TBI-based Conditioning Regimen Research Articles

Efficacy and Safety of Total Body Irradiation Versus Chemotherapy Conditioning for Hematopoietic Stem Cell Transplant in Adult Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.

Hematopoietic stem cell transplantation (HSCT) is a potentially curative option for adults with acute lymphoblastic leukemia (ALL) who have achieved remission. This systematic review and meta-analysis compare the efficacy of total body irradiation (TBI) versus chemotherapy (CHT) based regimens for conditioning in adult ALL patients being prepared for HSCT. A comprehensive literature search was conducted in MEDLINE, Embase, the Cochrane Library, and relevant trial registries from their inception to August 2024. The inclusion criteria encompassed all randomized controlled trials (RCTs) and cohort studies that compared TBI with CHT as conditioning regimens prior to HSCT in adult patients with ALL. The primary outcomes assessed were overall survival (OS) and event-free survival (EFS). All statistical analyses were carried out using RevMan version 5.4, using a random-effects model. This meta-analysis includes 20 cohort studies and one RCT. The relative risk (RR) for OS was 1.37 (95% CI: 1.20-1.57), while the RR for EFS was 1.28 (95% CI: 1.15-1.43), highlighting the superior efficacy of TBI-based regimens in this patient population. TBI was also superior in terms of relapse rate (RR 0.71). The 2 regimens were comparable in terms of nonrelapse mortality, acute graft-versus-host disease (GVHD), and chronic GVHD. When used for conditioning prior to HSCT, TBI-based conditioning regimens demonstrate superior OS, EFS, and relapse outcomes compared to CHT-based regimens.

1087: TBI-based conditioning regimen vs chemotherapy prior to transplant in ALL. A study from the SFGM-TC.

1087: TBI-based conditioning regimen vs chemotherapy prior to transplant in ALL. A study from the SFGM-TC.

Early Tapering of Cyclosporine Is Feasible in Haploidentical Stem Cell Transplantation: A Single Center Experience.

Cyclosporine-A (CsA) and post transplantation cyclophosphamide (PTCy) are common agents used for graft versus host disease (GVHD) prophylaxis in Haploidentical hematopoietic cell transplantation (haplo-HCT). However, the impact of CsA cessation timing in the posttransplant setting on clinical outcomes is uncertain. We aimed to investigate the impact of a novel approach that integrated early CsA cessation with PTCy utilization. This study was a single arm retrospective study carried out at a tertiary referral hospital hematology and bone marrow transplantation center between 2009 and 2022. The patients who received haplo-HCT with ATG, PTCy and CsA as GVHD prophylaxis were included. CsA was planned for cessation starting at day 45 to day 60. Acute and chronic GVHD were evaluated and graded. CsA blood concentrations and its impact on acute and chronic GVHD was evaluated. Thirty-one patients composed of 19 (61.3%) male and 12 (38.7%) female patients with a median age of 31 years (20-58). Busulfan and TBI based conditioning regimens were the most utilized regimens. The majority of donors were first degree relatives. Stem cell origin was peripheral blood for all patients. GVHD prophylaxis consisted of ATG, CsA and PTCy. Acute GVHD was observed in 9 (29%) cases, whereas chronic GVHD was seen in 3 (9.7%) cases, with 2 of them having overlapping GVHD. Age, gender, number of chemotherapy lines, transplant characteristics, infused CD34 cell count, and engraftment durations were similar among patients with and without GVHD. Patients with GVHD had similar 1st, 2nd, 3rd and 4th week CsA concentrations compared to patients without GVHD (p>0.05). The presence of GVHD was not associated with worse progression free survival and overall survival (p=0.6, p=0.5, respectively). CMV reactivation was more common in the GVHD group. In the current study, we did not find an impact of CsA concentration on GVHD and post-transplant outcomes in Haplo-HCT setting. Therefore, together with the use of PTCy, early CsA cessation can be an option; further studies are needed to understand all aspects of this approach.

Effects of Total Body Irradiation on Hematopoietic Cell Transplantation Outcomes in Pediatric Acute Myeloid Leukemia with Prior Central Nervous System Involvement

