Hematopoietic Stem Cell Transplantation For AML Research Articles

Overcoming relapse: prophylactic or pre-emptive use of azacitidine or FLT3 inhibitors after allogeneic transplantation for AML or MDS.

Relapse remains the most critical obstacle in treatment by allogeneic hematopoietic stem cell transplantation (HSCT). Non-relapse mortality has improved annually, but relapse mortality remains high. Post-transplant maintenance treatment, such as hypomethylating agents and FMS-like tyrosine kinase 3 (FLT3) inhibitors, has been investigated for decades as a means of preventing disease relapse after HSCT. Other factors besides the relapse tendency of the primary disease that can affect the transition of estimated disease burden in patients undergoing HSCT are disease status at HSCT (non-remission, remission with minimal/measurable residual disease (MRD), and remission without MRD) and conditioning regimen intensity. Optimal selection of patients at high risk for relapse who can tolerate a long duration of therapy is pivotal for successful post-transplant maintenance therapy. In this review, we provide an overview of current progress in research on post-transplant maintenance treatment using azacitidine or FLT3 inhibitors for preventing disease relapse after HSCT for AML or MDS, and discuss the future outlook in this area.

Increased Inhibitory KIR-Ligand Interactions Confer Relapse Protection Following HLA Matched Unrelated Donor HCT for AML

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated graft versus leukemia effect (GVL) after hematopoietic stem cell transplant (HCT) for AML. There is considerable heterogeneity in the KIR gene and KIRL content of individuals, making it difficult to estimate the full clinical impact of NK cell alloreactivity following HCT. Herein, we validate a mathematical model accounting for KIR-KIRL interactions identifying donors with optimal NK cell-mediated alloreactivity and GVL. This retrospective study was performed on de-identified donor and recipient demographic and clinical outcomes data provided by the Center for International Blood and Marrow Transplant Research (CIBMTR). Donor recipient pairs (DRP) who underwent unrelated donor (URD) HCT for early and intermediate AML were included. KIR-KIRL interaction values were assigned as follows; if an inhibitory KIR (iKIR) on the NK cell encounters a ligand on its target, this will give the NK cell an inhibitory signal and this is scored as a single interaction(Figure 1b), as is the case, if there is no ligand for an inhibitory KIR, i.e., missing KIRL (mKIRL) (Figure 1c). Finally, activating KIR (aKIR) interacting with its ligands is similarly scored(Figure 1a). The absolute values of the iKIR and mKIR scores were summed to calculate the composite inhibitory-missing ligand (IM)-KIR score (Figure 1d). The study cohort was comprised of 2365 donor-recipient pairs (DRP) who underwent URD HCT for early or intermediate AML. Mean age was 53 years; 85% of DRPs were high-resolution 8/8 HLA-matched for HLA-A, -B, -C, and -DRB1. All patients received T cell replete grafts; 42% (n=996) received in vivo T cell depletion, 937 (94%) with anti-thymocyte globulin (ATG); 86% received a graft of mobilized peripheral blood stem cells (PBSC), 59% received myeloablative conditioning. This cohort was primarily of Caucasian descent (89%). When adjusted for recipient age, donor age, CMV status, KPS, GVHD prophylaxis, cytogenetics, disease status, conditioning regimen, in vivo T cell depletion, graft source, and sex match, relapse risk was significantly reduced in donor-recipient pairs (DRP) with higher inhibitory KIR-KIRL interaction and missing KIRL (mKIR) scores, with HR=0.86 (P=0.01) & HR=0.84 (P=0.02) respectively. This effect was not observed with activating KIR-KIRL interactions. Chronic GVHD and TRM were not significantly affected by iKIR, mKIR or aKIR. Given the significant individual impact of iKIR and mKIR, the summed inhibitory-missing ligand (IM-KIR) score was next assessed, and when this score was 5 (as opposed to <5), the IM-KIR score was also associated with lower relapse risk, HR 0.8 (P=0.004) (Figure 2a). Acute and chronic graft vs. host disease (GVHD), survival, GRFS, and relapse-free survival were not significantly different, likely due to increased TRM among these patients, HR 1.32 (P=0.01). Interaction analysis indicated that amongst the HLA matched DRP, ATG recipients with IM-KIR=5, had a lower relapse rate compared to those with an IM-KIR<5, HR 0.61 (p=0.001) (Figure 2b), among the cohort who did not receive ATG there was no significant difference in relapse among IM-KIR=5 and IM-KIR<5; thus, the use of ATG significantly modified the effect of IM KIR score in an interaction analysis (p=0.049), suggesting higher NK cell magnitude of KIR-KIRL interaction may compensate for the general increase of relapse in those who receive in vivo T cell depletion. Nevertheless, TRM was also increased in these patients, HR 1.49 (p=0.034), likely abrogating survival advantage from a lower relapse risk. This large international study confirms that unrelated DRPs with greater magnitude of inhibitory KIR-KIRL interactions confer significant relapse protection after MUD HCT in standard-risk AML. This challenges the notion that KIR are irrelevant to donor selection. Future clinical trials evaluating donor selection for URD HCT should include this measure to evaluate its value prospectively in uniformly treated patient cohorts, with adequate GVHD and antiviral prophylaxis to mitigate TRM. Disclosures No relevant conflicts of interest to declare.

