One-year Non-relapse Mortality Research Articles

Grade III-IV cytokine release syndrome is associated with inferior survival in patients undergoing haploidentical donor stem cell transplants.

7546 Background: Haploidentical transplant (HIDT) with post-transplant cyclophosphamide (pCY) is being increasingly used because of the universal availability of donor and rapid graft acquisition time. Cytokine release syndrome (CRS) is one of the commonly occurring complications in this population. The information on the impact of CRS on the post-HIDT outcomes is limited. Methods: We retrospectively evaluated 91 patients who underwent HIDT between June 2012 and June 2019 for the onset and severity of CRS. CRS was graded per ASTCT guidelines. The primary objective was to compare RFS (relapse-free survival), NRM (non-relapse mortality), OS (overall survival) and GVHD in patients with no CRS, CRS grade 1-2 and 3-4. Results: All received peripheral blood stem cells and pCY/tacrolimus/mycophenolate as GVHD prophylaxis. Fifty-six (62%) received reduced intensity and 35 (38%) received full intensity conditioning regimen. Ten (10.9%) had no CRS, 74 (81.3%) developed grade 1-2 CRS and seven (7.7%) experienced grade 3-4 CRS. Median time to onset of CRS was one day post-transplant. The most common symptoms were fever (87%), fatigue (30%), nausea/vomiting (24%), rigors (24%), diarrhea (20%) and rash (11%). Fifteen (20%) with grade 1-2 and six (85%) with grade 3-4 CRS received tocilizumab. Day +100 cumulative incidence of grade III-IV acute GVHD for no CRS, grade 1-2 and grade 3-4 CRS was 0%, 2.7%, and 14.3%, respectively (P = 0.36). One-year cumulative incidence of chronic GVHD for no CRS, grade 1-2 and grade 3-4 CRS was 30%, 31.9% and 14.3%, respectively (P = 0.70). One-year NRM for no CRS, grade 1-2 and grade 3-4 CRS was 30%, 16.5%, and 57.1%, respectively (P = 0.002). One-year RFS for no CRS, grade 1-2 and grade 3-4 CRS was 48%, 63.4% and 28.6%, respectively (p = 0.03). OS at 1-year for no CRS, grade 1-2 and grade 3-4 CRS was 60%, 73.9%, and 28.6%, respectively (P = 0.008). Multivariable analysis revealed that grade 3-4 CRS was associated with significantly higher NRM (HR 5.54, P = 0.002), worse RFS (HR 3.41, P = 0.011) and worse OS (HR 4.91, P = 0.001). Conditioning regimen, degree of HLA match and disease risk index did not affect post-transplant outcomes and were not predictors for developing CRS. Conclusions: Our study showed that grade 3-4 CRS was associated with inferior post-transplant outcomes. However, no impact on acute or chronic GVHD was noted. Therefore, early recognition and prompt management of CRS may help improve outcomes.

Microbiologically documented infections after adult allogeneic hematopoietic cell transplantation: A 5-year analysis within the Swiss Transplant Cohort study.

Infections are an important complication after allogeneic hematopoietic cell transplantation (allo-HCT). The present study aimed at determining the landscape of infections occurring in a large cohort of allo-HCT patients, as well as associated risk factors for infections and for one-year non-relapse mortality. This is a retrospective cohort study using STCS and EBMT databases to assess the one-year incidence rate of infection, as well as risk factors for infections and for one-year non-relapse mortality among adult allo-HCT patients transplanted between 2010 and 2014 in Switzerland. Univariable and multivariable quasi-Poisson and multivariable Cox regression models were used. Of 553 patients included, 486 had an infection with a global incidence rate of 3.66 infections per patient-year. Among a total of 1534 infections analyzed, viral infections were predominant (n=1138, 74.2%), followed by bacterial (n=343, 22.4%) and fungal (n=53, 3.5%) infections. At one year, the cumulative incidence of relapse and non-relapse mortality was 26% and 16%, respectively. 195 (35.3%) of patients had at least one episode of severe graft-versus-host-disease (GvHD). A center effect was observed, and underlying disease, donor type, cytomegalovirus serological constellation, and GvHD were also associated with the incidence rate of infections. There was an increased risk for one-year non-relapse mortality associated with all pathogens, specifically within two months of infection, and this remained true beyond 2months of a fungal infection. Despite advances to limit infections in this population, they still occur in most allo-HCT patients with a major impact on survival at 1year.

Enhanced Recovery Program in Older Patients Undergoing Allogeneic Stem Cell Transplantation (ER-SCT): First Year Outcomes

<h3>Background</h3> Older patients undergoing allogeneic stem cell transplant (SCT) have inferior outcomes. They have limited physiological reserves, which makes them more susceptible to toxic effects of conditioning regimens. Supportive care directed at maintaining and augmenting their limited functional reserve may reduce non-relapse mortality (NRM). We studied impact of a multidisciplinary supportive care and prehabilitation program (ER-SCT) and compared one-year NRM with a historical control group. <h3>Methods</h3> Between 1/1/15 and 9/30/18, 204 patients ≥ 65 years old underwent allogeneic SCT at our institution. ER-SCT program started on 10/1/17 and 57 of 64(89%) eligible patients participated during the first year. All 64 patients were included in the ER-SCT cohort, while patients treated between 1/1/15-9/30/17 were in the control group. ER-SCT program consisted of a prehabilitation phase prior to admission. Patients were evaluated by a multidisciplinary team consisting of a geriatrician, physical medicine and rehabilitation physician, physical therapist, occupation therapist, dietician, nurse, and a pharmacist specializing in SCT. Preexisting chronic conditions were optimized and recommendations were made for nutrition, exercise, and coping strategies. During hospitalization, fluid usage and medication choice / doses were optimized for older patients to prevent side effects such as fluid overload and delirium. Physical therapy, occupational therapy and nutrition counselling was continued. The team continued to follow and intervene as needed after discharge from the hospital. <h3>Results</h3> Median age was 68 (65-79) with 36 (18%) patients >than 70 years. Diagnoses included AML 96 (47%), MDS 57(28%), MPD 26 (13%), ALL 8(4%), and other 17 (8%). 103 (51%) had high or very high disease risk index (DRI). HCT-CI score was >3 in 80 (39%). Donor types included 127 (62%) matched unrelated, 57(28%) matched related and 20(10%) haploidentical. The NRM at 1 year was 13% in ER-SCT cohort vs 26% (p=0.03) in the control cohort. Multivariate analysis adjusting for GVHD prophylaxis and conditioning regimen, age, DRI, HCT-CI, donor type and graft source showed that ER-SCT HR=0.4 (0.2-0.9, P=0.02), comorbidity score < 4 HR 0.5 (0.3-0.9, P=0.02) and matched related donor HR 0.2 (0.1-0.7, P=0.008) were associated lower with NRM. <h3>Conclusion</h3> Although the data from this retrospective sequential cohort analysis cannot be conclusive, they do suggest that a multidisciplinary supportive care program (ER-SCT) may reduce NRM in older patients undergoing allogeneic SCT.

