Abstract 3087
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potential to cure wide types of hematological diseases. A patient has 30% of chance to find a ...HLA-identical sibling donor while the rest of patients should find an alternative unrelated donor. The use of 10/10 HLA matched unrelated transplants has been used as a main alternative and with its unavailability, when available, a 9/10 HLA mismatched unrelated transplant has been used. The outcome of this last mismatched transplant is not very clear and its use according to patient and disease conditions has not been well defined yet.
To evaluate the outcome of allo-HSCT from 9/10 HLA mismatched unrelated donors compared to those from 10/10 HLA identical unrelated donors and siblings; and to define which category of patients can benefit the more in each alternative.
We have retrospectively studied the outcome of 213 patients who received allo-HSCT for different hematological malignancies, 121 (57%) from HLA identical siblings, 63 (29%) from 10/10 HLA identical unrelated donors and 29 (14%) from 9/10 HLA mismatched unrelated donors treated during the same period of time between 2006 and 2011 at our institution. In the mismatched group, 12 patients had the mismatch at HLA-A locus, 7 at the HLA-B, 7 at the HLA-C and 3 at the HLA-DQ. Characteristics between the 3 groups were comparable except for: disease type between the 2 unrelated groups, sex-matching, CMV-matching and ABO-matching. The different characteristics are detailed in Table 1. Display omitted
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After HSCT, engraftment was significantly lower in the 9/10 HLA group (90%) than in the 10/10 HLA group (95%) than in the sibling group (99%), (p=0.03); the cumulative incidence of acute GVHD ≥2 at 3 months was 32% (23–41), 20% (15–26) and 27% (23–32) respectively; the cumulative incidence of extensive chronic GVHD at one year was 21% (13–30), 9% (5–13) and 17% (14–21) for the 3 groups respectively. After a median follow-up of 8 months (0–54) in the 9/10 HLA group, 10 months (0–60) in the 10/10 HLA group and 18 months in the siblings group, the median overall survival (OS) was 10 months (5–21), 18 months (11-NR) and 60 months (31-NR) respectively with a 2-years probability of 19% (8–44), 43% (31–59) and 63% (54–74) respectively. There was a higher but not significant relapse incidence at one year in the 9/10 HLA group compared to other groups while the transplant related mortality was significantly higher with a cumulative incidence at 1 year of 45% (35–55), (p<0.001) (Table1-results). In multivariate analysis, OS was negatively affected by unrelated donors 9/10 HR=5 (2.7–10), p=0.0001; 10/10 HR=2 (1.2–4), p=0.01, female donors HR=2 (1.4–4), p=0.03 and disease status < CR1 or <chronic phase (CP) 1 HR=3 (1.4–6), p=0.003; while the TRM was negatively affected by unrelated donors 9/10 HR=9 (4–20), p<0.001; 10/10 HR=4 (1.2–10), p=0.03, female donors HR=3 (1.2–7); p=0.01 and ABO minor incompatibility HR=2.5 (1.2–5), p=0.01. The funnel plot showing the adjusted TRM according to all covariates and comparing to the global population death rate, shows that the 9/10 HLA group has the worse TRM independently of any other factor.
We showed that allo-HSCT from 9/10 HLA mismatched unrelated donors have a significantly worse OS than those from matched unrelated donors and siblings; this was mainly due to an increased TRM in this group. Patients in first CR or CP could benefit the more from matched or 9/10 unrelated allo-HSCT while the use of transplants from 9/10 HLA unrelated donors in patients not in CR1 or CP1 should be limited to clinical trials. In view of these results, we should consider and evaluate the use of cord blood as an alternative source of transplant according to patient and disease conditions.
No relevant conflicts of interest to declare.
Abstract 4093
Relapse remains a major cause of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hematological diseases. During the last decade, many ...improvements have been achieved in the understanding of the disease- and patient-related conditions in order to obtain the optimal allogeneic effect but the relapse is still representative which leaded to the development of different chemo- and immuno-therapy strategies.
