastle HSCT dataset. A four-part cGVHD Dictionary was formed based on the databases, consensus, and evidence in the literature. The Dictionary is divided into: (1) Patient characteristics, (2) Transplant characteristics, (3) cGVHD characteristics and (4) patient-reported quality of life, symptom burden and functional indicators.

Effect of short-term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukemia: an analysis from the International Bone Marrow Transplant Registry

Allogeneic bone marrow transplantation (BMT) is the only curative therapy for chronic myelogenous leukemia (CML), though several studies indicate that prolonged survival can result from interferon-alpha (IFN-alpha) treatment. IFN-alpha is now often used as initial therapy for CML, before donor availability is known. Because identifying potential donors can take several weeks to months, it is important to know whether IFN-alpha adversely affects outcome of a subsequent BMT. If it does, initiation of IFN-alpha therapy might be delayed until donor availability is determined and avoided in patients for whom BMT is planned. We studied 873 patients who received HLA-identical sibling BMT for chronic-phase CML in 153 centers participating in the International Bone Marrow Transplant Registry. The object was to compare outcome in the 664 who received only hydroxyurea before BMT with outcome in the 209 who received IFN-alpha with or without hydroxyurea. The median duration of IFN-alpha therapy was 2 months (range, 1 to 39 months). Cox proportional hazards analysis was used to compare engraftment, graft-versus-host disease (GVHD), nonrelapse mortality, relapse, survival, and leukemia-free survival after adjustment for other prognostic variables. We found a higher risk of nonengraftment among patients given IFN-alpha than among those given hydroxyurea alone (2% versus 0.2%; P = 0.01). Patients who received IFN-alpha had a lower risk of relapse (relative risk, 0.17; 95% confidence interval, 0.04-0.70). Probabilities of GVHD, nonrelapse mortality, survival, and leukemia-free survival were similar in the two treatment groups. These results suggest that a short course of IFN-alpha does not adversely affect survival after a subsequent HLA-identical sibling BMT for chronic-phase CML. (Blood. 2000;95:410-415)

Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia

AbstractAllogeneic hematopoietic stem cell transplantation is the only curative therapy for myelodysplasia (MDS). To identify factors influencing transplantation outcome, we studied 452 recipients of HLA-identical sibling transplants for MDS from 1989 to 1997, reported to the International Bone Marrow Transplant Registry. Patients with treatment-related MDS or unclassified MDS were excluded. Median age was 38 years (range, 2-64 years). Sixty percent had refractory anemia with excess blasts (n = 136) or with excess blasts in transformation (n = 136). Conditioning regimens included total body irradiation in 199 (44%) cases. Marrow was T-cell depleted for 58 (13%) transplants. Cumulative incidences of neutrophil engraftment, grades II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were 91% (95% confidence interval [CI], 88%-93%), 36% (95% CI, 31%-40%), and 39% (95% CI, 33%-44%), respectively. Three-year transplantation-related mortality (TRM), relapse, disease-free survival, and overall survival rates were 37% (95% CI, 32%-42%), 23% (95% CI, 19%-27%), 40% (95% CI, 36%-45%), and 42% (95% CI, 37%-47%), respectively. Multivariate analyses showed that young age and platelet counts higher than 100 × 109/L at transplantation were associated with lower TRM and higher disease-free and overall survival rates. Relapse incidence was higher in patients with high percentages of blasts in the marrow at transplantation or presentation, with high International Prognostic Scoring System scores at diagnosis, and with T-cell–depleted transplants. These findings indicate that transplantation from an HLA-identical sibling offers the possibility of long-term, disease-free survival to patients with MDS. Best candidates are younger patients with a low percentage of blasts and preserved platelet counts.

Survival With Bone Marrow Transplantation Versus Hydroxyurea or Interferon for Chronic Myelogenous Leukemia

AbstractHydroxyurea, interferon, and HLA-identical sibling bone marrow transplantation are common therapies for chronic myelogenous leukemia (CML) in chronic phase. Which is best is controversial. The purpose of this study was to compare survival of patients with CML receiving HLA-identical sibling transplants versus hydroxyurea or interferon. The transplant cohort included 548 recipients of HLA-identical sibling transplants, reported to the International Bone Marrow Transplant Registry. The nontransplant cohort included 196 patients receiving hydroxyurea (n = 121) or interferon (n = 75) on a randomized trial of the German CML Study Group. Survivals were compared using proportional hazards regression with fixed and time-dependent variables to adjust for patient differences and changing risks over time. For the first 18 months after diagnosis, mortality was higher in the transplant than the nontransplant cohort (relative risk [RR], 5.85; P < .0001). From 18 to 56 months, mortality was similar (RR, 0.80; P = .38). After 56 months, mortality was lower in the transplant cohort (RR, 0.16; P < .0001). Seven-year survival probabilities (95% confidence interval) were 58% (50% to 66%) with transplant and 32% (22% to 41%) with hydroxyurea or interferon. There was a significant survival advantage for hydroxyurea or interferon in the first 4 years after diagnosis and for transplants starting 5.5 years after diagnosis. For transplants done within 1 year of diagnosis, the survival advantage for transplantation began earlier. Survival advantage for transplants was greater and occurred earlier in patients with intermediate- and high-risk prognostic features than in those with low-risk features. This study confirms higher early mortality, but a long-term survival advantage for HLA-identical sibling transplants over hydroxyurea or interferon in CML.