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&lt;0.01), and was significantly greater in patients with grade I versus grade II-IV aGVHD (45.2% versus 17.8%, p&lt;0.05). Patients with cGVHD showed a lower RR compared to patients without cGVHD (1-year RR 20.4% vs 48.5%, p&lt;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 &lt;90% (1-year OS 51.3% versus 21.4%, p&lt;0.01; 1-year RR 44.0% vs 89.3%, p&lt;0.01, respectively). Multivariate analysis identified grade I aGVHD (versus grade II-IV, p&lt;0.01), cGVHD (versus no cGVHD, p&lt;0.05), and chimerism ≥90% (versus &lt;90%, p&lt;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 &amp; Dohme Corp., Gilead Sciences, Inc.: Research Funding.

Reduced intensity allogeneic stem cell transplantation for younger patients with myelofibrosis.

Allogeneic stem cell transplantation (alloSCT) is a curative procedure for myelofibrosis. Elderly people are mainly affected, limiting the feasibility of myeloablative regimens. The introduction of reduced-intensity conditioning (RIC) made alloSCT feasible for older patients. Nevertheless, the incidence of myelofibrosis is not negligible in young patients, who are theoretically able to tolerate high-intensity therapy. Very few data are available about the efficacy of RIC-alloSCT in younger myelofibrosis patients. This study included 56 transplanted patients aged <55years. Only 30% had a human leucocyte antigen (HLA)-matched sibling donor, the others were transplanted from a fully-matched (36%) or partially-matched (34%) unrelated donor. All transplants were conditioned according the European Society for Blood and Marrow Transplantation protocol: busulfan-fludarabine + anti-thymocyte globulin, followed by ciclosporin and mycophenolate. One patient experienced primary graft failure. Incidence of graft-versus-host disease grade II-IV was 44% (grade III/IV 23%). One-year non-relapse mortality was 7% and the 5-year cumulative incidence of relapse was 19%. After a median follow-up of 8·6years, the estimated 5-year progression-free survival and overall survival (OS) was 68% and 82%, respectively. Patients with fully-matched donor had a 5-year OS of 92%, in contrast to 68% for those with a mismatched donor (P=0·03). The most important outcome-determining factor is donor HLA-matching. In conclusion, RIC-alloSCT ensures optimal engraftment and low relapse rate in younger myelofibrosis patients, enabling the possibility of cure in this group.

Lower Risk of One-Year Non-Relapse Mortality, Rapid Engraftment and Better NK Cell Recovery with GvHD Prophylaxis Based in Post-Transplant Cyclophosphamide/Bendamustine in Pediatric Hematopoietic Stem Cell Transplantation

Background Post-transplant cyclophosphamide (Pt-Cy) was a breakthrough in achieving immune tolerance after HSCT. Nevertheless, time to engraftment, GvHD, GvL effect, toxicity, and immune reconstitution are not yet optimal and can be improved. Evidence suggests that post-transplant bendamustine (Pt-Ben) can decrease GvHD and preserve GvL effect. Here we compare two GvHD prophylaxis platforms related to engraftment, GvHD, viral infections, lymphocyte recovery, and one-year non-relapse mortality (1y-NRM) in pediatric HSCT. Methods On Sept/2016 we introduced Pt-Ben to our standard Pt-Cy 50mg/kg/dose; days +3 and +4/Sirolimus aGvHD prophylaxis. The new protocol included Pt-Cy 50mg/kg/dose; day +3, Pt-Ben 200mg/m2/dose; day +4, and CSA starting on day +5. In both cohorts, we used low-dose methotrexate (MTX) in a subgroup of patients. We started G-CSF at day +10, and used rATG mainly for RIC transplants. We preferred PBSC as the cell source for donors >10 years of age. We compared Pt-Cy/Ben/csa cohort (39 cases; Sept/2016-June/2018) with Pt-Cy/sirolimus historical cohort (63 cases; Jan/2013-Aug/2016). We included all patients receiving one of the two protocols, except for Fanconi anemia patients (6 cases). We use non-parametric statistics to compare the median time of cell recovery. We used cumulative hazards to estimate 1y-NRM. We carried-out Cox's multivariate regression models (clustered by number of transplants/subject) to adjust hazard ratios (HR) by the following covariates: recipients age, sex, diagnosis, CMV status, MTX, ATG, TBI, conditioning intensity, infused CD34+ and total nucleated cells, haploidentical graft, donors age, and sex. Results Table 1 presents recipients, graft and donors characteristics by group. Table 2 shows frequencies of GvHD, viral infections, the median time to engraftment, and +30-day lymphocyte recovery. Acute GvHD II-IV was more frequent in the Pt-Cy/Ben/csa group, but III-IV was the same in both groups. The frequency of hemorrhagic cystitis was about half in the Pt-Cy/Ben/csa group compared to the other. Median time to blood cell recovery was faster in the Pt-Cy/Ben/csa group, particularly of platelet counts (11 vs. 20 days; P Conclusions GvHD prophylaxis with Pt-Cy/Ben/csa decreased by 3-times 1y-NRM, proved superior to Pt-Cy/sirolimus in engraftment and NK cell 30-day recovery. Although the historical cohort comparison is not absent of various biases, the association was robust after adjusting for many potential confounders. We consider that this novel strategy deserves further research in larger and better-designed studies.

