Reduced-intensity Conditioning Recipients Research Articles

Allogeneic Stem Cell Transplantation with Myeloablative Compared with Reduced- Intensity Conditioning for AML and Mds; 20 Years Later

Background. Allogeneic stem cell transplantation (SCT) with both myeloablative (MAC) and reduced intensity conditioning (RIC) regimens is effective therapyin AML and MDS. However, the relative merits of each may differin different settings and at different time-points after SCT. We have previously reported on the role of dose intensity in a group of 112 patients with AML/MDS given SCT with different regimens between 1999 and 2004 (ASH 2004, Leukemia 2005). At that time we showed that MAC was associated with lower relapse rate, higher non-relapse mortality (NRM) and similar overall survival (OS) as RIC. MAC was associated with survival advantage in patients with active leukemia at SCT. There is paucity of data on the comparison of these 2 approaches very late after SCT (beyond 20 years). Methods. We have now updated SCT outcomes in the same cohort with a median follow up of 20 years (range, 15-22) in order to better predict long-term outcome and confirm whether late events may have changed the initial conclusions. Updated follow-up is available for all but one patient. Results. The median age at SCT was50 years (18-70). Eighty-five patients had AML and 17 had MDS (IPSS int2 or high). Fifty-eight hadactive disease at SCT (>10% marrow blasts) and 54 were inremission. The donor was HLA-matched sibling (n=58), 1-Ag mismatchedrelated (n=6) or matched-unrelated (n=48). Twenty-nine patients (26%) had poor risk cytogenetics. Forty-five patients meteligibility criteria for standard MAC and were given intravenous-busulfan (ivBu, 12.8 mg/kg) and cyclophosphamide(BuCy). Sixty-seven patients were considered non-eligible for standardMAC and were given RIC with fludarabineand ivBu (6.4 mg/kg, FB2, n=41) or reduced toxicity conditioning (RTC) with fludarabine and myeloablative dosesof ivBu (12.8 mg/kg, FB4, n=26). The medianage of RIC, RTC and MAC recipients was 57, 51 and 42 years at transplantation, respectively (p=0.001) and a larger proportion of RIC/RTC recipients had unrelateddonors (p=0.01). In all, 31 patientsare alive and 81 have died, 50 of relapse and 31 of NRM.The median age at last follow-up was 66 years (35-81). The 20-year OS rate was 29% (20-37). The rate was 40% (26-54), 19% (7-31) and 19% (7-31) after BuCy, FB4 and FB2, respectively (P=0.19). The 20-year NRM was 29% (18-45), 27% (14-51) and 27% (16-45) respectively (Figure 1, P=0.94). The 20-year relapse mortality was 31% (20-48), 54% (38-77) and 54% (40-71), respectively (Figure 2, P=0.12). Five patients with relapse in the first 5 years are very long-term survivors with no recurrent disease following additional treatments. Forty patients were alive and disease-free 5 years after SCT with a 5-year OS of 42% (33-51). Fourteen patients died beyond 5 years, 3 from late relapse (6.6 -11.8 months after SCT) and 11 due to NRM. The causes of late NRM were second malignancies (n=6), cardiovascular disease (n=3), pulmonary disease (n=1) and liver disease (n=1). The risk of late NRM was 17% (6-47), 25% (7-83) and 44% (24-81) after BuCy, FB4 and FB2, respectively (P=0.29). The risk of late NRM was 14% (4-52) and 35% (21-59) in patients younger and older than 55 years at SCT, respectively (P=0.18). Late relapse mortality was low; 6 (8-37), 13% (2-78) and 7% (1-5), respectively (P=0.81). In all, the subsequent 15-year OS in those who were alive and disease-free 5-years after SCT was 78% (59-97), 63% (29-96) and 49% (22-76), respectively. The small number of events did not allow a meaningful multivariate analysis. Conclusions. With a long-term follow-up of 20 years, RIC/RTC is an acceptable alternative to MAC in ineligible patients. NRM is lower after RIC in the early post SCT period, but late NRM negates this early advantage and at longer follow-up there is no difference between the regimens. Relapse after RIC is higher at the first 5 years after SCT. However, late relapses beyond 5 years from SCT are rare after all regimens. In all, the very long-term OS is better after MAC. However, older age at SCT for RIC may be a major cause of these observations. Longer follow up of randomized studies is needed for more definite conclusions.

Early cessation of calcineurin inhibitors is feasible post–haploidentical blood stem cell transplant: the ANZHIT 1 study

AbstractHaploidentical hematopoietic stem cell transplant (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) is appropriate for those who lack matched donors. Most studies using PTCy have been retrospective making conclusions difficult. ANZHIT-1 was a phase 2 study conducted at 6 Australian allogeneic HSCT centers. The primary end points were disease-free and overall survival at 2 years after HSCT. The reduced-intensity conditioning (RIC) included fludarabine, cyclophosphamide, and 200 cGy total body irradiation, and the myeloablative conditioning (MAC) was IV fludarabine and busulfan. PTCy, MMF and a calcineurin inhibitor (CNI) were used for graft-versus-host disease (GVHD) prophylaxis. CNIs were weaned and ceased by day +120 in eligible patients on day 60. Patients (n = 78) with hematological malignancies were included in the study, with a median follow-up of 732 days (range, 28-1728). HSCT was RIC in 46 patients and MAC in 32 patients. Disease-free survival probability at 2 years was 67.5% (95% [CI], 53.2-85.6) for MAC recipients and 68.3% (95% CI, 56.3-83.01) for RIC recipients. Transplant-related mortality (TRM) on day 100 and year 1 was 4.9% (95% CI, 1.6-15.3) and 17.9% (95% CI, 8.8-36.5), respectively, in the MAC group compared with 3.1% (95% CI, 0.8.1-12) and 11.6% (95% CI, 6-22.4), respectively, in the RIC group. The median time for elective cessation of CNI was day 142.5 days, with no excess chronic GVHD (cGVHD) or mortality. Of the evaluable patients, 71.6% discontinued immunosuppression 12 months after transplant. This prospective haplo-HSCT trial using PTCY demonstrated encouraging survival rates, indicating that early CNI withdrawal is feasible and safe.

Allogeneic Stem Cell Transplantation in Patients >40 Years of Age With Acute Lymphoblastic Leukemia: Reduced Intensity Versus Myeloablative Conditioning.

