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Effect of pediatric- versus adult-type chemotherapy regimens on outcomes of allogeneic hematopoietic stem cell transplants for adult T-cell acute lymphoblastic leukemia in first complete remission
Qi, H. Z., Xu, J., Yang, Q. Q., Lin, R., Wang, Z. X., Zhao, K., Wang, Q., Zhou, X., Fan, Z. P., Huang, F., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
The optimal chemotherapy regimen pre-transplantation for adult T-cell acute lymphoblastic leukemia (T-ALL) patients remains unknown. Here, we compared the transplant outcomes in 127 subjects receiving pediatric- (N = 57) or adult-type (N = 70) regimens pre-transplant. The corresponding 3-year cumulative incidences of relapse (CIR) was 7% (95% CI: 3-11%) and 29% (95% CI: 23-35%; P = 0.02), leukemia-free survivals (LFS) was 86% (95% CI: 81-91%) and 57% (95% CI: 51-63%; P = 0.003), overall survivals (OS) was 88% (95% CI: 84-92%) and 58% (95% CI: 52-64%; P = 0.002), the 1-year NRM was 4% (95% CI: 1-7%) and 9% (95% CI: 4-14%; P = 0.40). Multivariate analysis showed that pediatric-type regimen was associated with lower CIR (Hazard Ratio [HR] = 0.31 [95% CI: 0.09-1.00]; P = 0.05), better LFS (HR = 0.34 [95% CI: 0.15-0.78]; P = 0.01) and OS (HR = 0.30 [95% CI: 0.13-0.72]; P = 0.01). Our results suggested that adult T-ALL patients undergoing allo-HSCT might benefit from pediatric-type chemotherapy.
PICO Summary
Population
Adults with T-cell acute lymphoblastic leukaemia in first complete remission (n=127)
Intervention
Paediatric-type chemotherapy regimen prior to transplant (n=57)
Comparison
Adult-type chemotherapy regimen prior to transplant (n=70)
Outcome
The corresponding 3-year cumulative incidences of relapse (CIR) was 7% (95% CI: 3-11%) and 29% (95% CI: 23-35%) for paediatric-type chemotherapy and adult-type chemotherapy respectively, leukemia-free survivals (LFS) was 86% (95% CI: 81-91%) and 57% (95% CI: 51-63%), overall survivals (OS) was 88% (95% CI: 84-92%) and 58% (95% CI: 52-64%; 02), the 1-year NRM was 4% (95% CI: 1-7%) and 9% (95% CI: 4-14%). Multivariate analysis showed that pediatric-type regimen was associated with lower CIR (Hazard Ratio [HR] = 0.31 [95% CI: 0.09-1.00];), better LFS (HR = 0.34 [95% CI: 0.15-0.78) and OS (HR = 0.30 [95% CI: 0.13-0.72]).
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Total body irradiation plus fludarabine versus thiotepa, busulfan plus fludarabine as a myeloablative conditioning for adults with acute lymphoblastic leukemia treated with haploidentical hematopoietic cell transplantation. A study by the Acute Leukemia Working Party of the EBMT
Swoboda, R., Labopin, M., Giebel, S., Angelucci, E., Arat, M., Aljurf, M., Sica, S., Pavlu, J., Socié, G., Bernasconi, P., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Optimal conditioning for adults with acute lymphoblastic leukemia (ALL) treated with haploidentical hematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide has not been established so far. We retrospectively compared outcomes for two myeloablative regimens: fludarabine + total body irradiation (Flu-TBI, n = 117) and thiotepa + iv. busulfan + fludarabine (TBF, n = 119). Patients transplanted either in complete remission (CR) or with active disease were included in the analysis. The characteristics of both groups were comparable except for patients treated with TBF were older. In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%, p = 0.03). There was a tendency towards reduced incidence of relapse after TBF (p = 0.11). Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49, p = 0.03). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34, p = 0.009) but an increased risk of relapse (HR = 2.59, p = 0.01) without significant effect on survival and graft-versus-host disease. We conclude that for haplo-HCT recipients with ALL, Flu-TBI may be preferable for individuals at high risk of NRM while TBF should be considered in cases at high risk of relapse.