To evaluate at a first time the different pre- and post-transplantation factors impacting the relapse occurrence after allo-HSCT, and at a second time, to evaluate factors impact the survival post-relapse including the different treatment options.
We have retrospectively studied the occurrence of relapse in 345 patients, 198 (57%) males and 147 (43%) females with a median age of 43 years (range17–66) who received allo-HSCT at our institution for hematological malignancies between years 2000 and 2011; 205 (59%) from siblings donors and 140 (41%) form unrelated donors. At transplantation, there were 148 (43%) patients in first complete response or first chronic phase (CR1/CP1), 66 (19%) in CR2/CP2 and 131 (38%) < CR2/CP2. Two hundred and six (60%) patients received a full intensity conditioning and 139 (40%) a reduced intensity one. The different patients and transplantations characteristics are detailed in Table 1.
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After HSCT, 336 (97%) patients engrafted. The cumulative incidence of acute GVHD≥2 at 3 months was 35% (95%CI 32–37); the cumulative incidence of extensive and limited chronic GVHD at one year was the same 15% (95%CI 13–17). After a median follow-up of 11.4 months (range 4–129), the median overall survival (OS) for the whole population was 19 months (range 12–33) with a 2-years probability of 47% (95%CI 42–53). Eighty eight (25.5%) patients relapsed with a cumulative incidence at one and two years of 19% (95%CI 17–21) and 22% (95%CI 20–24) respectively. Characteristics of relapsed patients are described in Table 1. After relapse, 65 (74%) patients were treated 21 (32%) received donor lymphocyte infusion (DLI) alone, 21 (32%) chemotherapy alone, 14 (22%) DLI + chemotherapy and 9 (14%) received other treatment and 23 (26%) were not treated due to deadly relapse.
The median OS from relapse was 4 months (range 3–5) and the one year probability of OS in patients who relapsed was 21% (95%CI 14–31). The multivariate analysis studying the impact of different variables on the occurrence of relapse showed a negative impact of disease status <CR/CP: HR=3.9 (2.4–6.7), p=0.0001, a negative impact of CMV status D+R-: HR=2.4 1.2–4.7, p=0.009 and a protective impact of cGVHD HR=0.37 (0.2–0.6), p=0.0002. The multivariate analysis studying the pre- and post-relapse variables on the survival after relapse showed a positive impact of ABO incompatibility Major ABO incompatibility: HR=0.39 (0.16–0.9), p=0.03, a negative impact of disease status <CR/CP: HR=2.4 (1.3–4.4), p=0.003 and a positive survival outcome in patients receiving DLI with or without chemotherapy HR=0.5 (0.3–0.8), p=0.005.
We showed that relapse after allo-HSCT in hematological malignancies is still a significant issue, disease status at HSCT and CMV matching worsen its occurrence while cGVHD can be protective. Survival rate after relapse is still very low reflecting the difficulty to find an optimal treatment, disease status at transplantation seem to have a long term effect while the use of DLI with or without chemotherapy can offer better results. In addition to the new chemotherapy molecules, immunotherapy should be used in order to enhance the graft-versus-leukemia effect not only after relapse, but also early in presence of a minimal residual disease.
No relevant conflicts of interest to declare.
Abstract 604
We recently demonstrated that a delayed time to find an unrelated HLA compatible donor and also to proceed to allogeneic-HSCT can worsen the transplantation outcome (Michallet et al. ASH ...2010). The French transplant registry has recently developed a software called “Easy Match” that predicts the number of HLA compatible donors for a given patient. The goal of our study is to validate this new program comparatively to a known score method (Tiercy et al. BMT 2007, 40; 515–522) and to improve the cost and search delay.
To accelerate the process of donor search using the results of EasyMatch program and define a new score for donor finding probability, in order to be time- and cost-efficient.
