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.
Testosterone deficiency in men surviving childhood acute leukemia after treatment with hematopoietic stem cell transplantation or testicular radiation: an L.E.A. study
Bone marrow transplantation. 2021
We included 255 patients from the L.E.A. French long-term follow-up cohort. All had received hematopoietic stem cell transplantation (HSCT) and/or testicular radiation for childhood acute leukemia and were older than 18 years at last L.E.A. evaluation. Total testosterone deficiency was defined as a <12 nmol/l level or by substitutive therapy, partial deficiency as normal testosterone with elevated luteinizing hormone (>10 UI/l). After myeloablative total body irradiation (n = 178), 55.6% had total deficiency, 15.7% partial deficiency, and 28.7% were normal. A 4-6 Gy testicular boost and a younger age at HSCT increased significantly the risk. After a Busulfan-containing myeloablative conditioning regimen (n = 53), 28.3% had total deficiency, 15.1% partial deficiency, 56.6% were normal (62.5% vs. 0% in patients without or with additional testicular radiation). A 24-Gy testicular radiation without HSCT induced total or partial deficiency in 71.4% and 28.6%, respectively (n = 21). Total testosterone deficiency increased the risk of metabolic syndrome: 25% vs. 12.1% in men with partial testosterone deficiency and 8.8% when Leydig cell function was normal (p = 0.031).
Occurrence of long-term effects after hematopoietic stem cell transplantation in children affected by acute leukemia receiving either busulfan or total body irradiation: results of an AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) retrospective study
Bone marrow transplantation. 2020
Patients given allogeneic hematopoietic stem cell transplantation (alloHSCT) present an increased incidence of long-term toxicities that can be attributed to the preparative regimen. We retrospectively analyzed in a population of 670 children receiving allo-HSCT for acute leukemia the occurrence of different late effects in function of the choice made between total body irradiation (TBI) and busulfan, as part of the preparative regimen. In univariable analysis, we found that patients treated with TBI developed cataract in 24% of the cases compared with 4% in patients treated with BU (p = 0.0001) and that the incidence of secondary malignant neoplasia (SMN) was higher in patients treated with TBI (18%) as compared with those prepared to the allograft with a Bu-based regimen (0%) (p = 0.019). Conditioning regimen did not show a statistically significant correlation with the occurrence of all the other investigated late effects. In multivariable analysis, TBI remained associated with the occurrence of cataracts (Relative Risk: 0.33 p = 0.012) and secondary malignancies (Relative Risk 3.96 x 10e-6 p < 0.001); however, other variables, as GvHD and disease type, were also correlated with these long-term sequels, indicating that in our study population the preparative regimen is not the only factor influencing the incidence of these complications.
Higher total body irradiation dose-intensity in fludarabine/TBI-based reduced-intensity conditioning regimen is associated with inferior survival in non-Hodgkin lymphoma patients undergoing allogeneic transplantation: Flu/2Gy TBI vs Flu/4Gy TBI in NHL
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
INTRODUCTION Disease relapse is the most common cause of therapy failure in non-Hodgkin lymphoma (NHL) patients undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT). It is not known whether or not increasing total body irradiation (TBI) dose from 2Gy to 4Gy in RIC-platform can provide improved disease control without increasing non-relapse mortality (NRM). Using the CIBMTR database we evaluated the outcomes of NHL patients receiving RIC alloHCT with either fludarabine (Flu)/2Gy TBI vs. Flu/4Gy TBI. METHODS In the CIBMTR registry, 413 adult NHL patients underwent a first alloHCT using either a matched related or unrelated donor between 2008-2017, utilizing a RIC regimen with either Flu/2Gy TBI (n=349) or Flu/4Gy TBI (n=64). The primary endpoint was overall survival (OS). Secondary endpoints included acute (a) and chronic (c) graft-versus-host disease (GVHD), NRM, relapse/progression and progression-free survival (PFS). RESULTS At baseline the Flu/2Gy TBI cohort had significantly fewer patients with KPS ≥90 and significantly more patients had a higher HCT-CI. On multivariate analysis the two conditioning cohorts were not significantly different in terms of risk of grade 3-4 aGVHD or cGVHD. Compared