Total Body Irradiation Regimen Research Articles

Prospective analysis of BKV hemorrhagic cystitis in children and adolescents undergoing hematopoietic cell transplantation

BK virus is one of the most common causes of hemorrhagic cystitis (HC) in children undergoing hematopoietic cell transplantation (HCT). Viruses can be found in urine and serum samples of immunocompromised patients. Malignant diseases, age, cell source, day of granulocyte reconstitution, conditioning regimen, or use of total body irradiation may play an important role in BKV epidemiology, development of hemorrhagic cystitis course, and outcome. The aim of this study was to evaluate the incidence, clinical course, and risk factors for BKV-HC in children undergoing HCT. A total number of 133 patients who were prospectively tested for BKV colonization/infection were enrolled into this multicenter analysis. Episodes of BKV-HC occurred in 36/133 (27%) enrolled subjects. In a univariate analysis for BKV-HC incidence, the following factors were significant: age >5 years, peripheral blood transplantation, matched unrelated donor (MUD) transplantation, busulfan-cyclophosphamide-melphalan conditioning regimen, and acute myeloblastic leukemia (AML) diagnosis. Presence of acute graft-versus-host disease (aGVHD) in liver and gut GVHD was a significant risk factor of BKV-HC. No BKV-attributed deaths were reported. In multivariate analysis, the incidence of HC was significantly higher in patients with AML, age >5 years, MUD transplants, and children with GVHD. HC is a frequent complication after HCT among children causes prolonged hospitalization but rarely contributes to death. We identified risk factors of BKV-HC development in children, with focus on aGVHD: we concluded that excessive immune reaction connected with GVHD and immunosuppression drugs might play a pivotal role in the development of BKV-HC.

Prophylactic Foscarnet for Human Herpesvirus 6: Effect on Hematopoietic Engraftment after Reduced-Intensity Conditioning Umbilical Cord Blood Transplantation

The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell transplantation (HCT), remains a major challenge. To potentially address this problem, we evaluated the effect of prophylactic foscarnet administered twice daily beginning on day +7 and continuing through engraftment in 25 patients. To determine the impact of foscarnet on HHV-6, engraftment, and other transplantation outcomes, we compared results in 61 identically treated patients with hematologic malignancies. Treatment and control groups underwent reduced-intensity conditioning UCB HCT with a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation 200 cGy with or without antithymocyte globulin (ATG), using sirolimus plus mycophenolate mofetil immune suppression. The treatment and control groups were similar in terms of age, disease risk, use of ATG, Hematopoietic Cell Transplantation Comorbidity Index, and graft CD34 cell dose; however, foscarnet-treated patients were less likely to receive a double UCB graft and to be treated more recently (2016 to 2018). The cumulative incidence of HHV-6 reactivation by day +100 was 63% for all patients (95% confidence interval [CI], 51% to 75%) and was not significantly different between the 2 groups. HHV-6 reactivation occurred at a median of 34 days in the foscarnet group and 25.5 days in the control group. The incidence of neutrophil engraftment at day 42 was higher in the foscarnet group compared with the control group (96%; [95% CI, 83% to 100%] versus 75% [95% CI, 64% to 85%]; P< .01). The cumulative incidence of platelet engraftment by 6 months was 92% (95% CI, 69% to 100%) for the foscarnet group versus 75% (95% CI, 60% to 90%) for the control group (P= .08), and multivariate analysis identified the use of foscarnet as an independent predictor of better platelet engraftment. No patients died as a result of graft failure in recipients of foscarnet, whereas 5 patients died from graft failure in the control group. Six-month overall survival (OS) and nonrelapse mortality (NRM) were better in the foscarnet group (96% versus 72% [P= .02] and 4% versus 18% [P= .07], respectively). Even though foscarnet prophylaxis did not prevent HHV-6 viremia, we observed a delay in time to HHV-6 reactivation, a trend toward differences in engraftment, NRM, and OS compared with historical controls.

Comparison of total body irradiation versus non-total body irradiation containing regimens for de novo acute myeloid leukemia in children.

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, P<0.0001) but relapse was lower (23% vs. 37%, P<0.0001) compared to non-TBI regimens. Consequently, overall (62% vs. 60%, P=1.00) and leukemia-free survival (55% vs. 52%, P=0.42) did not differ between treatment groups. Grade 2-3 acute graft versus host disease was higher with TBI regimens (56% vs. 27%, P<0.0001) but not chronic graft versus host disease. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%, P<0.001) but there were no differences in late pulmonary, cardiac or renal impairment. In the absence of a survival advantage, the choice of TBI or non-TBI regimen merits careful consideration with the data favoring non-TBI regimens to limit the burden of morbidity associated with endocrine dysfunction.

Once-a-day fractionated total-body irradiation: A regimen tailored to local logistics in allogeneic stem cell transplantation for acute lymphoblastic leukemia.

The objective of the study was to estimate the cumulative incidence (CI) of relapse, relapse-free survival (RFS) and overall survival (OS) in ALL patients after a once-a-day fractionated TBI (F-TBI) regimen with 9.9 Gy. The secondary objectives were evaluation of short and long-term toxicity and non-relapse mortality (NRM). Total body irradiation (TBI), as a part of the conditioning regimen before allogeneic stem cell transplantation (ASCT) for acute lymphoblastic leukemia (ALL), allows disease control by eradicating residual blast cells in the transplant recipient. Retrospective study conducted in patients with ALL who received between March 2003 and December 2013 a conditioning regimen with F-TBI and chemotherapy. Irradiation was delivered with 3.3 Gy once-a-day for three consecutive days. Eighty-seven patients were included. The median age was 19 years (range: 5-49 years). The 3-year CI of relapse was 30%. The estimated 3-year RFS and OS were 54% and 58%, respectively. Cumulative incidence of acute graft-versus-host disease (aGVHD) grade II-IV and chronic GVHD (cGVHD) was 31% and 40%, respectively. Interstitial pneumonitis was observed in 2 patients. The 3-year CI of NRM was 16%. In multivariate analysis, cGVHD was associated with a lower CI of relapse (RR = 0.26, 95% CI: 0.07-0.95, p = 0.04). High-risk cytogenetics was associated with a lower RFS (RR = 2, 95 CI: 1.04-3.84, p = 0.03). Grade II-IV aGVHD was an independent predictor of higher CI of NRM (RR = 6.7, 95% CI: 1.4-31.7, p = 0.02). Once-a-day F-TBI regimen is effective, safe and practical in patients who underwent ASCT for ALL.

