TBI-based Conditioning Research Articles

Influence of Total Body Irradiation Dose Rate on Idiopathic Pneumonia Syndrome in Pediatric Patients With Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

<h3>Purpose/Objective(s)</h3> To evaluate the relationship between total body irradiation (TBI) and other factors in the development of idiopathic pneumonia syndrome (IPS) in pediatric patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute leukemia. <h3>Materials/Methods</h3> Between 2006-2019, 121 pediatric patients with acute leukemia (84 lymphoblastic, 37 myeloid), ranging in age from 1 to 21 years (median 12), underwent allogeneic HCT at a single institution with matched sibling (n = 33), single unrelated cord blood (sUCB; n = 57), or double unrelated cord blood (dUCB; n = 31) donor. Pretransplantation conditioning included cyclophosphamide (100-120 mg/kg) with (n = 89) or without fludarabine (75 mg/m²) (n = 32). TBI was delivered in 8 b.i.d. fractions of 1.65 Gy over 4 days via opposed lateral beams of 6, 18, or 25 MV prescribed to midplane at umbilicus, with the patient in a semi-recumbent position, and without lung shielding. Aluminum lung compensator was utilized if predicted mid-lung point dose was ≥3% higher than prescription dose (n = 28). Dose rate was specified at 9-20 cGy/min and depended on linear accelerator availability. Patients were stratified by receipt of high-dose-rate (HDR; > 15 cGy/min; 36%) or low-dose-rate (LDR; ≤15 cGy/min; 64%) delivery. IPS was defined as pulmonary injury based on clinical symptoms, radiographic evidence, or pulmonary function testing within 100 days of HCT in the absence of concurrent infection. The association between treatment factors and IPS was examined. <h3>Results</h3> Overall, IPS developed in 22 (18%) patients from day 6 to 83 (median 20) after HCT. On univariate analysis, factors associated with IPS included donor type (matched sibling 12%, sUCB 12%, dUCB 35%, <i>P</i> < 0.01), HDR TBI (35% vs 9% for LDR, <i>P</i> < 0.01), and lower beam energy (35% for 6 MV and 15% for 18/25 MV, <i>P</i> = 0.04). The finding of beam energy significance is likely the result of the 6 MV cohort having a greater dose rate (median 16 cGy/min) than the 18/25 MV cohort (11 cGy/min). On competing risk regression analysis, the pre-specified factors of dose rate, beam energy, lung compensator, age, HCT comorbidity index, and donor type were included in the model. All factors except age (hazard ratio [HR] 1.09, <i>P</i> = 0.20) and lung compensator (HR 1.8, <i>P</i> = 0.17) showed an independent statistically significant association with IPS. Kaplan-Meier estimated 1-year survival was 73% for the entire cohort. Time-dependent effect of IPS did not show an association with overall survival (HR 1.2, <i>P</i> = 0.76). <h3>Conclusion</h3> TBI dose rate is an important variable in the risk of pulmonary toxicity in children treated with allogeneic HCT. TBI dose rates ≤15 cGy/min reduced the risk of posttransplantation IPS and should be strongly considered as an easily implemented parameter in pre-transplantation TBI-based conditioning.

Radiation-Free myeloablative allogeneic hematopoietic stem cell transplantation for adult acute lymphoblastic leukemia: A comparison of outcomes between patients with and without central nervous system involvement

For patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), total body irradiation (TBI) has been particularly advocated as a part of the conditioning regimen in case of extramedullary involvement in sanctuary sites such as the central nervous system (CNS), to ensure greater tissue penetration. In resource-limited countries lacking TBI facilities; however, ALL patients undergo radiation-free myeloablative conditioning, though its impacts on post-HSCT outcomes of the patients with pre-HSCT CNS involvement have not been analyzed. In this 14-year series of 278 adult (> 18 y) ALL patients undergoing TBI-free busulfan/cyclophosphamide conditioning allo-HSCT, we found that the long-term probabilities of overall survival, disease free survival, relapse and non-relapse mortality were not significantly different between CNS-involved and CNS-spared patients. Moreover, there was no statistically significant difference in the incidence of post-HSCT CNS relapse between CNS-involved and CNS-spared patients. Pre-HSCT cranial radiation therapy (CRT) showed no significant preventive effect on the likelihood of post-HSCT CNS relapse. Through multivariable regression analysis, grade III-IV acute graft-versus-host disease (GvHD), extensive chronic GvHD and post-HSCT relapse were ascertained as independent determinants of mortality (Adj.R2 = 53.9 %, F(12,265) = 28.1, P < 0.001), while other parameters including Philadelphia translocation, pre-HSCT CNS involvement and CRT were found to have no independent effect. Although this study was not an attempt to compare TBI-based vs. non-TBI conditioning, the TBI-free myeloablative allo-HSCT was shown to be feasible and an option for adult ALL patients with CNS involvement, considering the comparable outcomes between patients with and without CNS involvement.

Outcomes of pediatric patients with therapy-related myeloid neoplasms.

Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end-organ failure, as compared to only 20.9% of deaths in the reduced-intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD was associated with worse OS. In addition, a diagnosis of therapy-related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs.

Post-Irradiation Hyperamylasemia Is a Prognostic Marker for Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Pediatric Population: A Retrospective Single-Centre Cohort Analysis.