PICO Summary
Population
Adults with acute lymphoblastic leukemia (ALL) treated with haploidentical (n=haematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide (n=236)
Intervention
Fludarabine + total body irradiation conditioning (Flu-TBI, n=117)
Comparison
Thiotepa + iv. busulfan + fludarabine conditioning (TBF, n=119)
Outcome
In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%). There was a tendency towards reduced incidence of relapse after TBF. Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34) but an increased risk of relapse (HR = 2.59) without significant effect on survival and graft-versus-host disease.
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Thiotepa, busulfan and fludarabine conditioning-regimen is a promising approach for older adult patients with acute lymphoblastic leukemia treated with allogeneic stem cell transplantation
Banet, A., Bazarbachi, A., Labopin, M., Stocker, N., Duléry, R., Malard, F., Van de Wyngaert, Z., Genthon, A., Memoli, M., Legrand, O., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
For acute lymphoblastic leukemia (ALL) patients, total body irradiation (TBI)- based conditioning regimens are the first choice specially in young population. However, several studies have shown an equivalence in clinical outcomes with thiotepa-based conditioning regimen. We performed a retrospective study to evaluate the outcome of adult ALL patients who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with a thiotepa-busulfan-fludarabine (TBF) myeloablative conditioning regimen with reduced toxicity. Fifty-five patients received a TBF regimen. The median age of the patients was 51 years (range, 17 to 72.4). Most patients had a diagnosis of B-ALL (93%) with 7% having T-ALL. Two - and 5-year overall survival was 73.2% and 64%, respectively. At 2 years, leukemia-free survival and GVHD-free, relapse-free survival were 59.5% and 57.6%, and at 5 years, 53.4% and 51.8%, respectively. The 5-year non-relapse mortality was 15%. The day 180 cumulative incidence (CI) of grade II-IV acute GVHD and grade III-IV acute GVHD were 38.2% and 5.5%, respectively. At 2 years, the CI of chronic GVHD and extensive chronic GVHD was 16.9% and 1.9%, respectively. Our study results do suggest that using TBF as the conditioning regimen in adult ALL patients is a promising option with acceptable toxicity.
PICO Summary
Population
Adults with acute lymphoblastic leukaemia receiving allogeneic stem cell transplantation in centres in France and Lebanon (n=55)
Intervention
Thiotepa-busulfan-fludarabine (TBF) myeloablative conditioning regimen (n=55)
Comparison
None
Outcome
Two - and 5-year overall survival was 73.2% and 64%, respectively. At 2 years, leukemia-free survival and GVHD-free, relapse-free survival were 59.5% and 57.6%, and at 5 years, 53.4% and 51.8%, respectively. The 5-year non-relapse mortality was 15%. The day 180 cumulative incidence (CI) of grade II-IV acute GVHD and grade III-IV acute GVHD were 38.2% and 5.5%, respectively. At 2 years, the CI of chronic GVHD and extensive chronic GVHD was 16.9% and 1.9%, respectively.
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Allogeneic transplant compared to pediatric-inspired therapy for Philadelphia chromosome-negative adolescent and adult ALL in first complete remission
Haroon, A., Alfraih, F., Hanbali, A., Kotb, A., Somali, Z. A., Bahkali, F. N., Alhayli, S., Madien, H. M., Ahmed, S. O., Albabtain, A. A., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
BACKGROUND Pediatric-inspired non-transplant regimens for adolescent and adult ALL patients are becoming standard in many institutions. We aimed to compare a cohort of patients receiving a pediatric-inspired protocol to a cohort of patients treated with adult type ALL therapy followed by allografting after achieving CR1. METHOD Eighty-five adolescent and adult ALL patients treated with CALGB 19802 protocol who received MSD transplant in CR1 were retrospectively compared to a matched cohort of 72 adolescent and adult ALL patients treated with a modified version of Children's Cancer Group (CCG) 1900 protocol. RESULTS The five years OS in the allo-HCT cohort was 63.1% compared to 80.2% in the pediatric-inspired chemotherapy arm (P = 0.03). The five years EFS in the allo-HCT arm was 58.8% compared to 61.6% in the pediatric-inspired chemotherapy arm (P = 0.07). The five years DFS in the allo-HCT arm was 58.8% as compared to 71.9% in the pediatric-inspired chemotherapy arm (P = 0.07). The relapse rate in the allo-HCT cohort was 30.58% compared to 21.68% in the pediatric-inspired chemotherapy arm (P = 0.16). The NRM in the allo-HCT cohort was 10.59 as compared to 6.45 in the pediatric-inspired chemotherapy arm (P = 0.3). CONCLUSION For adolescent and adult patients with Ph-negative ALL, pediatric-inspired chemotherapy resulted in higher OS compared to allo-HCT.