Favorable Clinical Outcomes with Valacyclovir for Cytomegalovirus Prophylaxis Following Allogeneic Hematopoietic Cell Transplantation

Introduction Current guidelines recommend monitoring and preemptive therapy for cytomegalovirus (CMV) reactivation in patients receiving allogeneic hematopoietic cell transplantation (HCT). Treatment options are limited by side effects such as myelosuppression and renal toxicity. Effective CMV prophylaxis may avoid these complications. At our institution, patients receiving a reduced intensity conditioning regimen of anti-thymocyte globulin (ATG) and total body irradiation (TBI) receive valacyclovir 1 gram every 8 hours as antiviral prophylaxis. Objectives The primary objective was to compare the incidence of CMV reactivation or disease after allogeneic HCT in patients receiving valacyclovir (VAL) versus acyclovir (ACV) for viral prophylaxis. Methods This was a retrospective, electronic medical review of allogeneic HCT recipients receiving VAL 1 gram every 8 hours vs. ACV 400 mg every 12 hours for viral prophylaxis between January 1, 2009 and July 31, 2018. Adult patients were included under the following conditions: first allogeneic HCT from a related or unrelated donor, patient or donor seropositive for CMV, and receipt of a reduced intensity conditioning regimen containing ATG. Patients were excluded if they received antiviral therapy for a non-CMV infection prior to CMV reactivation or received an umbilical cord or haploidentical transplant. Patients were matched based on propensity scoring. Results Forty-five patients were included in the VAL group and 35 in the ACV group. There was a significantly lower incidence of CMV reactivation or disease leading to preemptive therapy by day +180 in the VAL group vs. ACV group (18% vs. 57%, p=0.0004). No patients in the VAL group and four patients (11%) in the ACV group developed CMV disease (p=0.0331). While there was no difference in median time to CMV reactivation, 100% of patients who reactivated in the ACV group vs. 38% of those who reactivated in the VAL group did so within the first 60 days post-transplant. Potentially due to this later CMV reactivation, there was a trend towards less neutropenia while on CMV therapy in the VAL group vs. the ACV group (12% vs. 55%, p=0.0882). Median peak CMV titers were also not significantly different between groups, but five of the 20 patients who reactivated in the ACV group (25%) vs. no patients in the VAL group had titers greater than 10,000 copies/mL. Three patients in the ACV group (9%) vs. no patients in the VAL group required foscarnet due to myelosuppression or CMV resistance (p=0.2742). Overall survival was lower in the ACV group vs. VAL group (median time to death: 300 days vs. 679 days, p=0.0067). Conclusion Valacyclovir prophylaxis is associated with a lower incidence of CMV reactivation and disease vs. acyclovir prophylaxis. Patients who reactivate CMV on VAL prophylaxis may have fewer complications related to their reactivation.

A compartment model for total body irradiation

Abstract Background Total body irradiation (TBI) is a standard procedure used in radiotherapy to eliminate any remaining cancerous cells following a chemotherapy treatment. However, there is no consensus regarding which TBI regimen (dose, dose rate, and fractionation) is the most efficient and least toxic. Also, we would like to know, how the TBI regime must be updated when it was interrupted by a natural disaster or blackout. Method ology: The Jones model of radiation-induced myelopoiesis is modified by adding new compartments for mutated and cancerous cells populations. This proposed carcinogenesis model is mathematically described by five non-linear coupled differential equations. Numerical and graphical solutions are obtained for U.S. and Canadian TBI regimens. To obtain stochastic solutions, transition rates that mediate the movement of cells among all compartments are replaced with random numbers. Results The developed algorithms and computational codes allowed us to quickly update a planned TBI regime after the patient's treatment was interrupted for a length of time. It is also showed that U.S. and Canadian TBI regimens killed about the same percentage of malignant cells (80%). The stochasticity procedure shows, on average, a mortality of about 83% of the malignant cells, which is in agreement with the deterministic solutions obtained for the US and Canadian TBI regimens. A stability analysis of the deterministic equations revealed only one equilibrium point, which is globally asymptotically stable. Conclusion The proposed TBI compartmental model allows for a quick update of an interrupted TBI regimen, and a comparison among different TBI regimens.

The impact of total body irradiation-based regimens on outcomes in children and young adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation.

Total body irradiation (TBI)-based conditioning is the standard of care in the treatment of acute lymphoblastic leukemia (ALL) that requires allogeneic hematopoietic stem cell transplantation (HSCT). However, TBI is known to be associated with an increased risk of late effects, and therefore, non-TBI regimens have also been utilized successfully. A recent study showed that patients that were next-generation sequencing-minimal residual disease (NGS-MRD) negative prior to allogeneic HSCT had a very low risk of relapse, and perhaps could avoid exposure to TBI without compromising disease control. We examined outcomes at our institution in patients that received a TBI or non-TBI regimen, as well as explored the impact of NGS-MRD status in predicting risk of relapse post transplant. This retrospective analysis included 57 children and young adults with ALL that received their first myeloablative allogeneic HSCT from 2012 to 2017 at the University of California San Francisco. Our primary endpoint was the cumulative incidence of relapse at 3 years post transplant. We demonstrated similar cumulative incidence of relapse for patients treated with either a TBI or non-TBI conditioning regimen, while NGS-MRD positivity prior to transplant was highly predictive of relapse. The presence of acute graft-versus-host disease was associated with decreased relapse rates, particularly among patients that received a TBI conditioning regimen and patients that were NGS-MRD positive prior to HSCT. Our data suggest that the decision to use either a TBI or non-TBI regimens in ALL should depend on NGS-MRD status, with conditioning regimens based on TBI reserved for patients that cannot achieve NGS-MRD negativity prior to allogeneic HSCT.