The implications of previous central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT) remain inadequately understood. Patients with CNS disease require more upfront CNS-directed intrathecal therapy, but little is known about whether transplant conditioning regimens should be intensified or if previous CNS involvement impacts post-HCT outcomes. While total body irradiation (TBI) remains standard for pediatric acute lymphoblastic leukemia myeloablative conditioning, it has been largely replaced with chemotherapy-only myeloablation in pediatric AML, primarily due to toxicity and late effects associated with TBI. In the setting of previous CNS involvement, it has been suggested that TBI-based myeloablation may have advantages due to superior CNS tissue penetration and thus decreased rates of AML relapse post-HCT. We analyzed a publicly available dataset derived from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry to characterize the impact of TBI in HCT preparative regimens in pediatric AML patients with a history of CNS involvement. The study dataset was obtained from the CIBMTR data repository. The study cohort included patients aged ≤21 years who underwent initial allogeneic HCT with myeloablative conditioning for de novo AML in the first or second complete remission (CR) between 2008 and 2016, who provided consent for research. Patients with mismatched related donor transplants and noncalcineurin inhibitor graft-versus-host disease (GVHD) prophylaxis were excluded. The dataset was further modified by excluding patients with missing disease site data or those with non-CNS extramedullary disease. Patients were categorized as CNS-positive or -negative AML (AML-CNS(+) and AML-CNS(-), respectively) based on the disease status at diagnosis. The Cox regression model and Fine-Grey methods were employed to delineate the effects of TBI and CNS disease on key HCT outcomes. The study cohort comprised 550 pediatric AML patients, of which 25% (n = 136) were AML-CNS(+). CNS involvement was more prevalent in patients aged 0 to 3 years, patients who were in the second CR, and those with a mismatched unrelated donor or umbilical cord blood. AML-CNS(+) patients demonstrated a lower relapse rate (hazard ratio: 0.50, 95% confidence interval: 0.33 to 0.76) compared to AML-CNS(-) patients, with comparable disease-free survival (DFS) and overall survival (OS) (P = .10 and 0.20, respectively) in the two cohorts. The entire TBI-treated cohort showed an association with increased risks of grade 2 to 4 acute GVHD, bloodstream infections, and endocrine dysfunction. TBI use within the AML-CNS(+) cohort was associated with a lower relapse rate but increased risks of nonrelapse mortality and a trend of higher grade 3 to 4 acute GVHD. In this population-based analysis of pediatric patients with de novo AML undergoing HCT, TBI-based conditioning regimens did not confer an advantage in DFS or OS compared to non-TBI regimens, irrespective of CNS disease status. However, TBI use was associated with increased risks of short- and long-term comorbidities. These findings underscore the need for careful consideration of TBI in pediatric AML.

Total body irradiation versus thiotepa/busulfan-based conditioning regimens for myeloablative allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia.

Total body irradiation (TBI)-based conditioning regimens are generally recommended for allogeneic HSCT (allo-HSCT) in patients with acute lymphoblastic leukemia (ALL). Recent evidence suggests that modern chemotherapy-based regimens may be as effective. This multicenter retrospective study compared the clinical outcomes of myeloablative allo-HSCT with thiotepa, busulfan, and cyclophosphamide/fludarabine (TTB) to TBI-based conditioning. Between 2002 to 2018, 63 and 114 patients received TTB- and TBI-based conditioning regimens, respectively. The 5-year cumulative incidence of relapse was lower in the TBI cohort compared to the TTB cohort (30% [95% CI, 22-38] versus 47% [95% CI, 36-59]; P = 0.03). Multivariate analysis identified T-ALL, Ph-negative B-ALL, and measurable residual disease associated with a higher relapse risk. The 5-year cumulative incidence of non-relapsed mortality (NRM) was significantly lower with TTB (12% [95% CI, 5-20]) compared to TBI (25% [95% CI, 18-33]) (P = 0.001). Multivariate analysis found TBI conditioning, older age, and advanced stages of ALL at transplantation associated with a higher NRM. No statistical difference was seen in overall survival (49% [95% CI, 40-58] and 46% [95% CI, 35-60]) in the TBI and TTB groups, respectively; P = 0.9). The study suggests that TTB-based conditioning may be a promising option for ALL patients undergoing allo-HSCT, as it resulted in similar OS and lower NRM than TBI-based conditioning.

Complications of total-body irradiation in allogeneic bone marrow transplantation: A review article

Hematopoietic stem cell transplantation commonly known as bone marrow transplantation (BMT) or allogeneic BMT (using healthy blood stem cells from a donor) is the preferred therapeutic option for numerous blood-related conditions, both malignant and non-malignant. It is often the sole therapy strategy and essential for relapsed and refractory hematologic malignancies. There have studies regarding BMT on regimen containing total body irradiation (TBI) and a regimen without TBI. It is expected that TBI-based conditioning regimens provide better antitumor effects than chemotherapy regimens. The primary objective of TBI is to eradicate the recipient's bone marrow, facilitating the successful engraftment of donor bone marrow. Acute lymphoid leukemia (ALL) is the principal indication for TBI in bone marrow transplantation. Other diseases including Hodgkin’s lymphoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), multiple myeloma (MM), etc., may benefit from TBI-based regimens; however, TBI use is associated with many side effects.The main complications of patients who underwent TBI-containing conditioning regimens in bone marrow transplantation are vomiting and nausea, with frequencies of approximately 66% and 35%, respectively. However, these events are easily managed. Acute complications include stomatitis, diarrhea, loss of appetite, temporary loss of taste, rash and asthenia. Moreover, veno-occlusive disease, interstitial pneumonitis, lung side effects, growth hormone deficiency, neurological side effects, cataracts, renal toxicity, endocrine impairments, and infertility are other complications in patients who underwent TBI-containing conditioning regimens in bone marrow transplantation. In review article, a complication of total-body irradiation in allogeneic bone marrow transplantation was assessed.