PICO Summary
Population
Adult and adolescent patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia at a single centre in Saudia Arabia (n=157)
Intervention
CALGB 19802 protocol with matched sibling donor transplant in first complete remission (allo-HCT, n=85)
Comparison
Modified version of Children's Cancer Group (CCG) 1900 protocol (pediatric-inspired chemotherapy, n=72)
Outcome
The five year overall survival in the allo-HCT cohort was 63.1% compared to 80.2% in the pediatric-inspired chemotherapy arm. The five year event free survival in the allo-HCT arm was 58.8% compared to 61.6% in the pediatric-inspired chemotherapy arm. The five years disease free survival in the allo-HCT arm was 58.8% as compared to 71.9% in the pediatric-inspired chemotherapy arm. The relapse rate in the allo-HCT cohort was 30.58% compared to 21.68% in the pediatric-inspired chemotherapy arm. The non-relapse mortality in the allo-HCT cohort was 10.59 as compared to 6.45 in the pediatric-inspired chemotherapy arm.
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Busulfan Plus Cyclophosphamide Versus Total Body Irradiation Plus Cyclophosphamide for Adults Acute B Lymphoblastic Leukemia: An Open-Label, Multicenter, Phase III Trial
Zhang, H., Fan, Z., Huang, F., Han, L., Xu, Y., Xu, N., Deng, L., Wang, S., Lin, D., Luo, X., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;:Jco2200767
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Editor's Choice
Abstract
PURPOSE It remains controversial whether busulfan-based versus total body irradiation (TBI)-based regimens have comparable outcomes in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). We investigated the efficacy and toxicity of busulfan plus cyclophosphamide (BuCy) and TBI plus cyclophosphamide (TBI-Cy) conditioning in allo-HSCT for adult standard-risk B-cell-ALL in first complete remission (CR1). PATIENTS AND METHODS We performed an open-label, randomized phase III trial at 13 hospitals in China. Eligible patients (age 14-65 years) had standard-risk ALL in CR1. Patients were randomly assigned (1:1) to BuCy (0.8 mg/kg four times per day on days -7 to -4 and cyclophosphamide 60 mg/kg once daily on days -3 to -2) or TBI-Cy (4.5 Gy TBI on days -5 to -4 and cyclophosphamide 60 mg/kg once daily on days -3 to -2). The primary end point was 2-year overall survival. Analysis was per protocol. This trial is registered with ClinicalTrials.gov (identifier: NCT02670252) and is complete. RESULTS Between January 2016 and February 2020, 275 patients were assigned to receive BuCy (273 assessed) and 275 to TBI-Cy (272 assessed). The 2-year overall survival was 76.6% (95% CI, 71.7 to 81.8) and 79.4% (74.7 to 84.4; P = .457; difference 2.9%; 95% CI, -4.1 to 9.8; P = .022), indicating noninferiority of BuCy. The 2-year relapse was 20.2% (95% CI, 15.6 to 25.1) and 18.4% (14.0 to 23.2; P = .616), and the nonrelapse mortality was 11.0% (95% CI, 7.6 to 15.0) and 11.0% (7.7 to 15.1; P = .988) in the BuCy and TBI-Cy groups, respectively. There were no differences in regimen-related toxicity, graft-versus-host disease, or late effects between the two groups. CONCLUSION The BuCy regimen has noninferior efficiency and safety as TBI-Cy (4.5 Gy × 2) for patients with adult standard-risk B cell-ALL in CR1 undergoing HLA-matched allo-HSCT.