A Phase IB Study of Blinatumomab (blina) in Patients with B Cell Acute Lymphoblastic Leukemia (ALL) and B-Cell Non-Hodgkin Lymphoma (NHL) As Post-Allogeneic Blood or Marrow Transplant (allo-BMT) Remission Maintenance

Background: AlloBMT can be curative as consolidation for high risk B ALL and NHL. However, long term survival is limited by transplant-related toxicity and particularly by disease relapse. Post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis limits GVHD and facilitates the use of alternative allograft sources. Moreover, following PTCy, cellular immune reconstitution is favorable for the integration of strategies to augment anti-tumor immunity. Blina, a CD19/CD3 bispecific T cell engager antibody construct, is effective in the treatment of CD19+ ALL and NHL. Blina leads to T cell activation that may enhance established posttransplant tumor-specific T cell responses, leading to a more potent graft-versus-tumor effect. Thus, we have undertaken a phase Ib trial to assess the tolerability and preliminary efficacy of blina as post-alloBMT remission maintenance in B-cell ALL and NHL. Methods: Patients ³18 years-old with high risk CD19+ B ALL or NHL who underwent alloBMT using PTCy were eligible including those with prior blina exposure. Patients had to be 60-180 days from transplant with documented count recovery and no evidence of disease progression. Patients had to be off all post-transplant immunosuppression including steroids for the treatment of GVHD for ≥4 weeks prior to treatment initiation, and without a history of grade ≥3 acute GVHD or severe chronic GVHD. Patients could receive two cycles of blina if they had evidence of disease (including MRD) at their pre- and/or post-transplant evaluations but otherwise received only one cycle. Blina was given as a continuous infusion at 9 mcg/day on C1D1-7 and 28 mcg/day on C1D8-28 and C2D1-28. Results: As of July 23, 2019, 12 adults (10 males/2 females) have enrolled including 4 patients with B ALL and 8 patients with NHL. Among the B ALL patients, two with known TP53 mutations were transplanted in CR1, while two with relapsed disease were transplanted in CR3. Among the NHL patients, five had large cell transformation (3 from follicular and 2 from CLL); one had relapsed primary CNS lymphoma (PCNSL); one had relapsed mantle cell lymphoma (MCL); and one had diffuse large B cell lymphoma (DLBCL). The median age was 53 (range, 30-73). All patients underwent alloBMT using a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation (TBI). Eight patients received allografts from haploidentical donors, three from matched-unrelated donors, and one from a matched-related donor. Five patients received peripheral blood allografts, and seven bone marrow. Two patients were enrolled after a second alloBMT, and 3/4 ALL patients previously received blina. Baseline characteristics are presented in Figure 1. Patients started blina a median of 144 days post-transplant (range, 90-180). One patient stopped treatment on day 5 due to a grade 2 tremor, and one patient required dose reduction on day 25 due to grade 4 neutropenia. Toxicities were otherwise mild and are presented in Figure 2. There were no exacerbations of GVHD. At a median follow-up of 13.7 months after BMT (range 3.8-23 months), ten patients remain in remission, while one patient suffered a third CNS relapse of ALL at 20.6 months after his 2nd transplant and another had relapse of his transformed lymphoma. Data on biomarkers including changes in T cell subpopulations in both BM and PB, and co-signaling molecule expression will be presented. Conclusions: Post-alloBMT maintenance therapy with blina is feasible with minimal toxicity. 83% of the very high risk patients treated on study remain in CR at a median of 13.7 months post-transplant. Based on promising safety and efficacy data from the phase IB, the plan is to proceed to the phase II portion of the study. Disclosures Webster: Amgen: Consultancy; Genentech: Research Funding; Pfizer: Consultancy. Wagner-Johnston:Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Luznik:Merck: Research Funding, Speakers Bureau; Genentech: Research Funding; AbbVie: Consultancy; WindMiL Therapeutics: Patents &amp; Royalties: Patent holder. Gojo:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Research Funding; Jazz: Consultancy, Honoraria; Amgen Inc: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Amphivena: Research Funding. OffLabel Disclosure: Blinatumomab is not labeled for use as post-transplant maintenance therapy or for use in the non-Hodgkin lymphoma.

Outcomes of Total Body Irradiation- Versus Chemotherapy-Based Myeloablative Conditioning Regimen in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide for Acute Lymphoblastic Leukemia: ALWP of the EBMT Study