The outcome in older patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory due to high relapse and nonrelapse mortality (NRM) rates. Allogeneic stem cell transplantation (alloHSCT) as postremission therapy has an important role in reducing relapse rate, albeit its application is limited in older adult patients due to alloHSCT-related morbidity and mortality. Reduced-intensity conditioning (RIC) alloHSCT has been developed as a less toxic conditioning regimen, but comparative studies with myeloablative conditioning (MAC) are limited in patients with ALL. In this retrospective study, RIC-alloHSCT (n = 111) was compared with MAC-alloHSCT (n = 77) in patients aged 41 to 65 y with ALL in first complete remission. MAC was predominantly applied by combining high-dose total body irradiation and cyclophosphamide, whereas RIC mainly consisted of fludarabine and 2 Gy total body irradiation. Unadjusted overall survival was 54% (95% confidence interval [CI], 42%-65%) at 5 y in MAC recipients compared with 39% (95% CI, 29%-49%) in RIC recipients. Overall survival and relapse-free survival were not significantly associated with type of conditioning after adjusted for the covariates age, leukemia risk status at diagnosis, donor type, and donor and recipient gender combination. NRM was significantly lower after RIC (subdistribution hazard ratio: 0.41, 95% CI, 0.22-0.78; P = 0.006), whereas relapse was significantly higher (subdistribution hazard ratio: 3.04, 95% CI, 1.71-5.40; P < 0.001). Collectively, RIC-alloHSCT has resulted in less NRM, but it was also found to be associated with a significantly higher relapse rate. These results suggest that MAC-alloHSCT may provide a more effective type of consolidation therapy for the reduction of relapse and that RIC-alloHSCT may be restricted to patients at higher risk for NRM.

Reduced-Intensity Conditioning Mitigates Risk for Primary Ovarian Insufficiency but Does Not Decrease Risk for Infertility in Pediatric and Young Adult Survivors of Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for many pediatric malignant and nonmalignant conditions. Gonadal insufficiency or infertility is present in almost all HSCT survivors who received a myeloablative conditioning (MAC) regimen. Reduced-intensity conditioning (RIC) regimens are being increasingly used in medically fragile patients or in patients with nonmalignant diagnoses to limit the toxicities associated with HSCT; however, the short-term and long-term gonadal toxicity of RIC regimens in pediatric and young adult survivors remains unknown. In this study, we compared the prevalence of gonadal insufficiency and infertility among pubertal and postpubertal pediatric and young adult survivors of HSCT who received a RIC regimen versus those who received a MAC regimen. Twenty-three females (RIC, n=8; MAC, n=15) and 35 males (RIC, n=19; MAC, n=16) were included in this single-center, retrospective cross-sectional study. Eligible patients were those with available laboratory results who were ≥1 year post-HSCT, age <40 years, and pubertal or postpubertal as assessed by an endocrinologist. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and anti-Müllerian hormone (AMH) levels were measured in females, and FSH, LH, total testosterone, and inhibin B (InhB) levels were measured in males. Twenty-one males (RIC, n=11; MAC, n=10) underwent semen analysis through a separate consent. Parametric and nonparametric analyses were undertaken to compare the RIC and MAC groups. Female patients who received RIC were less likely than those who received MAC to develop primary ovarian insufficiency, as demonstrated by elevated FSH (P=.02) and low estradiol (P=.01) or elevated LH (P=.09). Most females in the RIC (75%) and MAC (93%) groups had low AMH levels, indicating low or absent ovarian reserve, with no significant difference between the groups (P=.53). In males, there were no significant differences between the 2 groups in the prevalence of abnormal FSH, LH, testosterone, or InhB levels. Ten of 11 RIC males (91%) and 10 of 10 MAC males (100%) had azoospermia or oligospermia, at a median time to semen analysis from HSCT of 3.7 years (range, 1.3 to 12.2 years). RIC may pose less risk than MAC for primary ovarian insufficiency among female survivors of HSCT; however, both female and male recipients of either RIC or MAC regimens are at high risk for infertility. In the largest reported series of semen analyses of pediatric and young adult male recipients of RIC, azoospermia or oligospermia was found in nearly all (91%) RIC survivors. All patients undergoing HSCT should receive counseling about the high risk of gonadal toxicity, and efforts should be made to preserve fertility in patients undergoing either RIC or MAC.

449 - Sars-Cov-2 Infection and Vaccination in Recipients of Reduced-Intensity Conditioning, Posttransplantation Cyclophosphamide (PTCy)-Based Allogeneic Hematopoietic Cell Transplantation (HCT)

449 - Sars-Cov-2 Infection and Vaccination in Recipients of Reduced-Intensity Conditioning, Posttransplantation Cyclophosphamide (PTCy)-Based Allogeneic Hematopoietic Cell Transplantation (HCT)

Pharmacological Control of Recipient NK Cell Function By Venetoclax Promotes Engraftment and Limits GVHD Following Reduced Intensity Conditioning without Impacting the Graft Versus AML Effect

BackgroundThe outcome of allogeneic haematopoietic stem cell transplantation (alloHSCT) is a complex interaction between conditioning regimen intensity (efficacy vs toxicity), recipient immunology (rejection vs engraftment) and donor immunology (rejection vs engraftment, and GVHD vs GVL). We must find means to lower conditioning toxicity, promote donor engraftment and limit GVHD in order to improve alloHSCT outcomes.Aims: Optimize the use of BCL2 inhibitors to modify recipient NK cell function in mouse models of alloHSCT in order to minimize GVHD severity and onset, and retain GVL responses.Hypothesis: Therapeutic targeting of recipient NK cell frequency or function pre-transplant will allow reduced intensity conditioning (RIC) and promote both donor T cell engraftment and GVL whilst reducing the risks of GVHD.MethodsMHC-mismatched mouse model of alloHSCT: Donor BM and T cells from BALB/c (H2Kd) mice were injected into irradiated C57BL/6 (H2Kb) recipients. On day 0, C57BL/6 WT, or Bcl2fl/fl (Bcl2 deleted in NKp46+NK1.1+ cells) recipients were irradiated with a RIC dose of 2 x 400 rad, before i.v. injection of 7.5e6 BALB/c BM + 1e6 T cells. C57BL/6 WT mice were also treated on day -2 and -1 by oral gavage with 100 mg/kg Venetoclax (ABT-199) or vehicle, before receiving alloHSCT. Mice were monitored for onset of GVHD and tested for early engraftment (day 7-14 post-transplant), and late engraftment (up to day 50).Graft-versus leukaemia (GVL) AML model:8e5mixed lineage leukaemia cells (MLL-AF9) were injected i.v. on day 0 into C57BL/6 WT recipients. On days 8 and 9 mice were treated by oral gavage with 100 mg/kg Venetoclax or vehicle, before receiving alloHSCT on day 10. Mouse survival and AML burden in the BM was measured on day 30.ResultsWe found that at both a myeloablative radiation dose (1200 rad) and a RIC non-myeloablative dose (800 rad), recipient NK cells were significantly more radio-resistant than either CD8+ T or myeloid cells. However, when a RIC dose of 800 rad was used during alloHSCT, the rejection threshold was not overcome and engraftment failed. We investigated both genetic and pharmacological models of recipient NK cell suppression during alloHSCT with RIC, to promote donor cell engraftment, reduce GVHD, and retain GVL.Conditional deletion of Bcl2 in NK cells results in a 90% loss of NK cells in vivo . Bcl2fl/fl alloHSCT RIC recipients showed robust donor engraftment, but absence of the pro-inflammatory cytokine storm and substantially less GVHD as determined by clinical scores and gut histology, compared to WT recipients. Pharmacological inhibition of BCL2 in WT recipients recapitulated the transplant findings in Bcl2fl/fl recipients. We found that BCL2 inhibition by Venetoclax, a BCL2 antagonist approved in the treatment of AML, resulted in NK cell apoptosis in human cells . We extended our observations in Bcl2fl/fl recipients to show that pharmacological inhibition of BCL2 in WT mice with just two doses of Venetoclax resulted in rapid depletion of NK cells. Over 35% of alloHSCT WT recipient mice pre-treated with Venetoclax developed long-term full donor engraftment even in the setting of RIC, with minimal GVHD, and retained potent GVL effects against pre-established AML.ConclusionsVenetoclax depletion of NK cells in WT alloHSCT recipients in combination with RIC was: 1) well-tolerated, 2) associated with low rates of GVHD, 3) resulted in long-term donor haematopoietic cell engraftment, and 4) maintained a GVL response. Recipient NK cell inhibition may therefore represent a means by which to deliver alloHSCT more safely. DisclosuresRitchie:Amgen Inc.: Honoraria.

