Autologous Stem Cell Transplantation for Adult Acute Myelocytic Leukemia in First Remission : Better Outcome Following Busulfan and Melphalan Compared to Busulfan and Cyclophosphamide : A Retrospective Study from the Acute Leukemia Working Party of the EBMT

Rationale

Autologous stem cell transplantation for adult acutemyelogenousleukemia (AML) isa therapeutic option for good and intermediate risk patients. New compounds and new formulations in conjunction with pre andpost transplanttargeted therapy may improve outcome.

A recent EBMT retrospective survey investigating onBusulfanadministered IV (Nagler A et al:Haematologica. 2014 ) pre autologous stem cell transplantation (ASCT) suggested that the combination ofBusulfanand High doseMelphalan(BUMEL) was associated with the best overall survival. To address this question, we compared this regimen with the historical  Busulfanand Cyclophosphamide (BUCY) association.

Methods

Eligibilitycriteria consistedof all adult patients (age >18 years) with AMLautograftedin CR1, following a preparative regimen consisting of either BUCY or BUMEL, reported to the EBMT registry in the period from January 2005 to December 2013. The doses ofBusulfanwere either oral at 16 mg/kg over 4 days or IV at 12.8 mg/kg over 4 days. High doseMelphalanwas 140mg/m². The data came from 231 centers 23 ofwhich usedboth regimens. Therelationships between outcomes and patient, disease and transplant characteristics wasevaluated in multivariate analyses using the Cox model. 

Results

 1120 patients received BUCY and 436 BUMEL prior toautograftingin first remission. Patients receiving BUMEL were older (median 52 years versus 50 years, p=0.01) with less good risk diseases bycytogenetics(16% versus 28%, p=0.001). They wereautografted  with a longer interval from CR1 toautografting(120 days versus 104 days, p=0.001) and they were more frequently in a negative minimal residual disease (MRD) status by molecular biology (89% versus 82%, p= 0.03).

The nature of the pretransplantregimen interacted with the interval from diagnosis to autograftingon both relapse incidence (p=0.005) and leukemia free survival (p= 0.02): the outcome post BUMEL was superior to BUCY only in patients transplanted within less than six months post diagnosis. In these  patients, following BUMEL and BUCY respectively, the RI was 35%versus 50.6% (p< 10^-3), the LFS 61.1% versus 46.2% (p< 10^-3) and the OS 79.4% versus 64.8% (p= 0.003). There was no difference for NRM.

 When considering only patientsautograftedat the time when MRD detection was negative, the LFS at two years was 75.8% for 134 patients receiving BUMEL and 58.6% in the 371 patients receiving BUCY, with no significant difference (p= 0.1). The major cause of death in the two groups was leukemia recurrence.

Conclusion

We conclude that the BUMEL combination pre ASCT in AML CR1 is superior to BUCY when the transplant is performed less than 6 months after diagnosis. These registry data should be confirmed in awell designedtwo arm study assessing the role of ASCT in good risk and possibly intermediate -1 risk adult patients with AML. 

 

		p	HR	95% CI
NRM	BUMEL vs BUCY	0.450	1.376	0.599	3.16
	Age atTx/ 10years	0.001	1.064	1.025	1.10
	Time from diagnosis to Transplant.	0.900	0.999	0.984	1.01
	Cytogenetics :Intermediatevs good	0.610	0.709	0.191	2.63
	Poor versus good	0.710	0.708	0.112	4.46
	Missing	0.420	0.591	0.164	2.11
	centre (frailty)	0.360
RI	BUMEL vs BUCY	0.001	0.602	0.445	0.816
	Age at Transplant / 10years	0.005	1.012	1.003	1.020
	Time from diagnosis to Transplant:	0.720	1.000	0.996	1.004
	Cytogenetics : Intermediatevs good	0.510	1.145	0.764	1.714
	Poor versus good	0.031	1.799	1.055	3.067
	Missingversus good	0.480	1.150	0.779	1.699
	centre (frailty)	0.110
OS	BUMEL vs BUCY	0.002	0.614	0.449	0.841
	Age at Transplant / 10years	<10-4	1.025	1.014	1.036
	Time from diagnosis toransplant	0.94	0.999	0.995	1.004
	Intermediatevs good	0.88	1.036	0.649	1.653
	Poor versus good	0.11	1.632	0.901	2.956
	Missingversus good	0.81	1.058	0.672	1.665
	centre (frailty)	0.29
LFS	BUMEL vs BUCY	0.002	0.649	0.490	0.858
	Age at Transplant / 10years	<10-4	1.015	1.006	1.023
	Time from diagnosis to Transplant	0.740	1.000	0.996	1.004
	Cytogenetics : Intermediatevs good	0.590	1.110	0.755	1.630
	Poor vs good	0.046	1.679	1.008	2.796
	Missingversus good	0.590	1.106	0.763	1.604
	centre (frailty)	0.170

Multivariate analyses of prognostic factors inpatientsautograftedwithin 6 months

Figure 1: Leukemia free survival and overall survival of patients with AMLautograftedwithin 6 months from initial diagnosis, in first remission following high dose consolidation by BUMEL or BUCY in the period fromfromJanuary 2005 to December 2013 (EBMT registry).