Background The intensity of a conditioning regimen has significant impact on outcomes of allogeneic hematopoietic cell transplantation in acute leukemia. In acute lymphoblastic leukemia (ALL) patients undergoing matched donor transplant, total body irradiation (TBI)- based myeloablative conditioning (MAC) regimen was associated with improved leukemia free survival (LFS) compared to chemotherapy (CT)-based MAC (Eder S. et al. 2017). Haploidentical hematopoietic cell transplantation(haplo-HCT) with post-transplant cyclophosphamide (PTCy) has emerged as a safe alternative in absence of a matched donor. The optimal MAC in haplo-HCT setting is yet to be defined. We studied the outcomes of TBI- vs. CT-based MAC in ALL patients undergoing haplo-HCT and reported to the Acute Leukemia Working Party of the EBMT. Methods The study included 427 ALL (B-ALL-75%) patients, that underwent haplo-HCT with PTCy during the years 2010-2018, following TBI- (n=188, 44%) or CT- (n=239, 56%) based MAC. Regimen intensity was defined by EBMT criteria and cases with busulfan dose &amp;lt;9 mg/kg or TBI dose ≤6 Gy were excluded. All disease status were included (CR1=208, CR2+=135; advanced=84). Ninety-one (27%) patients had Philadelphia+ disease. Graft source was bone marrow in 229 (54%) patients. Fludarabine-TBI (72%) and thiotepa-busulfan-fludarabine (65%) were the most common TBI and CT-based regimens, respectively. Cyclosporin with mycophenolate was used as GVHD prophylaxis in 64% of patients. The patients, disease, and transplant related characteristics were similar in both cohorts. Median patient age was 32 yrs and the median follow ups for TBI and CT cohort were 20.7 (IQR-11.7-35.3) and 26.2 (IQR-10.2-41) months, respectively. Results In univariate analysis, day 100 incidences of acute GVHD II-IV and III-VI were 38% vs. 30% (p-0.07) and 19% vs. 13% (p-0.14) for TBI and CT cohort, respectively. Two-year overall and severe chronic GVHD incidences were 34% vs. 30% (p-0.51) and 17% vs. 12% (p-0.18) for TBI and CT cohort, respectively. Graft failure was reported in 6 (3%) and 19 (8%)(p-0.09) patients who received TBI and CT-based MAC, respectively. Death from veno-occlusive disease was reported in 4 (5%) TBI patients and 8 (7%) CT patients. There was no difference in reported deaths due to infection (28%) or interstitial pneumonitis (4%) among study cohorts. In multivariate analysis, TBI was associated with significant improvement in nonrelapse mortality (NRM) [HR=0.51, 95% CI:0.32-0.83, p&amp;lt;0.01] and LFS [HR=0.71, 95% CI:0.52-0.97, p-0.03] and higher incidence of aGVHD II-IV [HR=1.5, 95% CI:1.02-2.19, p-0.04]. Finally, relapse incidence (RI), acute GVHD (aGVHD) III-IV, OS and GVHD free relapse free survival (GRFS) did not differ between the groups. Two-year NRM, LFS and OS of TBI and CT cohort were 21% vs. 31% (p&amp;lt;0.01); 45% vs. 37% (p-0.05) and 51% vs. 47% (p-0.18), respectively (Figure 1). Other factors negatively impacting OS were disease status (CR2, HR=1.69, p-0.01 or advance, HR=2.62, p&amp;lt;0.01) and use of peripheral blood as graft source (HR=1.49, p-0.02). Interestingly, peripheral blood graft source also negatively impacted LFS (HR=1.44, p-0.02), aGVHD II-IV (HR=1.58, p-0.02 and GRFS (HR=1.54, p&amp;lt;0.01). Philadelphia+ disease was associated with reduced RI (HR=0.39, p-0.01) but had no impact on LFS (HR=0.80, p-0.29) or OS (HR=0.81, p-0.34)(Table 1). In a subgroup univariate analysis of patients &amp;lt;40 yrs old, TBI was associated with reduced 2-year NRM (19% vs. 28%, p-0.04) without impacting other outcome measures. In patients with pre-HCT disease status CR2 or advance disease, improvement in 2-year NRM (22% vs. 36%, p-0.02) was observed with TBI but no interaction was seen with other endpoints. Conclusions TBI based MAC resulted in significant reduction of NRM, translating into a better LFS without impacting aGVHD III-IV, chronic GVHD, RI or OS when compared to CT based MAC. Non-significant difference in OS between TBI and CT cohorts might be related to lower number of events, short follow-up and/or salvage therapies after relapse. These novel findings based on a large cohort of ALL patients, support the use of TBI based MAC and bone marrow graft in haplo-HCT with PTCy. Disclosures Dholaria: Celgene: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Angelucci:Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Apperley:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Preclinical Development of an Actinium-225-Labeled Antibody Radio-Conjugate Directed Against CD45 for Targeted Conditioning and Radioimmunotherapy

Introduction: Radiolabeled CD45 antibodies have demonstrated clinical promise as targeted conditioning treatments prior to bone marrow transplant (BMT) as a better tolerated and potentially more effective alternative to harsh chemotherapy and/or total body irradiation regimens for myeloablative conditioning. CD45 is expressed on all immune cells, including hematopoietic stem cells and both precursor and mature lymphoid and myeloid cells, with an average copy number up to 200,000 molecules per cell, making it an ideal antigen for directing targeted radiation for conditioning. It is also highly expressed on most lymphomas and leukemias, and approximately 50% of multiple myeloma, further offering the potential for mediating a substantial anti-tumor effect in treated patients. We describe the preclinical development of a novel anti-CD45 antibody radio-conjugate (ARC) that harnesses the power of alpha radiation by arming the pan-CD45 antibody BC8 with Actinium-225 (225Ac). 225Ac is a potent radionuclide with high linear energy transfer (80-100 keV/μm) yet short path length (50-80 μm) to deliver significantly more lethal double strand DNA breaks per alpha track than beta particles. In addition, the use of 225Ac for targeted conditioning has advantages of safe handling and ease of use and a long 10 day half-life that enables flexibility in preparation and use. Methods and Results: To generate 225Ac-BC8, the monoclonal antibody was first conjugated with the DOTA chelator, then labeled with 225Ac, achieving a labeling efficiency typically greater than 80%. 225Ac-BC8 was subsequently purified to high radiochemical purity by column chromatography. Using human CD45+ Ramos lymphoma cell line and EL4 as negative control, 225Ac-BC8 was shown to be stable and retain selective immunoreactivity following conjugation and labeling. To evaluate the anti-tumor potency of 225Ac-BC8, two CD45+ human multiple myeloma (MM) cell lines with high or low relative CD45 antigen density, U266 and H929, respectively, (Collette, et al. 2007) were tested by cell cytotoxicity assay. Following transient exposure (4 or 12 hours) to 225Ac-BC8, the ARC demonstrated potent dose-dependent MM cell killing 72 hours post-treatment, achieving greater than 90% cytotoxicity of both cell lines. To further assess the therapeutic potential of 225Ac-BC8, its anti-tumor activity was tested in subcutaneous (s.c.) xenograft models of H929 and U266. NOD-SCID mice bearing established s.c. tumors were randomized to receive a single dose of 300 nCi of 225Ac-BC8, 300 nCi of an irrelevant radio-conjugate 225Ac-18B7, naked BC8 antibody, or no treatment control. In both models, 225Ac-BC8 exerted complete and durable tumor control for the duration of study. None of the control groups exhibited any anti-tumor effect. Studies to evaluate 225Ac-BC8 in models of CD45+ lymphoma are ongoing. Since BC8 does not cross-react with mouse CD45 and only weakly with macaque CD45, biodistribution, dosimetry and imaging analysis was performed in mice using radio-labeled anti-mouse pan-CD45 surrogate antibody 30F11. SPECT/CT imaging and biodistribution was performed with 111In-labeled 30F11. Following IV administration, 111In-CD45 (30F11) rapidly cleared from the blood and accumulated in immune system organs including spleen, bone marrow, and lymph node. Dosimetry calculations for 225Ac-CD45 (30F11) were determined for absorbed dose to target organs. Only modest uptake was noted in the kidney, but significant uptake occurred in liver, the major site for catabolism of full-length antibodies. 225Ac-CD45 (30F11) is a useful molecule to study the tolerability and myeloablative properties of 225Ac-CD45 antibody for targeted conditioning prior to donor BMT, using B6-Ly5b donor cells in B6-Ly5a mice. Results of ongoing studies will also be presented. Conclusions: The pan-CD45 antibody BC8 was shown to be efficiently conjugated and labeled with the potent alpha emitter 225Ac to mediate robust and selective killing of CD45+ MM cells and xenografts. Biodistribution analysis confirmed selective uptake into organs of the immune system including homing to BM. Supported by ongoing myeloablative/BM reconstitution studies, these preclinical data support the development of 225Ac-BC8 as a novel potent and safe targeted conditioning approach for BMT. Reference: Collette, et al., (2007). Eur. Cytokine Netw. 18:120-126. Disclosures Ludwig: Actinium Pharmaceuticals: Employment, Equity Ownership. Dawicki:Actinium Pharmaceuticals: Research Funding. Geoghegan:Actinium Pharmaceuticals: Employment. Liang:Actinium Pharmaceuticals: Employment. Seth:Actinium Pharmaceuticals: Employment, Equity Ownership. Gokhale:Actinium Pharmaceuticals: Employment. Berger:Actinium Pharmaceuticals, Inc: Employment, Equity Ownership. Reddy:Actinium Pharmaceuticals: Employment. Dadachova:Actinium Pharmaceuticals: Consultancy, Research Funding; RadImmune Therapeutics: Consultancy, Research Funding.

