Total Body Irradiation Conditioning Regimen Research Articles

Efficacy of allogeneic hematopoietic stem cell transplantation based on a total body irradiation conditioning treatment regimen for adult acute lymphocytic leukemia

Objective: To analyze the efficacy of allo-HSCT with total body irradiation (TBI) and chemotherapy alone in the treatment of adult ALL and to explore the factors affecting prognosis. Methods: The clinical data of 95 adult patients with ALL who underwent allo-HSCT from January 2015 to August 2022 were included. According to the conditioning regimen, the patients were divided into two groups: the TBI plus cyclophosphamide (TBI/Cy) group (n=53) and the busulfan plus cyclophosphamide (Bu/Cy) group (n=42). Hematopoietic reconstitution after transplantation, GVHD, transplantation-related complications, relapse rate (RR), non-relapse mortality (NRM), OS, and LFS were compared, and the factors related to prognosis were analyzed. Results: The median time of neutrophil engraftment was 14 (10-25) days in the TBI/Cy group and 14 (10-24) days in the Bu/Cy group (P=0.106). The median time of megakaryocyte engraftment was 17 (10-42) days in the TBI/Cy group and 19 (11-42) days in the Bu/Cy group (P=0.488). The incidence of grade Ⅱ-Ⅳ acute GVHD (aGVHD) in the TBI/Cy and Bu/Cy groups was 41.5% and 35.7%, respectively (P=0.565). The incidence of grade Ⅲ-Ⅳ aGVHD in these two groups was 24.5% and 4.8%, respectively (P=0.009). The incidence of severe chronic GVHD in the two groups was 16.7% and 13.5%, respectively (P=0.689). The incidence of cytomegalovirus infection, Epstein-Barr virus infection, severe infection, and hemorrhagic cystitis in the two groups was 41.5% and 35.7% (P=0.565), 34.0% and 35.7% (P=0.859), 43.4% and 33.3% (P=0.318), and 20.8% and 50.0% (P=0.003), respectively. The median follow-up time was 37.1 months and 53.3 months in the TBI/Cy and Bu/Cy groups, respectively. The 2-year cumulative RR was 17.0% in the TBI/Cy group and 42.9% in the Bu/Cy group (P=0.017). The 2-year cumulative NRM was 24.5% and 7.1%, respectively (P=0.120). The 2-year LFS was 58.5% and 50.0%, respectively (P=0.466). The 2-year OS rate was 69.8% and 64.3%, respectively (P=0.697). In the multivariate analysis, the conditioning regimen containing TBI was a protective factor for relapse after transplantation (HR=0.304, 95% CI 0.135-0.688, P=0.004), whereas the effect on NRM was not significant (HR=1.393, 95% CI 0.355-5.462, P=0.634). Infection was an independent risk factor for OS after allo-HSCT in adult patients with ALL. Conclusion: allo-HSCT based on TBI conditioning regimen had lower relapse rate and lower incidence of hemorrhagic cystitis for adult ALL, compared with chemotherapy regimen. While the incidence o grade Ⅲ/Ⅳ aGVHD was hgher in TBI conditioning regimen than that in chemotherapy regimen.

TBI, etoposide, and cyclophosphamide conditioning for intermediate-risk relapsed childhood acute lymphoblastic leukemia.

In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care. We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025). Twenty patients with post-induction MRD ≥ 10-3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively. Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL.

Impact of Eltrombopag, a Thrombopoietin Mimetic on Hematopoietic Recovery after Total Body Irradiation for Stem Cell Transplantation

<h3>Purpose/Objective(s)</h3> Stem cell transplantation (SCT) is associated with anemia, thrombocytopenia and other bone marrow dyscrasia in the peri-transplant setting. We previously conducted a phase I clinical trial of patients undergoing SCT after total body irradiation (TBI) (≥ 400 cGy), which showed that eltrombopag (Epag), a thrombopoietin analog was very well tolerated in a cohort of SCT population. Epag is unique in that it has also shown multi-lineage effects of hematopoiesis (platelets, white blood cells [WBC], and red blood cells [RBC]) in patients with severe myelodysplastic syndrome. We compared our cohort of patients with historical data of patients who received standard SCT (without Epag), as well as with pair-matched patients in the historic group. We hypothesized that patients who received TBI and Epag would have reduced need for transfusion of blood products, and reduced platelet and WBC engraftment times. <h3>Materials/Methods</h3> Data in patients undergoing standard SCT (without Epag treatment) from 2005 - 2009 were retrospectively compared to our cohort of patients who received TBI and Epag in a phase I clinical trial. A two-sided t-test was conducted to evaluate the number of platelet and RBC transfusions, as well as platelet and neutrophil engraftment times between the two groups. In addition, pair-matched groups of patients selected from the standard SCT group were compared with the phase I study cohort controlling for variables such as age, sex, and TBI evaluated via two sample-t test to determine difference in transfusions of blood products. <h3>Results</h3> The TBI/Epag cohort from our phase I clinical trial (n=15) was compared to historical SCT cohort in our registry (n= 235) who received SCT (without Epag). Mean total number of platelet transfusions was 4.0 vs. 13.6 units (p < 1.59 × 10^0.6), and mean total RBC transfusion was 5.6 vs. 10 units (p<0.02), respectively. Time to platelet, and WBC engraftments were 15.3 days vs. 26.8 days (p < 6.07 × 10 ^0.05), and 12.1 days vs. 17.4 days (p< 0.01), respectively. The TBI/Epag cohort was compared with matched historical cohort by age (< 40 y/o), sex, and TBI conditioning regimen (n=4, 11, respectively), which showed mean total platelet transfusions of 13 vs. 16.5 units (P < 0.1), and mean RBC transfusions of 4.75 vs. 11.45 units, respectively (p< 0.01). TBI/Epag cohort was also matched to a second older age cohort (60 - 70 y/o), sex, and TBI conditioning (n = 4, 7, respectively). In this group, the mean number of platelet transfusion was 0.5 vs. 10.0 units (p< 0.04), and RBC transfusion was 2.25 vs. 8.29units (p <0.04). <h3>Conclusion</h3> Our data indicates that Eltrombopag markedly reduced the time to platelet engraftment, WBC engraftment, as well as the number of platelet and RBC transfusions, when compared with historical control groups, especially in the older aged cohort.