Impact of Age on the Outcomes of HCT for AML in CR1: Promising Therapy for Older Adults

Background Acute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The only curative therapy remains an allogeneic hematopoietic stem cell transplant (HCT), yet it is complicated by non-relapse mortality (NRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in a large cohort of patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1). Methods HCT recipients 60 years or older with AML in CR1 reported to the CIBMTR were included. Cox models were used to compare rates of overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), relapse, acute GHVD, chronic GVHD in 3 separate age groups: 60-64 years vs. 65-70 years vs. 70+ years (Figure 1A). Results 1,327 patients undergoing HCT from 2007-2017 were included. The three age cohorts (60-64; 65-69; 70+) were comparable in demographic and disease characteristics, except the older cohort had more males, more de novo AML, and a higher incidence of measurable residual disease (MRD) pre-HCT. Fewer had sibling donors and more were performed in recent years. With median follow-up of nearly 3 years, patients aged 60-64 had significantly better OS, DFS and lower NRM than those aged 65-69 and 70+. Those aged 65-69 and 70+ had similar outcomes (Figure 1). Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p=0.026). NRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥ 3. Conditioning intensity was not a significant predictor of outcomes with HR for OS for 60-69 cohort of 0.46 for RIC and 0.49 for MAC (p=0.38). There was no difference in the relapse rate, incidence of G3/4 acute GVHD, or incidence of moderate-severe chronic GVHD across the age cohorts. Poor risk cytogenetics, presence of MRD prior to HCT, cord blood as graft source, and transplant prior to 2016 were significant predictors of poor OS. Discussion In this large retrospective series of HCT for AML in CR1, age had a small effect OS and NRM after accounting for other predictors. High-risk features such as poor cytogenetics and presence of MRD prior to HCT were significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection. Table Disclosures Kebriaei: Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Jazz: Consultancy; Amgen: Other: Research Support; Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board. Weisdorf:FATE Therapeutics: Consultancy; Incyte: Research Funding.

Multiple Functional Donor Polymorphisms in IL1RL1 region Associate with Death Due to GvHD or Infection after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for AML and MDS