Allogeneic Transplantation for Myelodysplastic Syndrome in Adults over 50 Years Old Using Reduced Intensity/Non-Myeloablative Conditioning: Haploidentical Relative Versus Matched Unrelated Donor

Background: Allogeneic hematopoietic cell transplantation (HCT) has been a successful strategy to treat myelodysplastic syndrome (MDS). With only approximately one-third of patients having an HLA matched sibling, most transplants use mismatched relative (haploidentical) or unrelated donors. In the current analysis we sought to study outcomes after haploidentical related compared to HLA-matched unrelated donor HCT for MDS (de novo or therapy-related). Methods: We retrospectively studied 176 recipients of haploidentical related donor and 427 recipients of 8/8 HLA-matched unrelated donor HCT in the United States between 2012 and 2017. The primary outcome was overall survival. The effect of donor type on survival and other transplant outcomes were studied using a Cox regression model. Results: Patient and disease characteristics are presented in Table 1. Most transplants (85%) were for de novo MDS in both donor groups. Although all patients received reduced intensity regimens, the predominant conditioning regimens were confounded by donor type. Total body irradiation (TBI) 200 cGy/cyclophosphamide/fludarabine (TBI/Cy/Flu; 82%) was the predominant regimen for haploidentical HCT and fludarabine with busulfan or melphalan (Flu/Bu or Flu/Mel; 79%) without in vivo T-cell depletion was the predominant regimen for unrelated donor HCT. Similarly, graft-versus-host disease (GVHD) prophylaxis was also confounded by donor type. Posttransplant cyclophosphamide/calcineurin inhibitor/mycophenolate (PT-Cy/CNI/MMF) was the prophylaxis regimen for all haploidentical transplants. CNI/MMF (31%) or CNI/methotrexate (69%) was used for unrelated donor transplants. Peripheral blood was the predominant graft for both donor types. The median follow-up was 24 months (range 3-77) after haploidentical and 36 months (range 3-74) after unrelated donor HCT. Results of multivariate analysis, adjusted for HCT-CI, prior treatment with hypomethylating agents (HMAs), and IPPS-R did not show differences in survival by donor type (HR 0.98, p=0.85; 40% vs. 37%), Figure 1. However, the relapse rate (adjusted for prior HMAs, IPSS-R, and recipient sex) was higher after haploidentical compared to unrelated donor HCT (HR 1.60, p=0.002, 53% vs. 34%), which led to lower disease-free survival after haploidentical HCT (HR 1.30, p=0.03; 21% vs. 32%), Figure 1. To further test the effect of regimen intensity, low dose TBI regimens were compared to Flu/Bu and Flu/Mel; we did not observe a difference in relapse risk (HR 0.95, p=0.76). Non-relapse mortality did not differ by donor type (HR 0.88, p=0.46). Interval between diagnosis and transplant was also not associated with outcomes. Acute grade II-IV acute GVHD (HR 0.46, p&lt;0.001) and chronic GVHD (HR 0.34, p&lt;0.001) was less common after haploidentical HCT. The 1-year graft failure rate was higher after haploidentical compared to unrelated donor HCT (15% and 8%, respectively, p=0.02). Conclusion: Although the current analysis did not show differences in survival between haploidentical related and matched unrelated donor HCT, the higher relapse and consequently lower disease-free survival associated with the haploidentical HCT approach in this analysis (primarily TBI/Cy/Flu with PT-Cy/CNI/MMF) warrants caution. A more definitive comparison of the two donor types can be accomplished only if more haploidentical transplants were to use Flu/Bu or Flu/Mel conditioning. Figure 1 Disclosures Grunwald: Celgene: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Merck: Consultancy; Abbvie: Consultancy; Medtronic: Equity Ownership; Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Amgen: Consultancy; Trovagene: Consultancy; Cardinal Health: Consultancy; Janssen: Research Funding; Genentech/Roche: Research Funding; Novartis: Research Funding; Forma Therapeutics: Research Funding. Bolanos-Meade:Incyte Corporation: Other: DSMB fees. Bredeson:Otsuka: Research Funding. Gupta:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Mussetti:Takeda: Honoraria; BMS: Honoraria; Novartis: Honoraria; Italfarmaco: Honoraria. Nakamura:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Solh:Celgene: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.

