Significance of Busulfan Dose Intensity On Outcomes of Hematopoietic Cell Allografting for AML in Second Complete Remission or Beyond: A Report From the EBMT Acute Leukemia Working Party

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1929-1929
Author(s):  
Ali Bazarbachi ◽  
Myriam Labopin ◽  
Mohamed A. Kharfan-Dabaja ◽  
Gérard Socié ◽  
Nicolaus Kröger ◽  
...  
Keyword(s):  
Complete Remission ◽  
Cumulative Dose ◽  
Cumulative Incidence ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Number Of Patients ◽  
Donor Source

Abstract Abstract 1929 Background: Allogeneic hematopoietic cell transplantation (HCT) is associated with inferior outcomes in patients with more advanced stage AML. In such cases, reducing the ablative intensity of the preparative regimen could potentially compromise its efficacy. We hereby compare transplant outcomes of two preparative regimens, known as FB2 and FB4, in patients (pts) with AML transplanted in second complete remission (CR2) or beyond at EBMT participating centers. Materials and methods: Between 2003 and 2010, 128 (FB2=88 (69%), FB4=40 (31%)) pts with a median age of (FB2=60 (22–70) years, FB4=42 (19–65) years, p<0.0001), with AML in ≥CR2 (FB2 (CR2=85 (97%), CR3=3 (3%)); FB4 (CR2=38 (95%), CR3=2 (5%)), p=0.67, underwent allogeneic HCT. FB2 comprised intravenous (IV) busulfan cumulative dose of 6.4 ± 10% mg/kg, while FB4 cumulative dose was 12.8 ± 10% mg/kg. Cytogenetic risks groups were similar: FB2 (good=17, int=31, poor=6) and FB4 (good=6, int=7, poor=0), p=0.35. For pts treated with FB2, donor source consisted of matched-related donors (MRD)=32, matched unrelated donor (MUD)=39, mismatched unrelated donors (MMUD)=8, unknown=9. For FB4, donor source consisted of MRD=17, MUD=15, MMUD=6, unknown=2. Use of peripheral blood stem cells (PBSC) was higher in the FB2 group (92% vs. 70%, p=0.001). Administration of anti-thymocyte globulin (ATG) was also higher in FB2 conditioned patients (89% vs. 45%, p<0.0001). Results: Median follow-up time was 24 (3–76) months. Median time to absolute neutrophil count engraftment (days) was 16 (5–38) and 16 (9–29) days, for FB2 and FB4, respectively (p=0.45). The 2-year leukemia-free survival (LFS), cumulative incidence of relapse (CI-R), and of non-relapse mortality (NRM) was: LFS (FB2=47±5% vs. FB4=70±8%, p=0.01), CI-R (FB2=27±5% vs. FB4=19±7%, p=0.24), and NRM (FB2=25±5% vs. FB4=10±5%, p=0.06). The 2-year cumulative incidence of chronic GVHD was similar (FB2=41±6% vs. FB4=43±8%, p=0.8). On multivariable analysis, favorable impact on 2-year LFS was observed with FB4 conditioning (HR 0.66 (95%CI: 0.46–0.97), p=0.03) and with longer interval from diagnosis to transplantation (> median) (HR=0.49 (95%CI: 0.29,0.85), p=0.01). When the analysis was performed by age groups, the statistical advantage of FB4 on LFS was lost, likely because of small numbers in each subgroup. Indeed, for pts <50 yrs. (n=43; FB2=16, FB4=27), LFS was (FB2=50±13% vs. FB4=72±9%, p=0.11), whereas for pts ≥50 yrs. (n=85, FB2=72, FB4=13), LFS was (FB2=47±6% vs. FB4=67±13%, p=0.18). Conclusion: Although limited by the small number of patients, these results suggest that FB4 is a reasonable preferred conditioning in patients with AML in ≥CR2. Disclosures: No relevant conflicts of interest to declare.

Comparative Efficacy Analysis of Busulfan Dose Intensity Between Two Reduced Intensity Conditioning Regimens (FB2 vs. FB4) for Allogeneic HCT for AML in First Complete Remission: A Report From the EBMT Acute Leukemia Working Party

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4153-4153
Author(s):  
Mohamed A Kharfan-Dabaja ◽  
Myriam Labopin ◽  
Ali Bazarbachi ◽  
Rose-Marie Hamljadi ◽  
Didier Blaise ◽  
...  
Keyword(s):  
Complete Remission ◽  
Cumulative Dose ◽  
Cumulative Incidence ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Allogeneic Hct ◽  
Conditioning Regimens ◽  
First Complete Remission ◽  
Donor Source