Comparison of Acute Graft-Versus-Host Disease Mouse Models Established by TBI and BU/CY Conditioning Regimens

To investigate the effect of acute graft-versus-host disease (aGVHD) mouse models established respectively by total body irradiation (TBI) and busulfan combined with cyclophosphamide (BU/CY) conditioning regimens after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Bone marrow cells and splenic mononuclear cells were isolated respectively from femur, tibia, and spleen of C57BL/6 male mice (H-2Kb) which were selected as donors. After TBI pretreatment, BALB/c female mice (H-2Kd) were injected with donor bone marrow cells 1×107/50 μl and splenic mononuclear cells 2×107/100 μl through caudal vein, while CB6F1 female mice (H-2Kd/b) with donor bone marrow cells 2×107/100 μl and splenic mononuclear cells 1×108/500 μl after BU/CY pretreatment. The successful establishment of the aGVHD models were determined by post-transplant manifestations, rate of chimerism, target organ damage, etc. Results: After transplantation, mice of both groups showed listlessness, low activity, continued weight loss, and typical manifestations of aGVHD such as alopecia, hunched posture, diarrhea, and anal swelling. and died within 4 weeks. Flow cytometry detection showed complete chimerism in all the mice. Pathological examination of skin, intestines, liver, lung, and spleen tissues showed obvious aGVHD pathological changes. However, the weight loss, ruffled fur, and alopecia combined with severe scurf on those hair-free areas were significantly apparent in TBI group than BU/CY group, as well as higher aGVHD score, and the differences were statistically significant (P<0.05). Both TBI and BU/CY as conditioning regimens can successfully establish stable mouse models of aGVHD after fully allo-HSCT and haploidentical HSCT for further research about mechanism of aGVHD. BU/CY conditioning regimen can more truly simulate physiological status in vivo of patients with chemotherapy based conditioning regimen, while TBI conditioning regimen shows significantly more typical aGVHD symptoms and easier to operate.

Outcomes of Cord Blood Transplantation for Adult Patients with Hodgkin Lymphoma, a Eurocord and EBMT Lymphoma Working Party Study

Allogeneic stem cell transplantation represents an alternative for relapsed or refractory patients (pts) with Hodgkin Lymphoma (HL). In this setting, only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 133 adult pts with HL who underwent UCBT in EBMT centers. Histological subtype was nodular sclerosis in 65% of the pts. Median age at UCBT was 29 (18-65) years. Median follow-up was 37 (2-119) months and median year of UCBT was 2010 (2003-2015). Ninety pts had received a previous autologous transplantation (ASCT), while 19 had received 2 ASCT before UCBT; median time from ASCT to UCBT was 15 (2-281) months. Disease status at UCBT was complete remission (CR) in 45%, partial remission (PR) in 28% and relapse or refractory disease in 27% of the pts. Sixty percent of pts were male and 54% had a positive cytomegalovirus serology. Fifty-one percent (n=68) received a single UCBT and 49% (n=65) a double UCBT; 58% of pts received a graft with 2 or more HLA mismatch. The majority of the pts (n=104, 77%) underwent a reduced intensity conditioning regimen, the most frequent conditioning regimen (n=69) being Cyclophosphamide + Fludarabine + Total Body Irradiation (TBI) (2 Gy). Forty percent (n=46) of pts received anti-thymocyte globulin and Cyclosporine A + mycophenolate mofetil prophylaxis was given to 60% (n=80) of the pts. Median total nucleated cell (TNC) dose at cryopreservation was 3.99 (1.5-12.2) x107/Kg.The cumulative incidence (CI) of neutrophil engraftment at 60 days was 87% (81%-93%). The 100-day CI of acute grade II-IV GVHD was 26% (19%-35%). At 3 years, chronic GVHD was 30% (21%-41%). Relapse incidence (RI) and non-relapse mortality (NRM) were 40% (32%-50%) and 30% (23%-40%) at 3 years, respectively. The overall survival (OS) was 48% (39%-57%) and progression free survival (PFS) was 28% (21%-37%) at 3 years. Sixty-nine patients died: 27 of relapse and 39 of transplant related causes (infections, n=13, GVHD, n=7, idiopathic pneumonia syndrome n=6, EBV-PTLD n=2, VOD n=2 and others causes, n=9). According to disease status at UCBT, OS at 3 years was 68% (55%-79%) for pts in CR, 31% (18%-50%) for pts in PR and 26% (14%-44%) for pts in relapsed or refractory disease.In multivariate analysis, adjusted for median year of UCBT, Cyclophosphamide + Fludarabine + low dose TBI conditioning regimen, disease status at UCBT, conditioning intensity and type of UCBT, none of these factors were found to be associated with acute or chronic GVHD. 3-year RI and NRM were higher for pts in relapse or refractory disease at UCBT compared to pts in CR (HR=2.62, 95%CI 1.12-6.11, p=0.03 and HR=3.66, 95%CI 1.52-8.80, p=0.004, respectively). The use of Cyclophosphamide + Fludarabine + low dose TBI conditioning regimen was associated with a lower risk of NRM (HR=0.38, 95%CI 0.15-0.95, p=0.04) and also with a better OS (HR=0.37, 95%CI 0.18-0.76, p=0.006). OS was significantly worse for pts who underwent UCBT in PR (HR=1.97, 95%CI 1.02-3.80, p=0.04) and for those in relapse or refractory disease at transplant (HR=2.86, 95%CI 1.41-5.81, p=0.004). Pts transplanted in relapse or refractory disease have also a lower PFS (HR=3.12, 95%CI 1.71-5.71, p<0.001).In conclusion, UCBT is feasible in heavily pretreated pts with HL, if there are no other alternative donors. Conditioning with Cyclophosphamide + Fludarabine + low dose TBI is associated with a better OS and NRM. However, outcomes are poor for patients not in CR at the time of UCBT and one might consider the use of new therapeutic agents earlier before UCBT in this setting. DisclosuresZuckerman:BioSight Ltd.: Consultancy. Snowden:Sanofi: Honoraria. Robinson:Gilead: Honoraria, Other: Travel Grants; Takeda: Consultancy, Honoraria, Other: Travel Grants; Roche: Honoraria, Other: Travel Grants; Riemser: Consultancy.