Trem-Cel, a CRISPR/Cas9 Gene-Edited Allograft Lacking CD33, Shows Rapid Primary Engraftment with CD33-Negative Hematopoiesis in Patients with High-Risk Acute Myeloid Leukemia (AML) and Avoids Hematopoietic Toxicity during Gemtuzumab Ozogamicin (GO) Maintenance Post-Hematopoietic Cell Transplant (HCT)

Background: Allogeneic HCT is the standard of care for eligible patients with AML harboring high-risk features such as adverse-risk cytogenetics or measurable residual disease (MRD), however, the majority of these patients still relapse post-HCT and have very poor outcomes. The use of maintenance therapies intended to control post-HCT relapse is often limited by hematopoietic toxicity towards normal engrafted cells. GO (tradename: Mylotarg TM) is an anti-CD33 antibody-drug conjugate targeting CD33+ AML, but its use is limited by on-target, off-tumor hematopoietic toxicity toward CD33+ myeloid and progenitor cells. Tremtelectogene empogeditemcel (trem-cel; formerly VOR33) is a hematopoietic stem and progenitor cell product, manufactured from CD34+ cells isolated from a patient-matched donor, that has been modified by CRISPR/Cas9 gene-editing to lack CD33. Trem-cel was developed to protect normal hematopoietic cells from post-HCT CD33-directed therapies and allow exclusive targeting of residual leukemia. Methods: VBP101(NCT04849910) is a first-in-human Phase 1/2 open-label multicenter trial to establish the safety of using trem-cel as a donor allograft for CD33+ AML patients who are at high risk of relapse and undergoing myeloablative HCT followed by treatment with GO. Eligible patients (18-70 y) must have CD33+ AML with high-risk features for relapse, such as adverse-risk cytogenetics or MRD, and a 10/10 human leukocyte antigen (HLA)-matched related or unrelated donor. Donors undergo mobilization with G-CSF and plerixafor prior to apheresis. Trem-cel is manufactured from isolated CD34+ cells and cryopreserved. Patients undergo either a busulfan- or TBI-based myeloablative conditioning regimen prior to transplantation with trem-cel. After engraftment and recovery of a sufficient CD33-negative neutrophil count, patients begin maintenance therapy with GO in a 3+3 dose escalation strategy starting at 0.5 mg/m 2 every 28d for 4-8 cycles. Results: To date, 6 patients between 32-68 y (median 63.5 y) have been treated with trem-cel at a median dose of 5.2 x 10 6 CD34+ cells/kg (2.6 - 7.6) and CD33 editing efficiency of 88% (80 - 91). Primary neutrophil engraftment occurred in all patients after a median of 10 days (9 - 11) and platelet recovery occurred after a median of 16 days (15-22) excluding one patient with documented anti-platelet antibody (Fig 1). At the day 28 assessment, full peripheral blood (PB) myeloid chimerism was achieved in all patients and CD33 expression by flow was absent in a median of 94% of neutrophils (86-99) and 92% of monocytes (82 - 94), respectively. Comparable CD33 edits were detected in donor cells across myeloid and lymphoid lineages. GO dosing is ongoing at 0.5 mg/m 2 dose and neutrophil and platelet counts remain stable, suggesting protection from GO-mediated hematotoxicity. Following the 0.5 mg/ m 2 dose, the exposures of GO were predictively higher in the context of CD33-negative hematopoiesis relative to GO doses of 1-2 mg/m 2 (C max) and 4-5 mg/m 2 (AUC), respectively, in CD33+ relapsed/refractory AML patients. During GO dosing, the percent of CD33-negative cells increased in the PB and bone marrow (BM) across cell lineages consistent with enrichment of edited donor cells. Patients are followed for safety, hematologic protection from GO, disease status, and persistence of CD33 editing.