Effect of nucleated marrow cell dose on relapse and survival in identical twin bone marrow transplants for leukemia

AbstractThe impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transplantation outcome is controversial and may differ for allogeneic and identical twin (syngeneic) bone marrow transplants. We studied the association between cell dose and outcome in 100 unmanipulated identical twin bone marrow transplantations for leukemia, reported to the International Bone Marrow Transplant Registry between 1985 and 1994, using Cox proportional hazards regression for multivariate analyses. Cell doses ranged from 0.3 to 7.4 × 108 nucleated cells/kg (median, 3.0 × 108cells/kg). Median follow-up was 75 months. Five-year cumulative incidences of transplant-related mortality with high (more than 3 × 108 cells/kg) versus low (less than or equal to 3 × 108 cells/kg) cell doses were 2% (95% confidence interval [CI], 0% to 8%) versus 10% (95% CI, 4% to 20%), respectively. Five-year probabilities of leukemia-free survival were 53% (95% CI, 39% to 67%) and 37% (95% CI, 23% to 52%), respectively. In multivariate analysis, among patients surviving in remission at least 9 months after transplantation, those receiving high cell doses were at significantly lower risk for treatment failure (relapse or death) than those receiving low cell doses (RR, 0.27; 95% CI, 0.12 to 0.6;P = .001). Lower treatment failure resulted from fewer relapses in the high cell dose group (RR for relapse, 0.28; 95% CI, 1.2 to 0.66; P = .003). These findings suggest that outcomes after syngeneic bone marrow transplantation could be improved by transplanting more than 3 × 108 nucleated cells per kilogram. The benefit of high cell dose on relapse may represent a delayed graft-versus-leukemia effect.

Allogeneic Bone Marrow Transplantation for Low-Grade Lymphoma

Advanced low-grade lymphomas are usually incurable with conventional-dose chemotherapy. It is uncertain whether cures are possible with high-dose therapy and bone marrow transplant from a human leukocyte antigen (HLA)-identical sibling. We sought to determine the outcome of HLA-identical sibling bone marrow transplants in advanced low-grade lymphoma in an observational study of 113 patients conducted at 50 centers participating in the International Bone Marrow Transplant Registry (IBMTR). The median patient age was 38 years (range, 15 to 61). Eighty percent had stage IV disease at the time of transplantation. The median number of prior chemotherapy regimens was two (range, 0 to 5). Thirty-eight percent had refractory disease and 29% a Karnofsky performance score (KPS) less than 80%. All patients underwent allogeneic bone marrow transplantation from a HLA-identical sibling donor. The conditioning regimen included total-body irradiation (TBI) in 82% of patients; cyclosporine was used for graft-versus-host disease prophylaxis in 74%. Survival, disease-free survival, recurrence rate, treatment-related mortality, and causes of death were determined. Three-year probabilities of recurrence, survival, and disease-free survival were 16% (95% confidence interval [CI], 9% to 27%), 49% (95% CI, 39% to 60%), and 49% (95% CI, 39% to 59%), respectively. Higher survival was associated with pretransplant KPS ≥90%, chemotherapy-sensitive disease, use of a TBI-containing conditioning regimen, and age less than 40 years. We conclude that high-dose therapy followed by transplantation from a HLA-identical sibling leads to prolonged survival in some patients with advanced low-grade lymphoma. Most mortality is treatment-related, and recurrences are rare.© 1998 by The American Society of Hematology.

Efficacy of Methoxsalen Sterile Solution in Conjunction with the Therakos® Cellex® Photopheresis System in Pediatric Patients with Steroid-Refractory Acute GvHD: Interim Analysis

