Abstract

Abstract 2013

Purpose:

The introduction of reduced intensity conditioning (RIC) regimens has allowed performing allogeneic hematopoietic cell transplantation (HSCT) in previously discarded old or unfit patients. In this fragile population, non-relapse mortality (NRM) has been dramatically reduced, making the post-transplant disease control the remaining challenge. Over the last years, we have tuned the chemotherapy dose intensity of a busulfan based RIC regimen with the aim to better control disease while retaining a low toxicity profile. In this perspective, we retrospectively analyzed a cohort of patients with myeloid malignancies treated identically in two French centers.

Patients and methods:

From 2005 to 2010 in Marseille and Nantes we transplanted 165 patients (median age: 56.8 years (range:18–71); males: 83, females: 82) presenting AML (N=124) or MDS (N=41) following a similar conditioning regimen but for the dose of busulfan (Bu): 1/Fludarabine (30 mg/m2/day over 5 days) 2/, rabbit anti-thymocyte-globulins (r-ATG) (2.5mg/kg/day over 2 days) and 3/ i.v. or oral Busulfan (Bu) (130 mg/m2/day or 3.2 mg/kg respectively over 2 to 4 days) (table 1). Ciclosporin A was given as post graft immunosuppression. Initially higher Bu doses were proposed to patients under the age of 55, without comorbidities and with higher risk diseases. These indications were progressively extended over time when it became evident that toxicity was not dramatically increased.

Results:

With a median follow up of 20.7 months for surviving patients, 2 year overall survival (OS) and progression free survival (PFS) were 59.6% (95% CI: 51.8–68.6) and 54.9% (95% CI: 47–64) respectively. Cumulative incidence of grade 2–4 and 3–4 acute graft-versus-host diseases (aGvhD) at day 100 was 19.4% and 7.9% respectively. Cumulative incidence of chronic GvhD (all grades) and extensive chronic GvhD was 25% and 14.4% at 1 year post transplantation respectively. NRM was 11.7 and 15.4% at 12 and 24 months. Cumulative incidence of relapse (CIR) was 24% and 29.7% at 1 and 2 years.

Overall neither the patient age, nor the donor type or the dose of Bu influenced significantly OS, PFS or CIR in the whole cohort. Surprisingly, NRM was lower after 3 or 4 days Bu conditioning regimen (3.6% vs 21.3%, p=0.009).

AML patients transplanted in 1st complete remission (n=93): those patients had 2-year OS and PFS of 63.4% (95% CI: 53.3–75.3) and 60.9% (95%CI: 50.8–72.9) respectively. Two-year OS reached 66.4% (95%CI: 56.4–81.8) for patients with favorable/intermediate karyotype and 50.5% (95%CI: 33–77.3) for unfavorable, p=0.08. Patients with favorable or intermediate karyotype tend to have a better 2-year PFS (63.8%, 95%CI: 52.2–78.1) than unfavorable karyotype (52%, 95%CI: 34.5–78.3), p=0.2.

Patients under the age of 55 (n=76): this population presents overall a better outcome than older (OS: 63.9 (CI: 52.7–74.4) vs 56% (CI: 45.6–68.7), p=0.2, PFS: 60.5 (49.7–73.8) vs 50.4% (CI: 40–63.5), p=0.2, NRM: 9.4 vs 20.3%, p=0.07). In addition higher doses of Bu improved OS (77.5% vs 47.9%, p=0.058), PFS (71.6 vs 46.4%, p=0.1), without increase of NRM (2.2% vs 18.7%, p=0.03).

Conclusion:

This conditioning regimen using Fludarabin, Bu and r-ATG can result in good OS and PFS probabilities in myeloid malignancies. Given the patient population characteristics', the NRM can be considered as low. Interestingly enough even if patients who received 3 or 4 days of Busulfan were younger and had less comorbid conditions, which is a bias, they had a lower NRM than those who received only 2 days of bu. In younger patients higher doses of Bu seem to be associated with better prognosis. These encouraging results led us setting up a prospective study comparing different doses of Bu in poor risk myeloid malignancies undergoing HLA identical allo HSCT and ineligible for standard double alkylating agent or high dose TBI based conditioning.

Table 1.

Patients and transplant's characteristics.

Patients characteristicsN%
center Marseille 108 65,5 
 Nantes 57 34,5 
gender male 83 50,3 
 female 82 49,7 
age at transplantation < 55 years 76 46,1 
 ≥55 years 89 53,9 
diagnosis AML 124 75,2 
 MDS 41 24,8 
karyotype (AML) Favorable 11 8,9 
 Intermediate 81 65,3 
 Unfavorable 32 25,8 
 NR  
disease status AML CR1 93 56,4 
 AML CR> =2 23 13,9 
 AML refractory 4,8 
 MDS CR 10 6,1 
 MDS PR/SD 31 18,8 
transplants' characteristics    
donor type MRD 92 55,8 
 MUD 34 20,6 
 MMUD 14 8,5 
cell source PBSC 157 95,2 
 BM 4,8 
Day nb of Bx/BU 106 64,2 
 35 21,2 
 24 14,5 
Patients characteristicsN%
center Marseille 108 65,5 
 Nantes 57 34,5 
gender male 83 50,3 
 female 82 49,7 
age at transplantation < 55 years 76 46,1 
 ≥55 years 89 53,9 
diagnosis AML 124 75,2 
 MDS 41 24,8 
karyotype (AML) Favorable 11 8,9 
 Intermediate 81 65,3 
 Unfavorable 32 25,8 
 NR  
disease status AML CR1 93 56,4 
 AML CR> =2 23 13,9 
 AML refractory 4,8 
 MDS CR 10 6,1 
 MDS PR/SD 31 18,8 
transplants' characteristics    
donor type MRD 92 55,8 
 MUD 34 20,6 
 MMUD 14 8,5 
cell source PBSC 157 95,2 
 BM 4,8 
Day nb of Bx/BU 106 64,2 
 35 21,2 
 24 14,5 
Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.