Efficacy Of Total Body Irradiation Research Articles

A Phase II Study of Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Older Patients Using Fludarabine and Total Body Irradiation

Background: Older adults with acute lymphoblastic leukemia (ALL) have poor survival outcomes. Although allogeneic hemaptopoietic stem cell transplantation (allo-hsct) can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative allo-hsct. The 1-year disease-free survival (DFS) for patients ≥40 years who receive an allo-hsct for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of Total Body Irradiation (TBI) based regimens in adults with ALL when combined with cyclophosphamide (Cy). High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regimen of Flu/TBI 12 Gy is almost as effective as Cy/TBI 12 Gy in older adults with ALL undergoing allo-hsct.Methods: We conducted a single center, single-arm phase II clinical trial (NCT01991457) of Flu 40 mg/m 2 IV daily (days -7 to -4) and TBI 2 Gy X2 (days -3 to -1) (12 Gy total) as myeloablative conditioning for older adults (≥40 years old) or younger adults with significant comorbidities with ALL. The primary endpoint of the study was DFS. Secondary endpoints include overall survival (OS), relapse rate, NRM rate and incidence and severity of acute and chronic graft vs. host disease (GVHD). GVHD prophylaxis consisted of Tacrolimus and Methotrexate. Rabbit anti-thymocyte globulin (rATG) was added for unrelated donor type.Results: Nineteen patients were enrolled between October 2013 and February 2019 (Table 1). The median age was 54 years (44-63 years). There were 9 (47%) females and 19 (100%) Non-Hispanic Whites (NHW). The median KPS was 80 (70-100) and 3 (16%) patients had an HCT-CI of ≥3.Seven (37%) patients had Ph-negative B-cell ALL, 9 (47%) had Ph-positive B-cell ALL and 3 (16%) had lymphoid blast phase of chronic myeloid leukemia (CML-LBP). All patients were in CR1 at the time of transplant. Twelve (63%) patients had an 8/8 matched unrelated donor (MUD) and 7 (37%) had a matched related donor (MRD). The median time to neutrophil engraftment was 12 days (10-24 days). Day 100 post-transplant grades III-IV non-hematological and non-infectious adverse effects included mucositis (16%), acute kidney injury (16%), cardiovascular (11%) and elevated liver enzymes (5%).The cumulative incidence (CI) of grades II-IV and III-IV aGVHD at day 100 post-transplant was 26.1% (95% CI 19.3%-39.2%) and 16.2% (95% CI 12.4%-31.3%), respectively. The 2-year CI of mild, moderate and severe cGVHD was 5.0% (95% CI 2.1%-12.3%), 11.3% (95% CI 7.4%-33.3%) and 21.1% (95% CI 13.5%-40.3%), respectively (Table 2). There were 4 cases of cGVHD of the lungs (3=severe, 1=moderate). Other organs involved included skin (n=5), oral (n=5) and ocular (n=4).The CI of relapse and NRM at 2-years was 7.1% (95% CI 5.4%-20.7%) and 31.4% (95% CI 19.4%-50.1%), respectively (Figure 1). The 2-year DFS and OS rates were 63.2% and 68.4%, respectively (Figure 2a and 2b). The median OS was 40 months (95% CI 8.5-71.5).Conclusion: Flu/TBI (12 Gy) resulted in low incidence of relapse with a high DFS and OS rate in an older population with ALL. Increased incidence of severe cGVHD of the lungs was observed with this regimen. Further investigation into this regimen, as a myeloablative regimen for older patients with ALL, is warranted. [Display omitted] DisclosuresDi Stasi: University of Alabama at Birmingham: Current Employment; Syndax Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees. Saad: Incyte Pharmaceuticals: Consultancy; careDx: Consultancy; Amgen: Research Funding; Kadmon: Research Funding; OrcaBio: Research Funding; Magenta Therapeutics: Consultancy.

Tolerance and efficacy of total body irradiation and cladribine prior to allogeneic hematopoietic cells transplantation in patients with acute myeloid leukemia and myelodysplastic syndromes — synopsis of clinical study

Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) is a standard of care for patients with acute myeloid leukemia (AML) and patients with intermediate and high-risk myelodysplastic syndrome (MDS). Despite many years of experience. there is still no standard for conditioning regimen. The aim of this study is to analyse the efficacy and safety of a conditioning treatment with cladribine in combination with total body irradiation (TBI). Material and methods: A group of 40 adult patients referred for allo-HCT due to AML and MDS are to be enrolled in the study. The inclusion criteria are: informed consent, chemo-sensitivity for cladribine treatment regimens (when used in induction therapy), age 18–60, and performance status 0–2 according to World Health Organization. The conditioning regimen consists of cladribine and TBI at a total dose of 12 Gy in three fractions given over three consecutive days. The goal of the study is to assess the tolerability and efficacy of the regimen. Results: Our results may stimulate further investigation in this field i.e. phase III trials to compare this regimen to others. Conslusion: A myeloablative conditioning regimen consisting of total body irradiation in combination with cladribine may contribute to improved outcomes after allo-HCT for AML and MDS patients.