Background: Total body irradiation (TBI) is a mandatory step for patients with acute lymphoblastic leukemia (ALL), undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In the past, amylases have been reported to be a possible sign of TBI toxicity. We investigated the relationship between total amylases (TA) and transplant-related outcomes in pediatric recipients. Methods: We retrospectively analyzed the medical records of all the patients who underwent allogeneic HSCT between January 2000 and November 2019. The inclusion criteria were the following: recipient’s age between 2 and 18, diagnosis of ALL, no previous transplantation, and use of TBI-based conditioning. The serum total amylase and pancreatic amylase were evaluated before, during, and after transplantation. Cytokines and chemokines assays were retrospectively performed. Results: 78 patients fulfilled the inclusion criteria. Fifty-seven patients were treated with fractionated TBI, and 21 with a single-dose regimen. The overall survival (OS) was 62.8%. Elevated values of TA were detected in 71 patients (91%). The TA were excellent in predicting the OS (AUC = 0.773; 95% CI = 0.66–0.86; p < 0.001). TA values below 374 U/L were correlated with a higher OS. The highest mean TA values (673 U/L) were associated with a high disease-progression mortality rate. The TA showed a high predictive performance for disease progression-related death (AUC = 0.865; 95% CI = 0.77–0.93; p < 0.0001). Elevated TA values were also connected with significantly higher levels of proinflammatory cytokines, such as TNF-α, IL-6, and RANTES (p < 0.001). Conclusions: this study shows that TA is a valuable predictor of post-transplant OS and increased risk of leukemia relapse.

Myeloablative Conditioning With PBSC Grafts For T-Replete Haploidentical Donor Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide Results In Universal Engraftment, Low Rates Of Gvhd, NRM and Excellent Survival Outcomes: An Analysis Of Two Consecutive Phase II Studies From a Single Center

Lack of a matched sibling or suitably matched unrelated donor can be a significant barrier to allogeneic hematopoietic cell transplantation in patients who stand to benefit from this procedure. HLA-haploidentical donors are readily available for nearly all such patients. Whereas previous attempts at haploidentical donor hematopoietic stem cell transplantation (haploSCT) using standard immunosuppression or ex-vivo T-cell depletion have had relatively poor outcomes, a recent approach using a T-replete bone marrow graft with non-ablative conditioning and post-transplant cyclophosphamide (ptCy) for control of alloreactivity has proved to be remarkably well tolerated (Luznik et al BBMT 2008). However, relapse of malignancy remains a major challenge with the use of this non-myeloablative regimen. The use of myeloablative conditioning and a PBSC graft may help reduce the relapse rate following T-replete haploSCT but this has not been well studied. We enrolled a total of 41 patients on two consecutive prospective phase II trials of myeloablative haploSCT and ptCy using a T-replete G-CSF mobilized PBSC graft. The first trial (NSH 864) employed a high-dose busulfan-based preparative regimen (fludarabine 30 mg/m2/d d-6 to -2, Busulfan 110-130 mg/m2/d d-7 to -3 , Cy 14.5 mg/kg/d d-6&-5) [n=20], the second (NSH 922) utilized a TBI-based regimen (fludarabine 25 mg/m2/d x 3 d and TBI 150 cGy bid on d -4 to -1 [total dose 1200cGy]) [n=21]. Post-grafting immunosuppression consisted of Cy 50mg/kg/day on days 3 and 4, MMF through d 35, and tacrolimus through d 180 on both protocols. Eligibility was limited to patients ≤60 years of age with aggressive/advanced hematologic malignancies perceived to be at high risk of relapse following nonmyeloablative transplant. Leukemia patients in CR1 were eligible if they had either poor-risk cytogenetics/molecular studies or primary chemoresistance. Median patient age was 45 years (range 24-60). Twenty-five patients were transplanted in complete remission (CR) or in chronic phase (CP), while 16 patients were transplanted with advanced disease. No patient experienced graft failure, with a median time to neutrophil and platelet recovery of 16 and 25 days, respectively. All evaluable patients achieved sustained complete donor T cell and myeloid chimerism by Day +30. Median follow-up for survivors is 20 months (NSH 864 - 39 months; NSH 922 – 11months). The cumulative incidence of grades II-IV and III-IV acute GVHD at day +100 was 30% and 17% respectively. The cumulative incidence of chronic GVHD at one year post transplant was 41% (severe in 9%). Non-relapse mortality (NRM) at 12 and 24 months was 8% and 17% respectively. Cumulative incidence of relapse was 31% at both 12 and 24 months post-transplant. The relapse rate was lower in patients transplanted in CR/CP (18%) vs. those transplanted with advanced disease (49%, p=0.044). BK virus-associated hemorrhagic cystitis (HC) occurred in 56% of patients, and was severe (requiring hospital admission for bladder irrigation and/or pain management) in 19%. The incidence of HC and severe HC was significantly lower in patients receiving TBI-containing conditioning than those receiving Busulfan (38% vs. 75%, p=0.028 and 10% vs. 30%, p=0.13, respectively). With a median follow-up of 20 months, the estimated 2 year overall survival (OS) was 51% with a 52% estimated disease-free survival (DFS). In patients transplanted in CR/CP, 2-year DFS was 64% vs. 35% in patients transplanted with advanced disease (p=0.077). There was an encouraging trend to better 2-year DFS in patients receiving TBI-based conditioning than those receiving Busulfan, 75% vs. 40%, p=0.072. Myeloablative haploSCT with PBSC grafts and ptCy allows reliable engraftment with early donor T cell chimerism; low rates of GVHD, infectious complications, and NRM; and promising survival in patients with high-risk hematologic malignancies. Outcomes are particularly good in patients treated in CR/CP (18% relapse, 64% DFS). When compared with Busulfan-based conditioning, TBI-based conditioning is associated with less risk of HC and improved DFS. Myeloablative haploSCT is a valid option for patients with aggressive/advanced hematologic malignancies who lack timely access to a conventional donor.▪▪ Disclosures:No relevant conflicts of interest to declare.