Long-Term Toxicity after Total Body Irradiation-Based Conditioning Regimens for Allogeneic Stem Cell Transplantation

Total body irradiation (TBI) is an integral component of many conditioning regimens prior to allogeneic hematopoietic stem cell transplantation (HSCT). Few studies have investigated long-term sequelae. A large series of patients undergoing myeloablative and non-myeloablative regimens was studied. Adult patients undergoing allogeneic HSCT utilizing TBI-based conditioning regimens from 1995-2020 at our institution were included. Baseline treatment-related factors and long-term toxicities (developing, or persisting beyond, 6 months after HSCT) were collected. The cumulative incidence of long-term toxicities and overall survival (OS) were calculated. Cox regression was used to assess for predictors of toxicity. Five hundred fifty-two patients were analyzed: 378 myeloablative (typically 13.5 Gy/9fx) and 174 non-myeloablative (typically 2 Gy/1fx) TBI recipients. Median follow-up was 7.4 years for surviving patients. Cumulative incidences of long-term toxicities at 5 and 10 years are included in the Table. The most common toxicities were: pulmonary- infectious pneumonia and respiratory failure NOS; cardiac- heart failure and myocardial infarction; other endocrine- adrenal insufficiency and testosterone deficiency. The most common secondary malignancy was non-melanoma skin cancer. The proportion of all toxicities that were high-grade (3-5) for myeloablative and non-myeloablative regimens, respectively, were: pulmonary (65%, 52%), cardiac (66%, 39%), renal (23%, 27%), and other endocrine (3%, 18%). Increasing number of chemotherapy regimens (p = 0.05) and umbilical cord donor (p = 0.02) were associated with long-term pulmonary toxicity. Male sex (p = 0.03), increasing number of chemotherapy regimens (p<0.01), and elevated creatinine after transplant (p<0.01) were associated with long-term renal toxicity. Cataract development was associated with increasing age at transplant (p = 0.02). OS (5 years) was 40% (42% -myeloablative; 33%-non-myeloablative). Allogeneic HSCT, often preceded by TBI-based conditioning regimens, has significant survivorship challenges. Recipients of non-myeloablative regimens are still at risk of significant long-term multisystem toxicity despite much lower doses of TBI and chemotherapy. Pre-transplant factors such as cumulative chemotherapy exposure and age at transplant were associated with some toxicities.

Acute Pulmonary Toxicity after Allogeneic Stem Cell Transplantation Using Total Body Irradiation-Based Conditioning- Myeloablative vs. Non-Myeloablative Regimens

Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with a high risk of acute pulmonary toxicity, especially with total body irradiation-based (TBI) conditioning regimens. High-grade acute pulmonary toxicity occurs in ∼30% of patients when a myeloablative regimen is utilized (∼12-14 Gy). The risk of pulmonary toxicity with non-myeloablative regimens (∼2 Gy) is not well described. We evaluated the incidence and predictors of acute pulmonary toxicity after HSCT comparing myeloablative and non-myeloablative TBI-based conditioning regimens. All adult (≥ 18 y/o) patients undergoing allogeneic HSCT with TBI (1995-2020) at our institution were evaluated. The dose to the lungs was attenuated to 7-10 Gy in all patients undergoing myeloablative TBI. Acute pulmonary toxicity, occurring within 6 months of HSCT, was scored using CTCAE v5.0. The incidence of acute pulmonary toxicity was calculated using the Kaplan-Meier method, and logistic regression was performed to assess for independent risk factors. Five hundred fifty-two patients were included the analysis (myeloablative- 378; non-myeloablative- 174). Myeloablative TBI was most commonly 13.5 Gy/9Fx (335/378), while non-myeloablative TBI was delivered most often as 2 Gy/1Fx (165/174). Patients undergoing myeloablative TBI were younger than non-myeloablative patients (43 vs 58 years, p<0.001), but baseline pulmonary function parameters were similar. At 6 months after transplant, the cumulative incidences of any acute pulmonary toxicity for patients receiving myeloablative and non-myeloablative TBI were 39% and 33%, respectively (p = 0.11). The risk of low-grade (1-2) and high grade (3-5) pulmonary toxicity was 10% vs 12% (p = 0.59) and 28% vs 21% (p = 0.05), respectively, comparing myeloablative and non-myeloablative TBI. Proportions of high-grade toxicities among the myeloablative and non-myeloablative cohorts were as follows: infectious pneumonia (31% and 49%), bronchopulmonary hemorrhage (25% and 3%), respiratory failure NOS (17% and 10%), pleural effusion (5% and 1%), and pneumonitis (4% and 0%). Female sex (OR 1.52, p = 0.05) and refractory disease at the time of transplant (OR 2.25, p = 0.03) were associated with a higher risk of severe pulmonary toxicity on logistic regression. Younger age (OR 0.99, p = 0.35) and non-myeloablative TBI (OR 0.21, p = 0.60) were not significantly associated with a lower risk. The risk of acute pulmonary toxicity was high with both myeloablative and non-myeloablative TBI-based regimens, though high-grade toxicity was modestly higher in the myeloablative cohort. A better understanding of pulmonary toxicity in the setting of non-myeloablative TBI (∼2 Gy) is needed.