Late cardiac events and their impact on overall survival in patients receiving an allogeneic stem cell transplant.

12070 Background: There is limited data on the impact of cardiac disease on long term outcomes of allogeneic stem cell transplant (alloSCT). We sought to describe the importance of adverse cardiac events on long term outcomes of alloSCT. Methods: We performed a retrospective analysis of pts who underwent alloSCT from 2007 to 2017 and survived at least one year after transplantation. Late cardiac events were defined as occurring at least one year after transplant. Data was obtained through electronic medical records and the transplant database at Siteman Cancer Center. Univariate Cox proportional hazards model was used to assess the effect of baseline characteristics on cardiac events and overall survival. Time-dependent Cox model was used to determine the effect of cardiac events on overall survival. Gray’s sub-distribution methods, while accounting for death as a competing risk, were used to calculate the incidence of cardiac events. Results: 804 pts met our criteria (58.7% male, average age 49.7 years). Median duration of follow up was 59.3 months. Most pts were transplanted for acute myeloid leukemia (49.9%) and had a match-related or unrelated donor (56.1%). The majority received myeloablative conditioning (74.4%), and 34.6% received total body irradiation (TBI). The most common late cardiac events were an elevated troponin (20.9%), elevated brain natriuretic peptide (BNP) or N-terminal pro-BNP (16.9%), shock (15.3%), and reduced left ventricular ejection fraction (LVEF) defined as &lt; 45% (10.4%). Pts were at significantly increased hazard of developing late cardiac events if they were of male sex (HR 1.29, P = 0.026), had pre-existing diabetes (HR 1.45, P = 0.022), pre-existing atrial fibrillation or flutter (HR 1.77, P = 0.008), history of congestive heart failure (HR 1.82, P = 0.032) or increasing age at time of transplant (HR 1.02, P &lt; 0.001). Primary disease for alloSCT, donor type, TBI and myeloablative conditioning regimen had no significant association with late cardiac events. The cumulative incidence of developing any cardiac event in the period 1-5 years after transplant was 28.2% with a cumulative incidence of shock at 13.6%, reduced ejection fraction at 8.7% and an atrial arrythmia at 7.1%. Most cardiac events were associated with an increased risk of death (Table). Conclusions: Cardiac events after alloSCT have a substantial impact on overall survival. Efforts to optimally manage cardiac disease after alloSCT are likely to have a major benefit, and cardiac protection should be a major focus for post-alloSCT follow up.[Table: see text]

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

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

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

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

Perspectives on the Use of a Medium-Dose Etoposide, Cyclophosphamide, and Total Body Irradiation Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation: The Japanese Experience from 1993 to Present.

The outcome for adults with acute lymphoblastic leukemia (ALL) treated with chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) is poor. Therefore, allogeneic HSCT (allo HSCT) for adults aged less than 50 years with ALL is performed with myeloablative conditioning (MAC) regimens. Among the several MAC regimens, a conditioning regimen of 120 mg/kg (60mg/kg for two days) cyclophosphamide (CY) and 12 gray fractionated (12 gray in six fractions for three days) total body irradiation (TBI) is commonly used, resulting in a long term survival rate of approximately 50% when transplanted at the first complete remission. The addition of 30 mg/kg (15 mg/kg for two days) etoposide (ETP) to the CY/TBI regimen revealed an excellent outcome (a long-term survival rate of approximately 80%) in adults with ALL, showing lower relapse and non-relapse mortality rates. It is preferable to perform allo HSCT with a medium-dose ETP/CY/TBI conditioning regimen at the first complete remission in high-risk ALL patients and at the second complete remission (in addition to the first complete remission) in standard-risk ALL patients. The ETP dose and administration schedule are important factors for reducing the relapse and non-relapse mortality rates, preserving a better outcome. The pharmacological study suggests that the prolonged administration of ETP at a reduced dose is a promising treatment.

