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Clinical Trial
. 2018 Nov;5(11):e532-e542.
doi: 10.1016/S2352-3026(18)30156-X.

Fludarabine with a higher versus lower dose of myeloablative timed-sequential busulfan in older patients and patients with comorbidities: an open-label, non-stratified, randomised phase 2 trial

Uday R Popat  1 , Rohtesh S Mehta  2 , Roland Bassett  3 , Julianne Chen  2 , Benigno C Valdez  2 , Jitesh Kawedia  2 , Sairah Ahmed  2 , Amin M Alousi  2 , Paolo Anderlini  2 , Geath Al-Atrash  2 , Qaiser Bashir  2 , Stefan O Ciurea  2 , Chitra M Hosing  2 , Jin S Im  2 , Roy Jones  2 , Partow Kebriaei  2 , Issa Khouri  2 , David Marin  2 , Yago Nieto  2 , Amanda Olson  2 , Betul Oran  2 , Simrit Parmar  2 , Katayoun Rezvani  2 , Muzaffar H Qazilbash  2 , Nina Shah  2 , Samer A Srour  2 , Elizabeth J Shpall  2 , Richard E Champlin  2 , Borje S Andersson  2
Affiliations
Clinical Trial

Fludarabine with a higher versus lower dose of myeloablative timed-sequential busulfan in older patients and patients with comorbidities: an open-label, non-stratified, randomised phase 2 trial

Uday R Popat et al. Lancet Haematol. 2018 Nov.

Abstract

Background: Haemopoietic stem-cell transplantation (HCT) conditioning regimens that can reduce risk of relapse without increasing non-relapse mortality are needed. We aimed to test the safety of timed-sequential delivery of low-dose versus high-dose myeloablative busulfan in older patients and patients with comorbidities.

Methods: This non-stratified, open-label, randomised phase 2 trial was done at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients with haematological cancers aged between 5 and 75 years were eligible to participate in the study. Patients who had HIV or uncontrollable infections were excluded. Eligible patients were randomly assigned (1:1 by a computer-generated programme in block sizes of four) to receive a total intravenous busulfan dose to achieve an area under the curve of 16 000 μmol/min (16K group) or 20 000 μmol/min (20K group) on the basis of pharmacokinetic analysis, plus intravenous fludarabine 40 mg/m2 for 4 days. The investigators and the research nurses were masked to the block size to conceal allocation. The primary outcome was day 100 non-relapse mortality. All analyses were by modified intention to treat, including only patients who received at least one dose of the study drug. No interim analyses were planned and accrual is complete. This study is registered with ClinicalTrials.gov, number NCT01572662.

Findings: Between April 18, 2012, and Dec 9, 2015, 98 patients were enrolled. 49 patients were randomly assigned to the 16K group and 49 to the 20K group, one of which was removed from the study before starting the intervention. Median age was 60 years (IQR 54-67). 50 (52%) patients had an HCT-specific comorbidity index score of 3 or more, and 41 (42%) had a high or very high Disease Risk Index score. Day 100 non-relapse mortality was 4% (95% CI 0-10) in the 16K group and 6% (0-13) in the 20K group (p=0·65). Infection was the most common grade 3-5 toxicity in both the 20K group (25 [52%] of 48 patients) and the 16K group (24 [49%] of 49 participants). Mucositis (nine [19%] of 48 patients vs three [6%] of 49 patients), idiopathic pneumonia syndrome (nine [19%] of 48 patients vs two [4%] of 49 patients), and culture-negative neutropenic fever (16 [33%] of 48 patients vs eight [16%] of 49 patients) were more common in the 20K group than in the 16K group.

Interpretation: Myeloablative doses of busulfan administered in a timed-sequential manner with fludarabine is associated with low non-relapse mortality in older patients and patients with comorbidities. Additional studies are required to show whether this approach can reduce the risk of relapse.

Funding: Cancer Center Support Grant (US National Cancer Institute, National Institutes of Health).

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Conflict of interest statement

Disclosure of Conflicts of Interest: The authors declared no conflicts of interest.

Figures

Figure 1:
Figure 1:. Study Schema.
Patients were randomized to either 16K or 20K arm. All patients received out-patient dose of busulfan 80 mg/m2 on day −13 and day -12. Busulfan PK analysis was done after the first dose on day −13. Patients were then admitted on day −6 and received additional once daily IV doses of busulfan based on the PK analysis immediately after the completion of fludarabine 40 mg/m2 IV given once daily through day −3. HCT was performed on day 0.
Figure 2:
Figure 2:. CONSORT diagram illustrating patient flow.
A total of 98 patients were randomized equally to 16K and 20K arms including 49 patients each. One patient in the 20K arm withdrew from the study and did not receive the allocated intervention. Analysis included 49 patients enrolled in the 16K arm and 48 patients in the 20K arm. Two patients were lost to follow-up (day + 629 and day +1195 post HCT) in the 16K arm and one patient was lost to follow-up (day +652 post HCT).
Figure 3:
Figure 3:. Outcomes by treatment arm, univariate estimates:
(a) non-relapse mortality, (b) relapse, (c) progression free survival, and (d) overall survival. The numbers below figures 3c and 3d denote total number of patients at risk (number censored)
Figure 4:
Figure 4:. Outcomes by HCT-CI and DRI, univariate estimates:
(a) non-relapse mortality by HCT-CI, (b) overall survival by HCT-CI, and (c) overall survival by DRI. The numbers below figures 4b and 4c denote total number of patients at risk (number censored)
See this image and copyright information in PMC

References

    1. Bornhauser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, et al. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012;13(10):1035–44. - PubMed
    1. Lioure B, Bene MC, Pigneux A, Huynh A, Chevallier P, Fegueux N, et al. Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study. Blood. 2012;119(12):2943–8. - PubMed
    1. Ringden O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol. 2009;27(27):4570–7. - PubMed
    1. Mohty M, Labopin M, Volin L, Gratwohl A, Socie G, Esteve J, et al. Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood. 2010;116(22):4439–43. - PubMed
    1. Luger SM, Ringden O, Zhang MJ, Perez WS, Bishop MR, Bornhauser M, et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant. 2012;47(2):203–11. - PMC - PubMed

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