Myeloablative Hematopoietic Cell Transplantation (HCT) for Low and Intermediate Disease Risk Index Myeloid Malignancies Results in Better Outcomes Compared to Reduced Intensity HCT

The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) remains an unsettled question. The recent Blood and Marrow Transplant Clinical Trial Network BMTCTN 0901 randomized phase III study showed that Myeloablative conditioning (MA) results in better relapse-free survival and a trend towards better overall survival compared to reduced intensity conditioning (RIC). The findings of BMTCTN 0901 though contradicts several prior studies addressing the same question, was limited by the fact that most patients in the RIC received fludarabine/low dose Busulfan and the study was not designed to assess the effect of intensity on patients with different disease risk index (DRI) groups. Acute myeloid leukemia and myelodysplastic syndrome patients with low/intermediate DRI tend to respond well to chemotherapy and can potentially be cured with chemotherapy regimens alone. On the other hand, high and very high risk DRI myeloid malignancies have a high relapse rate and very low rates of success with chemotherapy only approach. We hypothesize that conditioning intensity benefit is limited to patients with low/intermediate risk DRI and no such benefit is seen in the high/very high risk DRI myeloid malignancy patients. To answer this question, we retrospectively analyzed AML/MDS HCT recipients with low/intermediate DRI to assess the impact of conditioning intensity on overall survival (OS), disease free survival (DFS), relapse, and non-relapse mortality (NRM). Survival was calculated using the Kaplan-Meier estimator. Univariate analysis with Gray test and log-rank test will be used for cumulative incidence and survival respectively. Cox regression models were built to study the effect of conditioning intensity adjusted for other significant factors on OS, NRM, DFS, relapse and graft-versus-host disease (GVHD). Conditioning intensity was retained in the cox models and other variables were selected to be included if the P-value was less than 0.05.A total of 232 consecutive allogeneic HCT recipients with low/intermediate DRI myeloid malignancy (AML 170, MDS 60) were included in the analysis with a median follow up of 37 months. Median age was 55 years (18, 75) and 83% were of white race. Patient and transplant related characteristics were as follows: 42% RIC, 11% Myeloablative high dose TBI, 47% non-TBI Myeloablative conditioning; 21% bone marrow graft; 31% matched related donor transplant MRDT, 47% matched unrelated donor transplant MUDT, 22% haploidentical donor HIDT; 49% had hematopoietic cell transplant comorbidity index HCT-CI ≥3 ; donor/recipient female to male 21%; and donor/recipient CMV +/+ 42%, -/- 19%, other 39%. Both MA and RIC groups had similar patient, disease and transplant related characteristics except for a higher percentage of MA recipients received methotrexate as part of their GVHD prophylaxis compared to RIC (78% vs 55%, p<0.001). Recipients of Myeloablative conditioning had better overall survival estimate (3-year 69% vs 57%, p=0.001), DFS (3-year 65% vs 51%, p=0.003) and lower relapse cumulative incidence (3-year 17% vs 32%, p=0.01) but similar NRM (3-year 19% vs 17%, p=0.04) to RIC recipients (figure 1). There was no difference in the cumulative incidence of grade 2-4 acute and moderate-severe GVHD between Myeloablative and RIC groups. Multivariate analysis revealed MA conditioning to be associated with better DFS (HR 0.58, 95% CI 0.39-0.88, p=0.01), lower relapse (HR 0.56, 95% CI 0.32-0.97, p=0.038) and similar NRM (HR1.11, 95% CI 0.54-2.26, p=0.781) compared to RIC. When same analysis was performed for high/very high DRI myeloid malignancy patients (N=247), conditioning intensity had no effect on OS, DFS, Relapse and NRM (P value>0.10 for all).Myeloablative conditioning results in better overall survival and disease control when compared to RIC among AML/MDS patients with low/intermediate DRI risk group. This benefit is not shown among high/very high DRI risk patients. [Display omitted] DisclosuresSolh:Celgene: Speakers Bureau; ADC Therapeutics: Research Funding; Amgen: Speakers Bureau.