Clinical Outcomes of Fludarabine and Melphalan With an 800 cGy Total Body Irradiation Conditioning Regimen in Patients With Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

IntroductionAllogeneic hematopoietic stem cell transplant with reduced-intensity conditioning is an effective therapeutic option for patients with refractory or relapsed aggressive non-Hodgkin lymphoma (NHL). Patients and MethodsWe retrospectively evaluated survival outcomes and the efficacy of our fludarabine/melphalan/total body irradiation (TBI) (FMT) regimen. A total of 89 patients had received the FMT regimen from 2007 to 2017. ResultsThe majority of patients (n = 81; 91%) belonged to the histologic subtype of aggressive NHL. The estimated 3-year overall survival and disease-free survival for the entire cohort during a median follow-up of 31 months were 47.1% (95% confidence interval, 36%-57%) and 45.4% (95% confidence interval, 35%-56%), respectively. The cumulative incidence rates of relapse and non-relapse mortality at 3 years were 33.1% and 13.8%, respectively. In analyses of risk factors affecting survival outcomes, chemosensitive disease status at transplant (hazard ratio [HR], 2.45; P = .010), delayed relapse after first-line chemotherapy (HR, 2.101; P = .009), no grade III to IV acute graft-versus-host disease (HR, 11.212; P < .001), and mild chronic graft-versus-host disease (HR, 0.448; P = .016) were independent significant predictors of favorable overall survival. Also, similar parameters were related to favorable disease-free survival. All non-hematologic toxicities occurred within 50 days after allogeneic hematopoietic stem cell transplant, and most of the adverse events were tolerable and manageable with a < 30% incidence. ConclusionOur FMT regimen shows favorable transplant outcomes with relatively low-risk toxicities, so it may be a promising strategy for patients with relapsed or refractory aggressive NHL.

Establishment and Evaluation of Gvhd Mouse Model for Allogeneic Hematopoietic Stem Cell Transplantation

Objective:To study the feasibility of using cyclophosphamide alone without total body irradiation (TBI) as conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and establish a graft-versus-host disease (GVHD) mouse model.Methods:Single cell suspension of spleen and bone marrow were prepared from donor C57/BL/6 mice (B6 mice) . The recipient B6D2F1 mice (F1 mice) were signed into 4 groups with 12 mice per each group. Groups I~III mice were conditioned with peritoneal injection of cyclophosphamide (300 mg/m2/d) on day -5, -4 and -3 of allo-HSCT, and group IV mice were used as control with saline injection. On day 0, group I mice were injected through tail vein with a mixture of 2×107 spleen cells, 5×106 bone marrow cells and 1×104 P815 cells; group II with 5×106 bone marrow cells and 1×104 P815 cells; group III with 1×104 P815 cells and group IV with RPMI1640 culture medium. The blood leukocyte counts were analyzed, GVHD score and the pathological leukemia infiltration of skin, liver and colon were evaluated and compared on day 30 after allo-HSCT.Results:(1) The GVHD scores of group I mice were 2 to 4 on day 14 post allo-HSCT, and mice started to die on day 15, eight (8) mice survived and the GVHD scores of them were 1 to 6 with a survival rate of 66.7% on day 30. Group II mice began to die on day 6 and only one survived on day 30 with a survival rate of 8.3%. All of group III mice died on day 18. Group IV mice survived (Figure 1).(2) The leukocyte counts in group I and group II were significantly increased on day 7 post allo-HSCT(p<0.05). There was also a significant difference in total leukocyte counts between groups I/II and group IV (p<0.05). The leukocyte counts in mice of groups I~III were significantly decreased, and there were a significant difference between group I and groups II/III/IV respectively (p<0.05) on day 14 post allo-HSCT. On day 21 after allo-HSCT, the leukocyte count of Group I and II mice were ≥1×109/L, which means that allo-HSCT were successful. The leukocyte counts in group I mice were again increased on day 28 post allo-HSCT. There was no significant difference between Group I and Group IV (p>0.05).(3) Pathological observation: The cell atrophy and necrosis in the hepatic portal area and slight infiltration of the leukemia cells in central vein were observed in group I recipient mice. The number of hepatocytes of the mice decreased, and the infiltration of the leukemia cells in the liver sinus were observed in group II. The liver was heavily infiltrated by leukemic cells in group III mice. The mouse livers were normal in group IV mice.Conclusion:It is feasible to establish GVHD model of the leukemia mice with cyclophosphamide conditioning regimen of allo-HSCT, and simple to operate. This is less harmful to people, animals and the environment.Discussion:The traditional animal model of GVHD is based on TBI conditioning regimen prior to allo-HSCT. However, the process can lead to systemic adverse reactions such as myelosuppression, radiation gastroenteritis, endocrine disorders and systemic function disorders, etc. in both the operators and animals. Therefore, the radiotherapy doses have to be low. At the same time, it is difficult to establish animal models of GVHD due to the uneven distribution of the doses. Cyclophosphamide was selected for the conditioning regimen of allo-HSCT in the study. Cyclophosphamide had the effect direct on killing tumor cells, induced recipients to tolerate the immune of donors, enabled to implant donor cells into recipients smoothly. The stable chimeras were obtained. There are a large number of T and B lymphocytes in donor's spleen cells. By injecting donor spleen cells and active immune cells derived from proliferation and differentiation of hematopoietic stem cells, the effects of graft-anti-leukemia are availably activated in recipients.AcknowledgmentsWe thank Dr Zhifu Xiang very much for his great helpful revisions. DisclosuresNo relevant conflicts of interest to declare.

