The safety and efficacy of a novel hypo-fractionated total marrow and lymphoid irradiation before allogeneic stem cell transplantation for lymphoma and acute leukemia
Clinical and translational radiation oncology. 2021;26:42-46
PURPOSE Total body irradiation (TBI) has been widely utilized as part of the conditioning regimen for hematopoietic stem cell transplantation (HSCT), but is associated with significant toxicities. Targeted TBI using helical Tomotherapy allows precise and homogeneous tumor coverage and excellent sparing of organs at risk. The purpose of this study was to evaluate the clinical outcomes of a novel hypo-fractionation strategy for patients receiving total marrow and involved lymphoid irradiation (TMLI) as part of the conditioning regimen before HSCT. METHODS AND MATERIALS 61 patients (7 acute myelogenous leukemia (AML), 33 acute lymphoblastic leukemia (ALL), 18 non-Hodgkin's lymphoma (NHL), 3 mixed acute leukemia (MAL)) received conditioning radiation treatment with TMLI (8 Gy to bone marrow, 10 Gy to involved field in 2 fractions per day) in conjunction with chemotherapy before transplantation. RESULTS The median age of 61 patients with TMLI was 24 (4-54) years. The prescribed dose covered the entire bone and involved target volume, and the dose of organs at risk (OAR) was reduced by 28%-78% of the prescription dose. Grade 1-2 nausea and vomiting occurred in 12 patients and grade 1-2 pain in 6 patients during radiotherapy. Fatigue occurred in 16 patients. 2 patients had diarrhea, enteritis, and 1 patient had fever. None of patient had grade 3-4 non-hematologic adverse reactions. Late (30 days after HSCT) grade 2 toxicities including reversible enteritis occurred in 3 patients. 5 patients developed infectious pneumonia. The 2 years progression-free survival (PFS) was 64.1% (95% CI: 0.16-0.22) and overall survival (OS) was 74.7% (95% CI: 0.19-0.24) for the 61 patients who had received their planned HSCT. The 2-year non-relapse mortality was significantly reduced to 5% in this patient cohort. CONCLUSIONS This study demonstrates that hypo-fractionated TMLI (8 Gy to bone marrow, 10 Gy to involved field in a single day) as a conditioning regimen for lymphoma and acute leukemia was feasible and the clinical outcomes were acceptable.
Comparison of total body irradiation versus non- total body irradiation containing regimens for de novo acute myeloid leukemia in children
With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, p<0.0001) but relapse was lower (23% vs. 37%, p<0.0001) compared to non-TBI regimens. Consequently, overall (62% vs. 60%, p=1.00) and leukemia-free survival (55% vs. 52%, p=0.42) did not differ between treatment groups. Grade II-IV acute GVHD was higher with TBI regimens (56% vs. 27%, p<0.0001) but not chronic GVHD. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%, p<0.001) but there were no differences in late pulmonary, cardiac or renal impairment. In the absence of a survival advantage, the choice of TBI or non-TBI regimen merits careful consideration with the data favoring non-TBI regimens to limit the burden of morbidity associated with endocrine dysfunction.
Children with de novo acute myeloid leukaemia (n=624)
Myeloablative conditioning regimen containing total body irradiation (TBI) (n=199)
Non-TBI regimens (n=425)
Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%) but relapse was lower (23% vs. 37%) compared to non-TBI regimens. Consequently, overall (62% vs. 60%) and leukemia-free survival (55% vs. 52%) did not differ between treatment groups. Grade II-IV acute GVHD was higher with TBI regimens (56% vs. 27%) but not chronic GVHD. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%) but there were no differences in late pulmonary, cardiac or renal impairment.