Background: Steroid-refractory acute graft-versus-host disease (SR-aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant in pediatric patients. Second-line therapies cause further immunosuppression, leaving patients vulnerable to life-threatening infections. Extracorporeal photopheresis (ECP) with methoxsalen (Uvadex®) sterile solution, in which apheresed leukocytes are photosensitized, exposed to ultraviolet A radiation ex vivo, and reinfused, is used to treat aGvHD because it has a low risk of infection, unlike systemic immunosuppressants. Safe use of ECP in children is not yet established. Aims: To report interim 4-week data from a 12-week phase 3 study evaluating the efficacy and safety of ECP using the photosensitizing agent methoxsalen with the Therakos® Cellex® Photopheresis System (Cellex; Mallinckrodt Pharmaceuticals, Bedminster, NJ) in pediatric/young adult patients with SR-aGvHD (NCT02524847). Methods: In this single-arm, open-label study, patients (aged 1-21 years; SR-aGvHD International Bone Marrow Transplant Registry [IBMTR] grade B-D) received ECP 3 times/wk for 4 weeks, followed by 2 times/wk for 8 weeks. Steroids were tapered according to physician discretion if SR-aGvHD responded to ECP. The primary endpoint was proportion of patients with an overall response (OR), defined using the Modified IBMTR Severity Index as complete response (CR; complete resolution of aGvHD in all evaluable organs, without next-line systemic treatment) or partial response (PR; improvement of 1 stage in ≥1 aGvHD target organ without progression in others or addition of next-line systemic treatment), after 4 weeks. The primary endpoint was considered significant if P&lt;0.005 for CR+PR vs the null hypothesis (10% response rate), which corresponded to CR+PR &gt;48%. Secondary outcome measures included safety, duration of response, steroid-sparing effect, and organ-specific response. Results: Of 25 patients enrolled, 25 were evaluable for safety (patients who received ≥1 ECP treatment) and 23 were evaluable for efficacy. Patients' mean age was 9.2 years, 44% were female, mean body mass index was 18.3 kg/m2, and the majority (n=18) had Grade 3 aGvHD. Twelve patients (48%) completed all study visits; 5 withdrew early (2 deaths, 1 CR; 3 withdrew due to inadequate efficacy, 2 of whom started second-line therapy, and 3 no longer required treatment) A median of 27 ECP treatments were administered (range 3-28). OR was 61% (14/23 evaluable patients); there were 3 CRs (13%) and 11 PRs (48%; P&lt;0.00001 vs null hypothesis; 95% CI: 36.6, 77.9). OR based on initial organ involvement and overall severity is in the Table. Of the 14 patients who responded by 4 weeks, 9 (64%) and 8 (57%) maintained response at 8 and 12 weeks, respectively. Time to disease progression was a median of 89 days (95% CI: 44.0, 104.0) after enrollment. Median duration of first response was 22.0 days (95% CI: 8.0, 49.0). Among 22 patients evaluable for steroid dose, 9 (41%) had ≥50% reduction in dose by week 4. 103 AEs (11 serious), including 2 deaths (cerebral aspergillosis; disease progression leading to respiratory failure), occurred in 19 patients. Of these, 99 (96.1%), including 2 on-study deaths, were considered unrelated to study treatment, and 4 (nausea, hypocalcemia, hypertension, anemia) possibly related. Conclusions: After 4 weeks of ECP using methoxsalen sterile solution and the Therakos Cellex Photopheresis System, the OR rate was 61%. These encouraging data warrant further investigation in pediatric/young adult patients with SR-aGvHD. Disclosures Kitko: Mallinckrodt: Honoraria; Novartis: Consultancy, Honoraria. Boodée:Mallinckrodt Pharmaceuticals: Employment. OffLabel Disclosure: UVADEXÃ'® (methoxsalen) Sterile Solution is indicated for extracorporeal administration with the THERAKOSÃ'® UVAR XTSÃ'® or THERAKOSÃ'® CELLEXÃ'® Photopheresis System in the palliative treatment of the skin manifestations of Cutaneous T-Cell Lymphoma (CTCL) that is unresponsive to other forms of treatment. Extracorporeal photopheresis (ECP) with methoxsalen (UvadexÃ'®) sterile solution is used to treat acute graft-versus-host disease (aGvHD), but there are few clinical trials in pediatric patients. This abstract reports on the interim results of a phase 3 clinical trial of ECP with methoxsalen used with the TherakosÃ'® CellexÃ'® Photopheresis System in pediatric/young adult patients with steroid refractory aGvHD.

Disease Progression, Hospital Readmissions, and Clinical Outcomes of Patients with Steroid-Refractory Acute Graft-Versus-Host Disease: A Multicenter Chart Review

Background: Acute graft-versus-host disease (aGVHD) post allogeneic hematopoietic stem cell transplantation (HCT) has a significant impact on morbidity and mortality. The standard first-line therapy for grade II-IV aGVHD is systemic corticosteroids (CS), which provide effective control in 40%-60% of patients. Patients may be unable to taper steroids due to new organ involvement or aGVHD flares. The objective of this retrospective multicenter study was to describe the clinical course, outcomes, and hospital readmissions for patients with aGVHD who were refractory to or dependent on systemic CS. Methods: A multicenter retrospective chart review was conducted at 11 large US academic and community transplant centers to identify patients who had their first HCT between Jan 1, 2014, and June 30, 2016, and subsequently developed grade II-IV aGVHD (defined by International Bone Marrow Transplant Registry Severity Index). Patients who participated in a GVHD prophylaxis trial or used Janus kinase inhibitors were excluded. Steroid dependence (SD)/steroid refractory (SR) was defined as the use of additional systemic anti-GVHD therapy, inability to taper high-dose steroids (≥1 mg/kg) by ≥25%, or tapering of CS dose by ≥25% but not &lt;10 mg/day. Clinical outcomes included changes in aGVHD grade or organs involved, aGVHD reoccurrence, and all-cause mortality. Results: Patient (N=168) mean age was 55 years, and 64% were male. The stem cell source was peripheral blood for 74% of patients. Median time from transplant to aGVHD diagnosis was 30 days (interquartile range [IQR]: 21-49). At the time of aGVHD diagnosis, most patients had grade I or II (65%; Figure 1) disease: 39% had skin involvement only; 38% had lower gastrointestinal (GI) involvement; and 37% had ≥2 organs involved (Figure 2). At the time of maximum aGVHD grade, most patients (66%) had grade III-IV disease: 25% had skin involvement only; 54% of patients had lower GI involvement; and 54% had ≥2 organs involved. Between the time of diagnosis and maximum aGVHD grade, 54% of patients had new organ involvement or an increase in aGVHD grade. Median time from diagnosis to maximum grade was 6.0 days. Of the 146 patients with grade II-IV aGVHD at diagnosis, 82% (119/146) were given systemic CS as first-line therapy, and 49% (72/146) initiated systemic CS on the day of diagnosis. Among the 119 patients, the average starting daily dose was 77 mg (0.9 mg/kg) for prednisone and 166 mg (1.8 mg/kg) for methylprednisolone. During follow-up (median 194 days from aGVHD diagnosis to death/last visit, IQR: 58-720), 36% of patients had an increase in steroid dose, and 88% were unable to taper below 10 mg/day. aGVHD recurred in 42% of patients (70/168) and was managed by increasing the CS dose in 79% of these patients. Over half of patients (53%; 89/168) received additional systemic anti-GVHD therapy; of those, 41% had an increase in CS dose before receiving additional therapy. Median time from CS initiation to additional therapy was 21 days. Frequently used additional therapies included sirolimus (19%), polyclonal antibodies (antithymocyte globulin/antilymphocyte globulin; 18%), mycophenolate mofetil (17%), tocilizumab (16%), extracorporeal photopheresis, and etanercept (both 13%). 26% (23/89) used ≥2 additional therapies. Overall, 57% of patients (95/168) required hospital readmission(s); 24% had ≥2 readmissions within 100 days post-HCT, with a mean inpatient length of stay of 50 days. Half (51%) of patients experienced an infection within the first 100 days post-HCT. Relapse of the underlying malignancy was reported in 35 patients (21%). Overall, 70% of patients (118/168) died at a median of 118 days (IQR: 62.0-234.1) from aGVHD diagnosis; 82% of patients with aGVHD progression died at a median of 116.0 days (IQR: 49-223), and 80% of patients with maximum grade III-IV aGVHD died at a median of 80 days (IQR: 42-216). Additionally, 86% of patients with lower GI aGVHD died at a median of 74.0 days (IQR: 44-174) (Figure 3). Conclusions: The majority of patients with aGVHD had severe and rapidly progressing disease. These findings indicate that clinical outcomes were poor among patients with SR and SD, with a mortality rate of 70% within 4 months of aGVHD diagnosis. Most patients required hospital readmission with an extended length of stay. The rapidly worsening clinical course further emphasizes the need for effective and tolerable therapies that prevent or reverse disease progression. Disclosures Yu: Incyte: Employment, Equity Ownership. Hanna:Asclepius Analytics: Employment. Paranagama:Incyte: Employment, Equity Ownership. Tang:Asclepius Analytics: Employment. Naim:Incyte: Employment, Equity Ownership. Galvin:Incyte: Consultancy.

