Bone Marrow Transplantation (2014) 49, 852–853 & 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt
LETTER TO THE EDITOR
Outcomes following second allogeneic haematopoietic transplants using fludarabine–melphalan conditioning Bone Marrow Transplantation (2014) 49, 852–853; doi:10.1038/ bmt.2014.23; published online 3 March 2014
Second allogeneic haematopoietic cell transplant (allo-HCT2) after first allograft offers the possibility of long-term survival after relapse;1–4 however, the optimal donor choice and conditioning strategy remain to be defined. All published series are retrospective and include a variety of conditioning regimens. The role of the conditioning regimen in allo-HCT2 outcomes is difficult to determine as the majority of the survival effect is thought to relate to GVL; however, recent studies have demonstrated that reduced-intensity conditioning (RIC) has improved outcomes compared with myeloablative conditioning (MAC) owing to a reduction in toxicity.5,6 No series has reported the outcomes in patients conditioned purely with fludarabine– melphalan (Flu-Mel), which is presently the commonest RIC regimen used in Australasia.7 Here, we report a series of patients
Table 1. Characteristics of patients receiving second allografts with Flu-Mel conditioning Variable n Age, years Years between transplants
a
Median (range) or N (% total) 15 47 (22–65) 2.9 (0.27–15.25)
Gender Male Female
9 (60) 6 (40)
Diagnosis AML ALL CML NHL
10 (67) 1 (7) 3 (20) 1 (7)
Disease status Remission/chronic phase Non-remission
9 (60) 6 (40)
First transplant conditioning RIC MAC
5 (33) 10 (67)
Prior chronic GVHD
8 (53)
Donor HLA-identical relative Unrelated HLA-mismatched relative Same donor for both transplants
10 (67) 3 (20) 2 (13) 9 (60)
Second transplant indication Relapse Othera
13 (87) 2 (13)
One case each of secondary AML and refractory thrombocytopenia.
receiving allo-HCT2 using Flu-Mel conditioning. Cumulative incidence curves were constructed with appropriate events as competing risks. Survival probabilities used the Kaplan–Meier method. Multivariate analysis was performed using Cox regression. We identified 15 adult patients reported to the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) having a second allogeneic transplant with Flu-Mel conditioning between 1998 and 2008. The median age at transplantation was 47 years (range 22–65), with six females and nine males (Table 1). The original diseases were: AML (n ¼ 10, three not in remission); Ph-positive ALL (n ¼ 1, not in remission); CML (n ¼ 3, one in accelerated phase, two in second chronic phase); and nonHodgkin lymphoma (NHL, n ¼ 1), with a median time to relapse of 1.88 years (range ¼ 0.27–15.25 years) after initial transplant. The indication for second allograft in 13 cases was relapse of primary disease after initial transplant, with 1 case of a secondary AML 15 years after allograft for CML, occurring without the Ph chromosome, and 1 case of refractory thrombocytopenia. The majority (n ¼ 10, 67%) had MAC for their first allograft, and 8 (53%) had documented prior chronic GVHD. Only three cases received DLI before second transplant. Second transplant conditioning was fludarabine 25–30 mg/m2 for 5 days, melphalan 120–140 mg/m2 on day 1, and ATG was used in three (20%) cases. Donors were HLA-identical (n ¼ 10) or 1-locus mismatched (n ¼ 2) relatives or HLA-matched unrelated donors (n ¼ 3). The same donor was used in 9 cases (60%), with 14 (93%) using PBSC grafts. GVHD prophylaxis was CYA and MTX in the majority (n ¼ 11, 73%), the remainder used these agents alone or with mycophenolate mofetil. CMV serostatus was negative/negative in five cases (33%). The median follow-up for survivors was 6.1 years (range 4.9–8.0 years). Cumulative incidence of non-relapse mortality (NRM) was 13% at 12 months. Grade II–IV acute GVHD and chronic GVHD cumulative incidences were 43% and 53%, respectively. Cumulative incidence of relapse was 33% at 2 years, and the probability of OS and disease-free survival (DFS) at 3 years was 53% and 29%, respectively (Figure 1). At last follow-up 10 patients had died, causes of death being relapse (n ¼ 6), GVHD, infection, pneumonitis or haemorrhage (each n ¼ 1). Two patients with AML subsequently relapsed, although they remained alive at the last follow-up after subsequent therapies. Significant hazards for death on univariate analysis were the presence of acute GVHD after allo-HCT2 (hazard ratio (HR) 6.83, P ¼ 0.02) or the presence of GVHD of any type after both transplants (HR 6.93, P ¼ 0.008). After multivariate modelling neither of these factors retained significance. No other factors reached significance for OS or DFS. We compared this series with a recently reported comparison group receiving their first Flu-Mel allografts with identical conditioning in the same time period,7 matched for age, sex and diagnosis. There was no difference in 5-year OS (48 vs 40% for first vs second, P ¼ 0.5) or 5-year DFS (40 vs 27%, P ¼ 0.5). Three patients remained alive and relapse free with a median OS of 5.6 years (range ¼ 2.2–6.6). Median age at transplant was 55 years. Two had relapsed CML resistant to imatinib, one being transplanted in accelerated phase and one in chronic phase. Only one had DLI before second allograft, with no response. One had acute promyelocytic leukaemia in fourth CR, after failing salvage
Letter to the Editor
853 1.0
Survival %
0.8
Group
CONFLICT OF INTEREST
DFS OS DFS-censored OS-censored
The authors declare no conflict of interest.