Metabolic Syndrome in Male Survivors of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Total Body Irradiation, Low-Grade Inflammation, and Hypogonadism

Metabolic syndrome (MetS) is a growing concern in survivors of pediatric hematopoietic stem cell transplantation (HSCT), but little is known about the underlying mechanisms. This study aimed to determine the prevalence and clinical presentation of MetS in male long-term survivors of pediatric HSCT and to investigate predisposing factors, including low-grade inflammation, altered fat distribution, and low testosterone levels. We included 98 survivors age 19 to 47 years at a median follow-up of 18 years (range, 8 to 35 years) after pediatric HSCT. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The prevalence and clinical manifestations of MetS were compared between our cohort and a control group of males from the background population (n=4767). Fat distribution was assessed by android/gynoid ratio from a whole-body dual-energy X-ray absorptiometry scan. Systemic inflammation was evaluated by IL-6 and high-sensitivity C-reactive protein (hsCRP). Serum testosterone levels were measured in morning samples. The prevalence of MetS was 30%, corresponding to the prevalence in the 50- to 80-year-old males from the background population. In individuals with MetS, hyperglycemia was more frequent in the HSCT survivors compared with age-matched controls with MetS (76% versus 20%; P < .001), whereas hypertension was more dominant in the control group with MetS (69% versus 93%; P=.01). In addition, normal or low body mass index was more commonly observed among HSCT survivors with MetS compared with age-matched controls with MetS (41% versus 11%; P=.002). MetS was more often associated with total body irradiation (TBI) compared with chemotherapy regimens (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.2 to 24.4; P=.02), lower testosterone levels (OR, 5.4; 95% CI, 1.3 to 23.6; P=.02), higher IL-6 levels (OR, 1.8; 95% CI, 1.2 to 2.8; P=.004), and higher hsCRP levels (OR, 1.8; 95% CI, 1.3 to 2.6; P < .001) (estimates per 2-fold increase). In addition, an increased android/gynoid (AG) fat ratio was strongly associated with MetS (OR, 2.1; 95% CI, 1.5 to 2.9; P < .001), even though only 7% of patients met the criteria for increased abdominal circumference. Our results indicate an increased risk of MetS in early adulthood after pediatric HSCT. The clinical manifestations differed from those seen in age-matched controls with MetS, indicating different pathophysiology driven by hyperglycemia, altered fat distribution (despite no clinical abdominal obesity), and low-grade inflammation. Risk factors included TBI-based conditioning and low testosterone levels. These results underline the importance of continuous clinical assessment of the cardiometabolic risk profile and stress the presence of important dissimilarities in the pathophysiology of MetS in HSCT survivors compared with the background population.

CMV Reactivation Post CD34+ Selected Allo-HCT Has Adverse Outcomes on Blood Counts Recovery

INTRODUCTION: CD34+ selection has been shown to be a highly effective method to reduce the incidence of acute and chronic graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT). However it is associated with delayed immune recovery and infections are a major cause of morbidity and mortality. The incidence of Cytomeglalovirus (CMV) reactivation after CD34+ selected allo-HCT has been reported as high as 62-84% in CMV seropositive patients and the incidence of CMV disease was 12.1% (Huang et al, BBMT 2016). CMV and its treatment are known to potentially affect marrow function early post HCT; however data are lacking in patients who reactivate CMV after CD34+ allo-HCT.AIM: To study the effects of CMV serostatus and CMV reactivation on blood counts recovery in the first year post CD34+ allo-HSCT.METHODS: CMV viremia was assessed starting on day of engraftment or day 14 post-HCT (whichever occurred first) by quantitative PCR assay if recipient or donor were CMV positive. Per institutional guidelines preemptive treatment with foscarnet, ganciclovir or valganciclovir is recommended when PCR is detected (>137 copies IU/ml). Patients' blood counts data was included from the day of transplant and up to 1 year post-transplant. We studied the effects on counts recovery of patients' CMV serostatus, CMV reactivation by day 50 post HCT, age, conditioning regimen and CD34+ dose. Due to skewness, WBC, ANC, PLT and absolute reticulocyte count values were log transformed. In order to determine the effects of covariates on counts recovery, a mixed effects model with patient specific random intercepts were fit, including both linear and quadratic terms for the time since transplant, as well as each covariate of interest. For all analyses involving CMV reactivation, only counts post day 50 were included.RESULTS: The analysis included 205 patients who underwent CD34+ allo-HCT between 4/2012-5/2016 for MDS, MPN, AML and ALL. Median age was 55.8 years (range 21.2-73.3). TBI-based conditioning regimen was used in 66 patients (32.1%) and graft source was PBSC in all patients: 178 (87%) from a matched donor; 66 (32%) from a matched related donor (MRD) and 112 (55%) from a matched unrelated donor (MURD) and 27 from mismatched donors (1 related and 26 unrelated donors). Median CD34+ dose was 7.57x106 CD34/kg (0.41-17.52) and median CD3+ dose was 2.1x103 CD3+/kg (0-47.2). CMV serostatus was positive in 119 pts (58%), negative in 77 pts (38%) and equivocal in 9 pts (5%). Ninety-one patients (71% of positive/equivocal pts) had CMV reactivation: median day 27 post HCT (range 14-50). Of the 91 patients who reactivated CMV, 19 (21%) were treated with foscarnet, 26(28%) with ganciclovir or valganciclovir and 28 (31%) with both agents. 19 (21%) also received CMV CTLs. CMV seropositive/equivocal status was associated with lower ANC in the first year post HCT (p=0.01), but had no effect on Hb and Plt counts. CMV viremia by day 50 correlated with lower absolute reticulocyte count (p=0.03), Hb (p=0.02) and ANC (p=0.02). In univariate analysis, other factors that affected blood counts included CD34+ dose < 7.57 x 10^6 (median) which was associated with lower ANC (p=0.004) and lower Plt count (0.008) and TBI based conditioning which was associated with lower ANC (p=0.005) but higher Plt count (p=0.02). In multivariate analysis, positive/equivocal CMV serostatus, lower CD34+ cell dose and TBI based conditioning, continued to be associated with lower ANC post allo-HCT. Thirteen patients (6%) received a CD34+ selected boost for poor graft function: 10 (8%) in the CMV positive/equivocal group and 3 (4%) in CMV seronegative group (p = 0.378). Despite adversely affecting blood counts recovery post -transplant, CMV serostatus and reactivation had no impact on survival, relapse and non non-relapse mortality.CONCLUSION: CMV reactivation affects blood counts recovery post CD34 selected allo-HCT. Despite being an early event, its adverse effects on peripheral blood counts persist for months post-transplant. Whether the cytopenia is driven mostly from CMV infection or from CMV directed therapy is unclear. More effective and less myelosuppressive therapies are needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High Progression-Free Survival after Reduced Intensity Total Body Irradiation-Based Conditioning in Patients Allografted for Chronic Myelomonocytic Leukemia (CMML)