Impact of Graft Composition on Graft-Versus-Host Disease in Peripheral Blood HLA-Identical Sibling Transplants: Protective Role of CD8 Cell Dose

Introduction and Objective:Acute graft-versus-host disease (aGVHD) is a leading cause of transplant related mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Data on the impact of graft composition, namely CD34 and T-cell subsets, and aGVHD is conflicting. We hypothesized an upper cell dose limit of CD34 would exist predictive of aGVHD without affecting engraftment and sought to explore T-cell subsets and their impact on aGVHD outcomes amongst peripheral blood progenitor cell (PBPC) HLA-identical sibling transplants (Allo-Sib).Methods:In an IRB approved protocol, consecutive Allo-Sib patients underwent HSCT for hematologic malignancy at our center from 1/2004 to 12/2012. Demographic and clinical data were prospectively collected and retrospectively confirmed. Patients received the entire D1 CD34 PBPC collection from their donors and from a second day of collection if necessary to achieve a dose of 4 x 106 CD34/kg cells. aGVHD prophylaxis was uniformly tacrolimus and mini-methotrexate. Tacrolimus was monitored to achieve a trough of 10-15 ng/ml. aGVHD was graded as per the International Bone Marrow Transplant Registry System. Exact binary logistic regression models were used to estimate the odds of aGVHD as a function of patient demographic and clinical data. For the association between cell counts and aGVHD, binary cut scores were determined by finding the point along the receiver operating characteristic curve that maximized sensitivity and specificity. Non-parametric Spearman correlation coefficients were used to estimate the association between CD34, CD3, CD4, and CD8 cell counts.Results:We analyzed 160 consecutive patients. In this mostly male (63%) population, median age was 51 and most patients underwent a myeloablative transplant (93%). Disease risk as per Armand et al 2012 was low 45%, intermediate 13.2%, and high 41.7%. Co-Morbidity Index by Sorror et al (HCT-CI) was 30.5% for 0, 33.8% for 1-2, and 35.8% for > 2. Sixteen patients (10%) developed grade II-IV aGVHD while 9 (6%) developed grade III-IV aGVHD. Median CD34 cell dose infused was 6.27 X 106/kg. Median CD3, CD4, and CD8 cell doses infused were 2.51 X 108/kg, 1.80 X 108/kg, and 0.66 X 108/kg, respectively. In univariate analysis, patients (n=67) receiving > 9.94 x 106 CD34/kg were 12 times more likely to develop grade III-IV aGVHD (odds ratio =12.308; p=0.01)(figure 1). Conversely, patients receiving > 0.50 x 108 CD8/kg were less likely to develop grade II-IV aGVHD (odds ratio = 0.30; p=0.049)(Figure 2), but not Grade III-IV aGVHD. The only other factor associated with aGVHD was a diagnosis of AML, which was protective (p=0.01). CD3 and CD4 cell counts did not correlate with aGVHD in our patient cohort. There was no correlation between engraftment and CD34, CD3, CD4, or CD8 cell dose. Finally, we found no direct correlation between CD34 cells counts and CD3, CD4, or CD8 cell counts.Conclusion:This study represents the largest evaluation examining the correlation between both infused CD34 cells and T-cell composition with aGVHD among patients undergoing strictly matched related donor HSCT. Importantly, the data demonstrates patients receiving > 10 x 106 CD34/kg have increased risk of developing clinically significant aGVHD, a dose that far exceeds adequate engraftment doses and serves now as a cap on CD34 cell dose in our program. Interestingly, our data suggests infusion of > 0.50 x 108 CD8/kg may protect from severe aGVHD whereas prior reports have demonstrated no association between CD8 cells and aGVHD. Further investigation is needed to better characterize the relationship between CD8 cells and aGVHD and better define the correlation between CD8 and CD34 cell doses in the development of aGVHD. DisclosuresNo relevant conflicts of interest to declare.