Fludarabine in Combination with Busulfan As Pretransplant Conditioning for Platelet Gene Therapy in Murine Hemophilia a with Inhibitors

Treatment of hemophilia A (HA) with inhibitors is costly, inconvenient, and incompletely effective. We have demonstrated that syngeneic transplantation of hematopoietic stem cells (HSCs) that are genetically modified to express FVIII in platelets restores hemostasis in HA mice with pre-existing anti-FVIII immunity under total body irradiation (TBI) preconditioning, a proof-of principle that platelet gene therapy could be a promising strategy for HA patients. Currently, Fludarabine along with busulfan (FB) has been shown to be highly effective as a preconditioning regimen for allogeneic HSC transplantation (HSCT) in the clinic. Thus, in this study, we aimed to evaluate if FB works as a clinically translatable preconditioning approach for platelet gene therapy of HA with pre-existing inhibitors. Fludarabine was intraperitoneally administered at 100mg/kg/day on Days -7 through -4, and busulfan was given at 25mg/kg/day on Days -2 and -1 into rhFVIII-primed FVIIInull mice. A TBI regimen of 6.6Gy was used as a parallel control. Platelet FVIII expression was introduced by transplantation of 2bF8 lentivirus (2bF8LV)-transduced HSCs. The peripheral blood recovery was monitored by blood count, and cell subset reconstitution was analyzed by flow cytometry. Animals were further analyzed by quantitative PCR (qPCR), FVIII assays, inhibitor assays, and tail bleeding test. Blood counts demonstrated that platelet numbers and hemoglobin levels in the FB group were similar to those in the TBI group after HSCT. The recovery of leukocytes in the recipients with FB conditioning was greater than that in the animals conditioned with TBI at the early stage (4-12 weeks after HSCT). The engraftments in the two groups were comparable in terms of donor- derived leukocyte chimerism during the study course. The percentage of leukocyte chimerism at each time point in the FB group (ranging from 68.6±12.3% to 83.5±8.5%, n=7) was not statistically significantly different than that in the TBI group (ranging from 66.5±15.8% to 74.5±14.8%, n=5-6). All recipients achieved more than 55% donor-derived leukocytes at 20 weeks after HSCT. When we looked into the cell subsets in the recipients, we found that FB preconditioning is favorable for donor-derived myeloid cell reconstitution (the average engraftment ranging from 81.3-85.4% in the FB group, 52.0-62.3% in the TBI group). qPCR results confirmed that HSCs were genetically modified by 2bF8LV in the recipients with either FB or TBI conditioning. The average copy number of the 2bF8 cassette per cell was 0.93±0.17 (n=7) in the FB group, which was not significantly different compared to the TBI group (0.79±0.11, n=6). The average platelet-FVIII levels at each time point ranged from 3.87-5.98 mU/108 platelets in the FB group and 2.21-10.47 mU/108 platelets in the TBI group, respectively. There was no significant difference between the two groups. To assess whether the bleeding phenotype was rescued in HA mice after receiving 2bF8 LV-transduced HSCs, we used a 6-hour (hr) tail bleeding test. All 2bF8 LV-transduced recipients stopped bleeding within 6 hrs with a remaining hemoglobin level of 62.7±20.6%, which was significantly higher than the FVIIInull control group (37.6±4.5%). Of note, none of the HA control mice stopped bleeding within 6 hrs. Notably, we found that both anti-FVIII inhibitor and total IgG titers declined with time in recipients under either FB or TBI preconditioning. When reduction of the inhibitor titer over time was calculated as a half-life (t1/2), there was no significant difference between the FB group and the TBI group. When the inhibitor titer dropped to undetectable, we further challenged recipients with 50 U/kg rhF8 weekly for 4 weeks. There were no detectable anti-FVIII inhibitors in the 2bF8LV-transduced recipients from either the FB or TBI group. In contrast, all the untransduced transplanted HA control mice produced various levels of inhibitors under the same challenge. These data indicate that 2bF8LV-transduced primed-HA mice under either FB or TBI conditioning may induce immune tolerance. In conclusion, fludarabine along with busulfan preconditioning successfully introduced therapeutic levels of platelet FVIII expression without evoking an anti-FVIII memory response in the transduced recipients with pre-existing immunity. Our data suggest that this approach may be a promising and clinically translatable strategy for gene therapy of hemophilia A. Disclosures No relevant conflicts of interest to declare.

More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling

AbstractDetection of minimal residual disease (MRD) pre– and post–hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non–total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.

Adverse Effects of Total Body Irradiation: A Single Institution Analysis

Total body irradiation (TBI) is commonly used as part of the conditioning regimen prior to stem cell transplant. While TBI may be valuable in this setting, several potential adverse effects have been reported in the literature. Data describing adverse effects of TBI have been primarily drawn from single institution retrospective analyses. We report one of the largest cohorts of TBI patients treated using multiple preparative chemotherapy and radiation regimens. The purpose of our study was to evaluate the potential acute, subacute, and late adverse treatment related toxicities. A retrospective chart review was performed on a cohort of 705 patients treated at our institution from 1995-2017. Based on availability of TBI records, 624 patients had evaluable documentation for analysis. Patients received one of four conditioning regimens including busulfan-fludarabine-2Gy TBI, fludarabine-melphalan-2Gy TBI, cyclophosphamide-12Gy fractionated TBI, and etoposide-12Gy fractionated TBI. Individual patients were evaluated for 13 specific CTCAE recognized adverse effects (dermatitis, alopecia, febrile neutropenia, lung infection, pneumonitis, oral mucositis, nausea, diarrhea, ARDS, cataracts, non-infective cystitis, secondary malignancy, and pulmonary fibrosis) and were graded based on CTCAE version 5.0. Overall median follow-up time was 59 months (95% CI 51, 62), and median survival was 42 months (95% CI 32, 59). The etoposide-12 Gy regimen showed a significantly higher mucositis rate compared to the other regimens, especially grade 3 mucositis (39.6%, p< 0.001). Otherwise, there were no significant differences in toxicity by regimen for the 13 adverse effects reviewed. The overall rate of secondary malignancy was low (n=1, 0.2%). Cataract formation occurred in 16.2% of patients without a significant difference between regimens (p = 0.32). Median time to cataract formation was relatively short, ranging from 1-4 years. There was no difference in pneumonitis rate among the four different regimens; however, the overall grade 3 or higher pneumonitis rate was relatively low (n=11, 1.8%, p = 0.15). TBI regimens delivered at our facility ranging from a single fraction of 2 Gy to fractionated 12 Gy regimens showed relatively low rates of radiation related toxicities. However, cataracts were a common toxicity with a relatively short onset time. Interestingly, cataract formation did not appear to be dose-dependent. Improved knowledge of the potential sequelae of TBI may prove beneficial for the initial counseling and long-term care of stem cell transplant patients.

The effectiveness of busulfan-based conditioning regimens for stem cell transplantation against lymphomas in children, adolescents, and young adults in Japan.