Early D-Dimer Value Is Highly Predictive of Non-Relapse Mortality in Children after Haploidentical Hematopoietic Stem Cell Transplantation

Background Alloreactivity has been implicated with endothelial damage, severe complications, and death after hematopoietic stem cell transplantation (HSCT). Allogenic reaction in HLA-haploidentical HSCT (HaploHSCT) is established early after graft infusion, and therefore, the severity of this reaction could be measured in the first days of graft infusion. Plasmatic D-Dimer (DD) has been used as a surrogate indicator of endothelial dysfunction and inflammation. We explored whether days +2 or +3 DD were predictive of one-year non-relapse mortality (1y-NRM) in post-transplantation cyclophosphamide-treated children after HaploHSCT. Methods In 2013, we started to measure DD in the first 7 days after graft infusion. We focus only on patients with peak DD taken on days +2 or +3. Data source was our pediatric HSCT registry, which is prospectively filled using information from the clinical charts, imaging, laboratory, and pathology reports. We excluded Fanconi anemia patients. The period of analysis was from Jan/2013 to June/2018. We used plasma DD measured by ELISA (ng/mL-FEU) and as reported by the clinical laboratory. DD was log-transformed for achieving normality. We divided DD in tertiles and we took the value between the 2nd and 3rd tertile as the final cutoff point. We used the cumulative hazards method to estimate 1y-NRM. Cox's multivariate regression models were used to adjust hazard ratios (HR) by covariates derived from the recipient, the graft, and the donor. Non-parametric ROC curve was constructed to estimate the AUC. Results We included thirty-two patients (0-18 years of age). Table 1 presents recipient, graft, and donor characteristics by DD. Nine patients died and had a DD geometric mean of 3048 ng/mL FEU, which is higher when compared to living patients (n=23; 1229 ng/mL FEU; P Conclusion We found 12-times more risk of 1y-NRM in children with DD ≥1700 ng/mL-FEU in day+2 or +3 after HaploHSCT. This relationship was independent of other covariates including aGvHD. This finding could be used to separate patients with high risk of NRM in an early HSCT phase, and therefore to introduce preemptive strategies to mitigate this risk. More research is needed to understand the mechanisms underlying this finding.

Outcome after autologous transplantation in the terms of comorbidity for patients with lymphoproliferative diseases: Single center experience.

e19502 Background: Autologous stem cell transplantation (ASCT) improves survival in patients with myeloma and lymphoma but is associated with morbidity and nonrelapse mortality (NRM). Hematopoietic cell transplant comorbidity index (HCT-CI) was shown to predict risk of NRM and survival after allogeneic transplantation. We tested the utility of HCT-CI as a predictor of NRM and overall survival (OS) in patients undergoing ASCT. Methods: We analyzed outcomes of 220 patients after high-dose melphalan and high –dose anti lymphoma chemotherapy during year 2000 to 2015. Individual comorbidities were prospectively collected at the time of ASCT. The impact of HCT-CI and other potential prognostic factors, including Karnofsky performance score (KPS), on NRM and survival were studied in multivariate Cox regression models. Results: HCT-CI score was 0, 1, 2, 3, and &gt;3 in 42%, 18%, 13%, 13%, and 14% of the study cohort, respectively. Subjects were stratified into 3 risk groups: HCT-CI score of 0 (42%) versus HCT-CI score of 1 to 2 (32%) versus HCT-CI score &gt; 2 (26%). Higher HCT-CI was associated with lower KPS &lt; 90 (33% of subject’s score of 0 versus 50% in HCT-CI score &gt; 2). HCT-CI score &gt; 2 was associated with melphalan dose reduction (22% versus 10% in score 0 cohorts). One-year NRM was low at 2% (95% confidence interval, 1% to 4%). On multivariate analysis, overall survival was inferior in groups with HCT-CI score of 1 to 2 (relative risk, 1.37, [95% confidence interval, 1.01 to 1.87], P = .04) and HCT-CI score &gt; 2 (relative risk, 1.5 [95% confidence interval, 1.09 to 2.08], P = .01). Factors that affect OS in the autologous recipients among lymphoma and myeloma patients were: HCT-CI, Karnofsky score, number of CD34+ cells/kg and time from diagnosis until transplant (p&lt;0.05). Factors that affect TRM/NRM were HCT-CI, ECOG, Karnofsky score and number of hospital days and body weight.(p&lt;0.05). Conclusions: ASCT for MM and lymphoma is associated with low NRM, and death is predominantly related to disease progression. Comorbidity evaluation during autologous transplantation for lymphoproliferative diseases can be a useful tool in predicting transplant outcome.

Alternative Donor Transplantation Using Intensified Conditioning, T-Cell-Replete HLA-Haploidentical Grafts and Post-Transplantation Cyclophosphamide in the Treatment of High-Risk and Advanced ALL: Feasibility and Outcome

Unmanipulated, T-cell-replete (TCR) HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PTCY) for selective in vivo T-cell depletion of allo-reactive T-cells has become a valuable treatment alternative in patients with various hematologic disorders who lack a conventional donor or need timely transplant due to aggressive disease. However, as of yet few data are available for the treatment of ALL with this approach, particularly in relapsed and refractory disease.To evaluate the outcome of TCR haplo-HSCT utilizing PTCY in the context of intensified conditioning in patients with high-risk, relapsed and refractory ALL, we retrospectively analysed 29 patients (B-ALL n=27, T-ALL n=2; 12 male; median age 42 years: range 8-68) transplanted between 2010 and 2015 in five German transplant centers including one pediatric. Disease was active (relapsed/refractory) in 14 patients (48%) while others were in first (35%) or subsequent remission (17%). Eleven patients (38%) had relapsed after a previous allogeneic transplantation. Patients not in CR received cytoreductive chemotherapy prior to the conditioning regimen, according to the "sequential therapy" concept (Schmid C et al., JCO 2005; Tischer J et al, Ann Hematol 2013). Conditioning was TBI-based in 15 adults consisting of fludarabine and +/- cyclophosphamide plus either 12 Gy TBI or 8 Gy TBI applied in patients older than 55 years; children (n=3) received 10-12 Gy TBI plus etoposide. In adults with relapse after a first allogeneic transplantation conditioning was drug-based replacing TBI with treosulfan (3 x 10-12 g/m2) and etoposide. Post-grafting immunosuppression was high-dose cyclophosphamide, tacrolimus or cyclosporine A (n=4) and MMF in all patients. 27/29 patients engrafted, while 2 patients died early in aplasia. No primary graft rejection was observed. Acute GvHD grade II-IV occurred in 7 patients (24%); no patient developed grade IV acute GvHD. Mostly mild to moderate chronic GvHD was observed in 6 patients (21%), and CI of chronic GvHD at 2 years was 25%. No patient died due to GvHD. Severe toxicity (grade III-IV) was observed in 12 patients (41%), most commonly mucositis (n=34%), diarrhoea (31%), hyperbilirubinemia and transient elevation of transaminases (28%) and hemorrhagic cystitis (21%). CMV reactivated in 11/23 patients at risk and EBV in 3 while no patient developed CMV disease or PTLD. Proven invasive aspergillosis was diagnosed in 2, probable invasive aspergillosis in 5 patients. One-year non-relapse mortality (NRM) was 10%. Patients grafted with active disease experienced a one-year NRM of 14%. One-year relapse incidence was 35%. After a median follow up of 31 months (range 7.1-53.6), estimated one-year and three-year overall and relapse-free survival was 72/49% and 55/41%, respectively.In summary, intensification of the preparative regimen is well tolerated in the setting of TCR haplo-HSCT using PTCY as GvHD prophylaxis with low GVHD rates and NRM in patients with high-risk, relapsed and refractory ALL, while providing effective anti-leukemic activity. Results are at least comparable to HLA-matched transplantation. Thus, we suggest that the donor pool can be safely expanded in patients with high-risk and advanced ALL who lack a conventional donor, and that unrelated donor transplantation might be challenged in patients suffering from aggressive disease in the future. DisclosuresAlbert:GSK: Research Funding.

