The safety and efficacy of a novel hypo-fractionated total marrow and lymphoid irradiation before allogeneic stem cell transplantation for lymphoma and acute leukemia
Clinical and translational radiation oncology. 2021;26:42-46
PURPOSE Total body irradiation (TBI) has been widely utilized as part of the conditioning regimen for hematopoietic stem cell transplantation (HSCT), but is associated with significant toxicities. Targeted TBI using helical Tomotherapy allows precise and homogeneous tumor coverage and excellent sparing of organs at risk. The purpose of this study was to evaluate the clinical outcomes of a novel hypo-fractionation strategy for patients receiving total marrow and involved lymphoid irradiation (TMLI) as part of the conditioning regimen before HSCT. METHODS AND MATERIALS 61 patients (7 acute myelogenous leukemia (AML), 33 acute lymphoblastic leukemia (ALL), 18 non-Hodgkin's lymphoma (NHL), 3 mixed acute leukemia (MAL)) received conditioning radiation treatment with TMLI (8 Gy to bone marrow, 10 Gy to involved field in 2 fractions per day) in conjunction with chemotherapy before transplantation. RESULTS The median age of 61 patients with TMLI was 24 (4-54) years. The prescribed dose covered the entire bone and involved target volume, and the dose of organs at risk (OAR) was reduced by 28%-78% of the prescription dose. Grade 1-2 nausea and vomiting occurred in 12 patients and grade 1-2 pain in 6 patients during radiotherapy. Fatigue occurred in 16 patients. 2 patients had diarrhea, enteritis, and 1 patient had fever. None of patient had grade 3-4 non-hematologic adverse reactions. Late (30 days after HSCT) grade 2 toxicities including reversible enteritis occurred in 3 patients. 5 patients developed infectious pneumonia. The 2 years progression-free survival (PFS) was 64.1% (95% CI: 0.16-0.22) and overall survival (OS) was 74.7% (95% CI: 0.19-0.24) for the 61 patients who had received their planned HSCT. The 2-year non-relapse mortality was significantly reduced to 5% in this patient cohort. CONCLUSIONS This study demonstrates that hypo-fractionated TMLI (8 Gy to bone marrow, 10 Gy to involved field in a single day) as a conditioning regimen for lymphoma and acute leukemia was feasible and the clinical outcomes were acceptable.
Comparison of total body irradiation versus non- total body irradiation containing regimens for de novo acute myeloid leukemia in children
With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, p<0.0001) but relapse was lower (23% vs. 37%, p<0.0001) compared to non-TBI regimens. Consequently, overall (62% vs. 60%, p=1.00) and leukemia-free survival (55% vs. 52%, p=0.42) did not differ between treatment groups. Grade II-IV acute GVHD was higher with TBI regimens (56% vs. 27%, p<0.0001) but not chronic GVHD. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%, p<0.001) but there were no differences in late pulmonary, cardiac or renal impairment. In the absence of a survival advantage, the choice of TBI or non-TBI regimen merits careful consideration with the data favoring non-TBI regimens to limit the burden of morbidity associated with endocrine dysfunction.
Children with de novo acute myeloid leukaemia (n=624)
Myeloablative conditioning regimen containing total body irradiation (TBI) (n=199)
Non-TBI regimens (n=425)
Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%) but relapse was lower (23% vs. 37%) compared to non-TBI regimens. Consequently, overall (62% vs. 60%) and leukemia-free survival (55% vs. 52%) did not differ between treatment groups. Grade II-IV acute GVHD was higher with TBI regimens (56% vs. 27%) but not chronic GVHD. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%) but there were no differences in late pulmonary, cardiac or renal impairment.