The last two authors contributed equallyElevated soluble Stimulation-2 (sST2), the decoy IL-33 receptor, in plasma/serum post-HSCT is a biomarker for death due to GvHD. ST2 is the product of IL1RL1 (2q12.1) and this ~.5Mb region contains >300 single nucleotide polymorphisms (SNPs) significantly associated (P<5x10-8) with plasma levels of sST2 in healthy participants from the Framingham Heart Study (FHS). Many of these SNPs are genome-wide associated with infection-related phenotypes, including asthma, Crohn's disease, ulcerative colitis and celiac disease. Given these relationships, we analyzed the association of ST2 SNPs with death due to GvHD or infection within one year after HLA-matched unrelated donor HCT for AML or MDS to identify functional SNPs that could potentially aid in donor selection.We measured plasma/serum sST2 levels in pre-HCT samples in a subset of AML and MDS patients (n=759) and their donors (n=757) from DISCOVeRY-BMT, a GWAS of >3,000 recipient-unrelated donor pairs reported to the CIBMTR between 2000-2011. After quality control (info>.8, MAF>.005), 3613 SNPs in the IL1RL1 region were tested for association with sST2 levels; 1541 donor SNPs associated with sST2 levels (P<.05), which validated 99% of the FHS sST2 SNP associations. To assess the contribution of these donor variants to post-HCT survival, we constructed competing risk models with clinical variables using stepwise Akaike Information Criterion (AIC), then tested each of the 1541 donor SNPs for association with each outcome in the two DISCOVeRY-BMT cohorts. Causes of death were previously adjudicated by a multi-member panel. Meta-analyses of the two cohorts identified 13 GvHD-death associated SNPs and 118 infection-death associated SNPs. Sensitivity analyses show 91/118 SNPs are still significant after excluding patients with a history of acute GvHD grade III-IV (Figure 1). When taking correlations into account, we found 10 and three independent SNPs (R2<.6) associate with death due to infection and GvHD, respectively. There were no overlapping SNP associations between GvHD-death or infection-death (Figure 1). For GvHD-death associated SNPs, alleles associated with higher sST2 levels associate with increased risk for GvHD-death, while for infection-death SNPs, alleles associated with higher sST2 levels reduced risk of infection-death.AIC multivariable models for GvHD-death included AML diagnosis, recipient obesity (>30 mg/kg2), peripheral blood cell source, donor age, rs1558645 (Pmeta=.001), and rs2310241(Pmeta=.0003), for which the risk alleles at each SNP increased risk of GvHD death ~1.5 fold. The model for infection-death included advanced disease at HCT, recipient/donor CMV status, peripheral blood cell source, rs13019803 (Pmeta=1.1 x 10-6), rs13015714 (Pmeta=5 x 10-4) and rs4851601 (Pmeta=2 x 10-6), with risk alleles at each SNP increasing risk of infection-death ~2-fold. To capture the total contribution of these donor variants to each outcome we created multi-allele models for GvHD-death (0-4 alleles) and infection-death (0-6 alleles).The multi-allele GvHD models showed a 1.5 fold increased risk of GvHD-death with each additional allele (Pmeta=3.4 x 10-6 ) (Figure 2). Individuals whose donors are homozygous for both risk alleles at each SNP have a ~3 fold, and ~2 fold higher risk of dying of GvHD versus those with zero, and 1-2 risk allele(s), respectively. The multi-allele infection models (0-6 alleles) show a ~2 fold increased risk of infection-death (Pmeta= 1.22 x 10-10) with each risk allele (Figure 2).sST2 is one of the most reproducible GvHD biomarkers to date. As hypothesized, specific alleles correlated with high sST2 levels in donors and with GvHD-death. Our novel finding is that some ST2 alleles associated with low sST2 levels correlated with infection-death. These results are not without precedent, for example the low-sST2 associated allele in rs13019803 (T) associates with higher mortality in the CHARGE consortium. The risk allele in rs13015714 (T) is significantly associated with lower IL1RL1 and IL18R1 (P= 5 x 10-10) gene expression in lung tissue, indicating biochemical functions for these SNPs. Importantly the non-risk allele in all 5 variants are common (>20%) across races and ethnicities, which means there is an opportunity to select donors without combinations of these variants and perhaps without the requirement of measuring the protein level pre-transplant. [Display omitted] DisclosuresMcCarthy:Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Lee:Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding; Takeda: Research Funding. Paczesny:Viracor IBT Laboratories: Patents & Royalties.

Influence Of Killer Immunoglobulin-Like Receptor (KIR) and HLA Genotypes On Outcomes After Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation For Patients With AML and MDS: A Report From The Center For International Blood and Marrow Transplant Research Immunobiology Working Committee