The role of stem cell transplant for lymphoma in 2017.

The role of stem cell transplant for lymphoma in 2017.

Checkpoint Blockade for Treatment of Relapsed Lymphoma Following Allogeneic Hematopoietic Cell Transplant: Use May be Complicated By Onset of Severe Acute Graft Versus Host Disease

▪Introduction: Allogeneic Hematopoietic-cell transplantation (allo-HCT) may elicit immunological graft versus-tumor effects against tumor cells. However, these immune responses can be misdirected towards normal host organs, resulting in graft-versus host disease (GVHD). Acute GVHD (aGVHD) develops after activation and maturation of antigen-presenting cells, which then leads to donor T-cell activation, expansion, and destruction of host tissue by effector cells. The programmed death (PD) pathway serves as a checkpoint to limit T-cell-mediated immune responses. Blocking the PD1 receptor results in T-cell activation, proliferation, and can induce a potent immunotherapeutic antitumor effect. In the post-allogeneic HCT setting there is concern that activating T-cells via PD1 blockade may induce GVHD (Blazar, J Immunol 2003). While there have been several cases of severe and even fatal transplant-related complications, including GVHD, when nivolumab was given for disease control prior to allo-HCT, less is known about its use in managing relapse after HCT. A few case reports suggest it may be safe (Herbeaux, ASH 2015; Angenendt, BMT 2015; Yared, BMT 2016).Methods:With IRB approval, we conducted a multicenter, retrospective analysis of lymphoma patients (pts) who received monoclonal antibodies against PD1 after allo-HCT. We contacted 10 U.S. transplant programs with the highest volumes of lymphoma pts undergoing HCT, as provided by the Center for International Bone Marrow Transplant Registry (CIBMTR), to derive an estimate of the safety and toxicity of PD1 blockade post allograft. Additional sites were surveyed based on recommendation from these initial 10 sites. Descriptive statistics were used to summarize patient characteristics and clinical outcomes. Response assessments were defined according to revised Lugano criteria (Cheson, 2014). GVHD stage/grade was recorded according to Consensus scoring severity index. PD1 and PDL1 immunohistochemical (IHC) stains were performed on 2 pts' liver biopsies treated at University of Colorado (CU).Results:We surveyed 23 sites with 21 replies to date. 8 sites reported no experience using anti-PD1 after allo-HCT. 13 sites identified 27 lymphoma pts (26 classical Hodgkin lymphoma) who received a monoclonal antibody against PD1 for relapsed disease after allo-HCT (24 nivolumab, 3 pembrolizumab). Table 1 highlights patient characteristics prior to treatment with anti-PD1. At a median follow up of 217 days (range 26-560) after the first dose of PD1 blockade, 22 of 27 (81%) remain alive. 3 pts died from GVHD and 2 died from lymphoma progression complicated by GVHD. Overall response rate (ORR) to anti-PD1 was 79% (CR+PR) in 24 assessable pts (13 CR, 6 PR, 2 SD, 3 PD). 10 of 27 pts (37%) developed aGVHD and in 19% it was severe (5 grade IV, 3 grade II, & 2 grade I) after PD1 blockade. 9 of 10 experienced liver aGVHD (4 stage IV, 1 stage III, 4 stage I). 3 of 4 cases with stage IV liver aGVHD were biopsy proven and distinct from typical hepatopathy associated with PD1 blockade. In the 2 cases with PD1 IHC stains, PD1+ lymphocytes were more frequently involved in the endotheliitis rather than the cholangitis component of GVHD. 8 of 10 experienced skin aGVHD (1 stage IV, 5 stage III, 1 stage II, & 1 stage I). Only 2 experienced gut aGVHD (1 stage IV, 1 stage III). The 10 who developed aGVHD received a total of 1-3 doses (median 1) of anti-PD1. Median day of aGVHD onset from first dose of anti-PD1 was 15 (range 8-28). Of the 10 pts who developed aGVHD, 4 of 10 (40%) responded to treatment (2 CR, 2 PR). Only 1 patient responded to steroids alone. An additional 4 pts who did not experience aGVHD had new or worsening classic chronic GVHD (cGVHD) after anti-PD1. Overall 52% (14/27) of the pts in this analysis developed new or worsening acute or chronic GVHD after PD1 blockade (10 aGVHD, 4 cGVHD).Discussion/Conclusion: PD1 blockade was associated with a high ORR (79%) in heavily pretreated Hodgkin lymphoma patients relapsing following allo-HCT, suggesting a strong graft versus tumor effect. However, some patients developed severe and treatment refractory GVHD in this setting. Prospective study of PD1 blockade after allo-HCT is warranted. Potential risks and benefits of PD1 blockade after allo-HCT should be discussed with each patient, and they should be carefully monitored for aGVHD after PD1 blockade. [Display omitted] DisclosuresKamdar:Seattle Genetics: Speakers Bureau. Saad:Astellas: Research Funding; American Porphyria foundation: Research Funding; Alexion: Honoraria; Spectrum: Honoraria. Ganguly:Janssen: Research Funding; Onyx: Speakers Bureau; Seattle Genetics: Speakers Bureau. Hari:Merck: Research Funding; BMS: Honoraria. Hamadani:Celgene: Honoraria, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Merck: Research Funding. Jagasia:Therakos: Consultancy. Armand:Sequenta Inc: Research Funding; Merck: Consultancy, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Infinity Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