Comparing the outcomes between TMLI and non-TMLI conditioning regimens for adult high-risk acute lymphoblastic leukemia patients undergoing allogeneic hematopoietic stem cell transplantation: a single-center experience
Leukemia & lymphoma. 2020;:1-9
This study aimed to retrospectively evaluate the outcomes of adult patients with high-risk acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) with either total marrow and lymphoid irradiation (TMLI)-containing or non-TMLI conditioning regimen. Seventy adult patients with high-risk ALL who received allo-HSCT were enrolled in this study and divided into two groups based on the conditioning regimen type (TMLI group: n = 29 and non-TMLI group: n = 41). We noted significant statistical differences in the 1-year estimated cumulative incidence of relapse (25% vs. 46.5%, p = 0.018), the 1-year estimated overall survival (73.1% vs. 52.6%, p = 0.033) and disease-free survival (65.2% vs. 48.2%, p = 0.026) but found no considerable difference in transplant-related mortality (12% vs. 13.4%, p = 0.619) between patients in the TMLI and non-TMLI groups. The TMLI-containing regimen is safe and alternative for patients with high-risk ALL undergoing allo-HSCT.
Once-a-day fractionated total-body irradiation: A regimen tailored to local logistics in allogeneic stem cell transplantation for acute lymphoblastic leukemia
Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology. 2020;25(3):436-441
Aim: The objective of the study was to estimate the cumulative incidence (CI) of relapse, relapse-free survival (RFS) and overall survival (OS) in ALL patients after a once-a-day fractionated TBI (F-TBI) regimen with 9.9Gy. The secondary objectives were evaluation of short and long-term toxicity and non-relapse mortality (NRM). Background: Total body irradiation (TBI), as a part of the conditioning regimen before allogeneic stem cell transplantation (ASCT) for acute lymphoblastic leukemia (ALL), allows disease control by eradicating residual blast cells in the transplant recipient. Materials and methods: Retrospective study conducted in patients with ALL who received between March 2003 and December 2013 a conditioning regimen with F-TBI and chemotherapy. Irradiation was delivered with 3.3Gy once-a-day for three consecutive days. Results: Eighty-seven patients were included. The median age was 19 years (range: 5-49 years). The 3-year CI of relapse was 30%. The estimated 3-year RFS and OS were 54% and 58%, respectively. Cumulative incidence of acute graft-versus-host disease (aGVHD) grade II-IV and chronic GVHD (cGVHD) was 31% and 40%, respectively. Interstitial pneumonitis was observed in 2 patients. The 3-year CI of NRM was 16%. In multivariate analysis, cGVHD was associated with a lower CI of relapse (RR=0.26, 95% CI: 0.07-0.95, p=0.04). High-risk cytogenetics was associated with a lower RFS (RR=2, 95 CI: 1.04-3.84, p=0.03). Grade II-IV aGVHD was an independent predictor of higher CI of NRM (RR=6.7, 95% CI: 1.4-31.7, p=0.02). Conclusions: Once-a-day F-TBI regimen is effective, safe and practical in patients who underwent ASCT for ALL.
Irradiation free conditioning regimen is associated with high relapse rate in Egyptian patients with acute lymphoblastic leukemia following allogeneic hematopoietic stem cell transplantation
Journal of the Egyptian National Cancer Institute. 2020;32(1):28
BACKGROUND Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for adult patients with acute lymphoblastic leukemia (ALL). Cyclophosphamide plus total body irradiation (TBI/Cy) or plus busulfan (Bu/Cy) is a widely used pre-transplant conditioning regimen for ALL. We retrospectively compared the overall survival (OS), disease-free survival (DFS), and other transplant outcomes of allo-HSCT in 119 adult patients with ALL who received an HLA-matched sibling allo-HSCT using TBI-based versus non-TBI-based conditioning regimens. Patients were divided into two groups by their conditioning regimen: TBI/Cy or Bu/Cy. RESULTS Median OS was 11 months in the TBI/Cy group and 6.2 months in the Bu/Cy group. Median DFS was 11.1 months in the TBI group versus 6.8 months in the Bu group, without a statistically significant difference. A higher risk of relapse was observed with the Bu/Cy regimen (HR 2.709, CI 95% 1.106 to 6.638, p = 0.029). Patients who received a transplant in ≥ CR2 were associated with poor DFS. CONCLUSION Despite the high relapse rate in the non-TBI regimen (Bu/Cy), both regimens had no statistically significant differences in OS, DFS, and NRM. Additional prospective studies are indeed warranted to evaluate the long-term outcomes of radiation-free regimens, including oral and intravenous busulfan, and compare these regimens with TBI-based ones.