Comparison of Myeloablative versus Reduced-Intensity Conditioning Regimens in Allogeneic Stem Cell Transplantation Recipients with Acute Myelogenous Leukemia with Measurable Residual Disease-Negative Disease at the Time of Transplantation: A Retrospective Cohort Study

The ideal conditioning intensity in allogeneic hematopoietic stem cell transplantation (HSCT) is evolving. Previous prospective studies comparing myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC) regimens in adults with acute myelogenous leukemia (AML) have shown mixed results. In many of these studies, patients were not stratified based on measurable residual disease (MRD). We evaluated the effect of conditioning intensity on the outcomes of AML patients in complete remission (CR) with flow cytometry evidence of MRD negativity. A total of 135 patients age 20 to 75 years with AML in CR1 or CR2 and flow cytometry evidence of MRD negativity who underwent allogeneic HSCT at our center between 2011 and 2019 were evaluated. We compared overall survival (OS), relapse-free survival (RFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD) in recipients of MAC (n=89) and RIC (n=46). Although the patients receiving RIC were older (62 versus 51 years; P < .0001), there were no statistically significant differences between the groups in terms of Eastern Cooperative Oncology Group and European Leukemia Network risk criteria and disease status (CR1 or CR2) at the time of transplantation. At a median follow-up of 24.6 months, no statistically significant differences in OS (hazard ratio [HR], 0.78; 95% confidence interval [CI] 0.42 to 1.42, P=.411) or RFS (HR, 1.004; 95% CI, 0.48 to 2.09, P=.99) were identified. The cumulative incidence of NRM (HR, 0.595; 95% CI, 0.24 to 1.48; P=.2644) and relapse (HR, 1.007; 95% CI, 0.45 to 2.23; P=.9872) was not different between the 2 groups. Grade II-IV and grade III-IV acute GVHD were more frequent in the MAC group (39.3% verses 19.9% [P=.018] and 19.3% versus 2.3% [P < .001], respectively), as was moderate/severe chronic GVHD (23.6% versus 15.8%; P=.038). Our data indicate that conditioning intensity did not appear to affect OS, RFS, NRM, and relapse risk in patients with MRD-negative AML as measured by flow cytometry. RIC resulted in less severe acute and chronic GVHD.

Long-term results of reduced-intensity conditioning allogeneic hematopoietic cell transplantation for older patients with acute myeloid leukemia: a retrospective analysis of 10-year follow-up data.

The long-term outcomes of allogeneic hematopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC) remain inconclusive. To address this issue, we conducted a nationwide registry-based study of patients with acute myeloid leukemia (AML) age 50 years or older who underwent allogeneic HCT in complete remission using RIC (n = 284) or myeloablative conditioning (MAC, n = 190) between 2002 and 2007. The median follow-up period for surviving patients was 10.1 years for RIC recipients and 10.4 years for MAC recipients. The 10-year probabilities of overall survival, relapse, and non-relapse mortality were 36.4%, 30.0%, and 35.7% for RIC recipients, and 39.8%, 26.3%, and 35.5% for MAC recipients, respectively. Multivariate analysis revealed that the conditioning intensity did not affect overall mortality (P = 0.184), relapse (P = 0.904), or non-relapse mortality (P = 0.387). For the 218 patients qualifying for propensity score-matched pairing (109 pairs), RIC was found to be associated with similar survival (P = 0.095) and relapse (P = 0.467), and significantly lower non-relapse mortality (P = 0.046) compared with MAC. Our results confirm the long-term efficacy of RIC allogeneic HCT for older patients with AML and mitigate concerns over an increase in late relapse.

Increasing Use of Potentially Inappropriate Medications in Older Allogeneic HCT Recipients Leads to Higher NRM

Background The American Geriatric Society has established criteria (Beers criteria) for Potentially Inappropriate Medications (PIMs) in older (65+y) adults (J Am Geriatr Soc. 2019 Apr;67(4):674-694). The use of PIMs in allogeneic hematopoietic cell transplant (allo-HCT) and its impact on outcomes is unknown. Methods The use of PIMs, in defined categories [anticholinergics, central nervous system (CNS), benzodiazepines, gastrointestinal (GI), genitourinary (GU), and narcotics] in older (≥ 65y) allo-HCT recipients were compared to younger recipients [(40-64y undergoing reduced intensity conditioning (RIC)] during initial HCT admission (day-14 to +28 post HCT). Use of PIMs was defined as the number of days a patient received 1 or more PIMs between d-14 to +28. Medications were retrieved from medical records and categorized by Beers criteria for 354 allo-HCT recipients ≥ 40y in 2 groups (40-64y RIC, n=240; and 65+y RIC, n=114). Poisson regression determined the log use of PIMs in the 2 groups. In 65+y group, we evaluated the impact of PIMs on the incidence of CTCAE grade 3 and 4 toxicities; and non-relapse mortality (NRM). All analyses were adjusted or length of hospital stay. Results All PIMs: The median (range) days of all PIMs in 65+y RIC recipients [94 (24-279)] was similar to 40-64y RIC recipients [101 (8-441), p=0.48, confirmed in Poisson regression (Figure 1) [65+y RIC vs 40-64y RIC log change 0.0, p=1.0). Patients with a high (vs. low) HCT-CI score received more days of all PIMs (p=0.02). PIM Categories (Figure 1) were compared and 65+y recipients received fewer days of benzodiazepines (log change -0.18, p=0.04) or narcotics (-0.21, p=0.04), but more days of anticholinergics (0.22, p=0.03) and GI PIMs (0.16, p 65+y group: In adjusted regression analysis, increasing days of narcotics was associated with a 1.6 fold (95% CI 1.1-2.6, p=0.03) higher risk of NRM. Increasing days of narcotics was also associated with a 1.66 fold (95% CI 1.02-2.69) greater odds of grade 3-4 toxicities, p=0.04 (Figure 2). More days of all PIMs was associated with a 5 times greater odds of discharge to rehab or a nursing facility (95% CI 1.43-10.0, p Conclusions Older recipients (65+y) receive PIMs as frequently as younger recipients (40-64y). Females, those with a high HCT-CI and UCB recipients receive PIMs more frequently. Amongst older recipients, use of PIMs, particularly narcotics, was associated with a higher NRM and higher risks of grade 3-4 toxicities. Identifying and reducing use of PIMs in older HCT recipients may help lower the burden of adverse events and associated health care costs.

Allogeneic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome (MDS) Using Treosulfan Based Compared to Standard Reduced-Intensity or Myeloablative Conditioning Regimens. a Report of the Chronic Malignancies Working Party of EBMT