Healthcare Burden, Risk Factors, and Outcomes of Mucosal Barrier Injury Laboratory-Confirmed Bloodstream Infections after Stem Cell Transplantation

Mucosal barrier injury laboratory-confirmed bloodstream infections (MBI-LCBIs) lead to significant morbidity, mortality, and healthcare resource utilization in hematopoietic stem cell transplant (HSCT) patients. Determination of the healthcare burden of MBI-LCBIs and identification of patients at risk of MBI-LCBIs will allow researchers to identify strategies to reduce MBI-LCBI rates. The objective of our study was to describe the incidence, risk factors, timing, and outcomes of MBI-LCBIs in hematopoietic stem cell transplant patients. We performed a retrospective analysis of 374 patients who underwent HSCT at a large free-standing academic children's hospital to determine the incidence, risk factors, and outcomes of patients that developed a bloodstream infection (BSI) including MBI-LCBI, central line–associated BSI (CLABSI), or secondary BSI in the first year after HSCT. Outcome measures included nonrelapse mortality (NRM), central venous catheter removal within 7 days of positive culture, shock, admission to the pediatric intensive care unit (PICU) within 48 hours of positive culture, and death within 10 days of positive culture. One hundred seventy BSIs were diagnosed in 100 patients (27%): 80 (47%) MBI-LCBIs, 68 (40%) CLABSIs, and 22 (13%) secondary infections. MBI-LCBIs were diagnosed at a significantly higher rate in allogeneic HSCT patients (18% versus 7%, P = .007). Reduced-intensity conditioning (OR, 1.96; P = .015) and transplant-associated thrombotic microangiopathy (OR, 2.94; P = .0004) were associated with MBI-LCBI. Nearly 50% of all patients with a BSI developed septic shock, 10% died within 10 days of positive culture, and nearly 25% were transferred to the PICU. One-year NRM was significantly increased in patients with 1 (34%) and more than 1 (56%) BSIs in the first year post-HSCT compared with those who did not develop BSIs (14%) (P ≤ .0001). There was increased 1-year NRM in patients with at least 1 MBI-LCBI (OR, 1.94; P = .018) and at least 1 secondary BSI (OR, 2.87; P = .0023) but not CLABSIs (OR, 1.17; P = .68). Our data demonstrate that MBI-LCBIs lead to substantial use of healthcare resources and are associated with significant morbidity and mortality. Reduction in frequency of MBI-LCBI should be a major public health and scientific priority.

Feasibility and Outcome of Sequential Therapy in the Setting of HLA-Haploidentical Transplantation Utilizing Reduced-Intensity Conditioning, T-Cell-Replete Grafts and Post-Transplantation High-Dose Cyclophosphamide in the Treatment of High-Risk AML and MDS

Hematopoietic stem cell transplantation is a potent curative treatment option for patients suffering from high-risk AML and MDS. However, not in all of our patients a suitable HLA-matched donor could be identified in time.To evaluate the feasibility and outcome of T-cell-replete (TCR) HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) utilizing post-transplantation high-dose cyclophosphamide (PTCY) in the context of sequential therapy in patients with high-risk, relapsed/refractory and progressive AML and MDS, we retrospectively analyzed the course of 64 patients (AML n=61, MDS n=3; median age: 50 years; male n=30) transplanted between 2009 and 2015 at our center. Disease was advanced in 55 patients including 24 patients with relapse after a first allogeneic transplantation. 54 patients presented with active disease at time of haplo-HSCT. Donors (median age: 38 years; male n=30) were fully HLA-haplotype mismatched (5/10 HLA-loci) in 48 cases (77%). All patients received sequential therapy prior to haplo-HSCT combining cytoreductive chemotherapy (clofarabine n=34; FLAMSA n=25; FLAG-Ida n=2; others n=3) and reduced-intensity conditioning (RIC) which was started after three days of rest thereafter. Conditioning was drug-based in 42 patients receiving fludarabine, cyclophosphamide (CY) and melphalan (110 mg/m2) while it was TBI-based in the others (n=22) consisting of fludarabine and CY plus either 4 (n=20) or 2 Gy TBI (n=2). Post-grafting immunosuppression was high-dose CY given on day + 3 and +4, tacrolimus and mycophenolate mofetil (both started on day +5) in all patients. Unstimulated bone marrow was the graft source in 37 patients.One graft rejection was observed after conditioning with 2 Gy TBI. Neutrophil/platelet engraftment was achieved in 49/58 evaluable patients at a median of 16 (range: 14-27) and 20 (range: 13-74) days, respectively. Acute GvHD grade II-IV occurred in 19 patients (30 %) while it was severe (grade III-IV) in only 3 (5 %). Chronic GvHD was most frequently mild (n=9) to moderate (n=8); one severe chronic GvHD occurred. Severe (grade III-IV) mucositis, hemorrhagic cystitis and hand-foot syndrome/rash were observed in 10, 5 and 2 patients, respectively; no patient developed VOD. Kidney failure requiring hemodialysis occurred in 7 patients. CMV reactivation was observed in 28 of 47 patients at risk (59 %) and EBV in 3, while only one patient developed CMV disease (pneumonia) and no patient developed PTLD. Probable or proven (n=2) invasive aspergillosis was diagnosed in 10 patients. One-year non-relapse mortality was 27.5 % (95% CI 17-41). After a median follow up of 21 months (range: 3-64), estimated one-year overall survival (OS) was 55 % (95 % CI 41-66), and one-year disease-free survival (DFS) was 43 % (95 % CI 26-51). At two-years after sequential haplo-HSCT OS and DFS were both 39 % (95 % CI 26-51).In summary, sequential therapy in the setting of RIC-TCR haplo-HSCT using PTCY is well tolerated with low rates of GvHD and acceptable NRM in patients with high-risk AML and MDS, while providing an effective anti-leukemic activity in advanced disease. Results are comparable to data of a historical cohort of patients with high-risk AML and MDS undergoing sequential therapy using the FLAMSA-RIC protocol in a HLA-matched setting, as reported by our group previously. Thus, we suggest that donor availability can be expanded in patients with high-risk and advanced AML/MDS who lack a conventional donor or need promptly access to a donor due to aggressive disease. DisclosuresHausmann:Sanofi-Aventis: Other: advisory board. Tischer:Sanofi-Aventis: Other: advisory board. Off Label Use: clofarabine in adults; efficacy is shown in myeloid blasts;.