High Progression-Free Survival after Reduced Intensity Total Body Irradiation-Based Conditioning in Patients Allografted for Chronic Myelomonocytic Leukemia (CMML)

Impact of Donor Type in Patients with Acute Myeloid Leukemia Given Allogeneic Hematopoietic Cell Transplantation after Low-Dose TBI Based Regimen: A Study from the Acute Leukemia Working Party of the EBMT and Eurocord

Backround. Low-dose total body irradiation (TBI)-based nonmyeloablative conditioning regimens are widely used in acute myeloid leukemia (AML) patients in first or second complete remission (CR) at the time of transplantation. With these regimens the burden for tumor eradication relies mostly on immune-mediated graft-versus-leukemia (GVL) effects that can be impacted by donor type. Here we assessed the impact of donor type in a large cohort of AML patients transplanted in CR after low-dose TBI-based nonmyeloablative conditioning regimens.Methods. Inclusion criteria included >= 18 years of age, de novo or secondary AML in CR1 or CR2, transplantation between 2004 and 2015, conditioning with fludarabine + 2 Gy TBI with or without pre- or post-transplant cyclophosphamide, no in vitro or in vivo T cell depletion of the graft (besides post-transplant cyclophosphamide), and either an HLA-matched sibling donor (MSD), a 10/10 HLA-matched unrelated donor (MUD), an HLA-haplo-identical donor (Haplo) or a single or double umbilical cord blood (CBT).Results. Data from 1357 patients receiving grafts from MSD (n=594), MUD (n=442), Haplo (n=77) or given single or double CBT (n=244) were included. The proportion of patients transplanted in CR1 was 87%, 80%, 66% and 60% in MSD, MUD, Haplo and CBT groups, respectively (P<0.001) while median patient age at transplantation was 58, 63, 57 and 55 years, respectively (P<0.001). The proportion of patients with secondary AML was 16%, 22%, 21% and 20% in MSD, MUD, Haplo and CBT groups (P=0.04). Median follow-up was 49, 25, 17 and 48 months, respectively (P<0.001). Graft rejection occurred in 2% of each MSD and MUD recipients, 7% of haplo patients and 8% of CBT recipients (P<0.001). Grade III-IV acute GVHD was more frequent in CBT (16%) than in MUD (9%), haplo (8%) or MSD (7%) recipients (P<0.001). In contrast, chronic GVHD was less frequent in CBT (27%) and in haplo (30%) patients than in MSD (50%) and MUD (52%) recipients (P<0.001). Two-year OS and GRFS were 60% and 30% in MSD patients, 56% and 41% in CBT recipients, 54% and 24% in MUD recipients, and 42% and 35% in haplo patients, respectively (P=0.02 for OS and P=0.03 for GRFS ; Figure 1). Two-year incidences of relapse and nonrelapse mortality (NRM) were 33% and 12% in MSD patients, 29% and 20% in MUD recipients, 34% and 17% in CBT recipients, and 37% and 21% in haplo patients, respectively (P=0.7 for relapse and P<0.001 for NRM). In multivariate analyses, in comparison to MSD patients, each other donor type was associated with a significantly higher NRM. Interestingly, CBT was associated with a higher incidence of grade III-IV acute GVHD (HR 2.9, P=0.001) but a lower incidence of chronic GVHD (HR=0.4, P<0.001) than MSD resulting in a significantly worse GVHD-free relapse free survival (GRFS) the first 100 days (HR=1.5, P=0.02) but significantly better GRFS beyond day 100 (HR=0.6, P=0.001). Finally, there was a suggestion for lower OS in haplo patients (HR 1.5, P=0.08). Factors associated with worse OS included intermediate and adverse-risk cytogenetics and secondary AML. AML relapse, GVHD and infections were the primary causes of death of 24%, 6% and 4% of MSD recipients, 21%, 7% and 7% of MUD recipients, 22%, 5% and 14% of haplo recipients, and 25%, 8% and 5% of CBT recipients, respectively.Conclusions. In this large cohort of AML patients transplanted in CR following low-dose TBI-based nonmyeloablative conditioning regimen there were no significant differences in OS and LFS between MSD, MUD and UCB while there was a suggestion for lower LFS and OS with haplo due to a higher incidence of death from infection. Since this regimen relies nearly exclusively on GVL effects for tumor eradication, our data suggest that the intensity of GVL effects is comparable with these four donor types. Further studies including more haplo patients are needed to confirm these results. [Display omitted] DisclosuresSavani:Jazz Pharmaceuticals: Speakers Bureau. Mohty:Sanofi: Honoraria, Speakers Bureau.