to Flu/2Gy TBI, the Flu/4Gy TBI conditioning was associated with a significantly higher risk of NRM (HR 1.79, 95%CI=1.11-2.89, p=0.02), and inferior OS (HR 1.51, 95%CI=1.03-2.23, p=0.03). No significant differences were seen in the risk of relapse/progression (HR 0.78, 95%CI=0.47-1.29, p=0.33) or PFS (HR 1.09, 95%CI=0.78-1.54, p=0.61) between the two regimens. Comparing Flu/2Gy TBI vs. Flu/4Gy TBI cohorts the 5-year adjusted outcomes were; NRM (28% vs. 47%; p=0.005), relapse/progression (35% vs. 29%; p=0.28), PFS (37% vs. 24%; p=0.03) and OS (51% vs. 31%; p=0.001), respectively. Relapse was the most common cause of death in both cohorts. CONCLUSIONS In NHL patients undergoing Flu/TBI-based conditioning, augmenting TBI dose from 2Gy to 4Gy is associated with higher NRM and inferior OS, without any significant benefit in terms of disease control. 2Gy is optimal dose in the RIC Flu/TBI platform for lymphomas.
Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study
Bone marrow transplantation. 2020
Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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.
Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;:Jco2002529
PURPOSE Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients = 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). RESULTS Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
What is known?
Allogeneic haematopoietic stem cell transplantation (HSCT) provides a potential curative treatment option for paediatric patients with high risk acute lymphoblastic leukaemia (ALL). Pre-transplant conditioning regimes with total body irradiation (TBI) have resulted in encouraging overall and relapse-free survival but may cause serious long-term side effects. As a result, several studies have investigated TBI-free regimes. A large meta-analysis (1) which included seven randomised controlled trials comparing TBI-based with chemoconditioning regimes demonstrated significantly lower treatment related mortality (TRM) but no overall survival (OS) advantage with TBI-based regimes. A further small randomised study (2) found significantly higher event-free survival (EFS) with TBI-based regimes in patients with unrelated donors, but a non-significant difference only in patients with matched sibling donors. Concerns about late effects of TBI on growth, cognitive function and secondary malignancy however remain. A single centre retrospective study (3) in paediatric ALL concluded that triosulphan based regimes were safe and efficacious while a similar review (4) in adult patients suggested that busulphan and clofarabine could provide an alternative to TBI. This paper reports on the FORUM study. It compares TBI with chemoconditioning regimes to investigate whether optimal chemoconditioning regimens could replace TBI in paediatric patients with high-risk ALL.
What did this paper set out to examine?
This is the largest randomised, controlled, open-label, international, multicentre, phase III trial comparing TBI plus etoposide with chemoconditioning (fludarabine, thiotepa and busulfan or triosulfan) in paediatric ALL to date. It investigates whether chemoconditioning is non-inferior to TBI-based regimes with the primary endpoint of OS. It is also the first study to directly and prospectively compare these regimes in terms of disease-free survival and short- and long-term adverse events. The study aimed to recruit 1000 patients.
What did they show?
Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. Patients ≤18 years old at diagnosis and aged 4-21 at HSCT with high risk ALL in complete morphological remission with HLA compatible related or unrelated donor were included in the study. Patients were randomised 1:1 to 12Gy TBI with etoposide versus fludarabine, thiotepa and busulfan or triosulphan conditioning. Patients were well matched for baseline characteristics and demographics. Randomisation was stopped early due significant inferiority of chemoconditioning compared with TBI-based regime.
Following randomisation of 417 patients, a futility stopping rule was applied because patients receiving chemoconditioning with fludarabine, thiotepa, and busulfan or treosulfan had inferior OS to those receiving TBI plus etoposide. Two-year OS was 0.91 (95% CI, P <.0001) following TBI versus 0.75 (95% CI) following chemoconditioning. Median follow up was 2.1 years. Relapse was the commonest reason for treatment failure and out of 67 patients who relapsed, there was no difference in OS between conditioning regimes. There was no difference in serious adverse events or GvHD rates between the groups.