For the first step, we retrospectively analyzed 217 patients transplanted between 2009 and 2011 after finding an unrelated donor (identical or not) or cord blood units. We used the EasyMatch software which realized a “qualitative” analysis that consisted on checking that each HLA recipient phenotype was found among all possible pair wise combinations of 2 haplotypes of the different sets of haplotypes. Various “quantitative” analyses calculated the likelihood associated to each recipient phenotype for a given set of HLA genes, in a given population, at low versus high resolution typing. The EasyMatch software gave for each patient a number of potential donors sharing the same phenotype as the patient. We validated the probability given by the EasyMatch program with the known published score method.
For the second step, we used the new defined score prospectively for 62 new patients, directing the search in donor or cord blood files as stipulated by the probability to find a suitable 10/10 donor. We, therefore, analysed the number of complementary typing asked for each group of patients (before and after new score), and the delay between registration of the patient and identification of the donor or cord blood.
Our 217 patients were classified in 3 different categories according to the combined results of the EasyMatch software and the HLA score (Tiercy):
- Score 0 with low probability to find a suitable 10/10 donor (96% of transplantations performed with a non 10/10 donor in our study). The choice of the source will be defined considering the HLA characteristics of the recipient; in case of class I rare allele or rare HLA-BC linkage disequilibrium, a cord blood unit will be easier and more rapidly available. A complementary help should be given by an associated analysis with 4-digit haplotypes using the HaploStats program (http://www.haplostats.org/home.do).
- Score 1 with a median probability to identify a suitable 10/10 donor (67% of transplantations performed with a non 10/10 donor in our study).
- Score 2 with high probability to find a suitable 10/10 donor (95% of transplantations with a 10/10 donor in our study).
The number of supplementary HLA typing and the delay to identify a suitable donor or cord blood was significantly reduced when using the new score, in each of the three categories (table).
The EasyMatch program provides us (1) easy tracking of mismatches (2) estimation of the number of potential donors (3) selection of population following ethnic origin of patients and a high prediction when number of potential donors is higher than 5 or <1. Its use could be improved when coupled with a second scoring system.
In conclusion, the use of this new scoring system allows time and cost spare. In case of low chance to find a donor, physicians can switch to searching for unrelated HLA mismatched donor or a CBU, or to use another alternative treatment in order to keep an optimal result.TableScoreBefore scoreAfter scorep0Median nb of supplementary typingn=75n=31<0.001Delay (days)7.86.5144371Median nb of supplementary typingn=39n=120.003Delay (days)7.24.7561282Median nb of supplementary typingn=103n=190.05Delay (days)2.51.744630
Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Abstract 4180
Graft-versus-host disease (GvHD) is one of the most important complications after allogeneic hematopoietic stem cell transplantation (HSCT) and influences morbidity and mortality, even ...when the donor is a human leucocyte antigen (HLA)-matched sibling. Polymorphisms at genes coding for several proinflammatorycytokines and for their related receptors or receptor inhibitors are involved in this complication.
To assess the role of cytokine gene polymorphisms on acute GvHD (aGVHD), we analysed 189 pairs of donor and recipients transplanted from HLA identical sibling for malignant hematological diseases between 2000 and 2007, using a non T depleted graft after a myeloablativeor a reduced intensity conditioning regimen.
The median age of the recipients at transplantation was 43.4 years (1–68). Two third of the patients received bone marrow before myelo-ablative conditioning regimen and the median delay between diagnosis and transplantation was 9 months (1–76).
Five different polymorphisms from 3 cytokine genes were analyzed: IL-10 –592C/A, -819C/T and -1082G/A, IL-1b -511A/G and TGFb1 –509C/T.
All the pairs were studied for each gene polymorphism using the Taqman technology as previously described (Malkki2007). Each kit contains several primers pairs for amplification and two allele-specific probes, each of them conjugated with a different fluorescent marker. After amplification, analysis was driven on a Roche LC480 platform. The interpretation of the final results was performed using allelic discrimination specific software.