Long-Term Outcomes of Total Body Irradiation Plus Cyclophosphamide Versus Busulfan Plus Cyclophosphamide As Conditioning Regimen for Acute Lymphoblastic Leukemia: A Comparative Study

Introduction: Total body irradiation-Cyclophosphamide (TBI-Cy) and Busulfan-Cyclophosphamide (Bu-Cy) are the most commonly used conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HCT) for acute lymphoblastic leukemia (ALL). TBI-based conditioning regimens may have a better antitumor effect at sanctuary cites compared to chemotherapy regimens. However, some controversy still remains concerning the role of TBI in adult ALL. Therefore, we aimed to retrospectively investigate long-term treatment outcomes of ALL patients post allo-HCT and identify prognostic factors and the impact of the conditioning.Methods: We enrolled consecutive patients with ALL who underwent alloHCT from 1990 to 2016 in our center, following a TBI- or a Busulfan (Bu)-based conditioning regimen. TBI at 14.4Gy was divided at 6 fractions over 3 days and Bu (mainly oral) at 4mg/kg/day. Both regimens included 120mg/kg Cy. Graft source was mainly mobilized peripheral blood stem cells.Results: We studied 151 ALL (114 B-ALL, 35 T-ALL and 2 biphenotypic) patients aged 28±12 years, transplanted in CR1 (60), other CR (33) or relapsed/refractory disease (58) from sibling (87), HLA matched (42) or mis-matched (17) unrelated and alternative donors (5). TBI-based conditioning was administered in 84, whereas non-TBI in 67. No differences were observed in baseline characteristics, except for disease phase, disease risk index (DRI) and graft source. The majority of non-TBI patients had relapsed/refractory disease at transplant (50.7% versus 28.6% in TBI-conditioning, p=0.043) and subsequently significantly higher DRI (p=0.025). Furthermore, bone marrow was the graft source in significantly higher number of non-TBI patients (28.4% versus 8.3% in the TBI group, p=0.001).With a follow-up of 19.0 (0.5-170.5) in TBI and 14.5 (1.2-319.1) months in the non-TBI group, there was no difference in the incidence of acute (Grade 2-4) or chronic GVHD, thrombotic microangiopathy, bacterial or fungal infections. Only viral infections were significantly increased in the non-TBI group (59% versus 41% in the TBI group, p=0.03). Therefore, there was no significant difference in the cumulative incidence (CI) of treatment-related mortality (5-year CI of 24.1% in non-TBI versus 27.7% in the TBI group, p=0.678) or relapse mortality (5-year CI of 29.2% in non-TBI versus 37.1% in the TBI group, p=0.283).Overall survival (OS) was similar in the TBI and non-TBI group (5-year 46.7% compared to 35.8%, p=0.201). In the multivariate analysis, unfavorable pre-transplant predictors of OS were age (p=0.024), higher disease risk index (DRI) (p=0.007) and female to male donor (p=0.006). Disease-free survival (DFS) was similar in the TBI and non-TBI group (5-year 47.1% compared to 35.4%, p=0.134), with age, higher DRI and female to male donor being unfavorable predictors. When the analysis was limited to patients transplanted in CR1 (40 in the TBI versus 20 in the non-TBI group), there were also no significant differences.Interestingly, age predicted OS and DFS only in the TBI group. TBI patients younger than 40 years had significantly high OS (55.1%, p=0.023) and DFS (55.5%, p=0.02) versus the older ones. Older TBI patients had higher TRM (43.3% versus 20.1%, p=0.135) and relapse mortality (45.8 versus 24.7, p=0.238) that did not reach levels of statistical significance. However, the same was not true for the non-TBI group (p=0.233 for DFS, p=0.326 for OS).Conclusion: In our retrospective data of the last 3 decades, the type of conditioning regimen did not influence the outcome of transplantation. Based on our results, high dose TBI is a feasible conditioning in terms of a prolonged DFS and OS for younger patients and seems an efficient tool to cure high-risk ALL in CR1. It should be kept in mind that intravenous BU is also used with stable pharmacokinetics. Since our data were not powered to appraise superiority of one regimen in terms of efficacy and toxicity, the choice between TBI or Bu conditioning regimens is still under consideration. Treatment is complex for adult ALL patients and remains a field of debate and a challenge for prospective studies in the future. DisclosuresGavriilaki:European Hematology Association: Research Funding.