Comparison of Two Analytical Methods for Busulfan Therapeutic Drug Monitoring
European journal of drug metabolism and pharmacokinetics. 2020
BACKGROUND AND OBJECTIVES Busulfan (Bu) is an old drug, but is still well recommended as an alkylating agent during conditioning therapy, before hematopoietic stem cell transplantation. Although its dose administration is standardized and based on patient weight, therapeutic drug monitoring is required in order to maintain its exposure [as area under the concentration-time curve (AUC) from 0 to infinity AUC(0-8)] within a narrow therapeutic range and, if necessary, to adjust the dose with as short a lead time as possible. The aim of the study is to evaluate the agreement (as calculated AUC) between a gold standard analytical method and a new one that is faster and easier. METHODS We analyzed 221 plasma samples from 37 children (0.25-16 years; 4-62.5 kg) and 11 adults (21-59 years; 45-80 kg), corresponding to 52 AUC values (ng h/mL). The drug exposure was calculated, simultaneously, by two validated analytical methods. The reference method was a high-performance liquid chromatography (HPLC) assay combined with an ultraviolet detector (UV). The test method had a triple quadrupole mass spectrometer (MS) as detector; the clean-up procedures of the samples were different and faster. RESULTS The agreement between the two methods (reference and test) was evaluated in terms of Bu exposure differences based on Lin's concordance correlation coefficient (CCC) and represented by the Bland-Altman plot. The CCC between the AUC of the two methods was excellent (0.868; 95% CI: 0.802-0.935). The precision of the measures (expressed by Pearson's italic "r") was 0.872, and the accuracy (accounted by the bias correction factor) was 0.996. CONCLUSIONS We can conclude that the HPLC-MS/MS assay represents a very good alternative to the reference.
Decitabine prior to salvaged cord blood transplantation for acute myeloid leukaemia/myelodysplastic syndrome not in remission
Journal of clinical pharmacy and therapeutics. 2020
WHAT IS KNOWN AND OBJECTIVE Many refractory/relapsed haematological malignancies, in non-remission state, still have poor prognosis even after allogeneic haematopoietic stem cell transplantation. Recently, decitabine or umbilical cord blood transplantation (UCBT) seemed to be effective in these patients. However, few studies have added decitabine to myeloablative conditioning regimens for UCBT in patients with haematological malignancies not in remission. Therefore, the objective was to evaluate the clinical outcomes of patients with refractory/relapsed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) using decitabine as part of a myeloablative conditioning regimen prior to salvaged unrelated UCBT at our centre. METHODS We enrolled 20 consecutive patients with refractory/relapsed AML/MDS between 2013 and 2018. All patients were in non-remission state before transplantation. All transplants were performed with decitabine as part of the myeloablative conditioning regimen, which was decitabine + fludarabine/busulfan/cyclophosphamide. RESULTS AND DISCUSSION All patients achieved neutrophil and platelet engraftment. Incidence of grade III/IV acute graft-vs-host disease (GVHD) was 20.0%, which was also decreased compared to non-decitabine group (P = .025). The median follow-up time after UCBT was 29 months (range 14-64 months). The 2-year probability of GVHD-free relapse-free survival (GRFS) was higher in the decitabine group. Univariate showed that the decitabine group was associated with a higher GRFS than the non-decitabine group. The estimated probability of overall survival and relapse was 55% and 20.0%, respectively. WHAT IS NEW AND CONCLUSIONS Our results suggest that addition of decitabine as part of the myeloablative conditioning regimen prior to UCBT for refractory/relapsed AML/MDS in patients who are not in remission is safe and might be an effective treatment option.
Experience with a Reduced Toxicity Allogeneic Transplant Regimen for Non-CGD Primary Immune Deficiencies Requiring Myeloablation
Journal of clinical immunology. 2020
PURPOSE A need exists for reduced toxicity conditioning regimens that offer less toxicity while maintaining myeloablation, especially for primary immune deficiencies where myeloablation or high donor myeloid chimerism is required to achieve cure. We adapted a busulfan and fludarabine regimen by Gungor et al. for children and young adults undergoing allogeneic HCT for non-CGD primary immune deficiencies requiring myeloablation or high donor myeloid chimerism, and herein report our experience. METHODS We retrospectively reviewed records of 41 consecutive patients who underwent allogeneic HCT for Wiskott-Aldrich syndrome (n = 12), primary HLH/XLP (n = 10), CD40L deficiency (n = 7), or other (n = 12) primary immune deficiencies with a conditioning regimen containing pharmacokinetic-guided busulfan dosing which achieved a cumulative AUC between 57 and 74 mg/L × h (65-80% of conventional myeloablative exposure), along with fludarabine and alemtuzumab or anti-thymocyte globulin at 3 transplant centers between 2014 and 2019. RESULTS Forty-one patients underwent a first (n = 33) or second (n = 8) allogeneic HCT. Median age was 2.3 years (range, 0.3 years-19.8 years). All but one patient (97.5%) achieved neutrophil recovery at a median of 14 days (range, 11-34 days). One patient developed sinusoidal obstruction syndrome and two patients developed diffuse alveolar hemorrhage. Four patients developed grades II-IV acute GVHD. Three patients developed chronic GVHD. One-year overall survival was 90% (95% confidence interval [CI] 81-99%) and event-free survival was 83% (95% CI 71-94%). CONCLUSIONS Our experience suggests that a reduced toxicity busulfan-fludarabine regimen offers low toxicity, low incidence of grades 2-4 GVHD, durable myeloid engraftment, and excellent survival, and may be considered for a variety of primary immune deficiencies where myeloablative HCT is desired.
Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study
Bone marrow transplantation. 2020
Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P < 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.
Addition of thiotepa to total body irradiation and cyclophosphamide conditioning for allogeneic hematopoietic stem cell transplantation in pediatric acute lymphoblastic leukemia
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Total body irradiation (TBI)/cyclophosphamide (CY) is a standard of care conditioning regimen in allogeneic hematopoietic stem cell transplant (HSCT) for pediatric acute lymphoblastic leukemia (ALL). This study sought to identify whether the addition of thiotepa (TT) to TBI/CY improves HSCT outcomes for pediatric patients with ALL. A retrospective analysis was performed on 347 pediatric ALL patients who underwent HSCT between 1995 and 2015, with 242 receiving TBI/CY/TT and 105 patients receiving TBI/CY. There were no statistical differences in age, donor source, or CR status between the two groups. Comparison of the TBI/CY/TT versus TBI/CY groups demonstrated no difference in transplant related mortality at 1 (11% vs 11%), 5 (13% vs 16%) or 10 years (16% vs 16%). There was lower relapse in the TBI/CY/TT group at 1 (14% vs 26%), 5 (24% vs 36%), 10 (26% vs 37%) and 15 years (26% vs 37%) (p?=?0.02), but was not statistically significant on multivariate analysis. The TBI/CY/TT group showed a trend toward improved disease free survival (DFS) at 5 (59% vs 47%), 10 (56% vs 46%) and 15 years (49% vs 40%) (p?=?0.05) but was not statistically significant on multivariate analysis. Comparing overall survival at 5 (62% vs 53%), 10 (57% vs 50%) and 15 years (50% vs 44%) demonstrated no statistical difference between the two groups. The addition of thiotepa to TBI/CY demonstrated no increase in transplant related mortality for pediatric ALL HSCT, but was unable to demonstrate significant benefit in disease control. Minimal residual disease status remained the key risk factor impacting both relapse and DFS. More studies are warranted to better clarify the benefits of using thiotepa in conditioning for ALL HSCT.
Impact of the type of anthracycline and of stem cell transplantation in younger patients with acute myeloid leukaemia: long-term follow up of a phase III study
American journal of hematology. 2020
We provide a long-term evaluation of patients enrolled in the EORTC/GIMEMA AML-10 trial which included a total of 2157 patients, 15-60 years old, randomized to receive either daunorubicin (DNR, 50 mg/m(2) ), mitoxantrone (MXR, 12 mg/m(2) ), or idarubicin (IDA, 10 mg/m(2) ) in addition to standard-dose cytarabine and etoposide for induction chemotherapy and intermediate dose cytarabine for consolidation. Younger patients who reached complete remission with complete (CR) or incomplete (CRi) recovery were then scheduled to receive an allogeneic hematopoietic stem cell transplantation (HSCT) if they had a HLA-identical sibling donor; in all other cases, an autologous HSCT had to be administered. At an 11-year median follow-up, the 5-, 10- and 15-year overall survival (OS) rates were 33.2%, 30.1% and 28.0%, respectively. No significant difference between the 3 randomized groups regarding OS was observed (P=0.38). In young patients, 15-45 years old, no treatment difference (P=0.89) regarding OS was observed, while in patients 46-60 years old, MXR and IDA groups had a trend for a longer OS as compared to the DNR group (P=0.029). Among younger patients without a favourable MRC cytogenetic risk subgroup who achieved a CR/CRi after induction chemotherapy, those with a HLA-identical sibling donor had higher 10- and 15- year OS rates than those without. In older patients who reached CR/CRi, the long-term outcomes of those with or without a donor was similar. In conclusion, long-term outcomes of the study confirmed similar OS in the 3 randomized groups in the whole cohort of patients. This article is protected by copyright. All rights reserved.