In our study, the frequencies of the TGFb1, IL1b, and IL-10 genotypes in recipients and donors were almost equal, and were consistent with previously reported results for the Caucasoid population and with the NCBI SNP databases.
Univariate analysis found a significant negative impact of donor genotypes carrying IL1b A allele (p=0,02) or IL10–592 A allele (p=0,03) on aGvHD.
We did not find any effect associated with IL10–819 and -1082 polymorphisms, but as previously described (Lin 2003), the presence of IL10 A-T-A haplotype in the donor, significantly increased the risk of aGVHD (p=0.043). We performed a multivariate analysis on aGVHD incidence taking into account TGFb1–509, IL-10–592 and IL1bpolymorphisms, together with other known risk factors.
A higher incidence of aGVHD was found in pairs where donor has an IL1b A allele (HR 4,16 - p=0,0031) and increased when the donor is A/A (HR>15 – p=0,0091). For IL10–592, the impact of the A allele was found different when carried by the donor (higher risk of aGVHD, HR 3,52 – p=0,00083) or the recipient (lower risk of aGVHD, HR 0,48 – p=0,024), but this effect seems only significant in pairs where donor did not carry any A allele (rec AC × don CC – HR 0.2 – p=0.05). Donor with TGFb1–509 T allele was found to have a significant lower risk of aGVHD (HR 0,42 – p=0,02). (table 1).
The role of the cytokine cascade in the physiopathology of GVHD is well established. Our study documents the possible role of IL-1b, TGFb1and IL10 gene polymorphisms in this setting.
A proven association of cytokine gene polymorphisms with acute GVHD would enable the clinician to modify the therapeutic strategy and enhance the outcomes.Table 1CytokineAllele recHRpAllele donHRpRecx donReferenceHRpIL1bA2.130.036AG × AGGG × GG4.160.0031GG × AGGG × GG4.350.028AA × AAGG × GG>150.0091TGFbT0.420.02CC × CTCC × CC0.250.012CT × CTCC × CC0.140.0013IL10-592A0.480.024A3.520.00083AC × ACCC × CC2.460.038CC × ACCC × CC4.930.013ACx CCCC × CC0.20.05
Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Abstract 5070
In a recent phase III trial, azacitidine was demonstrated to significantly prolong OS compared with conventional care regimens in patients classified in intermediate-2 and high-risk ...myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS) (Fenaux et al. 2009). This study used the French- American-British (FAB) classification for MDS and included approximately one third of patients with refractory anemia with excess blasts in transformation (RAEB-t; 20% to 30% bone marrow blasts). WHO criteria now define AML as ≥20% BM blasts. Using those criteria, RAEB-t is now considered as AML.
We conducted a retrospective analysis on patients who received azacitidine between August 2005 and November 2011 at our institution for MDS or AML. Patients were identified through the hospital database and individual charts were reviewed. The primary objective was to investigate the outcome of patients receiving azacitidine in a daily clinical practice in high risk MDS and AML patients and to evaluate its impact on overall survival (OS). Secondary objectives were hematological response rate and transfusion spare. Patients were included if they received at least one cycle of azacitidine. Disease status was defined by both the French American British (FAB) and the World Health Organization (WHO) classification systems, and risk was scored by the International Prognostic Scoring System (IPSS). All analyses were conducted using R statistical software. Descriptive statistics were used for baseline characteristics. Kaplan-Meier estimates were used to calculate overall survival (OS).