Disease relapse is a significant cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HCT). In the setting of reduced-intensity conditioning (RIC), a graft-versus-leukemia (GVL) effect is critical for successful outcomes in patients with advanced myeloid malignancies. A GVL effect has been attributed in part to donor-derived alloreactive natural killer (NK) cells, which are regulated by interaction of KIRs with their HLA-class I ligands. Several models of NK reactivity (missing KIR ligand, centromeric haplotype-B content, non-tolerized KIR2DS1) have been associated with improved outcomes following HLA-matched, HLA-mismatched, related, and unrelated donor HCT, particularly for AML patients given myeloablative conditioning. The effect of KIR-HLA combinations on outcomes after RIC HCT, however, is not known. We retrospectively analyzed donor-recipient KIR/HLA genotypes from 929 URD HCTs facilitated by the National Marrow Donor Program for patients with AML (n=624) or MDS (n=305) treated with RIC between 1990 and 2007. 664 donor-recipient pairs were 10/10 HLA-matched and 265 were 9/10 HLA-matched. 332 (37%) patients received ATG and 73 (8%) received alemtuzumab. P-values less than 0.01 were considered significant. We hypothesized that donor-recipient KIR-HLA interactions may be associated with improved post-transplant outcomes following RIC HCT for AML and MDS. Patients lacking the HLA-Bw4 ligand for donor inhibitory KIR3DL1 experienced lower relapse following HCT at 1 year (27 vs 36%, p=0.002) and 5 years (31 vs 42%, p=0.003) compared to patients with the Bw4 ligand (Figure). The lower risk for relapse was confirmed in multivariate analysis (HR 0.71, p=0.005). However, there was no significant association of Bw4 ligand with disease-free survival (HR 0.84, p=0.05) and overall survival (HR=0.97, p=0.70). Risk for acute GVHD was higher among patients lacking KIR ligands after adjusting for other clinical factors. In particular, patients lacking HLA-C2 for donor KIR2DL1 experienced higher grade 2-4 (HR 1.3, p=0.005) and 3-4 acute GVHD (HR 1.5, p=0.002), and patients lacking multiple KIR ligands experienced higher grade 3-4 acute GVHD (HR 1.5, p=0.007). The analysis was then restricted to AML patients, the patient population with greatest reported KIR-HLA effects. Patients whose donors were KIR2DS1+ and HLA-C2C2 (n=33) had higher transplant-related mortality (TRM) (HR, 2.4, p=0.002) compared to all other patients. There was no significant effect of KIR2DS1 with HLA on relapse. In a multivariate analysis, lack of HLA-C2 in AML patients was associated with higher grade 2-4 (HR 1.4, p=0.002) and 3-4 acute GVHD (HR 1.5, p=0.01), and risk for grade 3-4 acute GVHD was higher in patients lacking multiple KIR ligands (HR 1.6, p=0.005). There were no significant associations between donor homozygosity for the centromeric B-haplotype (cenBB) or overall B-haplotype KIR content and RIC HCT outcomes.Overall, these results suggest that in the RIC HCT setting, lack of Bw4 ligand for KIR3DL1 is associated with a lower risk of relapse for AML/MDS. This observation corroborates previous findings in myeloablative HCT transplants. Furthermore, tolerance of donor KIR2DS1 by HLA-C2C2 was associated with worse outcome, as manifested by higher TRM, in AML patients. In contrast, it appears that in RIC HCT homozygosity for the centromeric B-haplotype does not have a significant role in leukemia relapse. The associations of KIR ligands with acute GVHD were not previously observed suggesting that NK cell alloreactivity depends on multiple variables, including RIC. Further elucidation of the biology of NK cell alloreactivity in the RIC setting may provide guidance for future approaches to help optimize conditions for generating GVL reactions without GVHD and less TRM in this transplant population. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: long-term follow-up

Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: long-term follow-up

Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloblastic Leukemia (AML) or Myelodysplastic Syndrome (MDS) in Patients (pts) Older Than 50 Years: a Retrospective Single Center Study