Role of measurable residual disease quantified by 4 to 6 color flow cytometry before allogeneic hematopoietic stem cell transplantation for high-risk Philadelphia-negative acute lymphoblastic leukemia

Background: Measurable residual disease (MRD) status before allogeneic hematopoietic stem cell transplantation (AHSCT) is commonly associated with a high risk of relapse. It is still uncertain whether AHSCT could overcome the negative impact of MRD positivity (MRD+), especially in patients with high-risk Philadelphia negative acute lymphoblastic leukemia (Ph-negative ALL). Materials and methods: An observational retrospective study was conducted on patients with high-risk Ph-negative ALL who underwent AHSCT between January 2005 and June 2022. The patients selected were in complete remission (CR): with 80% in CR1 (n = 69) and 20% in CR2 (n = 17). Graft sources were bone marrow (BM) in 71% of patients and peripheral blood stem cells in 29% of patients. The conditioning regimen was TBI or chemotherapy-based (CT). Bone marrow MRD level was quantified using 4-6 color multiparametric flow cytometry (MFC). The threshold for MRD positivity was ≥ 0.1%. Results: The study included 86 patients (45 B-ALL and 41 T-ALL) with a median age of 18 years (range, 4–55 years). The median level of MRD pre-AHSCT (pre-MRD) was 0.4×10-3 (range, 0.01-75.6×10-3). After a median follow-up of 25 months (range 1-205 months), the cumulative incidence of relapse (CIR) was significantly higher in the MRD+ group (39% vs. 20%, p = 0.04). The median time of relapse post-AHSCT was 14 months (range, 1-203 months) in the MRD+ group and 32 months (range, 4-209 months) in the MRD- group (p = 0.28). Non-relapse mortality (NRM) was 15% in both groups (p = 0.97). The 2-year estimated overall survival (OS) and event-free survival (EFS) were 61% vs. 74% (p = 0.07) and 58% vs. 70% (p = 0.10) in the MRD+ and MRD- groups, respectively. A subgroup analysis in MRD+ patients showed that a TBI-based conditioning regimen was distinctly associated with lower CIR (22% vs. 60% respectively, p = 0.04), improved OS (82% vs. 36% respectively, p = 0.007) and better EFS (73% vs. 38%, p = 0.04) compared to CT-based. In a multivariate analysis, pre-AHSCT MRD+ status and non-TBI-based conditioning were significantly associated with inferior OS (OR, 2.30; 95% CI, [1.027-5.168], p = 0.04 and OR, 3.91; 95% CI, [1.624-9.418], p = 0.002, respectively). The only predicting factor of lower EFS was the non-TBI-based regimen (OR, 2.82; 95% CI, [1.308-6.097], p = 0.008). Non-TBI-based and CR2 were significantly associated with higher CIR (OR, 6.25; 95% CI, [1.947-20.055], p = 0.002 and OR, 4.74; 95% CI, [1.197-18.791], p = 0.03, respectively). Peripheral stem cell source was significantly associated with higher NRM (OR, 6.55; 95% CI, [1.488-28.820], p = 0.01). Conclusion: High-risk Ph-negative ALL patients with MRD ≥ 10-3 prior AHSCT had lower OS compared to MRD- patients and may benefit from TBI as a conditioning regimen before AHSCT.

Optimizing Management of the Central Nervous System in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Stem Cell Transplantation

PurposeTo evaluate clinical outcomes and patterns of failure, specifically in regards to the central nervous system (CNS), in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) using total body irradiation (TBI)-based conditioning regimens. Methods and MaterialsAll adult patients (aged ≥18 years) with ALL undergoing allogeneic HSCT using TBI-based conditioning regimens treated from 1995 to 2020 at Duke University Medical Center were evaluated. Various patient, disease, and treatment-related factors were collected, including CNS prophylaxis and treatment interventions. Clinical outcomes, including freedom from CNS relapse, were calculated using the Kaplan-Meier method for patients with and without CNS disease at presentation. ResultsOne hundred and fifteen patients with ALL were included the analysis (myeloablative, 110; nonmyeloablative, 5). Of the 110 patients undergoing a myeloablative regimen, most (n = 100) did not have CNS disease before transplant. For this subgroup, peritransplant intrathecal chemotherapy was administered in 76% (median of 4 cycles) and 10 received a radiation boost to the CNS (cranial irradiation, 5; craniospinal, 5). Only 4 failed in the CNS after transplant, none of whom received a CNS boost, with freedom from CNS relapse at 5 years of 95% (95% confidence interval (CI), 84-98%). Freedom from CNS relapse was not improved with a radiation therapy boost to the CNS (100% vs 94%, P = .59). Overall survival, leukemia-free survival, and nonrelapse mortality at 5 years were 50%, 42%, and 36%, respectively. Among the 10 patients with CNS disease before transplant, 10 of 10 received intrathecal chemotherapy and 7 received a radiation boost to the CNS (cranial irradiation, 1; craniospinal, 6) and none subsequently failed in the CNS. A nonmyeloablative HSCT was pursued for 5 patients because of advanced age or comorbidities. None of these patients had prior CNS disease or received a CNS or testicular boost, and none failed in the CNS after transplant. ConclusionsA CNS boost may not be necessary in patients with high-risk ALL without CNS disease undergoing a myeloablative HSCT using a TBI-based regimen. Favorable outcomes were observed with a low-dose craniospinal boost in patients with CNS disease.