Abstract Abstract 4153 Background: better understanding of the bona fide immunological benefits derived from the donor immune effector cells resulted in development of reduced-toxicity regimens, which are associated with lesser toxicities and improved non-relapse mortality (NRM). However, reducing the toxicity of allogeneic hematopoietic cell transplantation (HCT) conditioning regimens without compromising its efficacy remains an imperative goal to broaden applicability of allogeneic HCT. We compare outcomes of two preparative regimens, known as FB2 and FB4, in patients (pts) with AML transplanted in first complete remission (CR1) at EBMT participating centers. Materials and methods: between 2003 and 2010, 437 (FB2=225 (51%), FB4=212 (49%)) pts with a median age of (FB2=57 (21–75) years, FB4=41 (18–68) years, p<0.0001), with AML in CR1, underwent allogeneic HCT. FB2 comprised intravenous (IV) busulfan cumulative dose of 6.4 ± 10% mg/kg, while FB4 cumulative dose was 12.8 ± 10% mg/kg. Cytogenetic risks groups were comparable: FB2 (good=8, int=144, poor=24) and FB4 (good=7, int=54, poor=9), p=0.27. For pts treated with FB2, donor source consisted of matched-related donors (MRD)= 112, matched unrelated donor (MUD)=80, mismatched unrelated donors (MMUD)=16, unknown=17. For FB4, donor source was MRD=160, MUD=29, MMUD=15, and unknown=8. Use of peripheral blood stem cells (PBSC) was higher in the FB2 group (96% vs. 83%, p <0.0001). Use of anti-thymocyte globulin (ATG) was also higher in FB2 group (79% vs. 33%, p<0.0001). FB4 allograft recipients (80% vs. 67%, p=0.003) and donors (77% vs. 56%, p<0.0001) had higher incidence of CMV seropositivity. Results: median follow-up time was 28 (2–89) months. Median time to absolute neutrophil count engraftment (days) was 17 (2–110) and 15 (7–45), for FB2 and FB4, respectively (p<0.0001). For pts <50 yrs. of age (n=208; FB2=56, FB4=152), the 2-year leukemia-free survival (LFS), cumulative incidence of relapse (CI-R), and of NRM was: LFS (FB2=60±7% vs. FB4=64±4%, p=0.45), CI-R (FB2=32±6% vs. FB4=20±4%, p=0.04), and NRM (FB2=7±4% vs. FB4=16±3%, p=0.17). Conversely, for pts aged ≥50 yrs. (n=229, FB2=169, FB4=60), outcomes were: LFS (FB2=63±4% vs. FB4=42±7%, p=0.02), CI-R (FB2=22±3% vs. FB4=29±6%, p=0.42), and NRM (FB2=15±3% vs. FB4=29±6%, p=0.06). Cumulative incidence of acute (≥grade 2) and chronic GVHD were similar: acute (FB2=51 (23%) and FB4=53 (26%), p=0.54) and chronic (FB2=48 ±3, FB4=44±2, p=0.51). Conclusion: in pts < 50 years of age, FB2 results in worse 2-year CI-R compared to FB4, but with similar 2-year NRM and LFS. For pts ≥50 years of age, FB2 results in superior 2-year LFS likely due to lower NRM. FB2 is a reasonable preferred option in pts ≥50 years with AML in CR1. Disclosures: No relevant conflicts of interest to declare.

Chimerism Analysis Is Predictive of Relapse-Free Survival After Allogeneic Transplantation for MDS

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1332-1332
Author(s):  
Sanjay R. Mohan ◽  
Lisa Rybicki ◽  
Matt Kalaycio ◽  
Ronald Sobecks ◽  
Brian J. Bolwell ◽  
...  
Keyword(s):  
T Cell ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Lower Probability ◽  
Unrelated Donor ◽  
Univariable Analysis ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Chimerism Analysis