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment in MDS, and also in many cases of AML, 2 diseases where median age is higher than 50 years.Aim: Analyse the outcome of patients older than 50 years who received an allogeneic hematopoietic stem cell transplantation (HSCT) for MDS or AML, in Saint-Louis Hospital from January 1997 to December 2007.Method: 48 patients (pts) aged from 50 to 68 years (median: 56) received an HSCT for MDS (N=28) or AML (N=20) during this period. AML pts had intermediate (n=15) or high risk cytogenetics (n=3). 8 pts had failure to initial induction chemotherapy. FAB classification for MDS was: RAEB (n=8), RAEBt (n=6), secondary AML (n=2) or refractory anemia (n=2). Maximal IPSS score was high, intermediate-2 and intermediate-1 in 11, 14 and 4 pts. Ten pts with MDS received an “AML-like” chemotherapy and 5 received demethylating agents before transplant. 18 of the AML pts were in complete remission (CR) at time of transplant (CR1, n=15; CR2, n=3) and 2 were in relapse at time of HSCT. 10, 9 and 9 patients with MDS had < 5%, 5–10% and > 10% blasts in bone marrow at time of HSCT.Results: 19 patients with AML (95%) and 16 patients with MDS (57%) received a HSCT from an HLA-identical sibling donor. Other pts received a matched unrelated donor. Thirty-two pts, including 9/20 and 23/28 had at least one co-morbidity according to Sorror score. The conditioning regimen was myeloablative (MAC) in 14 pts (29%). Reduced intensity (RIC) was fludarabine based in 34 pts, associated with either 2 Gy TBI (n=25) or chemotherapy (n=9). All pts engrafted. 35 pts had acute graft-versus-host disease (GVHD): grade I in 11, grade II in 18 and grade III in 6. GVHD incidence did not differ between pts who received a MAC or a RIC regimen. Two-year overall survival (OS) was 41% (95% CI: 26–57). OS and relapse-free-survival (RFS) were similar after MAC or RIC regimen (OS: 29% vs 35% and RFS: 29% vs 30%). Short-term non-relapse mortality (NRM) was lower in patients who received a RIC as compared to patients who received a MAC regimen but was similar at long-term (6-month NRM = 21% vs 9% and 12-month NRM = 21 vs 19 %). Patients with AML or MDS had similar OS and RFS (OS: 42 vs 41%; RFS: 37 vs 26% at 2 years for AML and MDS, respectively). NRM was not significantly higher in pts with MDS (26 vs 10% at one year) whereas relapse rate was not significantly higher in pts with AML (13 vs 6%).Conclusion: HSCT for AML or MDS after 50 years is a curative option for pts with related or unrelated HLA-identical donor regardless kind of conditioning regimen and co-morbidity at time of transplantation.

Allogeneic Hematopoietic Stem-Cell Transplantation in AML and MDS Using Myeloablative Versus Reduced Intensity Conditioning: Long-Term Follow-up.

Allogeneic stem-cell transplantation (SCT) with both myeloablative and reducedintensity conditioning (RIC) is effective therapy in AML and MDS. However, the relative merits of each may differ in different settings and the long-term outcome is less defined. We have previously reported on the role of dose intensity in a group of 112 patients (pts) with AML/MDS given allogeneic SCT with different regimens (Leukemia 2006). We showed that survival was similar with myeloablative conditioning and RIC in pts given SCT in remission, but was inferior in pts given RIC in active disease due to high post transplant relapse rates. We have now updated SCT outcomes with an additional 3-year follow-up in the same cohort, to better predict long-term outcome and confirm that late events did not change the initial conclusions. The study group included 112 consecutive pts with AML/ MDS transplanted over a 5-year period. The median age at SCT was 50 years (18–70). Eighty-five pts had AML (39 secondary) and 17 had MDS (all with excess of blasts). Fiftyeight had active disease at SCT (>10% marrow blasts) and 54 were in remission. The donor was HLA-matched sibling (n=58), 1-ag mismatched related (n=6) and matched-unrelated (n=48). Forty-five pts met eligibility criteria for standard myeloablative conditioning and were given intravenous-busulfan (12.8 mg/kg) and cyclophosphamide (ivBuCy). Sixtyseven pts were considered non-eligible for standard myeloablation due to advanced age (over 55 years for sibling SCT or over 50 years for mismatched or unrelated SCT), extensive prior therapy, organ dysfunction, recent fungal infection or poor performance status. These pts were given RIC with fludarabine and intravenous-busulfan (6.4 mg/kg, FB2, n=41) or modified myeloablative regimen with fludarabine and myeloablative doses of intravenous-busulfan (12.8 mg/kg, FB4, n=26). The median age of this group was 55 years compared with 42 years in the first group, and a larger proportion had SCT from unrelated donors. With a median follow-up of 5.1 years (3.3–8.6), 45 pts are alive and 67 have died (45 relapse, 22 non-relapse causes). Overall survival (OS) at 5 years was 48%, 31%, and 38% after ivBuCy, FB4, and FB2, respectively (p=NS). Active disease at SCT and poor-risk cytogenetics were the most significant factors predicting reduced survival in multivariable analysis with hazard ratios of 3.5 (p=0.0001) and 1.7 (p=0.04), respectively. Advanced age, secondary disease, donor and conditioning type had no prognostic significance. Myeloablative conditioning and RIC had similar outcomes when leukemia was in remission at SCT; estimated 5-year OS been 49%, 50% and 58% after ivBuCy, FB4, and FB2, respectively (p=NS). There was a non-statistically significant trend for lower non-relapse mortality (NRM) but higher relapse rate with FB2 resulting in similar OS in this setting. However pts with active disease could only be salvaged by myeloablative regimens (classical or modified). Among the later group, OS was 41% and 19% after ivBuCy and FB4, respectively, but no FB2 recipient survived (p=0.009). This was related to significantly higher relapse rates with the less intensive regimens in this setting (p=0.0005), while NRM was similar. These observations confirm with a longterm follow-up that RIC is associated with favorable outcome and low toxicity in pts in remission at SCT and therefore can be further studied in prospective trials comparing it to myeloablative regimens even in pts eligible for the later. However, RIC is a poor option for pts with active disease. Pts with active disease not eligible for standard myeloablation can still tolerate the modified myeloablative regimen (FB4) and a fraction can be salvaged. These observations merit further study in randomized prospective studies.

Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity

Allogeneic stem-cell transplantation (SCT) with both myeloablative and reduced-intensity conditioning (RIC) is an effective therapy in AML/MDS. However, the relative merits of each may differ in different settings. To define the role of dose intensity, we analyzed SCT outcomes of 112 consecutive patients with AML/MDS. A total of 45 patients met eligibility criteria for standard myeloablative conditioning and were given intravenous-busulfan (12.8 mg/kg) and cyclophosphamide (ivBuCy). A total of 67 noneligible patients were given RIC with fludarabine and intravenous-busulfan (6.4 mg/kg, FB2, n=41) or a modified myeloablative regimen with fludarabine and myeloablative doses of intravenous-busulfan (12.8 mg/kg, FB4, n=26). The overall survival (OS) at 2 years was 50, 49 and 47% after ivBuCy, FB4 and FB2, respectively (P=NS). Nonrelapse mortality was higher after ivBuCy, 22 vs 8% (P=0.05), but relapse rates were lower. Active disease at SCT was the most significant predictor of reduced survival in multivariable analysis (HR 4.5, P=0.0001). Myeloablative and RIC regimens had similar outcomes when leukemia was in remission at SCT; however, patients with active disease could only be salvaged by myeloablative conditioning. Among the latter, OS was 45% after ivBuCy but no FB2 recipient survived (P=0.02). Patients with active disease, ineligible for standard myeloablation, could tolerate modified myeloablation well; however, long-term outcome cannot be determined yet.

Prognostic Factors for Outcome of Patients Undergoing Allogeneic HSCT from Unrelated and Related Donors for AML and MDS: A Retrospective Analysis.

PURPOSE: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for many patients with myeloid leukemia, especially in refractory or relapsed disease. To determine prognostic factors that correlate with outcomes after HSCT in adults with AML and MDS we analysed several clinical and haematological parameters.PATIENTS AND METHODS: In this unicenter retrospective study, we studied 120 adults who received allogeneic HSCT for AML (n=88) or MDS (n=32) between 1993 and 2003. The median age was 44 years (range 21–72), included were 59 male and 61 female patients. 42% of the patients were transplanted in first complete remission (CR1), 17% were transplanted in CR after salvage therapy and 41% were in relapse or refractory to induction or salvage therapy. The grafts consisted in 88 cases (73%) of PBSCT and in 32 cases of bone marrow, in 34% unrelated donors were used. The medium number of infused CD34+ cells was 5.51x106/kg. As conditioning regimen standard myeloablative therapies without (53%) or with (25%) TBI, or a non-myeloablative regimen including TBI (22%) were used. The prognostic impact for several groups with different clinical and hematological parameters were assessed by univariate and multivariate analyses using the Cox regression model.RESULTS: One-year and three-year probabilities of overall survival (OS) were 52% (48% to 57%) and 38% (36% to 43%). In univariate analysis, remission status and cGvHD were significantly associated with OS (CR vs. non-CR p=0.00001; cGvHD vs. non-cGvHD p=0.00001). Median OS for patients who underwent transplantation in CR were 2374 vs 180 days and for chronic GvHD 2374 vs 294 days. One-year and three-year probabilities of relapse were 30% (31% to 17%) and 31% (34% to 24%). CR, cGvHD and ablative regimens resulted in a lower relapse rate (p=0.00001; p=0.0002, p=0.028). One-year and three-year probabilities of transplant-related mortality (TRM) were 27% (28% to 30%) and 34% (32% to 40%). Extensive cGvHD, transplantion before 1997 and unrelated donor were significantly associated with higher TRM (p=0.03; p=0.04; p=0.03). Multivariate analysis was performed to test for the prognostic role of those factors that had achived a p-value of 0.25 or less in the Log-Rank test. For OS, sex, donor, tbi, remission status, and cGvHD and time from diagnosis to transplantation were included. For a better OS and lower RR especially the remission status and the occurrence of cGvHD were significant prognostic factors for the outcome after allogeneic transplantation (OS: p=0.0001, p=0.001; RR: p=0.0001, p= 0.001); sex and time from diagnosis to transplantation were also predictive for a better OS (p=0.007, p= 0.045) and the use of non-tbi based regimens resulted in a lower RR (p=0.006); for TRM, transplantions before 1997 and unrelated donors were detect as significant prognostic factors (p=0.027, p=0.033).CONCLUSION: Remission status at transplantation and the occurrence of cGvHD are the major prognostic factors for the outcome after allogeneic HSCT in AML and MDS. We therefore conclude that allogeneic stem cell transplantation should be performed early in haematological remission in patients with high-risk AML and MDS, if a suitable donor is available.