Late Fatal Infections Remain Higher Than Expected in Adults Receiving Allogeneic Stem Cell Transplant

▪Introduction:Life expectancy remains lower than expected in long-term survivors after allogeneic stem cell transplant (HCT) compared to the age and sex matched population. Infection has been reported to account for 10-20% of deaths occurring 2 years or later after HCT. We performed an analysis of late fatal infections (LFI) in HCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).Methods:Adult patients (pts) who underwent first HCT between 01/1995 and 12/2011, reported to the CIBMTR and surviving disease-free at 2 years following HCT were included in the analysis. Pts transplanted at centers with follow up completeness index < 80% at 4 years post HCT were excluded. Late fatal infections were described and their cumulative incidence was calculated as death from infectious complications occurring at least 2 years after HCT in eligible subjects. Risk factors for LFI were identified using Cox regression models. Pts with late relapse or second HCT (after 2 years) were censored at the event.Results:There were 10,336 pts from 267 centers included in the analysis. The median age at transplant was 44 (18-79) years. Myeloablative and reduced intensity/non-myeloablative conditioning was given to 6,807 (66%) and 3,339 (32%) pts respectively. Bone marrow, peripheral blood and cord blood were used as the graft source in 3,479 (34%), 6,347 (61%) and 510 (5%) pts respectively. Clinically significant fungal infections prior to HCT, were reported in 884 (9%) pts and 318 pts (3%) were HIV positive. A history of acute GVHD (aGVHD), limited or extensive cGVHD within 2 years of HCT was reported in 3,559 (34%), 1,315 (13%) and 4,912 (48%) pts respectively. Overall 2245 pts (22%) died from any cause.Infection, as the primary or a contributing cause of death, was reported in 687 (7%) subjects, thus LFI contributed to 31% of all late deaths. Bacterial infections were the most commonly reported LFI (Table1). The cumulative incidence of LFI in pts increased with time, with estimates of 2%, 3%, 5%, 5% and 6% at 3, 5, 8, 10 and 12 years respectively.In multivariate analysis, increasing age >20 years, receipt of MUD or MMUD, history of aGVHD or extensive cGVHD within 2 years of HCT, male sex, and TBI-based conditioning regimens were associated with increased risk of LFI (Table 2).Conclusions:LFI in HCT recipients remain high and contributed to third of all deaths occurring at least 2 years after HCT. Age, HLA match, male gender, and a history of both aGVHD and cGVHD were associated with an increased risk of LFI. Risks of LFI do not diminish but increase up to 12 years of follow up. [Display omitted] DisclosuresNorkin:Celgene: Honoraria, Research Funding. Flowers:Pharmacyclics: Consultancy. Savani:Jazz Pharmaceuticals: Speakers Bureau.

Low-Toxicity/High-Efficacy HLA Haploidentical Transplantation for Elderly/Unfit Patients with Acute Leukemia

Allogeneic hematopoietic transplantation is the most powerful therapy for patients with acute leukemia at high risk of relapse. For HLA haploidentical transplantation, we recently applied a protocol consisting of a high-intensity TBI-based conditioning regimen and a peripheral blood CD34+ hematopoietic stem cell graft combined with the adoptive transfer of naturally occurring regulatory T cells (Tregs) and conventional T cells (Tcons). No post-transplant pharmacologic immune suppressive GvHD prophylaxis was given. Such a protocol was associated with remarkably low GvHD and relapse rates (Martelli MF et al., Blood. 124:638-644, 2014; reviewed in Mancusi A et al., Blood 128:2616-2623, 2016).However, patients who are unfit (because of multiple chemotherapy cycles, previous transplants, infections, or co-morbidities) or elderly are not expected to withstand high-intensity conditioning regimens. For these patients, we developed a reduced-toxicity version based on total marrow and total lymphoid irradiation (TMI/TLI) (Rosenthal J et al., Blood. 2011;117:309-315). TMI/TLI (13.5 Gy and 11.5 Gy respectively) were administered by means of Helical Tomotherapy HI-ART (in 9 fractions delivered two times a day in 4 and a half days). Target volumes were defined as the skeletal bone and major lymph node chains and spleen. In patients with ALL the brain was added as target volume. TMI/TLI was followed by chemotherapy with Thiotepa (2,5mg/kg/day for 2 days), Fludarabine (30 mg/m2/day for 5 days) and Cyclophosphamide (15 mg/kg/day for 2 days). As per our high-intensity protocol, the hematopoietic stem cell graft was foregone by an infusion of 2x10e6/Kg freshly isolated CD4/CD25/FOXP3-positive Tregs and a subsequent infusion of 1x10e6 Tcons. No post-transplant pharmacologic immune suppressive GvHD prophylaxis was given. To date 19 patients with high-risk acute leukemia in remission were enrolled (16 AML, 3 ALL). Median age was 57 years (range: 22-68). All patients engrafted. Four patients developed aGvHD grade ≥ 2. Transplant-related mortality was 21% (2 patients died of infections, 1 of VOD and 1 of aGvHD). Remarkably, no relapse or cGvHD were observed. With a median follow up of 12 months (range: 1-24), 15 of the 19 patients are alive. Thus, leukemia/cGvHD-free survival is 79%. Of course, these data need to be confirmed in a larger cohort of patients and with longer follow up.In conclusion, the present transplantation protocol was designed to make HLA haploidentical transplantation feasible and effective for unfit or elderly patients with high-risk leukemia. It combines a reduced-toxicity conditioning regimen with safe cellular immunotherapy of leukemia. To date, the clinical results are excellent and extremely encouraging. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Non-TBI Based Conditioning Regimen in Peripheral Blood Stem Cell Transplantation (PBSCT) for Adult Acute Lymphoblastic Leukemia Patients: A Single Center Experience

