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.
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.
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.
Comparison of Different Conditioning Regimens in Allogeneic Hematopoietic Stem-Cell Transplantation Shows Superiority of Total Body Irradiation-Based Regimen for Younger Patients With Acute Leukemia: A Nationwide Study
Clinical lymphoma, myeloma & leukemia. 2019
BACKGROUND The optimal the conditioning regimens for allogeneic hematopoietic stem-cell transplantation, especially for East Asian patients, remains unknown. PATIENTS AND METHODS We collected and analyzed clinical and survival data of 4255 patients from the Korean National Health Insurance Claims Database. RESULTS Between 1562 myeloablative conditioning and 2693 nonmyeloablative conditioning groups, the overall survival was not statistically different. However, in the myeloablative conditioning group, the overall survival of the total body irradiation-based regimen was better than that of chemotherapy-alone regimen (P = .005). In subgroup analysis, the superiority of the total body irradiation-based regimen was especially prominent in acute leukemia (P = .012 for acute myeloid leukemia; P = .005 for acute lymphoblastic leukemia) and for younger patients (< 50 years old vs. ≥ 50 years old, P = .015). CONCLUSION Total body irradiation combination might be the best conditioning regimen for young patients undergoing hematopoietic stem-cell transplantation for acute leukemias in Korea.
Total Body Irradiation and Risk of Diabetes Mellitus; A Meta-Analysis
Asian Pacific journal of cancer prevention : APJCP. 2019;20(3):885-891
Objective: Hematopoietic stem cell transplant (HSCT) has recently emerged as a cure for previously "incurable" diseases and is being explored and attempted in many other fields including congenital and acquired non-malignant diseases. However, the long-term side effect associated with HSCT especially Total Body Irradiation (TBI) is still understudied. Therefore, we attempted to establish association between TBI and risk of developing Diabetes Mellitus (DM) or impaired glucose metabolism (IGM). Methods: We searched for titles of articles in MEDLINE (PubMed), EMBASE, and Cochrane library in August 2018 that evaluated the association between TBI in the setting of HSCT and DM or IGM. We conducted a random effect meta-analysis of 11 studies involving a total of 13,191 participants and reported the pooled MD (mean difference) for the development of DM/IGM after TBI as part of the conditioning regimen for HSCT. Results: We found a significant increase in the risk of developing DM/IGM after TBI is used as part of the conditioning regimen compared to other types of conditioning regimen with the pooled MD being 5.42, 95% Confidence Interval (CI) 2.51-11.71, I2=92.4%. Conclusion: TBI as a conditioning regimen in the setting of HSCT significantly increases the risk of developing DM/IGM. Therefore, we recommend close monitoring and screening for diabetes mellitus in patients who underwent TBI before HSCT.
Splenic irradiation before allogeneic stem cell transplantation for myelofibrosis
Medical oncology (Northwood, London, England). 2019;36(2):16
Splenectomy before allogeneic stem cell transplantation (ASCT) for patients with myelofibrosis (MF) remains a matter of debate, and conflicting results have been reported to date. The procedure seems to fasten post-transplant hematological recovery, but it does not have an impact on survival. The role of pre-transplant splenic irradiation (SI) is much more difficult to evaluate. Forty-four patients (25 males and 19 females) with MF at median age of 49 years at diagnosis (range 14-67) underwent ASCT. The post-transplant outcome was compared between irradiated and non-irradiated patients. Eleven patients received irradiation before transplantation. Median dose of radiation was 1000 cGy (range 600-2400). There was no difference in median time to engraftment between patients with and without previous radiotherapy. Acute and chronic graft versus host disease (GVHD) occurred in 47% and 36% of patients, respectively. There was no difference in GVHD incidence between groups. Eight patients relapsed/progressed in irradiated group versus 17 in non-irradiated (70% vs. 51%; p = 0.3). Transformation to acute myeloid leukemia was observed in 3 patients: 2 in irradiated and 1 in non-irradiated group. In total, 22 patients died with no statistical difference in death rate between irradiated and non-irradiated subjects. The probability of overall survival after transplant for the entire cohort at 2 years was 54% (72% for irradiated and 48% for non-irradiated patients; p = 0.25). Splenic irradiation prior to ASCT for myelofibrosis has not beneficial effect on post-transplant outcome.
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
Clinical lymphoma, myeloma & leukemia. 2019
INTRODUCTION Allogeneic 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 METHODS We 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. RESULTS The 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. CONCLUSION Our 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.