What are the implications for practice and for future work?
While TBI is associated with potentially serious long-term side effects, this study supports growing evidence demonstrating improved outcomes for patients undergoing TBI-based conditioning. Here patients receiving TBI-based conditioning had a significantly lower risk of relapse and TRM than those given chemoconditioning.
Of note, TRM in this trial was low compared to previously reported studies. FOCUS reported a 2-year OS and EFS rate of 0.91 and 0.91 respectively, which is the lowest documented TRM in HSCT for high-risk paediatric ALL to date. Additionally, other risk factors thought to impact on outcomes (e.g. leukaemia phenotype, MRD pre-transplant, donor type, etc) were not found to be significant in FOCUS. Only remission status (CR1 vs CR2) and conditioning regime influenced OS and EFS. This may be in part explained by the strong attempts within this study to reduce MRD prior to HSCT in all patients.
This was a noninferiority study which required a sample size of 1000 patients with 2-year minimum follow-up to make analysis of primary outcomes feasible. As the majority of relapses in paediatric ALL occur in the first 24 months, it is unlikely that longer follow up would result in dramatic changes to outcomes.
Non-randomised recruitment in FORUM to assess long-term side effects of TBI, such as secondary malignancy, in FORUM is ongoing. However, no difference in adverse events or incidence of GvHD was found between study groups. The study reports a composite end point of 2-year GVHD-free, relapse-free survival of 72% (95% CI) following TBI plus etoposide and 51% (95% CI, p= .0003) following chemoconditioning which might be a benchmark for future investigations.
Patients diagnosed with acute lymphoblastic leukaemia at or before 18 years of age, who underwent HSCT aged 4-21 years (n=413)
TBI conditioning (n=212)
Chemoconditioning: fludarabine, thiotepa, and either busulfan or treosulfan (n=201)
The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91) versus chemoconditioning (0.75). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 and 0.02 following TBI and 0.33 and 0.09 following chemoconditioning, respectively.
Total body irradiation + fludarabine compared to busulfan + fludarabine as "reduced-toxicity conditioning" for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation in first complete remission: a study by the Acute Leukemia Working Party of the EBMT
Bone marrow transplantation. 2020
The optimal conditioning for patients with acute myeloid leukemia in first complete remission treated with allogeneic hematopoietic cell transplantation (allo-HCT) has not been defined so far. In this retrospective study, we compared two "reduced-toxicity" regimens: intravenous busulfan at a total dose of 9.6?mg/kg (3 days)?+?fludarabine (Bu3/Flu) and total body irradiation at a dose of 8?Gy?+?fludarabine (TBI8Gy/Flu). In the entire study cohort (n?=?518), the probabilities of overall survival (OS), leukemia-free survival (LFS), relapse and non-relapse mortality (NRM) at 2 years for Bu3/Flu and TBI8Gy/Flu were 62% vs. 72.5% (p?=?0.051), 59.5% vs. 65% (p?=?0.15), 30% vs. 20% (p?=?0.01), and 10% vs. 14% (p?=?0.18), respectively. In multivariate model for patients <50 years old, TBI8Gy/Flu was associated with improved LFS (hazard ratio (HR)?=?0.5, p?=?0.04), OS (HR?=?0.31, p?=?0.004), and survival free from both graft-versus-host disease and relapse (HR?=?0.55, p?=?0.03), as well as tendency to reduced risk of relapse (HR?=?0.53, p?=?0.08). Among patients aged 50 years or older the use of TBI8Gy/Flu was associated with increased incidence of NRM (HR?=?3.9, p?=?0.0009), with no significant impact on other outcome measures. We conclude that the use of TBI8Gy/Flu as "reduced-toxicity" regimen may be advised in younger patients with AML referred for allo-HCT.
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.