Early Post-Transplantation Tacrolimus Levels Correlate with Acute Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation from Related and Unrelated Donors

Introduction: Acute graft-versus-host disease (aGVHD) is a leading cause of transplant related mortality following allogeneic hematopoietic stem cell transplantation (HCT). The most widely used aGVHD prophylaxis regimen is a combination of a calcineurin inhibitor and a short course of methotrexate. Results of studies on the optimal blood levels of the calcineurin inhibitor tacrolimus to prevent aGVHD are mixed, with some showing no correlation and others indicating that trough levels between 7-15 ng/mL required to adequately prevent aGVHD. Currently, the established target trough level for this agent is 10 to 20 ng/mL. We retrospectively evaluated the relationship between tacrolimus blood concentration and the incidence of grade II-IV aGVHD in a large cohort of adult patients following allogeneic HCT from either an HLA-matched related or matched unrelated donors.Methods: We evaluated all related/unrelated allografts between January 2004 and December 2012 at the Cardinal Bernardin Cancer Center at Loyola University. Inclusion criteria included age 18 years or older, first allogeneic HCT for a hematological malignancy, and use of tacrolimus and short term methotrexate for aGVHD prophylaxis. Donors included human leukocyte antigen (HLA) identical sibling (Allo-Sib) or unrelated donors (MUD) either fully matched or 1 antigen mismatched (10%). Both myeloablative and non-myeloablative conditioning regimens were included. Disease risk was defined by the ASBMT classification and Co-Morbidity Index by Sorror et al (HCT-CI). Infusional tacrolimus was initiated on day -2 of HCT at dose of 0.03 mg/kg/d and AM trough blood concentrations measured every other day during the entire hospital stay with the goal of maintaining a level of 10-15 ng/ml and then twice weekly after discharge. Dose adjustments or withholds were based primary on serum creatinine and trough levels per a set protocol that withholds for levels greater than 20 ng/ml or creatinine greater than 2.0 mg/dl. Acute GVHD was graded based on the International Bone Marrow Transplant Registry System. Univariate and multivariate analyses exploring all risk factors for aGVHD were performed.Results: A total of 428 patients met the inclusion criteria. Median age was 48.5 years with a male predominance (60.6%). HCT-CI was evenly distributed with 121 (28.2%) low risk, 151 (35.3%) intermediate risk, and 156 (36.4%) high risk. Per ASBMT disease risk classification, more patients had high disease risk (n=211, 49.3%); 64 (15%) with intermediate risk, and 153 (35.7%) with low risk. Acute GVHD II-IV developed in 186 (43%) patients in this largely myeloablative patient population (89%), with donor source split nearly evenly between MUD (45%) and Allo-sib (55%). An extensive univariate analysis for the factors associated with the development of aGVHD was developed (Table 1). The strongest predictor of aGVHD was a level of tacrolimus < 5 ng/ml in weeks 3 and 4 after transplant: of those with no aGVHD only 16.9% had a level < 5 ng/ml during these weeks vs 27.4% with aGVHD (p = .009). Other tacrolimus trough cut points, i.e. 10 ng/ml, 2.5 ng/ml and the mean (13.4 ng/ml in each group) were not associated with a higher rate of aGVHD. In the univariate analysis, AML and allo-sib grafts were noted to be associated with lower risk of aGVHD. In multivariate analysis (Table 2), tacrolimus levels less than 5 ng/ml in weeks 3 or 4 was found to be the most statistically significant factor in predicting aGVHD incidence (Odds ratio 82 95% CI 1.13-2.94; p = .01); other significant factors include HCT-CI (p = .02) and graft source (p = .04).Conclusion: In one of the largest retrospective studies examining the correlation of early tacrolimus blood concentrations and acute GHVD incidence, we show that trough tacrolimus levels less than 5 ng/ml in weeks 3-4 following Allo-Sib or MUD HCT is a strong predictor for an increased risk of aGVHD. We affirm that higher HCT-CI and donor source are risk factors for aGVHD after allografts. This not only helps define more accurately the lower limits of acceptable tacrolimus levels, but appears to emphasize the importance for close monitoring and dose adjustment of these levels at a time when patients are typically discharged to the outpatient setting. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Unrelated Male Donors Versus Sibling Parous Female Donors: Impact on Transplant-Related Outcomes