Maternal administration of busulfan before in utero transplantation of human hematopoietic stem cells enhances engraftments in sheep

In utero transplantation (IUT) of human hematopoietic stem cells has been conducted in sheep, which are used as large animal models of human hematopoietic reconstitution and models for clinical IUT; however, the levels of engraftment have generally been low. Busulfan (BU), a myeloablative agent, is often administered to patients before hematopoietic stem cells transplantation to improve the engraftment. In this study, hematopoietic activity was evaluated in adult sheep after administering BU at different doses. Next, pregnant ewes were administered BU, and dams as well as their fetuses were evaluated, as BU readily crosses the sheep placenta. Then, the BU dose with the desired outcomes was selected and administered to pregnant ewes at 2 or 6 days before performing IUT using human cord blood CD34(+) cells. The engraftment was evaluated in recipients that underwent IUT in the presence or absence of BU. As a result, hematopoietic activity was safely and transiently suppressed in adult sheep treated with 5 to 7.5 mg/kg BU. BU crossed the sheep placenta, and fetal sheep were indeed conditioned by administering 3 mg/kg BU to pregnant ewes. Engraftment of human CD34(+) cells in fetal recipients was enhanced when IUT was carried out 6 days post-BU. Up to 3.3% engraftment levels (in terms of bone marrow colony-forming units) were achieved with the IUT of 0.72 to 2.4 million CD34(+) cells when BU was used. BU can be administered to pregnant ewes to effectively condition the fetal recipient for IUT with enhanced engraftment of donor cells.

Safety and efficacy of total body irradiation, cyclophosphamide, and cytarabine as a conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia

Disease relapse still greatly interferes with the success of allogeneic hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL). This study retrospectively evaluated the long-term safety and efficacy of a conditioning regimen consisting of total body irradiation (TBI; 12 Gy), cyclophosphamide (CY; 60 mg kg(-1) , two doses), and high-dose cytarabine (Ara-C; 2 g m(-2) ; four doses) for patients with ALL. Fifty-five patients (median age: 31-years old) were evaluated. Stem cells were from human leukocyte antigen-identical siblings in 22 patients and from alternative donors in 33. There were no cases of early death before engraftment, and 100-day transplant-related mortality was 7.3%. With a median follow-up period of 9.6 years, 5-year overall and disease-free survival were 63.2% (95% CI: 46.5-79.9%) and 63.6% (95% CI: 47.1-80.1%) in patients with complete remission, respectively, both of which were significantly higher than the values of 27.3% (95% CI: 8.7-46.0%) and 22.7% (95% CI: 5.3-40.1%) for patients in advanced stages (P < 0.01). These results suggest that TBI and CY (TBI-CY) plus Ara-C could be a feasible and effective conditioning regimen for adult patients with ALL both in remission and in advanced stages, and a future study to compare this combination therapy with TBI-CY is required.

Total body irradiation plus cyclophosphamide versus busulphan with cyclophosphamide as conditioning regimen for patients with leukemia undergoing allogeneic stem cell transplantation: a meta-analysis

The aim of the study was to compare the therapeutic efficacy of total body irradiation (TBI)/cyclophosphamide (CY) versus BU/CY as conditioning regimen for leukemia. We electronically searched the Cochrane Central Register of Controlled Trials, Medline, Embase, CIBMTR and critically appraised all relevant articles (1990.01–2009.04). Comparative studies were evaluated on clinical therapeutic effects of TBI/CY and busulphan BU/CY regimens with assessement of engraftment, relapse, complications, and disease-free survival (DFS). Eighteen trials totaling 3172 patients have been assessed. Pooled comparisons of studies indicated that for patients with acute leukemia (ALL and AML), the TBI/CY regimen lead to lower rates of leukemia relapse, lower transplant-related mortality (TRM), and higher DFS, while for chronic myeloid leukemia (CML), the TBI/CY regimen had a higher rate of leukemia relapse, lower TRM, and similar DFS. The TBI/CY regimen was associated with similar occurrence of engraftment, acute and chronic graft-versus-host disease (GVHD), but with higher rates of cataract [odds ratio (OR) 12.69, p = 0.01], interstitial pneumonitis, later growth or development problems [OR 5.04, p = 0.008]. BU/CY regimen was associated with higher rates of complications like liver veno-occlusive disease [OR 0.43, p < 0.00001], hemorrhagic cystitis, and TRM. Our meta-analysis confirmed that different regimens and type of leukemia may affect the complications and outcome. An analysis of the effects of other regimens need to be carried out by large sample and well-designed clinical trials.