Allogeneic Hematopoietic Stem-Cell Transplantation in AML and MDS Using Myeloablative Versus Reduced Intensity Conditioning: The Role of Dose-Intensity.

Allogeneic stem-cell transplantation (SCT) with both myeloablative and reduced-intensity conditioning (RIC) is effective therapy in AML/MDS. However, the relative merits of each may differ in different settings. To define the role of dose-intensity we analyzed SCT outcomes of 112 consecutive patients (pts) with AML/MDS transplanted over a 5-year period. The median age was 50 years (18–70). Eighty-five patients had AML (39 secondary) and 17 had MDS (all with excess of blasts). Fifty-eight had active disease at SCT (>10% marrow blasts) and 54 were in remission. The donor was HLA-matched sibling (n=58), 1-ag mismatched related (n=6) and matched-unrelated (n=48). Forty-five pts met eligibility criteria for standard myeloablative conditioning and were given intravenous-busulfan (12.8 mg/kg) and cyclophosphamide (ivBuCy). Sixty-seven pts were considered non-eligible for standard myeloablation due to advanced age (over 55 years for sibling SCT or over 50 years for mismatched or unrelated SCT), extensive prior therapy, organ dysfunction, recent fungal infection or poor performance status. These pts were given RIC with fludarabine and intravenous-busulfan (6.4 mg/kg, FB2, n=41) or modified myeloablative regimen with fludarabine and myeloablative doses of intravenous-busulfan (12.8 mg/kg, FB4, n=26). The median age of this group was 55 years compared with 42 years in the first group, and a larger proportion had SCT from unrelated donors. With a median follow-up of 22 months (2-62), 63 pts are alive and 49 have died (34 relapse, 15 non-relapse causes). Overall survival (OS) at 2 years was 50%, 49%, and 47% after ivBuCy, FB4, and FB2, respectively (p=NS). Non-relapse mortality was higher after ivBuCy, 22% Vs 8% and 8%, respectively (p=0.05) although these patients were younger and in a better medical condition. This difference was related to higher risk of acute GVHD grade III-IV after ivBuCy while deaths due to organ toxicity were rare in all groups. Relapse rates were lower after ivBuCy but not reaching statistical significance. Active disease at SCT was the most significant predictor of reduced survival in multivariable analysis (HR 4.5, p=0.0001). SCT from unrelated donor and poor prognosis cytogenetics had borderline significance while advanced age and secondary disease had no prognostic significance. Myeloablative and RIC regimens had similar outcomes when leukemia was in remission at SCT with a trend for better outcome with RIC; estimated 2-year OS been 60%, 68% and 80% after ivBuCy, FB4, and FB2, respectively (p=NS). However patients with active disease could only be salvaged by myeloablative conditioning (classical or modified). Among the later group, OS was 45% and 39% after ivBuCy and FB4, respectively, but no FB2 recipient survived (p=0.02). These observations suggest that RIC is associated with favorable outcome and low toxicity in pts in remission at SCT and therefore can be further studied in prospective trials comparing it to myeloablative regimens even in pts eligible for the later. However, RIC is a poor option for pts with active disease. Those not eligible for standard myeloablation could still tolerate modified myeloablation and enjoy its merits. The modified myeloablative regimen has low toxicity and similar cytoreductive effect and therefore can be further studied in prospective studies comparing it to standard myeloablative regimens even in pts eligible for the later.