Introduction: The outcome of adult acute lymphoblastic leukemia (ALL) patients with chemotherapy only is not promising and overall survival (OS) does not exceed 30%. Allogeneic Hematopoietic Stem Cell transplantation (allo-HSCT) in first or beyond complete remission (≥CR1) has shown a superior OS rate of approximately 50 % over conventional chemotherapy protocols. Total body irradiation plus Cyclophosphamide (TBI/Cy) and oral busulfan plus cyclophosphamide (BU/Cy) are commonly used myeloablative conditioning regimens in ALL. TBI-based conditioning regimen is considered the standard of care.Aim: To compare the outcomes of allo HSCT using TBI/Cy and BU/Cy conditioning regimens in adult standard and high risk ALL patients in ≥CR1.Material and methods: We retrospectively analyzed the outcome of TBI/Cy and BU/Cy myeloablative conditioning regimen (MAC). BU/Cy cohort included 33 patients (9 females & 24 males) with a median age of 28 years (19-42). Myeloablative BU oral dose was 16mg/kg/4 days & Cy dose was 120 mg/kg IV over 4 days. TBI/Cy cohort included 45 patients (14 females & 31 males) with a median age of 24 years (19-46). TBI dose was 12 Gy fractionated for 5 days & Cy dose was 120mg/kg IV over 4 days. Both cohorts underwent allo-PBSCT at Nasser Institute Hospital, Cairo, between 1997-2010 (TBI group) and 2010-2017 (BU group) (Table1). All patients received graft-versus-host disease (GVHD) prophylaxis using cyclosporine-A (3mg/kg/day IV) from day -1 and methotrexate (15 mg/m2 IV) on day + 1 then 10 mg/m2 IV on days +3, +6 and +11. Post-transplant neutrophil and platelet engraftment were defined by three successive days with absolute neutrophilic count >=1x 109/L and platelet count >=20 x 109/L (without transfusion).Results:In the TBI arm, median time to neutrophil and platelet engraftment was 15 days (9-22) and 15 days (7-47), respectively vs. 14 days (10-22) and 12 days (10-21), respectively in the BU arm. 11/45 TBI patients (24.4 %) developed grade ≥2 acute-GVHD vs. 7/33 (21.2%) patients in the BU arm. Extensive cGVHD was reported in 8/45 (17.7 %) TBI arm vs. 6/33 (18%) patients in the BU arm. Limited cGVHD occurred in 5/45 (11.1%) TBI patients vs. 3/33 (9%) in the BU arm. Cumulative survival was 42.2 % and 15 months OS was 36.7% in the TBI arm vs. 63.6 % and 51.3 % in the BU arm (p= 0.02) (Figure 1). The incidence of sepsis and aGVHD as a cause of transplant related mortality (TRM) were significantly higher in the TBI arm vs. BU arm (p<0.001) (Table 2).Conclusions: Preliminary data demonstrates thatoutcome of BU/Cy is comparable to TBI/Cy as MAC regimen for Allo SCT inadult ALL. With limitation of resources, standard and high risk ALL patients may benefit from allo PBSCT using irradiation-free conditioning regimen associated with lower incidence of sepsis and aGVHD as a cause of transplant related mortality. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Post-transplant cyclophosphamide containing regimens after matched sibling, matched unrelated and haploidentical donor transplants in patients with acute lymphoblastic leukemia in first complete remission, a comparative study of the ALWP of the EBMT

BackgroundThere is no information on the impact of donor type in allogeneic hematopoietic stem cell transplantation (HCT) using homogeneous graft-versus-host (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) in acute lymphoblastic leukemia (ALL).MethodsWe retrospectively analyzed outcomes of adult patients with ALL in CR1 that had received HCT with PTCy as GVHD prophylaxis from HLA-matched sibling (MSD) (n = 78), matched unrelated (MUD) (n = 94) and haploidentical family (Haplo) (n = 297) donors registered in the EBMT database between 2010 and 2018. The median follow-up period of the entire cohort was 2.2 years.ResultsMedian age of patients was 38 years (range 18–76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II–IV and III–IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34% (p = 0.4); 13%, 15%, and 15% (p = 0.8); 35%, 50%, and 42% (p = 0.01); and 11%, 17%, and 21% (p = 0.2), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% (p = 0.8); and 21%, 18%, and 21% (p = 0.8) for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51% (p = 0.8); 66%, 69%, and 62% (p = 0.8); and 46%, 44%, and 35% (p = 0.9), respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better LFS.ConclusionsDonor type did not significantly affect transplant outcome in patient with ALL receiving SCT with PTCy.

T-cell prolymphocytic leukemia

T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell lymphoma. The diagnosis of T-PLL is made based on the criteria proposed in 2019 by the T-PLL International Study Group (TPLL-ISG). T-PLL may be diagnosed in an ‘active’ or an ‘inactive’ form. While T-PLL is most often characterized by an aggressive clinical course, approximately 20–30% of patients may have a stable or slowly progressive disease in the initial period. Only the active form requires treatment. The treatment initiation criteria were defined in the consensus proposed by the TPLL-ISG. Data on the effectiveness of various therapeutic approaches comes from small, non-randomized studies. No drug is approved for the treatment of T-PLL. The standard of care in the first line of treatment is intravenous alemtuzumab. Consolidation therapy in eligible patients consists of allogeneic hematopoietic stem cell transplantation, preferably after TBI-based conditioning. In the remaining patients, neither maintenance nor consolidation treatment is recommended. There is no standard therapy for the relapse, although, based on genome studies, many drugs may be potentially effective, including histone deacetylase inhibitors and BCL2 inhibitors.

