Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children
Ann E. WoolfreyClaudio AnasettiBarry E. StorerK DoneyLaurie A. MilnerEric L. SieversPaul A. CarpenterPaul J. MartinEffie W. PetersdorfFrederick R. AppelbaumJohn A. HansenJean E. Sanders
126
Citation
54
Reference
10
Related Paper
Citation Trend
Keywords:
Cumulative incidence
Total body irradiation
Acute lymphocytic leukemia
Total body irradiation (TBI)-based conditioning is the standard of care in the treatment of acute lymphoblastic leukemia (ALL) that requires allogeneic hematopoietic stem cell transplantation (HSCT). However, TBI is known to be associated with an increased risk of late effects, and therefore, non-TBI regimens have also been utilized successfully. A recent study showed that patients that were next-generation sequencing-minimal residual disease (NGS-MRD) negative prior to allogeneic HSCT had a very low risk of relapse, and perhaps could avoid exposure to TBI without compromising disease control. We examined outcomes at our institution in patients that received a TBI or non-TBI regimen, as well as explored the impact of NGS-MRD status in predicting risk of relapse post transplant.This retrospective analysis included 57 children and young adults with ALL that received their first myeloablative allogeneic HSCT from 2012 to 2017 at the University of California San Francisco. Our primary endpoint was the cumulative incidence of relapse at 3 years post transplant.We demonstrated similar cumulative incidence of relapse for patients treated with either a TBI or non-TBI conditioning regimen, while NGS-MRD positivity prior to transplant was highly predictive of relapse. The presence of acute graft-versus-host disease was associated with decreased relapse rates, particularly among patients that received a TBI conditioning regimen and patients that were NGS-MRD positive prior to HSCT.Our data suggest that the decision to use either a TBI or non-TBI regimens in ALL should depend on NGS-MRD status, with conditioning regimens based on TBI reserved for patients that cannot achieve NGS-MRD negativity prior to allogeneic HSCT.
Total body irradiation
Cumulative incidence
Regimen
Minimal Residual Disease
Cite
Citations (26)
Total body irradiation
Cumulative incidence
Regimen
Cite
Citations (2)
Cite
Citations (1)
The interaction of methotrexate and/or cyclophosphamide with the pharmacokinetics of 5-fluorouracil (5-FU) was studied in tumor-bearing WAG/Rij rats. Four groups were formed including treatment with single-agent 5-FU (eight rats); 5-FU plus methotrexate (11 rats); 5-FU plus cyclophosphamide (12 rats); and 5-FU, cyclophosphamide, and methotrexate (13 rats). The area-under-the-plasma-concentration/time curve, total-body clearance, elimination half-life, mean residence time, and steady-state volume of distribution were computed and compared. The mean residence time and elimination half-life of 5-FU increased when methotrexate was included in the combination. The increase was significant (P less than 0.05) for 5-FU, cyclophosphamide, and methotrexate versus 5-FU and cyclophosphamide.
Cite
Citations (12)
Objective:To assess the role of alternative hemi-body irradiation (AHBI) in patients with acute lymphoblastic leukemia(ALL).Methods: Eleven patients with ALL received two-step AHBI on day 15 (13～19) following high-dose chemotherapy. Upper hemi-body irradiation (UHBI) and lower hemi-body irradiation (LHBI) were sequentially given as a single dose of 6～9 Gy at an interval of 25 (13～37) days. Fourteen recipients of autologous hematopoietic stem cell transplantation(AHSCT) during the same period were chosen as the controls.Results: Hematopoietic reconstitutions were observed in all AHBI recipients.The 3 year disease free survival(DFS) rate and the cumulative incidence of AHBI related mortality in patients having received AHBI were (47.73±17.55)%and 0,respectively.The median follow-up period was 803.5 (428～1 446) days. The 3 year DFS and the cumulative incidence of AHSCT related mortality in 14 ALL patients in the AHSCT group were(53.88±14.08)%and 14%,respectively. There was no significant difference in 3 year DFS between AHBI recipients and AHSCT recipients with ALL in this two groups(P0.05).Conclusion: AHBI provided a feasible approach for ALL.This strategy has several advantages which include desirable effectiveness, low costs, practical operation, and acceptable side effects.
Total body irradiation
Cumulative incidence
Cite
Citations (0)
Abstract Background Hematopoietic stem cell transplantation can be curative for children with difficult‐to‐treat leukemia. The conditioning regimen utilized is known to influence outcomes. We report outcomes of the conditioning regimen used at the Alberta Children's Hospital, consisting of busulfan (with pharmacokinetic target of 3750 μmol*min/L/day ±10%) for 4 days, higher dose (250 mg/m 2 ) fludarabine and 400 centigray (cGy) of total body irradiation. Procedure This retrospective study involved children receiving transplant for acute lymphoblastic leukemia (ALL). It compared children who fell within the target range for busulfan with those who were either not measured or were measured and fell outside this range. All other treatment factors were identical. Results Twenty‐nine children (17 within target) were evaluated. All subjects engrafted neutrophils with a median [interquartile range] time of 14 days [8–30 days]. The cumulative incidence of acute graft‐versus‐host disease was 44.8% [95% confidence interval, CI: 35.6%–54.0%], while chronic graft‐versus‐host disease was noted in 16.0% [95% CI: 8.7%–23.3%]. At 2 years, the overall survival was 78.1% [95% CI: 70.8%–86.4%] and event‐free survival was 74.7% [95% CI: 66.4%–83.0%]. Cumulative incidence of relapse was 11.3% [95% CI: 5.1%–17.5%]. There were no statistically significant differences in between the group that received targeted busulfan compared with the untargeted group. Conclusion Our conditioning regiment for children with ALL resulted in outcomes comparable to standard treatment with acceptable toxicities and significant reduction in radiation dose. Targeting busulfan dose in this cohort did not result in improved outcomes.