There were 79 patients, 51 (65%) males and 28 (35%) females with a median age of 70 years (32–85). The indication of azacitidine was the first line treatment use for MDS, mainly refractory anemia with excess blasts, in 40 (51%) patients (group1) and treatment for patients who had AML and transformed, in 39 (49%) patients (group2). (post chemotherapy: n=16, first line: n=23). Patient characteristics, prognostic factors according to FAB classification, ISPP risk and cytogenetics for both groups are shown in table1. The median number of azacitidine cycles in groups 1 and 2 was 8 (1–30) and 3 (1–29) respectively. Evaluation after 6 cycles showed 55% of responders in group 1 and 31% in group 2; the rest of patients have progressed. The median OS for the group 1 was 24. 5 months (17. 8-NR) while in group2; it was 15. 5 months (11. 2-NR) for patients who received AZA in first line and 6 months (3. 9-NR) for patients with previous chemotherapy. In terms of transfusions number, we did not find any significant spare in terms of both RBC and platelets transfusion in group1 while there was a significant spare of 33% of red blood cells transfusions (p=0. 05) and 42% of platelets transfusions only in group 2 (p=0. 04). The multivariate analysis studying the impact of different variables on OS showed: a worse OS in AML patients with previous chemotherapy (HR= 9. 84 3. 56 – 27. 19 , p< 0. 001), a worse OS in patients with unfavorable caryotype (HR= 7. 30 2. 13 – 24. 98 , p< 0. 001), and a better OS in female patients (HR= 0. 31 0. 14 – 0. 68 , p= 0. 003).
Our study confirmed results from previous prospective study in MDS patients while AML patients not receiving azacitidine in first line do not seem to benefit from this treatment. Cytogenetics remain a major factor impacting OS with no significant impact of IPSS.
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Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Abstract 4527
The main objective of this study was to determine the impact of serum ferritin level on the different allogeneic HSCT outcomes in adult patients with hematological disorders in addition ...to other disease and patient variables. We evaluated the implication of iron overload in the HSCT mortality causes and the potential role of iron chelation. We included 158 patients, 100 males and 58 females with a median age of 45 years (18–67) who underwent allo-HSCT between 2002 and 2010. There were 83 AML, 10 CML (3CP, 2AP, 5BC), 11 MDS (10 acute phase; 1 CMML), 7 myeloproliferative disorders, 19 MM, 9 NHL, 6 HDG, 5 aplastic anemia and 3 hemoglobinopathies. Sixty-seven (42%) patients were sex mismatched (F→M:37; M→F:30); for ABO compatibility, 61% were compatible, 18% had minor incompatibility and 21% had major incompatibility. For CMV status, 36% were sero-negative, 15% were D+R-, 18% were D-R+ and 31% were D+R+. Concerning the HSCT procedures, 60 patients (38%) received PBSC and 98 (62%) received BM from 97 (61%) HLA related donors matched, n=76; mismatched, n=21, and 61 (39%) HLA unrelated donors matched, n=36; mismatched, n=25 after MAC n=64, (41%) or RIC n=94, (59%). At transplantation, 91 (58%) were in CR or CP CR1: n=61 (67%); ≥CR2: n=30 (33%) and the rest of patients were in less that CR or CP n=67 (42%). The median serum ferritin level at HSCT was 1327 microg./l (26–14136); 31(20%) patients had a level 26–500, 33 (21%) had a level 500–2500, and 94 (59%) >2500. There were no significant correlation between the different ferritin levels, disease kind and status at HSCT. Twenty two patients received iron chelating agents (Exjade, n=19; Desferal, n=3). After allo-HSCT, the cumulative incidence of acute GVHD ≥ II at 3 months was 14% (11–16.5) with 10.5% (8–13) for grade III and 7% (5–9) for grade IV; the 1 year cumulative incidence of limited and extensive chronic GVHD were 4% (2–6) and 12.4% (9–16) respectively. After a median follow-up of 18 months (1–106), the median OS was 25 months (16-NR) with a 2 years probability of 50% (43–59). The median PFS was 13.5 months (9–25) with a 2 years probability of 43% (34–50). The cumulative incidence of relapse at 1 year was 31% (27–34), the TRM rate was 6.5% (4.5–8.5) and 20% (17–23.5) at 3 months and 1 year respectively. We performed a multivariate analysis taking into account the patient age, gender, diagnosis, disease status a allo-HSCT, matching variables (sex, ABO, HLA, CMV), conditioning/HSC source and the different serum ferritin levels; the different results are shown in table1. Interestingly, we found that ferritin level >500 has a significant impact on OS which is explained by a significant higher TRM for patients with level >2500 and a significant mortality after relapse in patients with level 500–2500 (figure).
