Hematopoietic cell transplant in pediatric acute myeloid leukemia after similar upfront therapy; a comparison of conditioning regimens
Bone marrow transplantation. 2021
The impact of conditioning regimen prior to hematopoietic cell transplant (HCT) in pediatric AML-patients is not well studied. We retrospectively analyzed the impact of Busulfan-Cyclophosphamide (BuCy), Busulfan-Cyclophosphamide-Melphalan (BuCyMel) and Clofarabine-Fludarabine-Busulfan (CloFluBu) in pediatric AML-patients, with similar upfront leukemia treatment (NOPHO-DBHconsortium), receiving an HCT between 2010 and 2015. Outcomes of interest were LFS, relapse, TRM and GvHD. 103 patients were included; 30 received BuCy, 37 BuCyMel, and 36 CloFluBu. The 5-years LFS was 43.3% (SE?±?9.0) in the BuCy group, 59.2 % (SE?±?8.1) after BuCyMel, and 66.7 % (SE?±?7.9) after CloFluBu. Multivariable Cox regression analysis showed a trend to lower LFS after BuCy compared to CloFluBu (p?=?0.07). BuCy was associated with a higher relapse incidence compared to the other regimens (p?=?0.06). Younger age was a predictor for relapse (p?=?0.02). A strong correlation between Busulfan Therapeutic Drug Monitoring (TDM) and lower incidence of aGvHD (p?0.001) was found. In conclusion, LFS after BuCyMel and CloFluBu was comparable, lower LFS was found after BuCy, due to higher relapse incidence. CloFluBu was associated with lower incidence of aGvHD, suggesting lower toxicity with this type of conditioning. This finding is also explained by the impact of Busulfan monitoring.
Is microchimerism a sign of imminent disease recurrence after allogeneic hematopoietic stem cell transplantation? A systematic review of the literature
Blood reviews. 2020;:100673
Chimerism analysis following hematopoietic stem cell transplantation (HSCT) for leukemia is routinely applied in parallel with quantification of minimal residual disease (MRD) to identify imminent relapse. In the past decades, new methods with a lower limit of detection compared to standard methods have been developed, so-called microchimerism analysis. Microchimerism analysis is fast, simple, applicable across pre-HSCT disease-type and can be applied on peripheral blood allowing frequent testing during follow-up. Monitoring of microchimerism in blood could replace repeated bone marrow analysis for MRD and allow earlier detection of imminent relapse or graft failure. Clinical studies in single center cohorts have shown conflicting but promising results. There is currently no consensus on the interpretation of microchimerism analysis and heterogeneity of studies remains a major obstacle for inter-study comparisons and meta-analysis in this field. We have conducted a systematic review of studies investigating associations between microchimerism and relapse of leukemia post-HSCT. We summarize current evidence and provide suggestions for future research.
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.
Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Bone marrow transplantation. 2020
Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.
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.
Altered body composition in male long-term survivors of paediatric allogeneic haematopoietic stem cell transplantation: impact of conditioning regimen, chronic graft-versus-host disease and hypogonadism
Bone marrow transplantation. 2020
Changes in body composition related to metabolic syndrome are frequent among survivors of haematopoietic stem cell transplantation (HSCT), but insights into predisposing factors are incomplete, and it is unknown to what degree these changes persist at long term. We cross-sectionally investigated body composition by dual-energy X-ray absorptiometry in 98 male survivors of paediatric allogeneic HSCT. Median (range) age at follow-up was 28.1 (18.5-47.0) years and median (range) time from transplant was 18.3 (7.7-34.6) years. Lean Body Mass Index and Skeletal Muscle Mass Index were lower in patients compared to the reference population (mean (SD) standard deviation score (SDS) -1.29 (0.99), p < 0.001 and -1.20 (1.03), p < 0.001). Fat Mass Index was comparable to the reference population, but android/gynoid (AG) fat ratio SDS was higher (mean (SD) 0.46 (1.28), p < 0.001). These changes were found in patients treated with total body irradiation (TBI) as well as non-TBI regimens, although most pronounced in the former. Further, low lean mass was associated with chronic graft-versus-host disease, while high AG ratio was associated with lower testosterone levels. Since the combination of low lean mass and high AG ratio increases the risk of cardio-metabolic disease, these health issues should be monitored at long-term clinical follow-up after paediatric HSCT.
Declining mortality rates in children admitted to ICU following HCT
Pediatric transplantation. 2020;:e13946
We aimed to assess short- and long-term mortality, including factors associated with mortality, for children referred to a pediatric intensive care unit (ICU) at Rigshospitalet, Denmark, following haematopoietic cell transplantation (HCT). Data regarding admission to ICU and mortality following HCT for children below 16 years of age between 2000 and 2017 were retrospectively analyzed. We identified 55 ICU admissions in 39 patients following 46 HCTs. The overall in-ICU, in-hospital, 3-month, and 1-year mortality rates were 33.3%, 43.6%, 46.2%, and 51.3%, respectively. Patients admitted from 2000 to 2010 had a 3-month mortality of 63.2% and 1-year mortality of 68.4%, compared to 30% and 35% (P = .040 and P = .039) for patients admitted from 2011 to 2017. The main reason for ICU admission was respiratory failure (78.2%). Mechanical ventilation (MV) was associated with a higher long-term mortality (P = .044), and use of inotropes or vasopressors was associated with increased mortality at all times (all P > .006). Extracorporeal life support, renal replacement therapy, longer ICU stay, and longer time with MV were not associated with increased mortality. Over the past two decades, mortality was significantly reduced in pediatric HCT patients admitted to the ICU. The cause is probably multifactorial and warrants further studies. Our findings support admissions of critically ill pediatric HCT patients to intensive care with encouraging outcomes of even long-term admissions.