Younger patients (15-06 years old) with acute myeloid leukaemia (n= 2157)
Daunorubicin 50 mg/m(2 (DNR, n=721) in addition to standard-dose cytarabine and etoposide for induction chemotherapy and intermediate dose cytarabine for consolidation
Mitoxantrone 12 mg/m(2) (MXR, n=719), or idarubicin 10 mg/m(2) (IDA, n=717 ) in addition to standard-dose cytarabine and etoposide for induction chemotherapy and intermediate dose cytarabine for consolidation.
No significant difference between the 3 randomized groups regarding OS was observed. In young patients, 15-45 years old, no treatment difference regarding OS was observed, while in patients 46-60 years old, MXR and IDA groups had a trend for a longer OS as compared to the DNR group. Among younger patients without a favourable MRC cytogenetic risk subgroup who achieved a CR/CRi after induction chemotherapy, those with a HLA-identical sibling donor had higher 10- and 15- year OS rates than those without. In older patients who reached CR/CRi, the long-term outcomes of those with or without a donor was similar.
A Comparison of the BEAM and MITO/MEL Conditioning Regimens for Autologous Hematopoietic Stem Cell Transplantation in Hodgkin Lymphoma: An Analysis of Efficiency and Treatment-Related Toxicity
Clinical lymphoma, myeloma & leukemia. 2020
BACKGROUND Approximately half of patients with relapsed chemosensitive disease achieve robust responses with BEAM (BCNU, etoposide, cytarabine, and melphalan) and autologous stem cell rescue. The scarcity of comparative studies further limits alternative treatment protocols, such as the MITO/MEL (mitoxantrone, melphalan) protocol. PATIENTS AND METHODS In this retrospective multicenter study, we compared the BEAM and MITO/MEL regimens used before autologous hematopoietic stem cell transplantation (ASCT) in terms of efficacy and side effects in patients with Hodgkin lymphoma. Data met international accreditation rules. Before ASCT, 108 patients received the MITO/MEL, and 34 patients received the BEAM. RESULTS The median follow-up time was 36 months in the MITO/MEL group (range, 3-178) and 23 months in the BEAM group (range, 4-99). After ASCT, the 3-year expected overall survival and disease-free survival rates were 86.1% and 86.1% for the MITO/MEL group and 91.3% and 76.5% for the BEAM group, respectively. Although 50% of patients developed febrile neutropenia attacks in the MITO/MEL group, this rate was 91.1% in the BEAM group. The grade II and higher rates of hepatic, renal, gastrointestinal, and cardiac toxicities were similar in both groups. However, the rate of pulmonary toxicity was determined to be 1.9% in the MITO/MEL group and 29.4% in the BEAM group (P < .001). CONCLUSION The MITO/MEL conditioning regimen seems to be as effective as the BEAM regimen but has better tolerability in terms of pulmonary toxicity and may be used as an alternative option if necessary, depending on the comorbidity status of the patient.
Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: a meta-analysis
BMC pediatrics. 2020;20(1):176
BACKGROUND Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However, the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial. METHODS Research on pertinent literature was carried out at PubMed, EMBASE, Web of science, the Cochrane Library and ClinicalTrials.gov. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 muM x min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events. RESULTS Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 muM x min, the mean AUC value of < 900 muM x min significantly increased the incidence of graft failure (RR = 3.666, 95% CI: 1.419, 9.467). The incidence of VOD was significantly decreased with the mean AUC < 1350 muM x min (RR = 0.370, 95% CI: 0.205-0.666) and < 1500 muM x min (RR = 0.409, 95% CI: 0182-0.920). CONCLUSIONS In children, Bu mean AUC above the cut-off value of 900 muM x min (after every 6-h dosing) was associated with decreased rates of graft failure, while the cut-off value of 1350 muM x min were associated with increased risk of VOD, particularly for the patients without VOD prophylaxis therapy. Further well-designed prospective and multi centric randomized controlled trials with larger sample size are necessary before putting our result into clinical practices.