Disease Risk Index Is the Major Predictor of Outcome Following Myeloablative Haploidentical Hematopoietic Stem Cell Transplantation (haplo-HSCT) and Post-Transplant Cyclophosphamide (PT/Cy)

Disease Risk Index is the Major Predictor of Outcome Following Myeloablative Haploidentical Hematopoietic Stem Cell Transplantation (haplo-HSCT) and Post-Transplant Cyclophosphamide (PT/Cy)Although non-myeloablative (NMA) haplo-HSCT utilizing PT/Cy results in low rates of GVHD, infection, and non-relapse mortality (NRM), relapse remains the predominant cause of treatment failure, occurring in up to 50% of patients. To reduce the risk of relapse often associated with the use of NMA preparative regimens, we have developed a myeloablative haplo-HSCT utilizing PT/Cy. Sixty-four patients have been transplanted following either Busulfan-based (n=20) or TBI-based (n=44) myeloablative conditioning, T-cell replete PBSC infusion, PT/Cy, and tacrolimus/mycophenolate mofetil. Median age was 43 (range 21-60). Patient characteristics included a high/very high disease risk by the Dana-Farber/CIBMTR disease risk index (DRI) in 32 patients (50%), KPS<90 in 69%, and comorbidity index (CMI) of ≥2 in 58% of patients. The most common indications for transplant were AML, ALL, and advanced-phase CML in 55%, 20% and 12% of patients respectively. Median follow-up for surviving patients was 24 months. All patients have engrafted with no late graft failure. Grade II-IV, III-IV acute GVHD and moderate-severe chronic GVHD occurred in 46%, 23%, and 30% respectively. One-year NRM was 10%. Predicted three-year overall survival (OS), disease-free survival (DFS), and relapse are 53%, 53%, and 26% respectively. In multivariate analysis, high/very high DRI was the most significant negative predictor of OS (HR 13.26, p<0.001), followed by CMI≥2 (HR 3.54, p=0.01) and age (HR 1.26, p=0.038, per each 5 year increase in age). DRI was also significantly associated with DFS (HR 10.84, p<0.001), NRM (HR 15.0, p=0.004), and relapse (HR 8.85, p=0.004). In the 32 patients with standard risk disease (low/intermediate DRI), outcomes were significantly improved with one-year NRM of 0% and predicted 3-year OS, DFS, and relapse of 79%, 74% and 9% respectively. Conditioning regimen (TBI vs. Busulfan) had no significant impact on outcome. This analysis confirms that DRI is a strong predictor of outcome following myeloablative haplo-HSCT and PT/Cy and adds to a growing body of literature suggesting that haplo-HSCT is a safe and effective transplant option for patients lacking a matched sibling donor. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Targeted Oral Busulfan (BU)/Cyclophosphamide (CY)/VP-16 and Autologous Stem Cell Transplant (ASCT) for Hodgkin's (HL) and Non-Hodgkin's Lymphoma (NHL) Results in Excellent 5-Year Survival and Low Treatment-Related Mortality: Ten-Year Single Center Experience of 246 Consecutively Treated Patients

Targeted Oral Busulfan (BU)/Cyclophosphamide (CY)/VP-16 and Autologous Stem Cell Transplant (ASCT) for Hodgkin's (HL) and Non-Hodgkin's Lymphoma (NHL) Results in Excellent 5-Year Survival and Low Treatment-Related Mortality: Ten-Year Single Center Experience of 246 Consecutively Treated Patients.High-dose chemotherapy with ASCT has been a standard component of therapy for patients with HL and NHL for decades, however there are no randomized data supporting the superiority of any specific high-dose regimen. A recent retrospective CIBMTR analysis has suggested a potential benefit of BCNU-based regimens in patients with HL (Chen et al. Biol Blood Marrow Transplant 2015; 21:1046-1053). We present long-term outcome data for 246 consecutive HL and NHL patients receiving ASCT at a single institution between July 2004 and December 2014. All patients received a preparative regimen consisting of targeted oral BU (days -8 to -4, AUC targeted to 1200 µmol/L), CY (60mg/kg/d x 2 days, day -3, -2) and VP-16 (10mg/kg/d x 3 days, days -4, -3, -2). All treatment and post-transplant care was planned to be delivered in the outpatient setting, and patients were admitted only for complications more safely managed in the inpatient setting. The treatment cohort included 80 HL and 166 NHL (including 77 diffuse large B cell [DLBCL], 28 follicular [FL], 29 mantle cell [MCL], 27 T cell [TCL] lymphoma) patients, median age 50 [19, 71] (HL 33 [19, 67], NHL 54 [20, 71]). CIBMTR risk group was low (CR1), intermediate (chemosensitive relapsed or resistant disease), or high (chemorefractory) in 62 (25%), 158 (64%), and 26 (11%) respectively (8%, 70%, 22% for HL; 34%, 61%, 5% for NHL). Median follow-up for surviving patients was 64 months [6, 132]. Non-relapse mortality (NRM) by 100 days post-transplant occurred in one patient (0.4%) and one-year NRM was 0% and 3% for HL and NHL respectively. In NHL patients, 5-year OS for low, intermediate, and high CIBMTR disease risk patients was 86%, 74%, and 25%; corresponding 5-year DFS was 68%, 52%, and 25% respectively (figure 1). Five-year OS, DFS, and relapse was 77%, 59%, and 34% for DLBCL; 83%, 71%, and 20% for MCL; 76%, 48%, and 52% for FL; 70%, 48%, and 45% for TCL patients. In HL patients, 5-year OS for low, intermediate, and high CIBMTR disease risk patients was 100%, 82%, and 72%; corresponding 5-year DFS was 67%, 58%, and 17%; and relapse was 33%, 40%, and 83% respectively. Multivariate analysis demonstrated two factors that predicted inferior overall survival: age ≥55 years [HR 2.16, p=0.003], CIBMTR risk group (high vs intermediate/low) [HR 2.31, p=0.017]. High CIBMTR risk status was also a risk factor for DFS [HR 3.49, p<0.001] and relapse [3.65, p<0.001]. In summary, targeted oral Bu/Cy/VP-16 and ASCT results in low NRM and excellent long-term survival in patients with NHL and HL. Although CIBMTR high risk patients, defined by chemoresistance prior to ASCT, do not appear to benefit significantly from this approach, high-risk HL patients maintain a favorable outcome despite a high incidence of post-transplant relapse. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of 2 Carmustine-Containing Regimens in the Rituximab Era: Excellent Outcomes Even in Poor-Risk Patients