Total Body Irradiation Is Safe and Similarly Effective as Chemotherapy-Only Conditioning in Autologous Stem Cell Transplantation for Mantle Cell Lymphoma

Autologous stem cell transplant (ASCT) consolidation has become a standard approach for patients with mantle cell lymphoma (MCL), yet there is little consensus on the role of total body irradiation (TBI) as part of high-dose transplantation conditioning. We analyzed 75 consecutive patients with MCL who underwent ASCT at our institution between 2001 and 2011 with either TBI-based (n = 43) or carmustine, etoposide, cytarabine, melphalan (BEAM; n = 32) high-dose conditioning. Most patients (97%) had chemosensitive disease and underwent transplantation in first remission (89%). On univariate analysis, TBI conditioning was associated with a trend toward improved PFS (hazard ratio [HR], .53; 95% confidence interval [CI], .28-1.00; P = .052) and similar OS (HR, .59; 95% CI, .26-1.35; P = .21), with a median follow-up of 6.3 years in the TBI group and 6.6 years in the BEAM group. The 5-year PFS was 66% in the TBI group versus 52% in the BEAM group; OS was 82% versus 68%, respectively. However, on multivariate analysis, TBI-based conditioning was not significantly associated with PFS (HR, .57; 95% CI .24-1.34; P = .20), after controlling for age, disease status at ASCT, and receipt of post-transplantation rituximab maintenance. Likewise, early toxicity, nonrelapse mortality, and secondary malignancies were similar in the 2 groups. Our data suggest that both TBI and BEAM-based conditioning regimens remain viable conditioning options for patients with MCL undergoing ASCT.

The role of stem cell transplant for lymphoma in 2017.

The role of stem cell transplant for lymphoma in 2017.

Adult Umbilical Cord Blood Transplantation Using Myeloablative Total Body Irradiation, Fludarabine, and Thiotepa Conditioning

Introduction: Umbilical cord blood (UCB) extends the curative potential of stem cell transplantation to adult patients without a suitable donor. The most commonly used myeloablative preparative regimen results in an unacceptably high 6-month treatment related mortality rate of approximately 32% (Barker J et al. Br J Haematol. 2015). In an attempt to reduce treatment related mortality, we piloted a modified myeloablative regimen with total body irradiation (TBI), fludarabine, and thiotepa. We report clinical outcomes from a cohort of patients who received single or double UCBT after conditioning with this regimen.Methods: Thirty-one consecutive adult patients ≥ 18 years old with hematologic malignancies who underwent single or double umbilical cord blood transplantation at Duke University from 2010 to 2015 were included in this study. The conditioning regimen consisted of thiotepa 5 mg/kg/day i.v. x 2 days (days -11 to -10), TBI 150 cGy twice a day for total nine fractions (1350 cGy days -9 to -5), and fludarabine 40 mg/m2/day i.v. x 4 days (days -5 to -2). Cord blood units were matched to the recipient at 4 or more HLA loci (intermediate-resolution for A and B, high-resolution for DRB1). Graft versus host disease (GVHD) prophylaxis was with tacrolimus (target level 10-15 ng/ml) and mycophenolate mofetil 1000 mg TID. Antimicrobial prophylaxis and supportive care measures including GCSF administration until ANC > 1000 were conducted per institutional protocol. Probabilities of neutrophil and platelet recovery, acute and chronic GVHD, and treatment-related mortality were estimated by the cumulative incidence method. Relapse-free and overall survival rates were estimated by the Kaplan-Meier method.Results: Thirty-one patients (median age 46 years; range, 19-65) with hematologic malignancies were evaluated. Twenty-four patients (77%) had acute leukemia or myelodysplastic syndrome, while 7 patients (23%) had non-Hodgkin's lymphoma or multiple myeloma. By the "Disease Risk Index" (Armand P et al. Blood. 2014), 20 patients (65%) had low or intermediate risk disease, while 11 patients (35%) had high or very high risk disease. 30 patients underwent double UCB and 1 patient received single UCB transplantation. The median cryopreserved total nucleated cell dose was 5.4 x 107/kg (range: 3.2-8.4 x 107/kg). The cumulative incidence of neutrophil engraftment was 90% (95% CI, 82%-99%; Figure 1) at a median time of 21 days (95% CI, 19-26). Three patients did not have neutrophil engraftment; two patients had early death at days 7 and 14 prior to engraftment, while one patient had graft failure requiring second transplant. The cumulative incidence of platelet engraftment was 86% (95% CI, 75%-97%) at a median time of 47 days (95% CI, 37-73). Cumulative incidences of grades II-IV and grades III-IV acute GVHD were 48% (95% CI, 34%-69%) and 10% (95% CI, 3%-28%), respectively. The overall incidence of chronic GVHD was 40% (95% CI, 27%-59%), with 17% (95% CI, 8%-37%) of patients experiencing moderate to severe chronic GVHD. Treatment-related mortality at 6 months was 13% (Figure 2), while at 1 year and 3 years was 27% and 33%, respectively. With a median follow-up of 35.5 months (95% CI, 12.7-52.2), disease-free and overall survival at 3 years was 51% (95% CI, 29%-69%) and 57% (95% CI, 36%-73%), respectively.Conclusion: UCB transplantation with the modified myeloablative conditioning regimen of TBI, fludarabine, and thiotepa results in reliable neutrophil engraftment with reduced early treatment related mortality as compared to standard myeloablative conditioning consisting of TBI, fludarabine, and cyclophosphamide. It provides a promising disease-free and overall survival in an older (median age 46), heterogeneous patient population. This regimen represents a reasonable alternative to standard conditioning with TBI, fludarabine, and cyclophosphamide and warrants further study. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Low Dose Total Body Irradiation (600 cGy) as a Conditioning Regimen in Allogenic Hematopoietic Stem Cell Transplant in Children with Acute Lymphoblastic Leukemia