A Phase II Trial Evaluating The Efficacy of High-Dose Radioiodinated Tositumomab (Anti-CD20) Antibody, Etoposide and Cyclophosphamide followed by Autologous Transplantation, for High-Risk Relapsed or Refractory Non-Hodgkin's Lymphoma
American journal of hematology. 2020
Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age < 60 years with R/R NHL expressing CD20 were eligible. Mantle cell lymphoma (MCL) patients could proceed to transplant in first remission. Patients received I-131-tositumomab delivered at ≤ 25Gy to critical normal organs, followed by etoposide, cyclophosphamide and ASCT. 107 patients were treated including aggressive lymphoma (N=29), indolent lymphoma (N=45), and MCL (N=33). After a median follow-up of 10.1 years, the 10-year PFS for the aggressive, indolent, and MCL groups were 62%, 64%, 43% respectively. The 10-year OS for the aggressive, indolent, and MCL groups were 61%, 71%, 48% respectively. Toxicities were similar to standard conditioning regimens and non-relapse mortality at 100 days was 2.8%. Late myeloid malignancies were seen in 6% patients. High-dose I-131-tositumomab, etoposide and cyclophosphamide followed by ASCT appeared feasible, safe, and effective in treating NHL, with estimated PFS at 10-years of 43-64%. In light of novel cellular therapies for R/R NHL, high-dose RIT-containing regimens yield comparable efficacy and safety and could be prospectively compared. This article is protected by copyright. All rights reserved.
Impact of alemtuzumab dosing and low-dose total body irradiation on cytomegalovirus infection in allogeneic hematopoietic stem cell transplantation
Leukemia & lymphoma. 2020;:1-3
Surface Dosimetry of Patients Undergoing Total Body Irradiation: A Retrospective Analysis for Quality Assurance
Total body irradiation (TBI) is used prior to bone marrow transplantation as part of the conditioning regimen in selected patients. A linear accelerator-based technique was used at our treatment centre between June, 2004 and August, 2015. Patients were treated supine with extended source-to-surface distance (SSD) lateral fields, and prescription dose was 12 Gy delivered in six fractions, two fractions per day. Dose was prescribed to midplane at the level of the umbilicus and monitor units were calculated manually based on measured beam data. Dose variation within 10% of the prescribed midplane dose is considered acceptable for TBI treatment. This was achieved in our clinic by using compensators to account for missing tissue in the head and neck and lower leg regions. Lung attenuators were routinely used to correct for internal inhomogeneity, which resulted from low density lung tissue. The purpose of this study was to determine whether dose variation was within acceptable limits for these patients as part of a quality assurance process. Following chart review, 129 patients who received six-fraction TBI from 2004 to 2015 were included in this study. Patients receiving single fraction treatment were excluded. Metal oxide semiconductor field effect transistors (MOSFET) dosimetry was used to measure surface dose at four or five locations during patients' first fraction of TBI. Dosimetry was repeated during the second fraction for any site with variation greater than 10%. Statistical analysis was carried out on patient data, diagnosis and dosimetry measurements. Of the 129 patients who met the inclusion criteria, 50 were diagnosed with acute myelogenous leukemia, 30 with acute lymphoblastic leukemia and 11 with chronic myelogenous leukemia. The rest of the patients were diagnosed with lymphoma or myelodysplastic syndromes. The mean percent variation in dosimetry measurements taken at the specific locations ranged between 3.5% and 8.3%. The highest variation was found in measurements performed on the cheek. A high percentage of all dosimetry readings (85.5%) was within the acceptable range of +10% from the expected value. The highest number of individual readings taken at a specific location that fell outside this range were found at the cheek. We conclude that the linear accelerator delivered TBI at our centre meets the acceptable limits of dose variation over an 11-year period.