0.6
40%
0.4
27% 0.2
0.0 0
1
2 3 4 Years post transplant
5
Figure 1. OS and DFS following second allograft with Flu-Mel conditioning.
therapies that included tretinoin and arsenic. Remissions after first transplant ranged from 2.9 to 13.1 years. One had prior GVHD and used a different (unrelated) donor, the others used the same donor. After allo-HCT2 none developed acute GVHD but all three developed chronic GVHD. In this series of patients receiving second transplants with Flu-Mel, we report acceptable toxicity and survival compared with previous published series of second transplants, and comparable outcomes when compared with patients receiving their first Flu-Mel transplant. Key findings include an NRM incidence of only 13% after 1 year, and probability of DFS of 29% at 3 years. Flu-Mel is a popular RIC regimen worldwide.8,9 An Australian study reporting the outcomes of Flu-Mel first transplants found NRM of 22% after 1 year, with 3-year OS and DFS of 57 and 50%, respectively.7 We compared outcomes of allo-HCT2 recipients with those from the original Flu-Mel data set, finding no differences in survival. Although encouraging, this may reflect a positive bias in those selected as fit for allo-HCT2. The outcomes also compare favourably with previously published outcomes for allo-HCT2 using RIC, with reported NRM between 23 and 41%, and OS of between 27 and 38.5%.5,6,10 These reports include a variety of conditioning regimens, paediatric recipients and often count autografts as the first transplant. A recent German registry report found no benefit in using a different donor for allo-HCT2 although it was not detrimental, and that there may be an advantage in using a related donor for allo-HCT2.3 Given our small sample size and heterogeneous patient group, we could not undertake meaningful analysis of survival factors. However, it is useful to note that two relapse-free survivors used the original donor, all developed chronic GVHD subsequently, all had long initial remission durations and none had AML. In conclusion, we present a series of second allogeneic transplants in adults using Flu-Mel conditioning, demonstrating 29% 3-year relapse-free survival with acceptable toxicity. Clearly the long-term outcomes need further improvement, particularly for AML patients; however, Flu-Mel conditioning with or without donor change is an acceptable choice for second allograft.
& 2014 Macmillan Publishers Limited
I Bilmon1,3, I Nivison-Smith2, M Hertzberg3, D Ritchie4, M Greenwood5, A Spencer6, G Kennedy7, A Bryant8 and J Moore1 1 Department of Haematology, St Vincent’s Hospital, Darlinghurst, New South Wales, Australia; 2 Australasian Bone Marrow Transplant Recipient Registry, Darlinghurst, New South Wales, Australia; 3 Department of Haematology, Westmead Hospital, Westmead, New South Wales, Australia; 4 Department of Haematology, Royal Melbourne Hospital, Parkville, Victoria, Australia; 5 Department of Haematology, Royal North Shore Hospital, St Leonards, New South Wales, Australia; 6 Department of Haematology, Alfred Health, Melbourne, Victoria, Australia; 7 Department of Haematology, Royal Brisbane Hospital, Herston, Queensland, Australia and 8 Department of Haematology, Liverpool Hospital, Liverpool, New South Wales, Australia E-mail:
[email protected]
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Bone Marrow Transplantation (2014) 852 – 853