SU‐FF‐T‐233: Feasibility Study of Linac‐Based Intensity Modulated Total Marrow Irradiation (IM‐TMI)

Purpose: Standard total body irradiation (TBI) techniques are associated with both acute and chronic toxicities due to the large volume of normal tissue irradiated. Additionally, inhomogeneous dose distributions are known to be the cause of failures and relapses in the treatment of leukemia and lymphoma. The goal of this study is to investigate the feasibility of linac‐based intensity modulated total marrow irradiation (IM‐TMI) and to discuss the challenges associated with its clinical implementation. Methods: To evaluate the feasibility of linac‐based IM‐TMI, we performed an exploratory treatment planning using the CT scan of a TBI patient. Active bone marrow sites were defined and contoured as the clinical target volume (CTV) and a margin was added to create the planning target volume (PTV). Dose limiting organs included the lenses, lungs, liver, kidneys, and heart. IMRT plans were created using the Eclipse/Helios inverse planning system (Varian Inc., Palos Alto, CA) to deliver a total dose of 12 Gy. Dose volume histograms (DVHs) were calculated and subsequently compared with standard TBI‐DVHs. Results: IM‐TMI resulted in a significant reduction in the volume of normal tissue irradiated compared with conventional TBI. The median lung doses were 7.3 Gy and 8.8 Gy, while the maximum lung doses were 12.9 Gy and 15.5 Gy for IM‐TMI and conventional TBI, respectively. The maximum dose to the lenses was 7 fold less using the IM‐TMI approach. Similar results were also observed for liver, kidney, heart, small bowel, and spleen. Moreover, IM‐TMI resulted in a more homogeneous dose to the PTV with a median dose of 12.3 Gy vs. 10.5 Gy using standard TBI. Conclusions: Our results demonstrate that linac‐based IM‐TMI is capable of delivering a conformal dose to the target volume while reducing the dose to the surrounding normal tissue. Such an approach may improve the overall efficacy of TBI.

Recipient preparation for bone marrow transplantation. I. Efficacy of total-body irradiation and busulfan.

The efficacy of total body irradiation and busulfan were studied in recipient preparation for bone marrow transplantation. Male C57BL/6 (B6) mice were prepared for BMT with fractionated TBI or busulfan given in 4 equal doses over 3 days. Both TBI and busulfan are potent stem-cell killers. Both agents resulted in an exponential decrease in CFUs survival with increasing dose down to a 1 x 10(-4) CFUs survival. There appeared to be no break in the curve for either agent. Extrapolated fractional CFUs survival, as related to equivalent donor marrow engraftment or to equivalent 30-day survival without marrow transplantation, appeared lower for TBI as compared to busulfan. This may be due to the effect of busulfan and TBI on different stem-cell populations. Erythroid engraftment was tested after transplanting H-2 compatible LP marrow cells into treated B6 recipients. Greater than 80% of animals demonstrated complete engraftment with 3.4 mg busulfan or 1640 cGy TBI. At these 2 doses, the rate of recovery of donor marrow cellularity and CFUs content in treated recipients were identical for both preparative agents such that a selective effect on the host hematopoietic microenvironment harmful to engraftment was not seen. Complete engraftment in 100% of busulfan-prepared animals could not be achieved as such doses resulted in severe and fatal pulmonary vascular injury at 7-12 weeks posttransplant.

Dosimetry for a total-body irradiation chamber.

In the past few years there has been a rapidly growing interest in the problems of radiation protection in cases of exposure of large areas of the human body. In addition, much work has been done in the field of organ transplants, particularly with respect to the management of leukemia with bone-marrow transplants. It is of interest to note that more success has attended the studies on experimental animals than on man. It is postulated that one of the problems in evaluating the efficacy of total-body irradiation of man has been the difficulty of obtaining a fairly uniform dose of radiation throughout the entire volume of a patient. Certainly a system which provided such a uniform energy deposition would eliminate a variable in the ultimate evaluation of total-body irradiation. It is the object of this paper to describe a physical system designed and constructed with this in view and to report the initial results of the dosimetry connected with it, as well as the problems encountered. The irradiation chamb...