Male gonadal function after allogeneic hematopoietic stem cell transplantation in childhood: a cross-sectional, population-based study
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT), but detailed insights into patterns of male gonadal function at long-term is limited since studies have been retrospective without semen sample data. We investigated 1) the risk of azoospermia and testosterone deficiency, 2) the diagnostic value of markers of spermatogenesis, and 3) paternity at long-term follow-up after pediatric allogeneic HSCT. All surviving men ≥18 years of age transplanted in Denmark or Finland between 1980-2010 were invited to this cross-sectional study. Examinations included a semen sample, reproductive hormones, testicular volumes and screening for chronic graft-versus-host-disease (GvHD). Cumulative (pre-HSCT plus HSCT) treatment doses were calculated. Of 181 eligible patients, 98 participated median (range) 18 (8-35) years after HSCT. Sperm was found in 30 patients, azoospermia in 42, and azoospermia during testosterone substitution in 24 patients. A higher cumulative testicular irradiation dose was associated with increased risk of azoospermia and testosterone substitution (odds ratio [OR] per +1 Gy 1.27, 95%CI 1.14-1.46); p<0.001 and 1.21, 95%CI 1.11-1.38; p<0.001, respectively). All patients treated with >12 Gy had azoospermia and all but one treated with >16 Gy needed testosterone substitution. In patients treated with chemotherapy only (n=23), a higher cumulative cyclophosphamide equivalent dose was associated with increased the risk of azoospermia (OR per +1 g/m(2) 1.34, 95%CI 1.01-2.15; p=0.037). Pre-pubertal stage at HSCT was a risk factor for testosterone substitution (OR 15.31, 95%CI 2.39-315; p=0.017), while chronic GvHD was unrelated to gonadal dysfunction. Inhibin B was the best surrogate marker of azoospermia (area under the curve 0.91, 95%CI 0.85-0.98, 90% sensitivity and 83% specificity) compared to follicle-stimulating hormone and testicular volume. Of 24 males who had attempted to conceive, six had fathered children. In conclusion, the risk of male gonadal dysfunction after pediatric HSCT is high and depends primarily on the cumulative testicular irradiation dose and pubertal stage at transplant. Our findings pinpoint the need of fertility preservation before HSCT as well as prolonged follow-up of pediatric HSCT patients into adulthood.
The impact of donor type on the outcome of pediatric patients with very high risk acute lymphoblastic leukemia. A study of the ALL SCT 2003 BFM-SG and 2007-BFM-International SG
Bone marrow transplantation. 2020
Allogeneic HSCT represents the only potentially curative treatment for very high risk (VHR) ALL. Two consecutive international prospective studies, ALL-SCT-(I)BFM 2003 and 2007 were conducted in 1150 pediatric patients. 569 presented with VHR disease leading to any kind of HSCT. All patients >2 year old were transplanted after TBI-based MAC. The median follow-up was 5 years. 463 patients were transplanted from matched donor (MD) and 106 from mismatched donor (MMD). 214 were in CR1. Stem cell source was unmanipulated BM for 330 patients, unmanipulated PBSC for 135, ex vivo T-cell depleted PBSC for 62 and cord-blood for 26. There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years, median follow up of survivals was 4.88, range (0.01-11.72) years. The 4-year CI of extensive cGvHD was 13?±?2% and 17?±?4% (p?=?NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60?±?2% vs. 42?±?5%, p?0.001) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9?±?1% vs. 23?±?4%, p?0.001). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM. This paper demonstrates the impact of donor type on overall results of allogeneic stem cell transplantation for very-high risk pediatric acute lymphoblastic leukemia with worse results when using MMD stem cell source.
Children with very high risk acute lymphoblastic leukaemia (n=569)
Matched donor (MD) or matched sibling donor (MSD) transplantation (n=463)
Mismatched donor transplantation (MMD, n=106)
There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years,median follow up of survivals was 4.88 years. The 4-year CI of extensive cGvHD was 13± 2% and 17 ± 4% (p=NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60±2% vs. 42±5%) for the whole cohort. This difference does not exist if considering separately patients treated in the most recent study. There was no difference in 4-year CI of relapse. The 4-year NRM was lower for patients transplanted from MD (9±1% vs. 23±4%). In multivariate analysis, donor-type appears as a negative risk-factor for OS, EFS, and NRM.
Male Sexual Function after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Multicenter Study
There are many known endocrine complications after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood including increased risk of biochemical hypogonadism. However, little is known about sexuality in adulthood following childhood HSCT. In this multicenter study, sexual functions and possible risk factors were assessed comprehensively in two national cohorts (Finland and Denmark) of male adult survivors of childhood HSCT. Compared to a healthy control group (n = 56), HSCT survivors (n = 97) reported less sexual fantasies, poorer orgasms, lower sexual activity with a partner and reduced satisfaction with their sex life, even in the presence of normal erectile functions and a similar frequency of autoerotic acts. Of the HSCT survivors, 35% were cohabitating/married and 66% were sexually active. Risk factors for poorer self-reported sexual functions were partner status (not cohabitating with a partner), depressive symptoms, CNS and testicular irradiation. Sexual dysfunction increased by age in the HSCT group with a pace comparable to that of the control group. However, because of the lower baseline level of sexual functions in the HSCT group, they will reach the level of clinically significant dysfunction at a younger age. Hence, male survivors of childhood HSCT should be interviewed in detail about their sexual health beyond erectile functions.