PICO Summary
Population
People aged 14-65 years with standard-risk acute lymphoblastic leukaemia (ALL) in CR1, from 13 hospitals in China, enrolled in a randomised controlled trial (n=)
Intervention
Busulfan plus cyclophosphamide 0.8 mg/kg four times per day on days -7 to -4 and cyclophosphamide 60 mg/kg once daily on days -3 to -2 (BuCy, n=275)
Comparison
Total body irradiation (TBI) plus cyclophosphamide 4.5 Gy TBI on days -5 to -4 and cyclophosphamide 60 mg/kg once daily on days -3 to -2 (TBI-Cy, n=275)
Outcome
The 2-year overall survival was 76.6% (95% CI, 71.7 to 81.8) in the BuCy group and 79.4% (74.7 to 84.4; difference 2.9%; 95% CI, -4.1 to 9.8;) in the TBI-Cy group, indicating noninferiority of BuCy. The 2-year relapse was 20.2% (95% CI, 15.6 to 25.1) and 18.4% (14.0 to 23.2), and the nonrelapse mortality was 11.0% (95% CI, 7.6 to 15.0) and 11.0% (7.7 to 15.1) in the BuCy and TBI-Cy groups, respectively. There were no differences in regimen-related toxicity, graft-versus-host disease, or late effects between the two groups.
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Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study
Peters, C., Dalle, J. H., Locatelli, F., Poetschger, U., Sedlacek, P., Buechner, J., Shaw, P. J., Staciuk, R., Ifversen, M., Pichler, H., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;:Jco2002529
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Editor's Choice
Abstract
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.
Clinical Commentary
Dr. Julia Wolf, University Hospitals Bristol and Weston NHS Foundation Trust
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.
Results
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.
PICO Summary
Population
Patients diagnosed with acute lymphoblastic leukaemia at or before 18 years of age, who underwent HSCT aged 4-21 years (n=413)
Intervention
TBI conditioning (n=212)
Comparison
Chemoconditioning: fludarabine, thiotepa, and either busulfan or treosulfan (n=201)
Outcome
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.
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Higher Reported Lung Dose Received during Total Body Irradiation for Allogeneic Hematopoietic Stem Cell Transplantation in Children with Acute Lymphoblastic Leukemia is Associated with Inferior Survival: A Report from the Children's Oncology Group
Esiashvili, N., Lu, X., Ulin, K., Laurie, F., Kessel, S., Kalapurakal, J. A., Merchant, T. E., Followill, D. S., Sathiaseelan, V., Schmitter, M. K., et al
International journal of radiation oncology, biology, physics. 2019
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Editor's Choice
Abstract
PURPOSE To examine the relationship between lung radiation dose and survival outcomes in children undergoing total body irradiation (TBI)-based hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL) on Children's Oncology Group (COG) trial. PATIENTS AND METHODS TBI (1200 or 1320 cGy given twice daily in 6 or 8 fractions) was used as part of 3 HSCT preparative regimens; allowing institutional flexibility regarding TBI techniques, including lung shielding. Lung doses as reported by each participating institution were calculated for different patient setups, with and without shielding, with a variety of dose calculation techniques. The association between lung dose and transplant-related mortality (TRM), relapse-free (RFS) and overall-survival (OS) was examined using Cox proportional hazard regression model controlling for the following variables: TBI dose rate, TBI fields, patient position during TBI, donor type, and pre-HSCT minimal residual disease (MRD) level. RESULTS From a total of 143 eligible patients127 had lung doses available for this analysis. The TBI techniques were heterogeneous. The mean lung dose was reported as 904.5cGy (SD +/-232.3). Patients treated with lateral fields were more likely to receive lung doses ≥800cGy (p<0.001). Lung dose ≥800cGy influence on TRM was not significant (HR 1.78; p=0.21). On univariate analysis, lung dose ≥800cGy was associated with inferior RFS (HR 1.76; p=0.04) and OS (HR 1.85; p=0.03); in the multivariate analysis, OS maintained statistical significance (HR 1.85; p=0.04). CONCLUSION The variability in TBI techniques result in an uncertainty with reported lung doses. Lateral fields were associated with higher lung dose, hence better be avoided. Patients treated with lung dose <800 cGy in this study had better outcome. This approach is currently been investigated in COG AALL1331 study. Additionally, the Imaging and Radiation Oncology Core (IROC) Group is evaluating effects of TBI techniques on lung doses using a phantom.