Total body irradiation (TBI) is conditioning regimen in children with acute lymphoblastic leukemia (ALL) with a very high risk of relapse or in those who have not achieved remission and have relapsed and subsequently received allogenic hematopoietic stem cell transplantation (HSCT). A retrospective evaluation of 33 ALL patients in full remission with an indication of HSCT was performed to evaluate overall survival (OS) and event-free survival (EFS). The inclusion criteria included a myeloablative conditioning regimen of TBI at a dose of 600 cGy. The observed OS at 5 years was 50%, and the EFS of 32% we observed difference in the EFS stem cell origin; the peripheral blood (PB) 60%, and the umbilical cord blood (UC) accounted for 40%. Overall, 45% had a documented chimerism. The OS at 5 years from patients with chimeras was 75%, while those without chimeras had an OS at 5 years of 25%. The mortality in the first 100 days was 24%. A total of 24.2% of children presented with acute graft versus-host disease (GVHD), while 33% had chronic GVHD. Currently, there is no general agreement among all international centers regarding the optimum TBI dose. Our study reports an acceptable range of adverse events with a relatively low dose of 600 cGy.

Outcomes after use of two standard ablative regimens in patients with refractory acute myeloid leukaemia: a retrospective, multicentre, registry analysis

Cyclophosphamide plus intravenous busulfan has not been compared with cyclophosphamide plus total body irradiation (TBI) in adults with advanced refractory acute myeloid leukaemia before allogeneic haemopoietic stem-cell transplantation (HCT). We aimed to assess whether survival of patients receiving ablative intravenous busulfan-based conditioning regimens before a related or volunteer-unrelated donor HCT for refractory acute myeloid leukaemia is not inferior to that of patients receiving an ablative TBI-based regimen. In this retrospective, multicentre, registry-based study, we obtained data for patients (aged >18 years) with refractory acute myeloid leukaemia in active phase of disease, who had received HCT from an HLA-identical sibling or an unrelated donor after intravenous busulfan plus cyclophosphamide or cyclophosphamide plus TBI conditioning between 2000 and 2012. Data was obtained from the European Group for Blood and Marrow Transplantation registry. The primary endpoints of the study were overall survival and leukaemia-free survival. We obtained data for 514 patients who had received intravenous busulfan plus cyclophosphamide and 338 patients who had received cyclophosphamide plus TBI. The median percentage of blasts before HCT did not differ significantly between groups (20% [range 5-100; IQR 10-32] in the intravenous busulfan plus cyclophosphamide group vs 16% [5-95; 9-33] in the cyclophosphamide plus TBI group; p=0·16). Overall survival at 2 years did not differ between the groups in the univariate analysis (31·2% [95% CI 26·8-35·5] with intravenous busulfan plus cyclophosphamide vs 33·4% [28·1-38·7] wth cyclophosphamide plus TBI; p=0·65). Leukaemia-free survival at 2 years also did not differ between groups (25·0% [95% CI 21·0-29·0] vs 28·4% [23·4-33·5]; p=0·47). In multivariable analysis adjusting for differences between both groups, no difference was noted between the two groups in terms of overall survival (hazard ratio [HR] 0·99 [95% CI 0·83-1·20]; p=0·95) or leukaemia-free survival (HR 0·97 [0·81-1·16]; p=0·71). Main causes of non-relapse mortality were graft-versus-host disease (49 [10%] in the intravenous busulfan plus cyclophosphamide group vs 25 [7%] in the cyclophosphamide plus TBI group) and infection (36 [7%] vs 18 [5%]). From a practical standpoint, the use of intravenous busulfan plus cyclophosphamide is likely to be a valid and efficient alternative to cyclophosphamide plus TBI conditioning regimen for patients with refractory acute myeloid leukaemia, especially for those transplant centres without access to radiation facilities. None.

Allogeneic hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: potential benefit of medium-dose etoposide conditioning

The outcomes of adult acute lymphoblastic leukemia (ALL) patients with chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) are unsatisfactory. Therefore, allogeneic (allo) HSCT has been applied to those patients in first complete remission (CR1), and has shown a long-term survival rate of approximately 50 %. In terms of myeloablative conditioning (MAC) regimen, higher dose of cyclophosphamide (CY) and total body irradiation (TBI) (the standard CY + TBI) has been generally applied to allo HSCT. Other MAC regimens such as busulfan-based or etoposide-based regimens have also been used. Among those, medium-dose etoposide (ETP) in addition to the standard CY + TBI conditioning regimen appears to be promising for allo HSCT in adult ALL when transplanted in ALL patients aged under 50 years in CR1 and also in CR2, showing an excellent outcome without increasing relapse or transplant-related mortality (TRM) rates. By contrast, reduced-intensity conditioning (RIC) regimens have also been applied to adult ALL patients and favorable outcomes have been obtained; however, relapse and TRM rates remain high. Therefore, an allo HSCT conditioning regimen which deserves further study for adult ALL patients aged under 50 years in CR1 and CR2 appears to be medium-dose ETP + CY + TBI and RIC is suitable for patients aged over 50 years or for younger patients with comorbid conditions. On the contrary, new therapeutic strategies for adult ALL patients are increasingly utilized with better outcomes; namely, various tyrosine kinase inhibitors for Philadelphia chromosome (Ph)-positive ALL, human leukocyte antigen-haploidentical HSCT, and pediatric-inspired regimens for Ph-negative ALL. Therefore, the optimal treatment modality should be selected considering patient’s age, Ph-positivity, donor availability, risk classification, efficacy, and safety.