High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) improves outcomes in relapsed lymphoma, but the relative efficacy of different preparative regimens is not well defined. We included patients undergoing autologous HCT using BEAM (carmustine, 300 mg/m2, etoposide, cytarabine, and melphalan) or BEP (carmustine 600 mg/m2, etoposide, and cisplatin) between January 2004 and December 2013; 65 patients received BEP and 64 patients BEAM. Both cohorts were similar for advanced-stage disease, extranodal and bulky disease, and prior therapies. Median neutrophil and platelet engraftment was 10 and 20 days for both regimens, respectively. Febrile neutropenia, serum creatinine concentration increase, and electrolyte abnormalities were more frequent with BEP. Incidence of carmustine pneumonitis was not higher with BEP, likely the result of corticosteroid prophylaxis, although 2 cases of fatal pneumonitis were observed after BEP. One-year nonrelapse mortality was 6.8% after BEP and 0% after BEAM (P = .379). After a median follow-up of 39.4 months (range, 1 to 128), 4-year rates of overall survival (OS) after BEP and BEAM were 80.4% and 72.3%, respectively (P = .611). Diffuse large B cell lymphoma patients transplanted after early relapse post-rituximab-based first-line therapy presented 3-year rates of OS and progression-free survival (PFS) of 73.8% and 65%, respectively. There were no statistically significant differences in the OS and PFS of follicular lymphoma, mantle cell lymphoma, or Hodgkin lymphoma. BEP is a valid alternative to BEAM in autologous HCT. Although associated with more renal and electrolytic toxicities, BEP results in similar disease control and long-term survival as BEAM. Prospective studies are needed to confirm whether intensification of conditioning regimens for autologous HCT can improve disease control in high-risk relapsed lymphoma patients.

Randomized Trial of Busulfan with Cyclophosphamide Versus Busulfan with Fludarabine As Preparative Regimen to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia: A Study from the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

▪BackgroundThe combination of a myeloablative dose of intravenous (iv) busulfan with cyclophosphamide is the standard preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML) patients. However, in patients older than 40 years, this conditioning can be associated to high non relapse mortality (NRM). A similar myeloablative dose of busulfan combined to fludarabine was found associated to a lower NRM in older AML (Alatrash, BBMT 2011).Patients and study designThe Gruppo Italiano Trapianto Midollo Osseo (GITMO) conducted a Phase III, randomized, multicenter, trial to compare the standard myeloablative combination of iv busulfan (Busilvex®, Pierre Fabre, Boulogne, France) at a dose of 0.8 mg/kg/6h over two hours infusion for 4 consecutive days (16 doses), for a total dose of 12.8 mg/kg, in combination with cyclophosphamide at the dose of 60 mg/kg/day for 2 consecutive days for a total dose of 120 mg/kg (BUCY2 arm) or fludarabine at the dose of 40 mg/m2/day for 4 consecutive days, for a total dose of 160 mg/m2 (BUFLU arm). Eligible were patients with a diagnosis of AML in 1st or 2nd complete remission (CR) with an age ≥40 and ≤ 65 years, and the availability of an HLA compatible sibling or unrelated donor as defined by molecular high-resolution typing (4 digits) of the HLA gene loci class I (HLA- A, B, and C) and class II (DRB1). Excluded were patients with a t(15;17) or PML/RARα positive APL or with a t(8;21)(q22;q22) or an inv(16) or t(16;16)(p13;q22) positive AML in 1st CR. The GvHD prophylaxis was based on conventional Cyclosporine A and Methotrexate. In case of unrelated donors, anti Thymocyte Globulin (Thymoglobuline®, Sanofi-Aventis) was given at a total dose of 5 mg/kg (or 7.5 mg/kg, in case of HLA acceptable disparity) (one antigen/allele disparity in class I, or one allele disparity in class II). The primary study end-point was the one-year NRM using an intent-to-treat analysis. The required sample size was calculated assuming that the one-year NRM would have been halved (from 25% to 12.5%) in the BUFLU arm. The cumulative incidence of NRM was estimated by considering relapse as a competing event. All outcomes were evaluated from the date of transplantation. The study was approved by the Institutional Review Boards of each center.ResultsFrom July 2008 to February 2013, 25 centers in Italy and 1 in Israel, enrolled 245 patients who were randomly assigned to BUCY2 (n=121) or BUFLU (n=124), stratified according to donor type and remission (1st vs. 2nd or more). The main clinical features (balanced between the randomization arms) were as follows: the median age was 50 years, 209 patients (85%) were in 1st and 36 (15%) in 2ndCR and the ELN risk subgroups were good (11%), intermediate-1 (46%), intermediate-2 (20%) and adverse (23%). The donor was a sibling related (n= 112, 46%) or matched unrelated (n= 133, 54%) while the stem cell graft was the peripheral blood (PB, n= 168, 69%) or the bone marrow (BM, n= 77, 31%). The overall survival rate in the BUCY2 and BUFLU arm was 71% vs. 78% at 1 year, 65% vs. 62 % at 2 years and 56% vs. 57% at 5 years, respectively (P=ns). A non-significant lower incidence of relapse was documented in the BUCY2 vs. the BUFLU arm being 20.7% vs. 24.2% at 1 year, 25.6% vs. 29% at 2 years and 28.9 vs. 32.3 at 5 years, respectively. On the contrary, at 1 year, the overall NRM in the BUCY2 arm was 17.4% vs. 7.3% in the BUFLU (Gray Test P=0.02). At 2 years and throughout the study, the same significantly different NRM was observed between study arms being respectively 18.2% vs. 8.9% and 19% vs. 9.7% (Gray Test P=0.03) (Figure 1). Causes of NRM in the BUCY2/BUFLU arms were: infections 8/6, organ failures 9/0, GvHD 5/3, hemorrhage 1/1, others 0/2. All in all, at 1, 2 and 5 years the leukemia free survival of the BUCY2 and BUFLU arm was similar being 62% vs. 69%, 56% vs. 62% and 50% vs. 56%, respectively (P=ns) (Figure 2). The number of patients with grade III-IV acute GvHD was higher in the BUCY2 arm (P= 0.02). There were no significant between-group differences in the incidence of chronic GvHD.ConclusionIn AML patients older than 40 years, the reduced toxicity conditioning with iv BUFLU significantly reduced the NRM compared to BUCY2. The increased incidence of leukemia relapse in the BUFLU arm was not associated with a detrimental effect on overall and leukemia free survival. (Funded by a grant from the Agenzia Italiana per il Farmaco (AIFA), ClinicalTrial.gov Identifier: NCT1191957). [Display omitted] [Display omitted] DisclosuresRambaldi:Pierre Fabre Pharma: Consultancy.