The analysis on effect of iron chelating agents is ongoing and results will be communicated later.
Serum ferritin level has been previously shown to impact on allo-HSCT survival without a clear explanation of its implication and at which level; in our study, we demonstrated that this survival difference is caused in part by higher TRM and the other part by mortality after relapse.
In conclusion, we should give a better attention to iron overload, confer an efficient follow-up of this parameter and provide a treatment strategy after allo-HSCT especially when its level reaches 500μg/l at transplantation.
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Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Abstract Data from 42 adult patients with newly diagnosed minimally differentiated (M0) acute myeloid leukemia (AML) were reported. Clinical and biological characteristics at diagnosis were ...heterogenous. All patients received induction chemotherapy combining an anthracycline with cytarabine. Complete remission (CR) was achieved in 22 cases (52%). Most patients received continuation chemotherapy. Median disease-free survival (DFS) was 13.6 months with a 2-year survival rate of 28%. As post-remission therapy, 7 patients could be allografted and showed an encouraging outcome. Overall, 14 patients have relapsed (63%) after a median time of 10.2 months. Median overall survival (OS) was 20.5 months with a 5-year survival rate of 18%. This retrospective analysis points to a somewhat heterogenous group of AML in terms of biological features and outcome, and warrants a larger multicenter study with study in molecular biology to clarify treatment effects further.
Abstract 2038
Anti-HLA antibodies are associated with several complications in solid organ transplantations but their impact after allogeneic hematopoietic stem cell transplantation (HSCT) is not ...very well defined yet.
To evaluate the relevance of anti-HLA antibodies, we have retrospectively analyzed 107 peripheral blood allogeneic HSCT after reduced-intensity conditioning (RIC) regimen between 2005 and 2010. Acute myeloid leukaemia (n=52,48.5%) and multiple myeloma (n=18,17%) were the most common diagnosis in the cohort. The detection of anti-HLA antibodies was systematically performed in all patients before transplantation.
We found in 24 patients (22%) the presence of anti-HLA antibodies. There was no association between the presence of anti-HLA antibodies and engraftment, incidence of relapse or acute GvHD. The presence of anti-HLA antibodies was associated with worse survival in univariate analysis (HR 2.04; 95%CI,1.21–3.44, p=0.0056) and in multivariate analysis (HR 2.63; 95%CI, 1.32–5.25, p=0.006). The 3-year probability of OS was 34% (95%CI, 24–49) without anti-HLA antibodies and 16% (95%CI, 6–41) in their presence (Figure 1). The other significant factors on survival were the disease status at transplantation, the age, minor and major ABO incompatibilities between donor and recipient, the sex-mismatching and the CMV status. Moreover, the positive anti-HLA antibodies group showed a trend of higher TRM in univariate analysis (p=0.07) and in multivariate analysis (HR= 1.9; 95%CI, 0.94 – 3.9, p=0.076). The TRM at 3 years after transplantation were 31% (95%CI, 26–37) without anti-HLA antibodies and 46% (95%CI, 36–57) in their presence (figure 2). The causes of the pejorative effect of the anti-HLA antibodies were not defined yet but we observed microangiopathy associated with vascular endothelium damage which could be related to the presence of anti-HLA antibodies. Display omitted Display omitted
Our study suggests that anti-HLA antibodies should be tested and considered as an important prognostic factor for transplant outcomes after RIC HSCT.
No relevant conflicts of interest to declare.