Cumulative incidence
Total body irradiation
Regimen
Interquartile range
Cite
Citations (0)
The efficacy of current clinical leukemia treatment with high-dose cyclophosphamide, supralethal total-body irradiation (TBI), and bone marrow transplantation was evaluated in a rat model for human acute myelocytic leukemia. In rats, both at an early stage of disease and in an advanced stage after remission-induction with 1-beta-D-arabinofuranosylcytosine, treatment with cyclophosphamide (100 mg/kg i.p.) followed by either acute, unfractionated TBI (900 centigrays) or fractionated TBI (200 centigrays for seven doses; 450 centigrays for three doses) achieved cure in 90 to 100% and 75% of the animals, respectively. The remaining rats died from treatment-related toxicity despite isologous bone marrow transplantation. Applying the cyclophosphamide-TBI treatment regimens in advanced stage leukemia (tumor load, 5 X 10(9) cells) resulted in death from leukemia relapse in the majority of rats (71%). From the increase in life span after treatment, it was deduced that a 9-log leukemic cell kill was achieved at the most. There was no significant difference between the regimens using fractionated or unfractionated TBI. Toxicity-related deaths occurred mainly in the TBI group receiving 450 centigrays for three doses (38%). In another approach, (repeated) low-dose cyclophosphamide was given subsequent to high-dose cyclophosphamide-TBI treatment applied in advanced stage leukemia. This proved to be effective in eradicating residual leukemia in 80 to 90% of the rats without destroying the bone marrow graft. In general, the outcome of the various treatment regimens was predictable through accurate information on the tumor load at various stages of disease. The major obstacle in extrapolating the present experimental results to clinical practice is the lack of similar quantitative data in human leukemia.
Total body irradiation
Cite
Citations (16)
In tumor-bearing WAG/Rij rats the interaction of cyclophosphamide and/or 5-fluorouracil (5-FU) with methotrexate as manifested at the pharmacokinetic level was studied. Four groups were formed of at least ten animals. The control group, which received single-agent methotrexate, was compared with groups that received methotrexate plus cyclophosphamide, methotrexate plus 5-FU, and methotrexate plus cyclophosphamide plus 5-FU. There appeared to be an increase of 40% in the clearance of methotrexate by the triple combination. Cyclophosphamide especially diminished the terminal part of the concentration-time curve of methotrexate.
Cite
Citations (8)
The sequential treatment of mice with advanced leukemia L1210 employing a single injection of 2-chloro-4′,4″-di-2-imidazolin-2-ylterephthalanilide, dihydrochloride (NSC-38280) or cyclophosphamide followed by multiple treatment with methotrexate (MTX) was examined. Mice that received a single injection of NSC-38280 or cyclophosphamide followed by MTX given daily or every 4 days displayed more extensive increases in median survival time than did mice receiving MTX alone on a daily or every-4-day treatment schedule. An initial treatment with either NSC-38280 or cyclophosphamide followed by daily MTX was approximately twice as effective as daily MTX alone, whereas NSC-38280 or cyclophosphamide followed by MTX every 4 days was 3–4 times more effective than MTX alone every 4 days.
Nitrogen mustard
Cite
Citations (16)
Preliminary evidence indicates that the addition of low-dose total body irradiation (TBI) (2-4 Gy) to reduced intensity conditioning may reduce the rate of relapse in allogeneic stem cell transplants. In very high-risk patients receiving combination haploidentical single-unit cord blood transplants, we have added 4 Gy TBI to the widely used fludarabine, melphalan conditioning regimen, in hopes of reducing relapse and decreasing graft rejection.We retrospectively reviewed the posttransplant outcomes of patients who underwent haplocord stem cell transplant between May 2013 and March 2015 and who received fludarabine 30 mg/m day (D)-7 to -3, melphalan 140 mg/m D-2, and 2 Gy TBI D-4 and -3.All 25 patients achieved primary neutrophil engraftment after a median of 12 days. The median time to platelet engraftment was 27 days. The cumulative incidence of nonrelapse mortality was 16% by D+100 and 33% by 1 year. The cumulative incidence of grade III to IV acute graft-versus-host disease was 36% by D+100. The CIR was 13% by D+100 and 29% by 1 year. The estimated 1-year overall survival and progression-free survival were 40% and 37%, respectively. In a subgroup analysis, we compared the outcome of 13 acute myeloid leukemia patients receiving this conditioning regimen with age and disease risk index-matched acute myeloid leukemia patients receiving fludarabine-melphalan without TBI. The TBI group had lower incidence of relapse at 1 year (15% vs 54%, P = 0.05).Overall, combination fludarabine-melphalan with low-dose TBI after haplocord stem cell transplant assures good engraftment and leads to acceptable toxicity and disease control in the setting of high risk, heavily pretreated patients. These findings warrant further investigation at a larger-scale, prospective level.
Melphalan
Total body irradiation
Cumulative incidence
Regimen
Cite
Citations (18)