Conditioning regimens for stem cell transplantation (SCT) involving total body irradiation (TBI) are generally preferred over busulfan (BU)-based ones for lymphoid malignancies. However, reports of favorable results using BU against lymphomas have recently emerged. This study sought to compare the effectiveness of BU and TBI regimens for SCT against lymphomas. We retrospectively analyzed 893 lymphoma patients who underwent primary SCT in Japan between 1980 and 2015. The median age of all patients was 18 years (range, 0-30 years) with 589 males, 303 females, and 1 patient whose sex was unknown. Overall survival (OS) was not different between those receiving BU and TBI (P=0.672). OS in patients receiving autologous SCT was significantly better with BU over TBI regimens (P=0.038), particularly in children (0-15years) (P=0.024). Conversely, OS in adolescents and young adults (AYAs; 16-30years) receiving allogeneic SCT was significantly worse with BU over TBI regimens (P=0.035). Overall, BU regiments had comparable effectiveness to TBI conditioning regimens, and, although less effective for AYAs with allogeneic SCT, were particularly more effective than TBI regimens for children who received autologous SCT.

PB2340 INCIDENCE AND SEVERITY OF ORAL MUCOSITIS AMONG ALLOGENEIC STEM CELL TRANSPLANTATION PATIENTS FOLLOWING FOUR TYPES CONDITIONING REGIMENS

Background:Oral mucositis (OM) is a painful and debilitating complication of allogeneic hematopoietic stem cell transplantation (HSCT). Conditioning regimen correlates development of OM, but no studies have analyzed incidence and severity of OM among various condition regimens.Aims:This study was designed to evaluate the incidence and severity of OM receiving various conditioning regimens in early period after HSCT.Methods:We included 120 adult patients with a median age of 54.5 years (range 18 ‐ 72) who received allogeneic HSCT at Kindai University Hospital. Four conditioning regimens were administered for patients before transplantation based on the underlying diseases. Twenty‐two patients were received cyclophosphamide (CY)/total body irradiation (TBI) regimen (CY/TBI), 27 were received busulfan (BU)/CY regimen (BU/CY), 54 were received fludarabine (FLU)/BU regimen (FLU/BU), and 17 were received FLU/ melphalan (MEL) regimen (FLU/MEL). National Cancer Institute Common Toxicity Criteria for Adverse Events scale was used to assess the severity of OM. Severe OM defined as grade 2 to 4.Results:OM of any grades occurred 77.3% of CY/TBI, 48.1% of BU/CY, 85.2% of FLU/BU, and 70.6% of FLU/MEL. There were significant differences between CY/TBI and BU/CY (p = 0.05), and BU/CY and FLU/BU (p = 0.001). There was no patient with grade 4 OM. The incidence of severe OM (grade 2 ‐ 3) was 54.5% of CY/TBI, 18.5% of BU/CY, 57.4% of FLU/BU, and 52.9% of FLU/MEL. There were significant differences between CY/TBI and BU/CY (p = 0.02), BU/CY and FLU/BU (p = 0.0009), and BU/CY and FLU/MEL (p = 0.02).Summary/Conclusion:Incidence and severity of OM in patients receiving BU/CY regimen was the lowest among 4 types conditioning regimens.

PS964 COMPARISON OF CONDITIONING REGIMEN CONTAINING TOTAL BODY IRRADIATION OR NOT FOR AUTOLOGOUS TRANSPLANTATION IN ADOLESCENTS AND YOUNG ADULTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Background:Autologous stem cell transplantation (ASCT) still plays an role in treatment of acute lymphoblastic leukemia (ALL). A myeloablative conditioning therapy should be done before ASCT. Many trials comparing regimens with total body irradiation (TBI) and non‐TBI in allogeneic stem cell tansplantation have been reported. However, very limited analysis focused on patients with ALL undergoing ASCT.Aims:The present study was undertaken to analyse retrospectively the outcome following conditioning with TBI regimens versus non‐TBI regimens in ASCT in adolescents and young adults with Philadelphia chromosome‐negative ALL patient cohorts.Methods:We defined 14–29 years of age as AYAs. Seventy four AYAs of all 95 patients with ALL undergoing consecutive ASCT between January 2007 and December 2016 were included in the study at Lymphoma Center at Blood Disease Hospital of Chinese Academy of Medical Sciences. Patients were chose based on the following criteria: (1) CR1 before ASCT; (2) first ASCT; (3) peripheral blood stem cell; (4) Philadelphia chromosome‐negative; (5) no definite central nervous system disease. According to the conditioning regimens administered, patients were divided into the following two groups: TBI group (consisting of TBI and chemotherapy, n = 38) and non‐TBI group (consisting of only chemotherapy, n = 36). The details of TBI‐based conditioning were TBI plus melphalan ± etoposide(n = 21), TBI plus cyclophosphamide ± cytosine arabinoside or etoposide (n = 14), others (n = 3). The details of non‐TBI conditioning were busulfan plus melphalan (n = 6), busulfan plus cyclophosphamide and etoposide (n = 16), busulfan plus cyclophosphamide and cytosine arabinoside (n = 3), busulfan plus cyclophosphamide and idarubicin (n = 6), others (n = 5). All of patients were received with VDCP ± L induction regimen for 28 days, then patients were administered with four courses of intensive chemotherapy. All of patients received 8–10 intrathecal injections for preventing central nervous system disease. After ASCT, maintenance chemotherapy based on VP regimen was continued for 1–1.5 years.Results:The main features at the time of diagnosis and transplant characteristics (sex, age, number of leukocytes, phenotype, karyotype and molecular biology, interval from treatment to MRD negative, interval between CR1 to patients transplanted) are parallel between the two groups. The median follow‐up for the survivors was 56 months (range, 30 ‐ 130 months) for TBI group and 65 months (range, 27 ‐ 126 months) for non‐TBI group after ASCT, respectively (P = 0.563). The median neutrophil engraftment days were 11days (range, 8–19 days) and 12 days (range, 9–30 days) for TBI group and non‐TBI group (P = 0.432), respectively. The median days to platelet engraftment were 15days (range, 10–95 days) and 14.5 days (range, 9–90 days) (P = 0.656), respectively. Hepatic vein occlusion syndrome occurred in 1 patients administered by busulfan plus melphalan conditioning at the day of 32 from transplantation. Cataract occurred in TBI plus melphalan (n = 1) conditioning group and TBI plus melphalan and etoposide conditioning group (n = 1).Non TRM occurred. The 5‐year disease‐free survival (DFS) was 68.1 ± 7.6% in TBI cohort and 62.3 ± 8.4% in non‐TBI cohort (P = 0.906). The 5‐year overall survival (OS) was 67.5 ± 7.8% and 63.8 ± 8.6% (P = 0.694). The DFS and OS results were no differences between the two regimens in univariate analysis.Summary/Conclusion:These data indicate similar survival with non‐TBI conditioning, compared with TBI‐based conditioning, for ASCT in adolescents and young adults with Philadelphia chromosome‐negative ALL.image