PICO Summary
Population
Children with acute lymphoblastic leukaemia undergoing allogeneic stem cell transplantation (n=143)
Intervention
TBI (1200 or 1320 cGy given twice daily in 6 or 8 fractions), given with or without shielding, using heterogeneous TBI techniques.
Comparison
Lung doses as reported by each participating institution were calculated for different patient setups.
Outcome
The mean lung dose was reported as 904.5cGy. Patients treated with lateral fields were more likely to receive lung doses >/=800cGy. Lung dose >/=800cGy influence on TRM was not significant. On univariate analysis, lung dose >/=800cGy was associated with inferior RFS and OS; in the multivariate analysis, OS maintained statistical significance. The variability in TBI techniques resulted in an uncertainty with reported lung doses. Patients treated with lung dose <800 cGy had better outcome.
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Outcomes of allogeneic stem cell transplantation after inotuzumab ozogamicin treatment for relapsed or refractory acute lymphoblastic leukemia
Marks, D. I., Kebriaei, P., Stelljes, M., Gokbuget, N., Kantarjian, H., Advani, A. S., Merchant, A., Stock, W., Cassaday, R. D., Wang, T., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
BACKGROUND Attaining complete remission of acute lymphoblastic leukemia (ALL) before hematopoietic stem cell transplantation (HSCT) correlates with better post-transplant outcomes. Inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, has shown significantly higher rates of remission, minimal residual disease negativity, and HSCT versus standard chemotherapy in treating relapsed/refractory (R/R) ALL. We investigated the role of previous transplant, and proceeding directly to HSCT after remission, as factors in determining post-transplant survival in the setting of InO treatment for R/R ALL. METHODS The analyzed population comprised InO-treated patients who proceeded to allogeneic HSCT in two clinical trials (phase 1/2: NCT01363297 and phase 3: NCT01564784). Overall survival (OS) was defined as time from HSCT to death (any cause). RESULTS Of 236 InO-treated patients, 101 (43%) proceeded to allogeneic HSCT and were included in this analysis. Most received InO as first salvage (62%); 85% had no previous HSCT. Median (95% CI) post-transplant OS was 9.2 months (5.1, not estimable) with 2-year survival probability (95% CI) of 41% (32-51%). In first-HSCT patients (n=86), median (95% CI) post-transplant OS was 11.8 months (5.9, not estimable) with 2-year survival probability (95% CI) of 46% (35-56%); some patients relapsed and needed additional treatment before HSCT (n=28). Those who went directly to first HSCT upon remission with no additional salvage/induction treatment (n=73) fared best: median post-transplant OS was not reached with 2-year survival probability (95% CI) of 51% (39-62%). CONCLUSION In patients with R/R ALL, InO followed by allogeneic HSCT provided optimal long-term survival benefit among those with no previous HSCT who went directly to transplant after remission.
PICO Summary
Population
Patients with relapsed/refractory acute lymphoblastic leukaemia, participating in one of two clinical trials (n=101)
Intervention
Inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, and then proceeding to allogeneic transplantation.
Comparison
None
Outcome
Median post-transplant OS was 9.2 months with 2-year survival probability of 41%. In first-HSCT patients (n=86), median post-transplant OS was 11.8 months with 2-year survival probability of 46%; some patients relapsed and needed additional treatment before HSCT (n=28). Those who went directly to first HSCT upon remission with no additional salvage/induction treatment (n=73) fared best: median post-transplant OS was not reached with 2-year survival probability of 51%