<h3>Introduction</h3> Allogeneic stem cell transplantation (SCT) is potentially curative therapy for patients with MDS. Prior studies have shown no overall-survival (OS) advantage of any conditioning regimen over the others. Reduced-intensity conditioning (RIC) is usually associated with lower non-relapse mortality (NRM) compared to myeloablative conditioning (MAC), however, relapse rates are higher, resulting in similar OS. Fludarabine and treosulfan (FT) is a reduced-toxicity regimen with intense anti leukemia activity in patients with myeloid malignancies. We explored outcomes following FT conditioning in comparison with other regimens. <h3>Methods</h3> We retrospectively analyzed SCT outcomes of MDS patients reported to the chronic malignancies working party of EBMT (n=1722). The conditioning regimens were defined according to standard EBMT criteria and included FT (n=367), RIC (n=687) or MAC (n=668). <h3>Results</h3> FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0.001). More FT recipients had untreated MDS at SCT, 45%, 26% and 36%, respectively (P < 0.001). Disease status at diagnosis, cytogenetics, secondary origin and prior transformation to AML, were not different between the regimens. With a median follow-up of 20 months (1-171), 807 patients are alive, 328 died of relapse and 587 had NRM. The 5-year rates of relapse, NRM and OS for the entire group were 21% (95%CI, 19-23), 35% (95%CI, 33-38) and 44% (95%CI, 42-437), respectively. Relapse rates were similar after FT and MAC, 16% (13-21) and 19% (16-22), respectively, significantly lower than after RIC, 25% (21-28) (P = 0.003). Multivariate analysis (MVA) identified age >55 years (HR 1.42), advanced histology (RAEB 1/2, HR 2.01/ 1.73), prior transformation to AML (HR 1.87), refractory disease to prior therapies (HR 1.75) secondary origin (HR 1.33) and poor cytogenetics (HR 2.83) as associated with higher relapse risk. FT conditioning was associated with a lower risk (HR 0.63, P = 0.006). NRM was lower after FT and RIC than after MAC, 34% (29-39), 33% (30-37) and 38% (35-40), respectively (P = 0.05). MVA identified age >55 years (HR 1.39) and MAC (HR 1.34) as associated with higher NRM, while SCT from sibling donor (HR 0.81) and in CR (HR 0.80) were associated with a lower risk. In all, 5-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), after FT, RIC and MAC, respectively (Figure 1, P = 0.03). MVA identified age >55 years (HR 1.39), advanced histology (RAEB 1/2, HR 1.35/ 1.10), prior transformation to AML (HR 1.37), and poor cytogenetics (HR 1.58) as associated with lower OS. FT conditioning was associated with better OS (HR 0.79, P = 0.01). <h3>Conclusions</h3> FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved outcome over both RIC and MAC. FT might be the preferred regimen for SCT in MDS. These observations merit further study in randomized prospective trials.

Impact of Conditioning Intensity of Allogeneic Transplantation for Acute Myeloid Leukemia With Genomic Evidence of Residual Disease.

Patients with acute myeloid leukemia (AML) in remission remain at risk for relapse even after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) status before alloHCT has been shown to be prognostic. Whether modulation of the intensity of the alloHCT conditioning regimen in patients with AML who test positive for MRD can prevent relapse and improve survival is unknown. Ultra-deep, error-corrected sequencing for 13 commonly mutated genes in AML was performed on preconditioning blood from patients treated in a phase III clinical trial that randomly assigned adult patients with myeloid malignancy in morphologic complete remission to myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC). No mutations were detected in 32% of MAC and 37% of RIC recipients; these groups had similar survival (3-year overall survival [OS], 56% v 63%; P = .96). In patients with a detectable mutation (next-generation sequencing [NGS] positive), relapse (3-year cumulative incidence, 19% v 67%; P < .001) and survival (3-year OS, 61% v 43%; P = .02) was significantly different between the MAC and RIC arms, respectively. In multivariable analysis for NGS-positive patients, adjusting for disease risk and donor group, RIC was significantly associated with increased relapse (hazard ratio [HR], 6.38; 95% CI, 3.37 to 12.10; P < .001), decreased relapse-free survival (HR, 2.94; 95% CI, 1.84 to 4.69; P < .001), and decreased OS (HR, 1.97; 95% CI, 1.17 to 3.30; P = .01) compared with MAC. Models of AML MRD also showed benefit for MAC over RIC for those who tested positive. This study provides evidence that MAC rather than RIC in patients with AML with genomic evidence of MRD before alloHCT can result in improved survival.

Cognitive Function and Quality of Life in Vorinostat-Treated Patients after Matched Unrelated Donor Myeloablative Conditioning Hematopoietic Cell Transplantation

Myeloablative conditioning allogeneic hematopoietic cell transplantation (HCT) puts patients at greater risk for significant cognitive and quality of life decline compared with recipients of reduced-intensity conditioning or autologous HCT. Vorinostat, a histone deacetylase inhibitor, has been shown to have neuroprotective and neurorestorative effects in preclinical models of neurologic diseases. Thus, within the context of a myeloablative conditioning phase II clinical trial of vorinostat combined with tacrolimus and methotrexate for graft-versus-host disease prophylaxis, we conducted an ancillary study to evaluate feasibility of assessing associations between vorinostat and neurocognitive function and quality of life (ClinicalTrials.gov NCT02409134). Nine patients (mean age, 53 years; range, 36 to 66) underwent computerized neuropsychological testing (Cogstate) and completed surveys of mood (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), and quality of life (Functional Assessment of Cancer Therapy–General). Control cohorts from a separate concurrent longitudinal study (19 autologous and 18 allogeneic HCT patients, who matched the vorinostat patients on relevant medical and demographic variables) completed the same test battery. All allogeneic patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched unrelated donors. The total neurocognitive performance score of vorinostat patients did not change significantly across the study duration (ie, baseline, day 30, day 100, and day 160). Depression, anxiety, and quality of life also did not differ significantly across time. In univariate analyses (analysis of variance), vorinostat-treated patients showed no difference in neurocognitive function or quality of life compared with autologous and allogeneic control subjects. However, when medical variables were accounted for in a linear mixed effects regression model, the total neurocognitive performance of vorinostat-treated patients was comparable with autologous control subjects. Notably, autologous control subjects performed significantly better than allogeneic control subjects (estimate, .64; standard error, .23; P ≤ .01). Moreover, a smaller percentage of vorinostat-treated patients were classified as mildly, moderately, or severely impaired across neurocognitive domains as well as time points compared with both control cohorts. Thus, vorinostat may have neurorestorative or neuroprotective effects in the HCT setting. Accordingly, we recognize the need for a future, full-scale randomized controlled trial to further examine this hypothesis.