Trial in Progress: A First-in-Human Phase 1/2 Study of Hematopoietic Stem Cell Transplantation (HCT) with VOR33 (CD33-Deleted Allograft) Followed By Treatment with Gemtuzumab Ozogamicin (GO) in Patients with CD33+ Acute Myeloid Leukemia (AML) Who Are at High-Risk of Post-HCT Relapse

Background: Allogeneic HCT is the standard of care for eligible patients with AML harboring high-risk features such as adverse-risk cytogenetics or minimal residual disease (MRD). However, the majority of such patients still relapse post-HCT and have very poor outcomes. The use of maintenance therapies intended to control post-HCT relapse is often limited by hematopoietic toxicity towards normal engrafted cells. Gemtuzumab ozogamicin (GO, tradename: Mylotarg) is an FDA-approved anti-CD33 antibody-drug conjugate targeting CD33+ AML, but its use is limited by on-target hematopoietic toxicity towards CD33+ myeloid and progenitor cells. VOR33 is a CRISPR/Cas9 gene-edited allogeneic hematopoietic stem and progenitor cell (HSPC) product lacking CD33 protein that was developed to protect normal hematopoietic cells while exclusively targeting leukemia with CD33-directed therapies. VOR33 is manufactured from CD34+ cells isolated from healthy human leukocyte antigen (HLA)-matched donors. Pre-clinical murine and primate transplant studies using CD33-deleted HSPCs demonstrated unaltered long-term engraftment, multi-lineage hematopoietic differentiation and function, as well as long-term persistence of CD33 gene-edited hematopoietic cells. Additionally, subsequent treatment with GO eradicated CD33+ leukemia cells while the normal hematopoietic cells that reconstituted from CD33-edited HSCs were preserved. The improved therapeutic index for GO in combination with VOR33 has the potential to allow effective targeting of residual leukemia in AML patients post-HCT without dose-limiting hematopoietic toxicity. Study Design and Methods: VBP101(NCT04849910) is a first-in-human Phase 1/2 open-label multicenter trial to establish the safety of using VOR33 as a donor allograft for CD33+ AML patients who are at high risk of relapse and undergoing myeloablative HCT followed by treatment with low-dose GO. Participants (18-70 y) must have a diagnosis of CD33+ AML, an HLA-matched related or unrelated (10/10) donor and be a candidate for myeloablative HCT. Additional key inclusion criteria include CR1/CRi/CR2 with intermediate/poor cytogenetics and the presence of MRD. Patients with 5-10% bone marrow-only blasts with any cytogenetic risk are also eligible. Key exclusion criteria include prior auto/allo-HCT or prior treatment with GO. Related and unrelated donors undergo mobilization with G-CSF and plerixafor prior to cell collection. Manufacturing of VOR33 and isolation of an unmanipulated backup graft are performed centrally and both are cryopreserved. Subjects undergo either a busulfan- or TBI-based myeloablative conditioning regimen prior to transplantation with VOR33. After engraftment and recovery of a sufficient CD33-negative neutrophil count (~Day 60), patients begin maintenance therapy with GO. Part 1 of the study will enroll 9-18 evaluable patients to be treated in a 3+3 dose-escalation strategy with GO (0.5-2.0 mg/m2) in a 28-day cycle for up to 4 cycles. Part 1 will evaluate the safety of VOR33/GO and will determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of GO. The Part 2 expansion phase will enroll an additional 12 patients to further evaluate the safety of VOR33 and the preliminary efficacy of VOR33 and GO at the RP2D. A separate cohort is included for early relapse with treatment per the investigator's choice and may include use of GO. The primary endpoint is to assess the safety of VOR33 as measured by successful neutrophil engraftment at 28 days post-HCT. Secondary endpoints include time to neutrophil and platelet engraftment, assessment of the overall safety of VOR33 and GO (GvHD, graft failure, transplant-related mortality, RP2D, and MTD), non-hematological GO-related toxicities, GO pharmacokinetics, the efficacy of VOR33 in conferring protection from GO-related hematological toxicities, percent CD33 negative myeloid cells over time and survival rates (RFS and OS). Exploratory endpoints include the persistence of VOR33 gene editing and immune reconstitution. Study follow-up is 2 y with up to 15 y long term follow-up in a rollover safety study, VBP201 (NCT05309733). A Dose Escalation Committee and Data Safety Monitoring Committee will review GO dosing levels and monitor overall trial safety, respectively. VBP101 is currently open for enrollment and recruiting patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patient-Reported Outcomes in Long-Term Survivors of Autologous Hematopoietic Cell Transplantation for Hodgkin and Non-Hodgkin Lymphoma: Secondary Analysis from Two Multi-Center Randomized Controlled Trials of Hematopoietic Cell Transplant Survivorship Interventions