Phase II Trial Of Medium-Dose VP-16, Cyclophosphamide and Total-Body Irradiation Conditioning Regimen Before Allogeneic Stem Cell Transplantation For Acute Lymphoblastic Leukemia In Adults

BackgroundThe prognosis of adult patients (pts) with acute lymphoblastic leukemia (ALL) is dismal, and allogeneic stem cell transplantation (allo-SCT) is performed in most pts. However, even for pts treated with allo-SCT using the standard regimen of cyclophosphamide with total body irradiation (CY/TBI), the prognosis is not satisfactory due to a high rate of relapse. We previously reported excellent outcomes in adult pts with ALL undergoing allo-SCT conditioned with medium-dose VP-16, CY and TBI (medium-dose VP/CY/TBI). We therefore conducted a prospective nationwide multicenter phase II trial (UMIN trial number 000001672) to evaluate the efficacy of this conditioning regimen. MethodsThe eligibility criteria of this study were as follows: (1) diagnosis of ALL or acute biphenotypic leukemia (ABL), (2) aged 15-49 years, (3) in CR, (4) first SCT, (5) PS (ECOG) 0-2, (6) intact organ function, and (7) HLA-serologically 6/6 matched donor. Pts with Burkitt leukemia were ineligible for this study. Conditioning regimen consisted of medium-dose VP (15 mg/kg once daily i.v. for two days) and CY (60 mg/kg once daily i.v. for two days) combined with fractionated TBI (total dose: 12 Gy). Stem cell source was limited to bone marrow (BM) or peripheral blood stem cell (PBSC). The primary endpoint of this study was event-free survival (EFS) at one year after SCT, and the events were defined as death or relapse. The expected 1-year EFS was estimated to be 75%, and the threshold 1-year EFS was estimated to be 55%, on the basis of our previous observations. ResultsBetween February 2009 and August 2011, 52 pts were enrolled, and 50 pts met the criteria. Among 50 eligible pts, the median age was 33.5 years (range, 17-49 years), and 15 pts (30%) were over 40. Twenty-three (46%) pts were female. Forty-eight (96%) pts had ALL and 2 (4%) had ABL. Nineteen (38%) pts were Philadelphia chromosome (Ph)-positive. Forty-seven (94%) pts were in first CR at SCT, and 3 (6%) in second CR. Among pts with ALL in first CR (n=45), 38 (84%) had high-risk disease. Twenty-six (52%) pts underwent SCT from a related donor and 24 (48%) from an unrelated donor. Forty (80%) pts received BM and 10 (20%) received PBSC. All pts achieved neutrophil engraftment. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 38% and 8%, respectively, and that of chronic GVHD was 54%. After 1-year follow-up of the final enrollment (range, 379-1218 days), the 1-year EFS was 76% (95% confidence interval (CI): 62-86%, Figure). One-year overall survival was 80% (95% CI: 66-89%). No pts died within 100 days after SCT and 1-year non-relapse mortality (NRM) was 14% (95% CI: 6-25%). No secondary malignancies were observed during the-follow-up period. The 100-day and 1-year relapse rate was 2% (95% CI: 0-9%) and 10% (95% CI: 4-20%), respectively. The 1-year EFS for pts with high-risk and standard-risk disease was 76% (95% CI: 59-87%) and 71% (95% CI: 26-92%), Ph-positive and negative pts was 79% (95% CI: 53-92%) and 76% (95% CI: 56-88%), and pts over 40 years and under 40 years was 73% (95% CI: 44-89%) and 77% (95% CI: 59-88%), respectively. In univariate analysis, high-risk disease, Ph-positivity and higher age were not significant risk factors for EFS. ConclusionsThe results demonstrate that the conditioning regimen of medium dose VP/CY/TBI for allo-HCT in adult pts with ALL enable good disease control without increase in NRM, even for relatively high age pts and pts with high-risk disease. A phase III trial comparing this regimen with standard CY/TBI regimen for adult pts with ALL is warranted. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Peripheral Blood Stem Cells Versus Bone Marrow Grafts For HLA-Matched Unrelated Donor Transplantation In Adult Patients With Acute Myeloid Leukemia; The Role Of Low-Dose Rabbit Anti-Thymocyte Globuline In The Prophylaxis Of Graft-Versus-Host Disease