The Dilemma of Conditioning Intensity: When Does Myeloablative Conditioning Improve Outcomes for Allogeneic Hematopoietic Cell Transplantation

The impact of conditioning intensity on different disease risk index (DRI) groups has not been evaluated. We retrospectively analyzed acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) hematopoietic cell transplantation (HCT) recipients in 2 groups based on DRI, to assess the impact of conditioning intensity on overall survival (OS), disease free survival (DFS), relapse, and nonrelapse mortality (NRM).A total of 380 patients with either high/very high (n = 148) or low/intermediate DRI (n = 232) myeloid malignancy (AML, n = 278; MDS, n = 102) were included in the analysis. Median follow-up for survivors was 35 months. Median age was 58years (range, 18 to 75). Patient and transplant-related characteristics were 41% reduced-intensity conditioning (RIC), 59% myeloablative conditioning (MAC), 13% bone marrow graft, 29% matched related donor, 49% matched unrelated donor, 22% haploidentical donor, and 52% HCT-specific comorbidity index ≥ 3. Among patients with high/very high DRI, there was no difference in OS, DFS, relapse, and NRM between RIC and MAC conditioning groups. For low/intermediate risk DRI recipients of MAC had better 3-year OS estimate (69% versus 57%, P = .001), DFS (65% versus 51%, P = .003), and lower relapse (3-year cumulative incidence, 17% versus 32%; P = .01) but similar NRM (19% versus 17%, P = .04) to RIC recipients. On multivariable analysis MAC was associated with better DFS (hazard ratio [HR], .58; 95% confidence interval [CI], .39-.88; P = .01), lower relapse (HR, .56; 95% CI, .32 to .97; P = .038), and similar NRM (HR, 1.11; 95% CI, .54 to 2.26; P = .781) compared with RIC in the low/intermediate DRI group. Intensity had no impact on HCT outcomes in the high/very high DRI group.MAC improves DFS and relapse compared with RIC among AML/MDS patients with low/intermediate DRI. The finding of no such benefit in high/very high DRI needs to be further explored in a larger cohort with a longer follow-up.

Ovarian function after hematopoietic cell transplantation: a descriptive study following the use of GnRH agonists for myeloablative conditioning and observation only for reduced-intensity conditioning.

Gonadal failure is a health and quality-of-life concern in hematopoietic cell transplant (HCT) survivors. While ovarian dysfunction is nearly universal following myeloablative (MA) conditioning, the risk is unclear after reduced-intensity conditioning (RIC). Gonadotropin-releasing hormone agonists decrease ovarian failure rates following conventional chemotherapy, but little is known about its effectiveness with HCT. We investigated the impact of leuprolide on ovarian function after MA conditioning and monitored ovarian function after RIC in this descriptive pilot study. Post-menarchal females <50 years undergoing HCT with adequate baseline ovarian function (follicle-stimulating hormone (FSH) level <40 mIU/mL and normal menstruation) were eligible. Prior to MA conditioning, leuprolide was administered. Those undergoing RIC were observed. FSH was measured at various time points. Seventeen women aged 12-45 years were evaluated (7 in the intervention group and 10 in the observation group). Compared to the historical high rate of ovarian failure after MA conditioning, 3 of 7 evaluable Lupron recipients had ovarian failure at a median of 703 days post transplant. Ovarian failure occurred in 1 of 10 recipients of RIC at a median follow-up of 901 days. In conclusion, leuprolide may protect ovarian function after MA conditioning. Additionally, RIC with cyclophosphamide, fludarabine and low-dose TBI has a low risk of ovarian failure.

RIC versus MAC UCBT in adults with AML: A report from Eurocord, the ALWP and the CTIWP of the EBMT

Nonrelapse mortality (NRM) is the first cause of treatment failure after unrelated cord blood transplantation (UCBT) following myeloablative conditioning (MAC). In the last decade, reduced-intensity conditioning (RIC) regimens have been developed with the aim of reducing NRM and allowing older patients and those with medical comorbidities to benefit from UCBT. The aim of the current retrospective study was to compare transplantation outcomes of acute myeloid leukemia (AML) patients given UCBT after either RIC or MAC. Data from 894 adults with AML receiving a single or double UCBT as first allograft from 2004 to 2013 at EBMT centers were included in this study. 415 patients were given UCBT after RIC while 479 patients following a MAC. In comparison to MAC recipients, RIC recipients had a similar incidence of neutrophil engraftment and of acute and chronic graft-versus-host disease (GVHD). However, RIC recipients had a higher incidence of disease relapse and a lower NRM, translating to comparable leukemia-free (LFS), GVHD-free, relapse-free survival (GRFS) and overall survival (OS). These observations remained qualitatively similar after adjusting for differences between groups in multivariate analyses. In conclusion, these data suggest that LFS and OS are similar with RIC or with MAC in adults AML patients transplanted with UCBT. These observations could serve as basis for a future prospective randomized study.

Low Dose Unfractionated Heparin (UFH) Prophylaxis Is a Safe Strategy for the Prevention of Hepatic Sinusoidal Obstruction Syndrome (SOS) in Adult Allogeneic Stem Cell Transplant (HSCT) Recipients

Background: Hepatic SOS is a serious complication after allogeneic HSCT. It has been reported elsewhere that in the period between 1979-2007, the overall mean incidence of hepatic SOS was 13.7% (95%CI:13-15). While prophylactic procedures are widely used, there is no uniform consensus on the optimal strategy for the prevention of this disease. Low dose UFH have been used but its benefit in the prevention of SOS and the potential associated risk of serious bleeding complications have not been fully established.Methods: We evaluated 730 adult allograft recipients transplanted 01/2003-12/2013 for hematologic malignancies [401 (55%) acute leukemia/ MDS, 235 (32%) lymphoma, 64 (9%) multiple myeloma, 30 (4%) CML/myeloproliferative disorder]. The majority received myeloablative conditioning (n = 466, 65%) with either total body irradiation-based (n = 243) or busulfan-based (n = 233), followed by non-myeloablative conditioning (n = 143, 19%) and reduced intensity (RIC) (n = 111, 15%). Approximately half of the patients had T-cell depleted (TCD) grafts (402, 55%). All patients had SOS prophylaxis with low dose heparin 100 units/kg given as continuous IV over 24 hours from admission to day +21 or engraftment. Prior allogeneic HSCT, non-malignant or refractory disease, dual prophylaxis with UFH/ursodiol or therapeutic anticoagulation at the time of allograft admission were all excluded.Results: The median age was 51 (range 21-65) years, and 415 (56%) were male. During the 10 year study period only 15 patients developed hepatic SOS with a day 100 incidence of 2% (95%CI:1-3). When evaluated by conditioning intensity, myeloablative and reduced intensity conditioning recipients had a day 100 incidence of 3% (95%CI:2-4) (Figure) whereas none of the NMA recipients developed SOS. Univariate analysis showed that age, HLA-match, previous hepatitis B or C exposure did not influence SOS development (Table). There was a significantly higher incidence of hepatic SOS in recipients of unmodified (3%) versus TCD grafts (1%), p= 0.025. The median time to SOS onset was 29 days (range 5-57). Six patients received supportive care only whereas 9 had defibrotide therapy. Of those, 7 patients developed severe SOS resulting in multi-organ failure (5 supportive care, 2 defibrotide). Four of 15 patients diagnosed with hepatic SOS are alive at last follow up (7 deaths attributed to SOS). Bleeding complications occurred in 26/730 patients (4%) of which only 4 (0.5%) patients had significant grade 3-4 bleeding. The day 100 grade II-IV and III-IV acute liver GVHD is 2% (95%CI:1-3) and 0.5% (95%CI:0.2-1), respectively. The incidence of day 100 TRM was 9% (95%CI:7-11) for the entire cohort of patients.Conclusion: To our knowledge, this is the largest analysis evaluating the use of low dose UFH for the prevention of hepatic SOS. We demonstrated that UFH prophylaxis is associated with a low incidence of hepatic SOS, is well tolerated, and severe bleeding complications are uncommon. Low dose UFH may be consider as a strategy for the prevention of hepatic SOS in selected patients. Further prospective studies comparing UFH to other hepatic SOS prophylaxis methods are warranted.TableUnivariate analysis of variables potentially associated with day 100 SOS.Variable(95% CI)p-valueAge (years)0.745< 402% (1-6)≥ 402% (1-3)HLA-match0.8578/82% (1-4)≤ 7/82% (1-5)Graft0.025TCD1% (0.3-2)Unmodified3% (2-6)Conditioning regimen0.054Myeloablative/RIC3% (2-4)Non-Myeloablative0 (NA)Myeloblative conditioning type0.353Busulfan-based2% (1-5)TBI-based3% (2-6)Hepatitis B & C Serologies0.089Negative2% (1-3)Positive8% (0.4-30) [Display omitted] DisclosuresBhatt:Spectrum: Consultancy. Off Label Use: Use of low dose unfractionated heparin for the prevention of hepatic SOS. van den Brink:Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; Merck: Honoraria; Tobira Therapeutics: Other: Advisory board attendee. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.