Abstract 1957▪▪This icon denotes a clinically relevant abstract
The FLAMSA sequential chemotherapy regimen followed by RIC for allo-HSCT and prophylactic donor lymphocyte transfusion (pDLT) was ...introduced a few years ago as a salvage therapy for patients with refractory or high risk AML/MDS. This retrospective analysis aimed to assess the outcome of 40 patients with refractory or high risk AML/MDS who received a salvage FLAMSA sequential chemotherapy (including a subgroup of patients who received a modified FLAMSA regimen incorporating Busulfan instead of total-body irradiation (TBI)).
This series included 30 males and 10 females with a median age of 52 years (range, 32–66) treated in 2 transplant centres in France. Diseases characteristics were as follow: progressive or refractory disease after rescue treatment for first relapse (n=21), early relapse without any further salvage therapy (n=4), and primary induction failure (PIF; n=4). The series also included 7 patients with high risk MDS (IPSS ≥ 1.5), and another 4 patients in first CR but having a very poor prognosis based on cytogenetics features (CR group hereinafter). According to cytogenetics and molecular markers, 12 patients were classified in the “standard risk” cytogenetics risk group, while 21 patients had an unfavourable/poor profile. Data were not available for 7 patients.
The FLAMSA regimen included Fludarabine (30 mg/m2/d), cytarabine (2 g/m2/d) and amsacrine (100mg/m2/d) from day −12 to day −9. In addition, priming with G-CSF once daily was done in 12 patients. After 3 days of rest, a RIC regimen was administered. In 28 patients, the RIC regimen included 4 Gy. TBI, ATG 5 mg/kg total dose, and cyclophosphamide (40 mg/kg in case of matched related donors, and 60 mg/kg for unrelated or mismatched donors). In the remaining 12 patients, TBI was replaced by I.V. Busulfan 3.2 mg/kg/d for 4 days. Per protocol, pDLT was planned to be given from day +120 in patients who were not receiving immunosuppression and were free of GvHD. Eighteen patients were transplanted using an HLA identical sibling donor, and 22 received transplant from an unrelated donor (14 matched 10/10 and 8 mismatched 9/10).
After allo-HSCT, 39 patients (97.5%) engrafted. In the CR group (n=4), after a median follow-up of 5 months (range, 3–31) all patients were still alive in CR at last follow-up. In the remaining 36 patients, 9 patients developed acute GVHD ≥2 with a cumulative incidence at 3 months of 18% (95%CI, 10–26). At day 90 post HSCT, 23 (64%) patients could achieve hematological CR, and 14 of the 23 remained in CR at last follow-up.
After a median follow-up of 6 months (range, 1–60), the 2-years probability of OS was 30% (95%CI, 17–52), and the 2-years probability of PFS was 29% (95%CI, 17–50). The cumulative incidence of disease progression at 1 year was 25% (95%CI, 18–33). Interestingly, none of the patients who received Busulfan instead of TBI as part of the RIC, relapsed. The cumulative incidence of TRM at 3 months and 1 year were 14% (95%CI, 8–20) and 22% (95%CI, 15–29), respectively.
In the multivariate analysis (taking into account all relevant parameters such as priming with G-CSF, conditioning with or without TBI, related or unrelated donors, HLA matching and number of previous treatment lines), there was a significantly worsened PFS in patients who received transplant from a mismatched donor (HR=3.6; 95%CI, 1.3–10 p=0.01; below Figure). Also, when considering disease relapse, there was a highly significant impact of the type of RIC regimen (in favour of a FLAMSA regimen without TBI (p<0.0001, Figure).
Despite its limitations, results from this analysis confirm that a FLAMSA sequential chemotherapy regimen followed by RIC and allo-HSCT is a valid salvage therapy for patients with refractory or high risk AML/MDS. This study shows that HLA mismatched donors should be avoided in FLAMSA regimen. Moreover a modified FLAMSA regimen incorporating I.V. Busulfan instead of TBI is likely to allow better long-term disease control, warranting prospective evaluation. Display omitted
No relevant conflicts of interest to declare.
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