A Plasma Marker Panel Diagnostic for Dismal Transplant-Related Complications

Background: Non-infectious transplant-related complications (TRCs) following allogeneic hematopoietic cell transplantation (allo-HCT) are associated with unfavorable prognosis, but it’s difficult to predict the severity at the beginning of clinical symptoms. Inflammatory endothelial injury and hemostatic abnormality were found to play a critical role in the development of severe TRCs. This study aimed to explore plasma markers that could serve as independent predictors for dismal TRCs.Patients and methods: Patients who received allo-HCT between 2000 and 2013 and had available blood samples within 3 days after the initial symptoms of TRCs were included in the analysis. Patients who had undergone any prior transplantation within 6 months were excluded. A total of 185 patients were evaluated and the median age of patients was 46 years (range:16-68). TRCs within 100 days were categorized into three groups; complications with endothelial damage (ED), acute GVHD, and the other complications (OC). ED was defined as sinusoidal obstruction syndrome (SOS), transplant-associated microangiopathy (TAM), capillary leak syndrome (CLS) and idiopathic pulmonary syndrome (IPS). OC included pre-engraftment immune reaction, engraftment syndrome, hemophagocytic syndrome and organ dysfunction. If a patient experienced multiple TRC episodes, we analyzed the episode that developed first. Plasma angiopoietin-2 (ANG2), VEGF, thrombomodulin (TM), D dimer, plasmin-α2 plasmin inhibitor complex (PIC) and C-reactive protein (CRP) were measured. Multiple characteristics including plasma markers were evaluated for their association with overall survival (OS) and non-relapse mortality (NRM).Results: Median follow-up duration of surviving patients after transplant was 4.5 years. Sixty-five percent of the patients received allo-HCT for acute myeloid leukemia or myelodysplastic syndrome and the disease risk was high (not in remission) in 40% of the patients. The source of graft was bone marrow from unrelated donor in 38%, cord blood in 30% of the patients. Eighty-six percent of the patients received myeloablative conditioning regimen.Accumulative incidence of total non-infectious TRCs was 78.9% at day 100. ED was observed in 56 patients SOS (n=17), TAM (n=26), CLS (n=10) and IPS (n=3). These include 16 patients who also experienced grade III to IV GVHD in their post-transplant course. One-year NRM in patients with ED (45.8%) was significantly high compared to 13 patients with grade III-IV GVHD in the absence of ED (16.2%), 52 patients with grade I-II GVHD (10.3%), 26 patients with OC (4.8%), and 18 control patients who never experienced any TRCs or relapse within 100 days after transplant (0%).All candidate biomarkers except for VEGF and PIC at the onset of ED were significantly higher compared to the peak levels of the control patients by Kruskal-Wallis rank sum test. ANG2 and D dimer were significant for SOS, TAM and CLS, whereas CRP was significant for SOS, and TM was significant for SOS and TAM. Any biomarkers were not significantly elevated at the onset of GVHD or OC. Receiver operating characteristic curves for ANG2, D dimer, CRP and TM distinguished ED from the others with AUC of 0.92, 0.83, 0.76 and 0.74, respectively. ANG2 at the concentration of 4.8ng/ml provided a positive predictive value (PPV) of 77% and a negative predictive value (NPV) of 91% for ED. PPV and NPV reached 91% and 89% with a specificity of 97% by combining ANG2 positivity with either high D dimer (>4.3μg/ml) or high CRP (>4.3mg/dl). Additional biomarkers provided no further increased diagnostic accuracy.With adjusted analysis in 134 patients who developed non-infectious TRCs, the combined marker was independent risk factor for NRM (HR: 4.2; 95%CI, 2.2-7.9; p <0.001) and OS (HR: 3.1; 95%CI, 1.9-5.2; p<0.001). In patients with ED, the 3-year OS was significantly shorter in the high-ANG2 group than in the low-ANG2 group (28% versus 79%; p=0.022). In patients with GVHD in the absence of ED, the biomarker panel was unable to predict survival.Conclusions: Combination of ANG2, D dimer and CRP had significant powers for confirming the diagnosis of dismal TRCs at the onset of clinical symptoms. The high diagnostic accuracy would make them useful for real-time clinical judgment and early intervention. DisclosuresNo relevant conflicts of interest to declare.