▪Introduction:Optimal donor selection is critical to reduce morbidity and mortality from allogeneic hematopoietic cell transplant (HCT). HLA identical female parous sibling donors (pSIB) confer an increased risk of chronic graft vs. host disease (cGVHD) compared to male sibling donors, possibly from alloimmunization and exposure to fetal antigens during pregnancy. Unrelated donors (URD) also confer higher GVHD risk than sibling donors. While both pSIB and URD donors confer increased GVHD risk, they have never been directly compared. This study compares incidence of acute GVHD (aGVHD), cGVHD, survival, and treatment- related mortality in patients who received transplants from pSIB donors to male unrelated donors (mURD).Methods:A retrospective cohort study was completed using the Center for International Bone Marrow Transplant Registry (CIBMTR). We identified patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) who underwent a non-T cell depleted HCT from an HLA identical pSIB or a matched mURD between 2000-2012. Recipients were at least 25 years at time of transplant to ensure female sibling donors had biological opportunity to become parous. Primary outcome was Grade II-IV aGVHD, cGVHD, and overall survival (OS). Secondary outcomes were relative risk (RR) of leukemia free survival (LFS), transplant related mortality (TRM) and relapse.Results:We identified 892 pSIB donors and 1921 mURD donors. Median recipient age at transplant was 49 (pSIB) and 50 (mURD), p=0.14. Median donor age was higher in pSIB than mURD (48 vs. 32, p<0.001). Cumulative incidence of aGVHD was higher in mURD than pSIB at 100 days, 46% vs. 35%, p<0.001. Incidence of cGVHD at 100 days was also higher in mURD (9% vs. 4%, p<0.001), but was not different at 1 year (mURD 50%, pSIB 50%, p=0.99) or 2 years (mURD 56%, pSIB 56%, p=0.77). In multivariate analysis adjusting for other risks of GVHD (prophylaxis, graft source, gender, and transplant year), mURD had a 1.6 times higher risk of grade II-IV aGVHD (p<0.0001) and 1.23 times higher risk of cGVHD (p=0.0003) than pSIB donors (Table 1).A greater proportion of pSIB recipients were alive at 100 days (88% vs. 82%, p<.001), 1 year (62% vs. 57%, p=0.02), and 2 years (51% vs. 47%, p=0.02). However, in multivariate analysis donor type did not significantly affect OS (RR mURD 1.10, p=0.072), LFS (RR mURD 1.04, p=0.47), TRM (RR mURD 1.04, p=0.59), or relapse (RR mURD 1.03, p=0.62). Variables associated with OS included increasing recipient age (p<0.0001), Karnofsky performance status <90% (RR 1.37, p<0.0001), disease status at HCT (p<0.0001), and year of HCT (p<0.0001) (Table 2).Conclusion:Male URD confer a higher risk of grade II-IV acute and chronic GVHD compared to HLA-identical female parous sibling donors. Donor type does not significantly affect OS, LFS, TRM, or disease relapse. When available, female pSIB should be utilized rather than mURD donors to minimize toxicity of GVHD. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Splenic Irradiation and a Reduced-Intensity Conditioning Regimen Prior to Allogeneic Stem-Cell Transplantation for Myelofibrosis

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with myelofibrosis (MF). Reduced-intensity conditioning (RIC) regimens have been used to extend this therapy to older and sicker patients. Splenectomy prior to HSCT for MF has been shown to enhance neutrophil engraftment and decrease transfusion requirements, but has a reported operative mortality of 9% or higher. Splenic irradiation (sXRT) has been historically used as a palliative treatment in MF. We present our experience with a RIC regimen incorporating extracorporeal photopheresis (ECP) in combination with either pre-HSCT splenectomy or sXRT.Methods: The Tufts BMT database, the Center for International Bone Marrow Transplantation Registry (CIBMTR) database, and chart review were used to gather data. All patients underwent conditioning consisting of ECP administered on days -6 and -5, pentostatin 4mg/m2by continuous infusion over 48 hours on days -4 and -3, and a total dose of 600 cGy total body irradiation (TBI) administered in 3 fractions on days -2 and -1 (PPT). sXRT, when employed, was given in the week prior to start of PPT (days -6 to -11) with total doses ranging from 300 to 500cGy. Cyclosporine and methotrexate were used for GVHD prophylaxis. Patients surviving a minimum of six months were considered evaluable for response assessment. Complete hematologic response was defined as resolution of clinical signs of MF as well as normalization of peripheral blood counts (Hgb>10gm/dL, ANC>1000/µL, Platelets >100K and all counts below upper limit of normal) and the absence circulating blasts. Histological response could not be assessed due to lack of follow-up bone marrow data. Clinical improvement, stable disease, progressive disease, spleen response were defined using revised IWG-MRT guidelines. Overall survival (OS) was estimated using the Kaplan Meier method from time of stem cell transplant to death. Non-relapse mortality (NRM) was estimated from time of transplant to death, treating death due to MF and relapse as competing risks.Results: Ten patients (7 females, 3 males) with MF underwent allogeneic HSCT with PPT conditioning between February 2001 and December 2012. Median age was 54 years (40-60 years). Median time from diagnosis to transplant was 48 months (6-137 months). MF was primary in 8 and secondary to essential thrombocytosis in 2 patients. According to DIPSS scoring, 1, 2, 5 and 2 patients were low, intermediate-1, intermediate-2 and high risk respectively. Donors were equally distributed between matched related and matched unrelated. Bone marrow was used as the source in all but one patient. Nine patients (90%) had palpable splenomegaly. Six underwent splenectomy of which 1 died of a related complication (sepsis from abscess in the splenic bed). Three received sXRT prior to HSCT with no associated complications. All but one patient (who had a prior splenectomy) engrafted successfully. Median time to engraftment was 18 days (sXRT 18 days, splenectomy 19 days) for neutrophils and 26 days for platelets regardless of splenic therapy. Only 2 patients developed acute grade III-IV GVHD and 1 patient developed extensive chronic GVHD. 4/7 patients with a prior splenectomy were evaluable for disease response. Of these 2 had complete hematologic response, 1 had clinical improvement with eventual relapse, and 1 had progressive disease. Among the 3 patients receiving sXRT, 2 patients had complete hematologic response as well as a spleen response and 1 had stable disease.Three patients were alive at last follow-up. Causes of death included disease relapse (n=2), GVHD (=3) and sepsis (n=2). Cumulative incidence of NRM was 40% at 1 year. Five year OS was estimated at 30%.Discussion: Our data demonstrates that splenic XRT is well tolerated and equivalent to splenectomy in terms of engraftment outcomes and disease response. Survival and GVHD outcomes with PPT conditioning were similar to those reported with other RIC regimens. PPT is a reasonable conditioning regimen for these patients. Further study to optimize timing of HSCT and patient selection to reduce NRM is needed. DisclosuresComenzo:Millennium Pharmaceuticals: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Photopheresis As Part of Conditioning Reduces Incidence of Severe Graft Versus Host Disease: Fourteen Year Follow-up of a Novel Reduced Intensity Regimen for Allogeneic Hematopoietic Stem Cell Transplantation