BackgroundIn the setting of unrelated donor stem cell transplantation (URD-SCT), several data showed that peripheral blood stem cells (PBSC) resulted in faster engraftment but increased the risk of acute or chronic graft-versus-host disease (GVHD), while other transplant outcomes were comparable. However, there are some limitations in these data due to heterogeneous diseases or registry data characterized by various other treatment strategies. Notably, we have added low-dose rabbit anti-thymocyte globuline (ATG) only to the patients who received URD-SCT with PBSC because of their higher risk of developing GVHD. In this setting, we compared the long-term outcomes of URD-SCT using PBSC and bone marrow (BM) and studied the role of low-dose rabbit ATG in the prophylaxis of GVHD. MethodsBetween March 2004 and April 2012, 115 adult patients with AML underwent myeloablative (n=87) or reduced-intensity (n=28) conditioning HLA-matched URD-SCT with PBSC (n=70) or BM (n=45) grafts. All patients received tacrolimus and short-course methotrexate for GVHD prophylaxis. Low-dose rabbit ATG (Thymoglobuline®, 1.25 mg/kg for 2 days) was added only to the patients who received URD-SCT with PBSC grafts. The median follow-up of survivors was 44 months (range, 2-100) for PBSC transplants and 54 months (range, 8-105) for BM transplants (P=0.01). ResultsBaseline characteristics were not significantly different between the two groups except for total-body irradiation conditioning regimen (72.9% vs. 91.1%; P=0.02). PBSC transplants showed faster recovery of neutrophil (11 days vs. 13 days; P=0.03) and platelet (12 days vs. 18 days; P=0.01) counts than BM transplants. No difference was observed in the cumulative incidence of acute GVHD (grade ≥2) at 100 days (54.3% vs. 64.4%; P=0.38) and chronic GVHD at 4 years (61.4% vs. 60.0%; P=0.88) between the two groups. In spite of adding low-dose rabbit ATG, PBSC transplants did not show higher incidence of relapse compared to that of BM transplants (30.8% vs. 31.2%; P=0.53). Other transplant outcomes including non-relapse mortality (13.5% vs. 6.9%; P=0.24), disease-free survival (55.7% vs. 61.9%; P=0.80), and overall survival (63.3% vs. 63.2%; P=0.59) were comparable between the two groups. In multivariate analysis, graft source had no impact on transplantation outcomes. Regardless of graft source, transplants in ≥CR2 had higher relapse risk (hazard ratio, 2.45; 95 % CI, 1.04-5.76; P=0.04), poorer disease-free survival (hazard ratio, 2.68, 95% CI, 1.29-5.56; P=0.01) and overall survival (hazard ratio, 2.59; 95% CI, 1.20-5.59; P=0.02). ConclusionAdding low-dose rabbit ATG to the patients who received URD-SCT with PBSC may lower the incidence of acute and chronic GVHD comparably to that of URD-SCT with BM without increasing the incidence of relapse. Disclosures:No relevant conflicts of interest to declare.

Favorable Outcomes of Autologous Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Remission: On Behalf of the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT)

AbstractAbstract 2021 Background:Postremission treatment for adult Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-)ALL] in first remission remains elucidated and the role of autologous stem cell transplantation (auto-SCT) is still controversial in the application for Ph(-)ALL patients. We retrospectively analyzed the consolidative role of auto-SCT as a postremission therapy for adult Ph(-)ALL in first remission. Patients and Methods:Among 1962 adult Ph(-)ALL patients registered in the JSHCT database, we selected cases receiving auto-SCT with myeloablative preparative regimens in first complete remission from 1983 to 2009. Results:A total of 155 patients with 86 male patients were analyzed. The median age was 25 years (range: 16 to 74) and 79% of patients were less than 45 years of age at transplant. The number of patients having white blood cell (WBC) count <30000/ul and ≥30000/ul at diagnosis was 81 and 21, respectively. The number of patients showing B- and T-cell phenotypes was 80 and 21, respectively. Cytogenetic data were available in 96 patients, of which 69 patients had normal karyotypes. Most patients (84%) underwent auto-SCT before 2002, and 42 out of 155 patients received TBI combined conditioning regimens. With a median follow-up of 10 years, the 10-year overall survival rate of all 155 patients was 41% (95%CI: 33 to 49). Among patients younger than 45 years, the survival rate of adolescent and young adult (AYA) patients (aged 24 years or less) was comparable to that of patients aged 25 to 44 years (p= 0.110). Cumulative incidence of relapse and non-relapse mortality (NRM) at 10 year after auto-SCT was 47% (95%CI: 39 to 55) and 10% (95%CI: 6 to 16), respectively. In univariate analysis, factors associated with worse overall survival were age 45 years or more [Hazard ratio (HR): 1.67, p=0.038] and usage of conditioning regimens without total body irradiation (TBI) (HR: 1.51, p=0.110). Factors associated with decreasing relapse rates were usage of TBI conditioning regimens (HR: 0.35, p=0.069) and transplant year 2000 and later (HR: 0.35, p=0.141). In multivariate analysis, factors correlated with increasing the overall survival rate and decreasing the relapse rate were age less than 45 years [HR: 0.59 (95%CI: 0.36 to 0.96), p=0.034] and usage of TBI conditioning regimens [HR: 0.55 (95%CI: 0.31 to 0.99), p=0.048], respectively. There were no significant factors associated with NRM in univariate and multivariate analyses.We next performed comparison of auto-SCT with allogeneic stem cell transplantation (allo-SCT) in adult Ph(-)ALL patients. Patients undergoing allo-SCT were selected from the same JSHCT database. A total of 921 patients were identified as cases receiving allo-SCT with myeloablative preparative regimens in first complete remission. With a median follow-up of 4.95 years, the 4-year overall survival rate was 63% (95%CI: 51 to 59). Allo-SCT yielded better overall survival rate than that of auto-SCT (63% vs. 48% at 4 year, p=0.0004). In subset analyses, we limited analyses to the groups of patients younger than 45 years and receiving TBI regimens followed by auto-SCT (n=31) or allo-SCT (n=685). There were no differences in baseline patients’ characteristics between the two groups except age [auto-SCT: 20 years (range: 16 to 40) vs. allo-SCT: 28 years (range: 16 to 44), p<0.001]. The 4-year overall survival rates in patients undergoing auto-SCT and allo-SCT were 71% (95%CI: 52 to 84) and 66% (95% CI: 62 to 70), respectively (p=0.510, Figure. 1). No statistically significant factors were found in the analyses of relapse and NRM. Conclusions:Our analyses demonstrated that auto-SCT produced excellent results showing a plateau in long-term survival and that clinical outcome of auto-SCT was comparable to that of allo-SCT in some part of patients. Candidates who obtained most benefit from auto-SCT was those younger than 45 years and well tolerated with TBI combined myeloablative conditioning regimens. Since optimal timing of postremission therapy is critical for adult Ph(-)ALL patients, auto-SCT in first complete remission could be one of promising treatment strategies for the patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.