Calcineurin Inhibitor–Free Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide and Brief-Course Sirolimus Following Reduced-Intensity Peripheral Blood Stem Cell Transplantation

Calcineurin inhibitors (CNIs) form the foundation of current graft-versus-host disease (GVHD) prophylaxis regimens. We hypothesized that a CNI-free regimen consisting of post-transplantation cyclophosphamide (PTCy) and brief-course sirolimus would reduce chronic GVHD and nonrelapse mortality (NRM) after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation (PBSCT). Twenty-six patients (median age, 61 years) underwent unmanipulated PBSCT from an 8/8 locus-matched donor (matched related donor, n = 17; natched unrelated donor, n = 9). GVHD prophylaxis consisted of PTCy and brief-course sirolimus. Donor engraftment occurred in all patients. The cumulative incidence (CI) of grade II-IV acute GVHD, grade III-IV acute GVHD, and chronic GVHD was 46%, 15%, and 31% respectively. One-year NRM was 4%. The median time to immunosuppression discontinuation was day +138. With a median follow-up of 20 months, the estimated 2-year overall survival was 71%, estimated disease-free survival was 64%, and estimated relapse incidence was 32%. In patients with a lymphoid malignancy (eg, chronic lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin disease), 2-year disease-free survival was 100%, and there were no relapses. Good immune reconstitution was evidenced by low cytomegalovirus reactivation rate of 21% (4 of 19 at-risk patients). GVHD prophylaxis with PTCy and sirolimus achieves consistent donor engraftment, low rates of chronic GVHD and NRM, and excellent outcomes in recipients of HLA-identical related and unrelated donor allogeneic PBSCT.

Older Patients with Myeloma Derive Similar Benefit from Autologous Transplantation

Autologous hematopoietic cell transplantation (AHCT) for plasma cell myeloma is performed less often in people >70 years old than in people ≤70 years old. We analyzed 11,430 AHCT recipients for plasma cell myeloma prospectively reported to the Center for International Blood and Marrow Transplant Research between 2008 and 2011, representing the majority of US AHCT activity during this period. Survival (OS) was compared in 3 cohorts: ages 18 to 59 years (n = 5818), 60 to 69 years (n = 4666), and >70 years (n = 946). Median OS was not reached for any cohort. In multivariate analysis, increasing age was associated with mortality (P = .0006). Myeloma-specific mortality was similar among cohorts at 12%, indicating an age-related effect on nonmyeloma mortality. Analyses were performed in a representative subgroup comparing relapse rate, progression-free survival (PFS), and nonrelapse mortality (NRM). One-year NRM was 0% for age >70 years and 2% for other ages (P = not significant). The three-year relapse rate was 56% in age 18 to 59 years, 61% in age 60 to 69 years, and 63% age >70 (P = not significant). Three-year PFS was similar at 42% in age 18 to 59 years, 38% in age 60 to 69 years, and 33% in age >70 years (P = not significant). Postrelapse survival was significantly worse for the older cohort (P = .03). Older subjects selected for AHCT derived similar antimyeloma benefit without worse NRM, relapse rate, or PFS.

Second haematopoietic SCT using HLA-haploidentical donors in patients with relapse of acute leukaemia after a first allogeneic transplantation.

Haploidentical haematopoietic SCT (HSCT) using T-cell-replete grafts and post-transplant high-dose CY has found increasing acceptance. Our purpose was to evaluate the feasibility and outcome of this strategy as second HSCT incorporating donor change for acute leukaemia relapse after a first allogeneic transplantation. The courses of 20 consecutive adults (median age 37 years, 12 male) with AML (n=14), ALL (n=5) and acute bi-phenotypic leukaemia (n=1) were analysed retrospectively. Conditioning consisted of fludarabine, CY and either melphalan or TBIor tresosulfan+/-etoposide. Engraftment was achieved in 17 (85%), and a second remission was induced in 15 patients (75%) on day +30. The rate of grade II-IV acute GvHD was 35%, while chronic GvHD occurred in fivepatients. Most commonly observed grade III-IV toxicities were mucositis (30%), hyperbilirubinemia (20%), elevation of transaminases (20%) and creatinine (20%), while invasive fungal infection affected 30%. One-year non-relapse mortality (NRM) was 36%. At a median follow-up of 17 months, estimated 1-year OS was 45%, and 1-year relapse-free survival was 33%. This strategy was feasible and allowed for successful engraftment with a moderate rate of toxicity. Early outcome and NRM are at least comparable with results after a second HSCT from HLA-matched donors without donor change at HSCT2.

A conditioning platform based on fludarabine, busulfan, and 2 days of rabbit antithymocyte globulin results in promising results in patients undergoing allogeneic transplantation from both matched and mismatched unrelated donor

Conditioning regimen including fludarabine, intravenous busulfan (Bx), and 5 mg/kg total dose of rabbit antithymocyte globulin (r-ATG) (FBx-ATG) results in low incidence of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) from HLA-matched related or unrelated donors (MUD). However, whether this platform produces similar results in the setting of one mismatch unrelated donor (MMUD) Allo-HSCT is not known. We retrospectively analyzed patients aged less than 65 years who were diagnosed with hematological malignancies and received FBx-ATG regimen prior to Allo-HSCT from MUD (N = 74) or MMUD (N = 40). We compared outcome of MUD versus MMUD patients. There was no difference in the cumulative incidence of grades II-IV acute GVHD (MUD: 34% vs. MMUD: 35%, P = 0.918), but MMUD patients developed more grade III-IV acute GVHD (MUD: 5% vs. MMUD: 15%, P = 0.016). The cumulative incidences of overall chronic GVHD (MUD: 33% vs. MMUD: 22%, P = 0.088) and extensive chronic GVHD (MUD: 20% vs. MMUD: 19%, P = 0.594) were comparable. One-year NRM was similar in both groups (MUD: 16% vs. MMUD: 14%, P = 0.292); similarly, progression-free survival (MUD: 59% vs. MMUD: 55%, P = 0.476) and overall survival (MUD: 63% vs. MMUD: 61%, P = 0.762) were not different between both groups. With a median follow up of 24 months, 35 of 74 MUD patients (47%) and 19 of 40 MMUD patients (48%) were free of both disease progression and immunosuppressive treatment. We conclude that the FBx-ATG regimen results in low incidences of NRM and GVHD in both MUD and the MMUD recipients.