Allogeneic Stem Cell Transplantation in Myelodysplastic Syndrome; A More Favorable Outcome after Fludarabine and Treosulfan Conditioning. a Survey on Behalf of the Chronic Malignancies Working Party of the EBMT

Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for patients with myelodysplastic syndrome (MDS). So far, there is no proven advantage for any conditioning regimen over the others. Prior studies have shown that reduced-intensity conditioning (RIC) is associated with lower non-relapse mortality (NRM) compared with myeloablative conditioning (MAC), however, relapse rates are increased, resulting in similar survival. Novel conditioning regimens that will reduce SCT-related toxicity while retaining maximal anti-leukemia effect will be of benefit. Fludarabine combined with treosulfan (FT) has been shown, in relatively small phase II studies, to be a reduced-toxicity regimen with intense anti leukemia activity and limited toxicity in patients with myeloid malignancies and possibly in particular in MDS. In this analysis we performed a retrospective analysis of all SCTs for MDS, performed between 2000 and 2011 and reported to the chronic malignancies working party (CMWP) of the EBMT (n=2516). We identified 480 patients given FT and compared their outcomes to patients given various MAC (n=1090) and RIC (n=946) regimens. FT and RIC recipients were older than MAC recipients, median age 59, 60 and 50 years, respectively (p=0.001). They were also more likely to have an unrelated donor, 56%, 57% and 50%, respectively (p=0.001) and to be given peripheral blood stem cell rather than bone marrow grafts, 92%, 94% and 79%, respectively (p=0.001). More FT recipients had previously untreated MDS at SCT, 33%, 20% and 24% while less had chemosensitive disease, 42%, 51% and 51%, respectively (p=0.001). The proportion of patients with chemo-refractory disease and with more than 10% marrow or peripheral blood blasts at SCT was similar in the three groups. More FT recipients had a prior history of transformation to AML, 15%, 9% and 9%, respectively (p=0.03). The proportion of patients with high and intermediate-risk cytogenetics was 13%, 21% and 18%, respectively (p=0.01). With a median follow-up of 21 months (range, 1-150), 1364 patients are alive, 456 patients died of relapse and 696 of NRM causes. The estimated 5 year overall (OS) and disease-free (DFS) rates for the entire group were 40% (95%CI, 37-43) and 35% (95%CI, 33-38), respectively. The 5-year OS rate of FT recipients was 47% (95%CI, 41-52). OS after the various RIC and MAC regimens was similar, 39% (95%CI, 34-43) and 38% (95%CI, 33-42), respectively, significantly shorter than after FT (p=0.02). DFS rates were 42% (95%CI, 37-47), 31% (95%CI, 27-36) and 35% (95%CI, 30-39), respectively (p=0.002). Relapse rates were similar after FT and MAC, 25% (95%CI, 21-30) and 29% (95%CI, 25-33), respectively, significantly lower than after RIC, 37% (95%CI, 33-41) (p=0.001). NRM was lower after FT and RIC than after MAC, 33% (95%CI, 28-38) and 32% (95%CI, 28-35), Vs. 36% (95%CI, 33-40), respectively (p=0.14). Multivariate analysis identified age> 55 years (HR 1.7, P=0.01), marrow blasts at SCT > 10% (HR 1.5, p=0.02), a history of transformation to AML (HR 1.7, p=0.01) and MDS refractory to prior therapy (HR 1.8, p=0.001) as poor prognostic factors for survival, while FT conditioning was protective (HR 0.6, p=0.02). Gender, cytogenetics, time from diagnosis to SCT, donor type and stem cell source were not predictive for survival. The predicting factors for increased relapse risk were RIC (HR 1.6, p=0.03), chemorefractory disease (HR 1.6, p=0.05), marrow blasts at SCT > 10% (HR 1.6, p=0.04), poor risk cytogenetics (HR 2.2, p=0.003) and prior transformation to AML (HR 1.8, p=0.0001). The predicting factors for increased NRM were MAC (HR 1.6, p=0.004), age > 55 years (HR 1.5, p=0.008), unrelated donor (HR 1.4, p=0.004), chemo-refractory disease (HR 1.5, p=0.05), marrow blasts > 10% (HR 1.6, p=0.01) and positive patient serology for CMV (HR 1.4, p=0.04). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved outcome over both RIC and MAC regimens. FT might be the preferred regimen for SCT in MDS. These observations merit further study in randomized prospective trials. DisclosuresNagler*:MEDAC, Germany: Honoraria, Research Funding. Beelen:MEDAC, Germany: Research Funding. Ciceri:MEDAC, Germany: Honoraria, Research Funding. Kröger:MEDAC, Germany: Research Funding.