High leukemia-free survival after TBI-based conditioning and mycophenolate mofetil-containing immunosuppression in patients allografted for chronic myelomonocytic leukemia: a single-center experience
Annals of hematology. 2020
This retrospective single-center analysis studied the impact of the conditioning and the graft-versus-host disease (GVHD) prophylaxis on outcome in unselected patients allografted for chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) secondary to documented prior CMML. A total of 44 patients (median age 61 years) allografted between 2002 and 2019 in our institution were analyzed. Fifteen patients had secondary AML. The conditioning regimen was fractionated 6-8 Gy total body irradiation (TBI) in combination with fludarabine in 33 (75%) patients. Eleven patients (25%) received alkylator-based conditioning therapy without TBI. For GVHD prophylaxis, a calcineurin inhibitor (CNI) backbone in combination with methotrexate (MTX) or mycophenolate mofetil (MMF) was applied in 21 and 23 patients, respectively. All patients allografted from an unrelated donor (UD) received antithymocyte globuline. In univariate analysis of the entire cohort, TBI-based conditioning and MMF-containing immunosuppression were associated with improved leukemia-free survival (LFS, HR 0.16, P < 0.001 and HR 0.41, P = 0.030, respectively). After stratification according to conditioning and GVHD prophylaxis into four groups (TBI-MMF [n = 17], TBI-MTX [n = 16], alkylator-MMF [n = 6], alkylator-MTX [n = 5]), TBI-MMF was associated with improved overall survival (OS) and LFS (P = 0.001 and P < 0.001, respectively). Patient and disease characteristics did not differ between the groups. The associations of TBI-based conditioning and MMF with prolonged LFS were observed across the CMML (n = 29), secondary AML (n = 15), and UD allograft (n = 34) subgroups. In summary, our study suggests that allografting based on intermediate-dose TBI conditioning and MMF-containing GVHD prophylaxis is associated with increased disease control in CMML. Larger (registry-based) studies are warranted to confirm our findings.
Body composition after allogeneic haematopoietic cell transplantation/total body irradiation in children and young people: a restricted systematic review
Journal of cancer survivorship : research and practice. 2020
PURPOSE To collate evidence of changes in body composition following treatment of leukaemia in children, teenagers and young adults (CTYA, 0-24 years) with allogeneic haematopoietic stem cell transplant and total body irradiation (HSCT+TBI). METHODS Papers were identified by searching Medline and Google Scholar, reference lists/citations and contacting key authors, with no date or language restrictions. Inclusion criteria were as follows: leukaemia, HSCT+TBI, aged ≤ 24 years at HSCT and changes in body composition (total fat, central adiposity, adipose tissue function, muscle mass, muscle function). Quality was assessed using a brief Newcastle-Ottawa scale. RESULTS Of 900 papers, 20 were included: seven controlled, five uncontrolled studies and eight case reports. Study quality appeared good. There was little evidence of differences in total fat/weight for HSCT + TBI groups (compared to healthy controls/population norms/short stature controls). There was some evidence of significantly higher central adiposity and differences in adipose tissue function (compared to leukaemic/non-leukaemic controls). Muscle mass was significantly lower (compared to healthy/obese controls). Muscle function results were inconclusive but suggested impairment. Case reports confirmed a lipodystrophic phenotype. CONCLUSIONS Early remodelling of adipose tissue and loss of skeletal muscle are evident following HSCT + TBI for CTYA leukaemia, with extreme phenotype of overt lipodystrophy. There is some evidence for reduced muscle effectiveness. IMPLICATIONS FOR CANCER SURVIVORS Body composition changes in patients after HSCT + TBI are apparent by early adult life and link with the risk of excess cardiometabolic morbidity seen in adult survivors. Interventions to improve muscle and/or adipose function, perhaps utilizing nutritional manipulation and/or targeted activity, should be investigated.