T-cell prolymphocytic leukemia

T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell lymphoma. The diagnosis of T-PLL is made based on the criteria proposed in 2019 by the T-PLL International Study Group (TPLL-ISG). T-PLL may be diagnosed in an ‘active’ or an ‘inactive’ form. While T-PLL is most often characterized by an aggressive clinical course, approximately 20–30% of patients may have a stable or slowly progressive disease in the initial period. Only the active form requires treatment. The treatment initiation criteria were defined in the consensus proposed by the TPLL-ISG. Data on the effectiveness of various therapeutic approaches comes from small, non-randomized studies. No drug is approved for the treatment of T-PLL. The standard of care in the first line of treatment is intravenous alemtuzumab. Consolidation therapy in eligible patients consists of allogeneic hematopoietic stem cell transplantation, preferably after TBI-based conditioning. In the remaining patients, neither maintenance nor consolidation treatment is recommended. There is no standard therapy for the relapse, although, based on genome studies, many drugs may be potentially effective, including histone deacetylase inhibitors and BCL2 inhibitors.

Impact of Total Body Irradiation-Based Myeloablative Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM.

Allogeneic Hematopoietic Cell Transplantation for Adolescent and Young Adult Patients with Acute Myeloid Leukemia

Limited data exist regarding the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) among adolescent and young adult (AYA) patients with acute myeloid leukemia (AML). Here we analyzed the features and outcomes of AYA patients with AML who had achieved complete remission (CR) and those who had not (non-CR) at allo-HCT. We retrospectively analyzed 2350 AYA patients with AML who underwent allo-HCT with a myeloablative conditioning regimen and who were consecutively enrolled in the Japanese nationwide HCT registry. The difference in overall survival (OS) between younger (age 16 to 29 years) and older AYA (age 30 to 39 years) patients in CR at transplantation was not significant (70.2% versus 71.7% at 3 years;P= .62). Meanwhile, this difference trended toward a statistical significance between younger and older AYA patients in non-CR at transplantation (39.5% versus 34.3% at 3 years; P=.052). In AYA patients in CR and non-CR, the age at transplantation did not affect relapse or nonrelapse mortality (NRM). In AYA patients in CR, no difference in OS was observed between those who received total body irradiation (TBI) and those who did not (71.1% versus 70.5% at 3 years; P=.43). AYA patients who received TBI-based conditioning had a significantly lower relapse rate and higher NRM than those who underwent non-TBI-based conditioning (relapse: 19.8% versus 24.1% at 3 years [P=.047]; NRM: 14.7% versus 11.1% at 3 years [P=.021]). In contrast, among the non-CR patients, there were no differences between the TBI and non-TBI groups with respect to OS (P=.094), relapse (P=.83), and NRM (P=.27). Our data indicate that outcomes may be more favorable in younger AYA patients than in older AYA patients in non-CR at transplantation, and that outcomes of TBI-based conditioning could be comparable to those of non-TBI-based conditioning for AYA patients.

Acute Lymphoblastic Leukemia in Children: Better Transplant Outcomes After Total Body Irradiation-based Conditioning.

Comparison of transplant outcomes in long-term follow-up of children after total body irradiation (TBI)- or chemotherapy-based conditioning allogeneic hematopoietic cell transplantation (allo-HCT). Patients undergoing allo-HCT for Acute lymphoblastic leukemia (ALL) conditioned either with TBI (n=55) or chemotherapy (n=84) were compared. The following transplant outcomes were analyzed: overall survival (OS), event-free survival (EFS), relapse incidence (RI), and graft-versus-host-disease (GVHD)-free-relapse-free survival (GRFS). All analyzed long-term transplant outcomes were significantly better for patients conditioned with TBI at 2 years after transplant. OS at 2 years was 84% after TBI and 60.5% after chemotherapy-conditioning (p=0.005). Risk factor analysis showed that two factors, TBI-based conditioning and transplant in first remission of ALL, significantly improved OS, EFS, GRFS, and decreased RI. TBI-based conditioning before allogeneic HCT in children with acute lymphoblastic leukemia provides significantly better transplant outcomes, when compared to chemotherapy-based conditioning.

Current Use of Total Body Irradiation in Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation.

Total body irradiation (TBI) is included in the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT), with unique advantages such as uniform distribution over the whole body and decreased exposure to cytotoxic chemotherapeutic agents. For individuals who lack matched sibling or matched unrelated donors, the use of haploidentical donors has been increasing despite challenges such as graft rejection and graft-versus-host disease (GVHD). Although a limited number of studies have been performed to assess the clinical role of TBI in haploidentical HSCT, TBI-based conditioning showed comparable results in terms of survival outcomes, rate of relapse, and GVHD in diverse hematologic malignancies such as leukemia, lymphoma, and multiple myeloma. Advances in supportive care, along with recent technical improvements such as restriction of maximum tolerated dose, appropriate fractionation, and organ shielding, help to overcome diverse adverse events related to TBI. Post-transplantation cyclophosphamide was used in most studies to reduce the risk of GVHD. Additionally, it was found that post-transplantation rituximab may improve outcomes in TBI-based haploidentical HSCT, especially in patients with B-cell lymphoma. Along with the advances of techniques and strategies, the expansion of age restriction would be another important issue for TBI-based haploidentical HSCT considering the current tendency toward increasing age limitation and lack of matched donors. This review article summarizes the current use and future perspectives of TBI in haploidentical HSCT.