MON-453 Endocrine, Bone, and Metabolic Disorders in Adults after Allogeneic Stem-Cell Transplant

Introduction Allogeneic hematopoietic stem cell transplantations (allo-HSCT) is often indicated in malignant hematologic diseases. Conditioning regimens, used to reduce the tumor burden and to prevent transplant rejection, are based on chemotherapy alone or combined with total body irradiation (TBI). Endocrine complications are frequent transplant-related side effects. They have been well described in children studies but less in adulthood. Objective To assess retrospectively endocrine, bone and metabolic disorders in adult patients, 12 months after allo-HSCT. Patients & Methods Inclusion criteria were : patients treated with allo-HSCT from 2006 to 2016 for a malignant hematologic disease; adult and in complete remission at exploration. Exclusion criteria were : anteriority of brain radiotherapy and prior HSCT. Twelve months after HSCT, each patient underwent fasting measurement of IGF1, TSH, fT4, FSH, LH, sex steroids, glycemia, insulin level, and lipid profile. Unless contraindication, adrenal and growth hormone functions were assessed with insulin hypoglycemia test. A dual X-ray absorptiometry was also performed. Results During the inclusion period, 249 patients received allo-HSCT at our institution. Among them, 148 stayed in complete remission 12 months after HSCT and 63 have been explored in our department. The study sample consisted of the 45 patients meeting the inclusion/exclusion criteria. 40 patients had insulin hypoglycemia test. Hypopituitarism was observed in 20 patients (44%) (14 GH deficiency, 8 central adrenal deficiency, 2 central hypothyroidism and 1 central hypogonadism). No predictive factor was found. One patient had central adrenal deficiency after 12 Gy TBI regimen without any corticotherapy. Hypothyroidism was observed in 6 patients (13,6 %), evenly distributed in subclinical, overt and central hypothyroidism. The risk of developing hypothyroidism was higher in patients aged less than 30 y/o at transplantation (OR = 8,5). All premenopausal women (n = 16) had premature ovarian failure. Half of the 18 men were suspected to have spermatogenesis disorder (elevated FSH). Five men had elevated LH with normal testosterone, and one had central hypogonadism possibly attributed to his obesity. Bone mineral density (BMD) was decreased in 33 patients (77 %). Twelve (28 %) had osteoporosis. Conditioning regimen with busulfan was protective of BMD decrease (OR = 0,66 [0,5-0,85], P = 0,02). Obesity was more frequent (20 %) than our national prevalence (14 %). There were no increase in insulino-resistance and diabetes prevalences. Twenty patients (45 %) had dyslipidemia, 14 of them hypertriglyceridemia. Conclusion Our study shows a high frequency of endocrine, bone and metabolic disorders 12 months after allo-HSCT during adulthood. Hypopituitarism is more frequent that previously described, using the gold standard of the GH and adrenal function exploration.

Impact of conditioning regimen on peripheral blood hematopoietic cell transplant.

AIMTo investigate infused hematopoietic cell doses and their interaction with conditioning regimen intensity +/- total body irradiation (TBI) on outcomes after peripheral blood hematopoietic cell transplant (PBHCT).METHODSOur retrospective cohort included 247 patients receiving a first, T-replete, human leukocyte antigen-matched allogeneic PBHCT and treated between 2001 and 2012. Correlations were calculated using the Pearson product-moment correlation coefficient. Overall survival and progression free survival curves were generated using the Kaplan-Meier method and compared using the log-rank test.RESULTSNeutrophil engraftment was significantly faster after reduced intensity TBI based conditioning [reduced intensity conditioning (RIC) + TBI] and > 4 × 106 CD34+ cells/kg infused. A higher total nucleated cell dose led to a higher incidence of grade II-IV acute graft-versus-host disease in the myeloablative + TBI regimen group (P = 0.03), but no significant difference in grade III-IV graft-versus-host disease. A higher total nucleated cell dose was also associated with increased incidence of moderate/severe chronic graft-versus-host disease, regardless of conditioning regimen. Overall and progression-free survival were significantly better in patients with a RIC + TBI regimen and total nucleated cell dose > 8 × 108/kg (3 years, overall survival: 70% vs 38%, P = 0.02, 3 years, progression free survival: 64% vs 38%, P = 0.02).CONCLUSIONTBI and conditioning intensity may alter the relationship between infused cell doses and outcomes after PBHCT. Immune cell subsets may predict improved survival after unmanipulated PBHCT.

The Dose per Fraction May be correlated with Late Kidney Toxicity after Total Body Irradiation: a Single Institution Experience

Background: The purpose of the present study was to retrospectively evaluate the subacute or late toxicities in the kidney, lung, and liver after two total body irradiation regimens, 12 Gy in 6 fractions (group A) and 12 Gy in 4 fractions (group B). Methods: Forty-two patients who underwent total body irradiation (group A, n=32; group B, n=10) between June 1997 and June 2013 were included in the present study. The median follow up period was 60 months (range: 3–219 months) for the patients in group A and 143 months (range: 5–220 months) for the patients in group B. We evaluated the renal, pulmonary, and hepatic toxicities using the Common Terminology Criteria for Adverse Events version 4.0. Results: There were 4 cases of chronic kidney disease (group A, n=1; group B, n=3). Although the cumulative incidence of chronic kidney disease differed significantly between the two total body irradiation regimens (p=0.014), the pulmonary and hepatic toxicities did not differ to a statistically significant extent. Conclusion: The present study suggests that a higher dose per fraction caused a higher incidence of chronic kidney disease.