Background: Autologous hematopoietic cell transplantation (AHCT) recipients with Hodgkin's and Non-Hodgkin's lymphoma (HL and NHL) who survive progression-free for ≥2years can expect a 5-year overall survival rate of 90% (Myers et al, Cancer, 2018). However, patient-reported outcomes (PROs) in long-term lymphoma survivors after AHCT have not been well described. We present secondary analyses from a combined baseline dataset from two multi-center randomized clinical trials of HCT survivorship interventions, enrolling at 18 US transplant centers, including a large cohort of 1-10-year lymphoma AHCT survivors. Our objectives were to describe health-related quality of life (HRQoL) and cancer and treatment-related distress (CTXD), and to examine their associations with available clinical and sociodemographic correlates. Methods: Cross-sectional data at the time of study enrollment were pooled from two trials: SCP (Survivorship Care Plan; NCT02200133) and INSPIRE (INternet Survivorship Program with Information and REsources; NCT01602211). The SCP study enrolled patients (N=456) who were in a stable remission 1-5 years after transplant and the INSPIRE study enrolled survivors (N=1177) who were 2-10 years post-transplant, between 2003-2014. This analysis was restricted to AHCT recipients with diagnosis of HL or NHL. Our objectives were to describe HRQoL and cancer related distress (CTXD), and to examine their association with available baseline correlates. HRQoL was assessed using SF-12 v2 (12-item short survey form) and described as physical component summary (PCS) and mental component summary (MCS) T-scores (higher scores indicated better functioning). Comparisons between SF-12 scores and age-matched population norm (mean score 50, standard deviation [SD] 10) were analyzed using paired t-tests. Distress was assessed using the CTXD instrument, which reports mean scores from 0 to 3, with higher scores indicating greater distress. Based on prior receiver operating characteristic analysis, CTXD score >1.1 was considered clinically significant. Multivariate linear regression models were performed to evaluate the association of PCS score, MCS score, and CTXD with the following variables: diagnosis (HL vs. NHL), sex, race/ethnicity, number of HCT, use of total body irradiation (TBI) for AHCT, subsequent allogeneic transplant, age at time of enrollment, and time since AHCT. Results: Of 522 HL and NHL AHCT recipients, 60% were male, 94% were Caucasian, 94 (18%) had HL, 428 (82%) had NHL; 26 (5%) received >1 HCT, including 16 (4%) who received a subsequent allogeneic HCT. 8% patients received TBI-based conditioning regimens. Median age at index AHCT was 55 (range: 17-80) years, and median time from AHCT to study entry was 5 (range: 2-11) years. The mean [±SD] PCS T-score in the study population (48.96 [±10.59]) was slightly lower than the population norm (50 [±10]) (p=0.03). Mean [±SD] MCS T-scores were not significantly different between patients (50.75 [±10.40]) and general population (50 [±10]) (p=0.16) (Figure 1). The mean CTXD score was 0.79 (±0.59), with 135 (26%) patients reporting clinically significant distress (mean score ≥ 1.1). Among CTXD domains, "health burden” and "uncertainty” accounted for the highest burden of clinically significant distress, with 42% and 35% of patients reporting distress in these domains, respectively (Figure 2). On multivariable analysis, older age at study entry was associated with higher MCS score (estimated slope: 1.3 [95% CI: 0.5-2.2]; p=0.002), although there was no association of age with PCS score or CTXD. We did not observe associations of other variables and PCS score, MCS score, or CTXD. Conclusions: Patients with HL and NHL who are long-term disease-free survivors of AHCT have lower physical HRQoL compared to general population, although the difference is not clinically meaningful. Mental HRQoL in HL and NHL AHCT survivors is similar to general population. Older age is associated with higher mental HRQoL. Approximately a quarter of patients report clinically significant cancer and treatment-related distress. Survivorship programs should continue to screen for, and address concerns regarding HRQoL and distress. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Twenty years of experience of a tertiary cancer center in total body irradiation with focus on oncological outcome and secondary malignancies