Fludarabine and Total Body Irradiation Conditioning Prior to Ablative Haploidentical Transplantation: Long-term Safety and Efficacy
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Although myeloablative conditioning (MAC) prior to haploidentical donor transplant (HIDT) with post-transplant cyclophosphamide is beig increasingly utilized, the optimal preparative regimen remains unclear. In our initial trial, the feasibility of HIDT following a MAC preparative regimen using fludarabine and 12Gy of total body irradiation was demonstrated in 30 patients. We now present long-term outcome results including an additional 52 patients, now with 47 months (16-96) median follow-up. Median patient age was 42 (19-61) years. The most common diagnoses were AML (51%) and ALL (33%), and 39% were high/very high disease risk index (DRI). Engraftment was universal with no cases of primary or secondary graft failure. Grade 3-4 acute graft-versus-host disease (GVHD) and moderate-to-severe chronic GVHD occurred in 17% and 23%, respectively. Non-relapse mortality (NRM) was 7% at 1 year and 13% at 4 years. Estimated 4-yr OS, DFS and cumulative incidence of relapse (CIR) was 67%, 60% and 27% respectively. CIR was significantly higher in patients with high/very high vs. low/intermediate risk DRI (38% vs. 20%, p=0.032), which led to inferior 4-yr OS (50% vs. 77%, p=0.001). Median time to systemic immunosuppressive therapy (IST) discontinuation was 7.8 months, with 84% of patients off IST at 2 years post-transplant. Current GHVD-, relapse-free survival (CGRFS) at 2, 3, and 4 years was 60%, 57% and 60% respectively. This approach to MAC HIDT results in universal engraftment, low rates of NRM, infection and clinically significant GVHD, relatively rapid IST discontinuation resulting in high rates of CGRFS and survival.
Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation
We examined the impact of total body irradiation (TBI) dose and fractionation on risk of subsequent malignant neoplasms (SMN) in the era of reduced intensity and non-myeloablative conditioning regimens for hematopoietic cell transplantation (HCT). Among 4,905 one-year survivors of allogeneic HCT for hematologic malignancies (N=4,500) or non-malignant disorders (N=405) transplanted between 1969-2014 we identified 581 SMNs (excluding squamous and basal cell of skin) in 499 individuals. With a median length of follow-up of 12.5 years, the cumulative incidence of SMN by 30 years after HCT was 22.0%. Compared to age, sex and calendar year matched SEER population rates, the standardized incidence ratio (SIR) of SMNs was increased 2.8-fold. The highest SIRs were for SMNs of bones (SIR 28.8), oral cavity (SIR 13.8), skin (SIR 7.3), central nervous system (SIR 6.0), and endocrine organs (SIR 4.9). The highest excess absolute risks (EAR) were seen with breast cancer (EAR 2.2) and cancers of the oral cavity (EAR 1.5) and skin (EAR 1.5) per 1000 person-years. The highest incidence of SMNs was in survivors exposed to unfractionated (600-1,00 cGy) or high dose fractionated (1,440-1,750 cGy) TBI. For patients receiving low-dose TBI, the incidence was comparable to myeloablative chemotherapy alone, although still 2-fold higher than in the general population. These data demonstrate a strong effect of TBI dose, and dose fractionation, and risk of SMNs after HCT. The cumulative incidence of SMN increases with follow-up time, thus HCT survivors require lifetime monitoring for early detection and effective therapy of SMNs.
National survey on total-body irradiation prior to reduced-intensity stem cell transplantation in Japan: The Japanese Radiation Oncology Study Group
Journal of radiation research. 2019
Reduced-intensity stem cell transplantation (RIST) minimizes the adverse effects of traditional hematopoietic stem cell transplantation, and low-dose total-body irradiation (TBI) is administered over a short period prior to RIST (TBI-RIST). Different institutes adopt different approaches for the administration of TBI-RIST, and since no study had previously investigated this issue, a survey of the TBI schedules in Japan was conducted. In October 2015, the Japanese Radiation Oncology Study Group initiated a national survey of TBI-RIST procedures conducted between 2010 and 2014. Of 186 institutions performing TBI, 90 (48%) responded to the survey, 78 of which performed TBI-RIST. Of 2488 patients who underwent TBI for malignant disease at these institutions, 1412 (56.8%) patients were treated for leukemia, 477 (19.2%) for malignant lymphoma, 453 (18.2) for myelodysplastic syndrome, 44 (1.8%) for multiple myeloma, and 102 (4.1%) for other malignant diseases. Further, 206 (52.0%) of 396 patients (a high proportion of patients) who underwent TBI for benign disease had aplastic anemia. The TBI-RIST equipment and treatment methods were similar to those used for myeloablative regimens. Routinely shielded organs included the lungs (43.6%), eyes (50.0%) and kidneys (10.2%). The ovaries (14.1%), thyroid (6.4%) and testicles (16.7%) were also frequently shielded, possibly reflecting an emphasis on shielding reproductive organs in children. TBI-RIST was performed more frequently than myeloablative conditioning in patients with benign disease. Genital and thyroid shielding were applied more frequently in patients treated with TBI-RIST than in patients treated with myeloablative conditioning. In conclusion, this study indicates the status of TBI-RIST in Japan and can assist future efforts to standardize TBI-RIST treatment methods and to design a future multicenter collaborative research study.