Myeloablative Versus Reduced Intensity Allogeneic Stem Cell Transplantation in Relapsed Hodgkin’s Lymphoma in Recent Years. a Retrospective Analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

Introduction. Allogeneic stem cell transplantation (allo-SCT) is a well established therapeutic alternative for those patients with refractory Hodgkin’s lymphoma (HL) who relapse after an autologous stem cell transplantation (ASCT), have chemosensitive disease and a HLA compatible donor available. The impact of the intensity of the conditioning regimen in the outcome of this procedure is still not well understood. An initial retrospective analysis from the European Group for Blood and Marrow Transplantation (EBMT) Lymphoma Working Party (LWP) (Sureda et al, JCO 2010) that compared myeloablative (MAC) with reduced intensity conditioning (RIC) protocols indicated that the high non-relapse mortality (NRM) associated to MAC-SCT translated into a non-significant improvement in progression free survival (PFS) for RIC recipients in spite of the higher relapse rate of the latter. As NRM for MAC-SCT might have decreased over time due to better patient selection, HLA typing and peri-transplant supportive measures, we hypothesize that overall results of more intensive protocols could compare better to RIC-SCT in recent years.Patients and Methods. We have included in this analysis adult patients with multiply relapsed classical HL treated with an allo-SCT between January 2006 and December 2010 and reported to the EBMT Database. Only first and second allo-SCT was included. Tandem ASCT-allo-SCT was excluded as well as cord blood transplantations and haplo-identical SCT. A total of 313 patients met the inclusion criteria (63 patients treated with a MAC and 250 patients treated with a RIC, definitions following the EBMT criteria). There were 173 males (55%) and 140 females (45%) with a mean age at diagnosis of 29 years and at SCT of 33 years. Mean time from diagnosis to SCT was of 43.3 months. 153 patients (49%) were chemorefractory at the time of allo-SCT and 166 patients (53%) had already failed a prior ASCT. Peripheral blood (PB) was used as the source of stem cells in 88% of the patients. Comparing MAC with RIC groups, the latter one was significantly older at allo-SCT (31 years vs 34 years, p=0.01), had a longer time interval between diagnosis and allo-SCT and preferentially received mobilized PB stem cells (82% vs 91%, p=0.01). There were also more prior autograft failures in the RIC group (56% vs 42%, p=0.006).Results. With a median follow up for alive patients of 32.5 (9.7 – 52.9) months, overall survival (OS) was 75% and 65%, PFS, 54% and 39%, NRM 11% and 12% and relapse rate after SCT of 37% at 1 year. There were no significant differences in NRM between MAC and RIC patients. Relapse rate was higher in the RIC group, although these differences did not reach statistical significance (55% vs 40% at 24 months, p=0.1). This lower relapse rate translated into an improvement in PFS for the MAC group (48% vs 37% at 24 months, p=0.08) with no differences in terms of OS (71% for MAC vs 61% for RIC at 24 months, p=0.4). Multivariate analysis after adjusting for disease status at the time of SCT showed that the use of RIC protocols was the only independent adverse prognostic factor associated to a higher relapse rate after SCT [HR 0.68, 95%CI (0.38 – 0.98), p=0.04] and to a lower PFS after the procedure [HR 0.65, 95%CI (0.43 – 0.98), p=0.04]. The intensity of the conditioning regimen did not have any impact n NRM in the multivariate analysis. Chemosensitive disease at SCT was the only independent prognostic factor for OS after SCT in the multivariate analysis [HR 1.70, 95%CI (1.17 – 2.46), p=0.005].Conclusions. This retrospective analysis shows that NRM after MAC protocols is not a significant clinical issue when allografting patients with HL nowadays. On the other hand, using MAC decreases the relapse risk in this highly resistant population of patients, translating into a significant improvement of PFS. MAC protocols should be considered when designing prospective clinical trials in patients with HL candidates for an allogeneic stem cell procedure. DisclosuresNo relevant conflicts of interest to declare.

Mixed Chimerism and Graft Loss in Pediatric Recipients of an Alemtuzumab-Based Reduced-Intensity Conditioning Regimen for Nonmalignant Disease

Reduced-intensity conditioning (RIC) regimens are increasingly used to reduce transplant-related mortality (TRM) for pediatric patients (pts) undergoing hematopoietic cell transplantation (HCT) for nonmalignant diseases. However, these pts are at increased risk for post-transplant mixed donor/recipient chimerism (MC) and/or primary and secondary graft failure (GF). Intervention with donor lymphocytes (DLI) or second transplants may be necessary, but there is limited information about timing and results of intervention. We retrospectively evaluated 31 consecutive pediatric recipients of an alemtuzumab-based RIC HCT at the Children’s Hospital of Philadelphia from May 2007 to December 2012 to determine the incidence of MC and GF, and timing of interventions. All pts received alemtuzumab (Campath) with either fludarabine (150mg/m2)/melphalan (140 mg/m2) (n=30) or fludarabine/busulfan (n=1). The timing of Campath differed according to disease. Pts with hematologic disorders and IPEX received Campath beginning day -21 or -22. Pts with hemophagocytic lymphohistiocytosis (HLH) received proximal (N=8) or intermediate (n=2 ) Campath starting at day -9 or -13, respectively. Diagnoses included HLH in 10 pts, hemoglobinopathy in 8 pts, primary immunodeficiency in 8 pts, and bone marrow failure in 5 pts. All grafts were unmanipulated bone marrow from matched sibling donors (45%), matched unrelated donors (52%) or mismatched related donor (3%). Donor chimerism was evaluated using polymerase chain reaction of microsatellite markers/short tandem repeats at regular intervals post-transplant. Four pts died of TRM (n=3) or early disease progression (n=1) and were not included in the analysis. Of the 27 surviving pts, 18 (66.7%) displayed MC (donor chimerism <100%) on at least one occasion, with 12 (44.4%) reaching a nadir MC level <80%. Two pts with MC≥80% experienced recurrent disease, one with HLH and one with auto-immune syndrome. Of the 12 pts with nadir MC<80%, 6 received DLI with 2 subsequent GFs. Of the remaining 6 pts who did not receive DLI, there were also 2 GFs. The overall incidence of GF/recurrence was 22.2% (6/27). Within the HLH group 7/7 surviving pts developed MC, with 5 (71.4%) reaching a nadir <80%. Despite DLI/boost in all 5 of these pts, 2 progressed to GF. The incidence of GF/recurrence in the surviving HLH pts was 42.9% (3/7) By contrast, in the non-HLH pts, only 11 of 20 (55.0%) surviving pts developed MC with 7 (35.0%) reaching a nadir<80%. Of these 7 with MC<80%, 2 progressed to GF for an overall incidence of GF/recurrence of disease of 15% (3/20). In summary, we observed a high incidence of MC and GF in recipients of Campath-based RIC, particularly in HLH pts. The role for DLI/boost in preventing GF in pts receiving RIC HCT for non-malignant disease who experience low/falling MC requires further study.