PurposeTotal body irradiation (TBI) is a common part of the myelo- and immuno-ablative conditioning regimen prior to an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Due to concerns regarding acute and long-term complications, there is currently a decline in otherwise successfully established TBI-based conditioning regimens. Here we present an analysis of patient and treatment data with focus on survival and long-term toxicity.MethodsPatients with hematologic diseases who received TBI as part of their conditioning regimen prior to allo-HSCT at Frankfurt University Hospital between 1997 and 2015 were identified and retrospectively analyzed.ResultsIn all, 285 patients with a median age of 45 years were identified. Median radiotherapy dose applied was 10.5 Gy. Overall survival at 1, 2, 5, and 10 years was 72.6, 64.6, 54.4, and 51.6%, respectively. Median follow-up of patients alive was 102 months. The cumulative incidence of secondary malignancies was 12.3% (n = 35), with hematologic malignancies and skin cancer predominating. A TBI dose ≥ 8 Gy resulted in significantly improved event-free (p = 0.030) and overall survival (p = 0.025), whereas a total dose ≤ 8 Gy and acute myeloid leukemia (AML) diagnosis were associated with significantly increased rates of secondary malignancies (p = 0.003, p = 0.048) in univariate analysis. No significant correlation was observed between impaired renal or pulmonary function and TBI dose.ConclusionTBI remains an effective and well-established treatment, associated with distinct late-toxicity. However, in the present study we cannot confirm a dose–response relationship in intermediate dose ranges. Survival, occurrence of secondary malignancies, and late toxicities appear to be subject to substantial confounding in this context.

Image Guided Volumetrically Modulated Total Body Irradiation (TBI): Progress on Single Institution Phase 2 Clinical Trial

<h3>Purpose/Objective(s)</h3> TBI is a backbone of many conditioning regimens for hematopoietic stem cell transplants but can lead to both acute and late toxicity including radiation-induced interstitial pneumonitis. The incidence of idiopathic pneumonia syndrome (IPS) after TBI-based myeloablative conditioning regimens ranges from 7% to 35%. The purpose of this study is to implement image guided volumetrically modulated technique (VMAT) for TBI with the goal of lung sparing and improved target coverage. <h3>Materials/Methods</h3> Nine patients have been treated using image-guided VMAT based TBI at our institution as part of a single-arm phase 2 clinical trial for patients undergoing myeloablative conditioning regimens. The trial was approved by our internal review board (IRB) in September 2020 and aims to accrue 15 patients within one year. All patients enrolled in the trial have signed informed consent. The primary endpoints of the study are the following dosimetric constraints: V100% ≥ 90%, D98% ≥ 85% of Rx dose for the planning target volume (PTV), and a mean lung dose < 9 Gy. PTV is defined as the body contour cropped 5 mm from the surface and excluding lungs and kidneys but extended 3 mm into these organs. Additional secondary dosimetric endpoints include mean dose to each individual kidney < 11 Gy, and maximum dose to 2cc of the entire body < 130% of Rx dose. Clinical endpoints include the occurrence of IPS in the first 100 days after transplant, occurrence of acute graft versus host disease (GVHD), transplant related mortality or mortality in the first 100 days following transplant. <h3>Results</h3> Patients were treated to 12 Gy in 8 BID fractions (n = 6) or 13.2 Gy in 8 BID fractions (n = 3) over four consecutive days. All patients were able to complete treatment to the prescribed dose as planned. All patient plans met dosimetric constraints of the study. The median PTV V100% was 93.2% of Rx dose (Max: 95.6%, Min: 92.1%), the median PTV D98% was 90.2% of Rx dose (Max: 94.3%, Min: 88.3%), and the median lung dose mean was 7.63 Gy (Max: 7.94 Gy, Min: 7.29 Gy). In addition, individual kidney mean doses were < 11 Gy, and body maximum dose (D_2cc) was < 130% of Rx dose for all patients. At this time, only one patient (12 Gy treatment) has reached the 100 day post-transplant follow-up with the following findings: no relapse on bone marrow biopsy, no pneumonitis, resolved acute GVHD overall grade 1 (skin: 1, GI: 0, Liver: 0), resolved dermatitis (grade 1), resolved vomiting (grade 2), ongoing diarrhea and nausea (grade 1, previously grade 2). <h3>Conclusion</h3> Our initial results indicate that primary and secondary dosimetric endpoints were achievable for all protocol patients treated thus far. As the trial progresses, secondary clinical endpoints at 100 day follow-up will be analyzed to evaluate occurrence of IPS, survival, and treatment related toxicities.

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.

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.

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.

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.

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.