Background: Reduced intensity conditioning (RIC) regimens have allowed the use of allogeneic hematopoietic stem cell transplantation (HSCT) in older and high risk individuals, though Graft versus Host Disease (GVHD) remains an issue. Host antigen presenting cells have been implicated in the pathogenesis of GVHD. Extracorporeal photopheresis (ECP) has been shown to modulate host antigen presenting cell function. Tufts Medical Center developed a novel RIC regimen incorporating ECP, pentostatin and reduced dose total body irradiation (PPT). We now report our 14 year experience with this regimen in 206 consecutive patients not eligible for a myeloablative HSCT.Methods: The Tufts BMT database, the Center for International Bone Marrow Transplantation Registry (CIBMTR) database, and chart review were used to gather data. All patients received a conditioning regimen consisting of ECP administered on days -6 and -5, pentostatin 4mg/m2 by continuous infusion over 48 hours on days -4 and -3, a total dose of 600 cGy TBI administered in 3 fractions on days -2 and -1. No antithymocyte globulin was given. All patients received GVHD prophylaxis with cyclosporine and 2 doses of methotrexate. Supportive care was provided per institutional guidelines.Overall survival (OS) was calculated from day 0 using the Kaplan Meier method. Cumulative incidence of non-relapse mortality (NRM) was calculated treating death due to primary hematologic malignancy or relapse as competing risks. Univariate associations between patient characteristics and outcomes were estimated using logistic regression or Cox proportional hazards models as appropriate.Results: 206 patients (56% males) underwent allogeneic HSCT with the PPT regimen between October 1999 and December 2013. Median age at transplant was 53 years (19-70 years) with 45% being older than 55 years. 31% had a prior autologous HSCT. Median time from diagnosis to transplant was 17 months (range 1-180 months). 59% of the transplants were from matched siblings and 41% were from unrelated donors. Marrow was utilized as the source of stem cells in 72% of the transplants. 92% transplants were HLA matched with 8% mismatched at one antigen. The most common indications for transplant were Acute Myelogenous Leukemia (AML) (35%), Myelodysplastic Syndrome (MDS) (16%) and Non-Hodgkin Lymphoma (NHL) (12%). Of the 73 patients with AML 33% were in first complete remission (CR1), 18% were in a second or greater complete remission (CR ≥2) and 49% had active disease at the time of transplant.Median times to neutrophil and platelet engraftment were 17 and 19 days, respectively. 17% of the patients never dropped their platelet counts below 20,000/mm3.The estimated 5 year overall survival (OS) for the entire cohort was 29% [95% CI (23%-36%)]. The estimates of OS by diagnosis are shown in Figure 1. The estimated non-relapse mortality (NRM) at 100 days was 17% [95% CI (13%-23%)]. The incidence of grade 3-4 acute GVHD was 20%. 54% of the patients developed chronic GVHD, of which only 17% were extensive stage.On univariate analysis for the entire cohort, the variables significant for a higher risk of death were 1-antigen mismatch [HR 1.96, p-value=0.01] and KPS <80 [HR 10.66, p-value <0.001]. Age, stem cell source and having an unrelated donor were not found to be significant. On multivariate analysis in the AML cohort, advanced age [aHR 1.37, p-value=0.02] and active disease [aHR 3.02, p-value=0.002] were significant factors for death. OS by remission status in the AML cohort is shown in Figure 2.Conclusions: PPT was well tolerated with low NRM and survival outcomes comparable to other RIC regimens. OS was independent of graft type (related versus unrelated) or stem cell source. Rates of severe acute and extensive chronic GVHD were low, possibly due to the use of ECP and its modulation of the host antigen presenting cells. OS in patients with AML was comparable to other RIC regimens despite almost half of the patients having active disease at the time of transplant. Our long term follow-up data of 14 years shows that PPT remains a novel regimen for patients not eligible for full intensity conditioning. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.