Abstract Abstract 1332 Chimerism analysis permits evaluation of the extent of donor engraftment following allogeneic hematopoietic cell transplantation (HCT) via differentiation between donor- and recipient-derived cells. Though relapse remains a major cause of treatment failure post-HCT for hematologic malignancies, the clinical utility of chimerism analysis for the early detection of morphologic relapse varies between different diseases and remains controversial. The predictive value of chimerism analysis for relapse rates and mortality in myelodysplastic syndromes (MDS) is not well-described. We reviewed serial chimerism results for 72 consecutive patients (pts) who underwent allogeneic HCT for MDS between 1999 and 2009; 9 pts were excluded from analysis due to lack of appropriately timed chimerism studies. Donor engraftment was initially assessed 28 days post-HCT and then at 2-week intervals through day 100. Chimerism studies were performed with peripheral blood using a short tandem repeat assay by PCR-based analysis. Acute and chronic GVHD rate, relapse-free survival (RFS), and overall survival (OS) were assessed for patients with donor leukocyte chimerism and T-cell chimerism ≥95% and <95%. The median age was 51 years (range 20–70) and 52% were male. The median time from MDS diagnosis to HCT was 5.4 months; 9 pts (14%) were in complete remission at the time of HCT, 11 (18%) were in partial remission, 17 (27%) had relapsed or refractory disease, and 26 (41%) were untreated. HCT-comorbidity index was low in 25 pts (40%), intermediate in 18 (29%), and high in 20 (32%). 31 pts (49%) received sibling donor HCT and the remainder received an unrelated donor graft. 40 (63%) received bone marrow and 23 (37%) received peripheral stem cells. Myeloablative (MA) busulfan- or cyclophosphamide-based preparative regimens were used in 47 pts (75%) and a non-myeloablative (NMA) regimen with fludarabine and TBI was given to the remaining pts. 61 pts achieved ≥95% donor leukocyte chimerism at a median of 29 days and 39 evaluable pts achieved ≥95% donor T-cell chimerism at a median of 42 days. Two pts did not achieve donor leukocyte chimerism ≥95% and 9 did not achieve donor T-cell chimerism ≥95% at any timepoint. Univariable analysis of prognostic factors for relapse showed that donor leukocyte chimerism ≥95% was significantly associated with lower probability of relapse (hazard ratio [HR] 0.11, 95% confidence interval [CI] 0.02–0.51, p=.005), whereas prior exposure to radiation therapy (excluding exposure during HCT preparative regimen) was associated with increased probability of relapse (HR 3.48, 95% CI 1.14–10.60, p=.028). Multivariable analysis implicated donor leukocyte chimerism <95% as the only independent risk factor for relapse. Transplant type (MA vs NMA) and cell source did not significantly impact the likelihood of relapse. Donor leukocyte chimerism ≥95% was not associated with acute or chronic GVHD. Univariable analysis of risk factors for survival showed that donor leukocyte chimerism ≥95% was associated with improved RFS (HR 0.29, 95% CI 0.09–0.97, p=.045) but not OS, both findings of which were confirmed on multivariable analysis. Donor T-cell chimerism ≥95% was not significant in univariable analysis; however, in multivariable analysis, controlling for comorbidity scores, donor T-cell chimerism <95% was associated with lower risk of chronic GVHD (HR 0.18, 95% CI 0.04–0.88, p=.034) but did not significantly impact relapse, RFS, or OS. In conclusion, achievement of a high donor leukocyte chimerism post-HCT for MDS is associated with improved RFS. Donor T-cell chimerism, however, is not predictive of outcome and its routine use for MDS pts should be reevaluated. Pts with donor leukocyte chimerism <95% might be considered for immunologic interventions such as withdrawal of immunosuppression or donor lymphocyte infusion. Disclosures: No relevant conflicts of interest to declare.

HCT-CI Has Prognostic Value in Acute, but Not Chronic Gvhd Specific Survival

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3915-3915
Author(s):  
Marc Poch Martell ◽  
Nada Hamad ◽  
Fotios V. Michelis ◽  
Jieun Uhm ◽  
Feras Alfraih ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Immunosuppressive Treatment ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Allogeneic Hct

Abstract Introduction : Graft-versus-host disease (GVHD) is a major cause of treatment failure in allogeneic hematopoietic cell transplantation (HCT). The hematopoietic cell transplant-specific comorbidity index (HCT-CI) predicts transplant-related mortality (Sorror, et al: Blood, 2005; Raimondi, et al: Blood, 2012), but its prognostic value has not been well explored in the setting of GVHD. It is hypothesized that patients with a high HCT-CI score would have worse outcomes after developing GVHD compared to those with a low HCT-CI score. In this retrospective study we calculated the pre-transplant HCT-CI and analysed its relationship with GVHD specific survival (GSS). Methods : A total of 541 patients who received allogeneic HCT at Princess Margaret Cancer Centre between 2000 and 2012 were included in this retrospective cohort study. The GSS was defined as the time from diagnosis of GVHD (for acute and chronic GVHD separately) until death from a GVHD-related cause, including organ dysfunction directly related to GVHD and infection in the setting of GVHD and immunosuppressive treatment. The GSS in relation to the HCT-CI was analysed using the Cox proportional hazard regression model. The GSS was plotted using the Kaplan-Meier method and the Log-rank test was used for comparison. Results : The incidence of all grades of acute GVHD and grade 2-4 acute GVHD was 68.7±2.1% and 54.9±2.3%, respectively. The incidence of chronic GVHD by the NIH consensus criteria was 72.9±2.8%. With a median follow-up duration of 24 months among survivors after a diagnosis of GVHD, the 2-year rates of acute GSS (aGSS) and chronic GSS (cGSS) were 60.7±2.9 and 74.6±2.7%, respectively. Univariate analysis demonstrated that the HCT-CI score as a continuous variable was prognostic for aGSS (p=0.001, HR 1.198, 95% CI [1.082-1.325]), showing that an increase in the HCT-CI score by 1 resulted in an increase in mortality by 20%. However, for cGSS, there was only borderline statistical significance with a p-value of 0.068 (HR 1.130 95% CI [0.991-1.289]). Patients were divided into 3 groups according to their HCT-CI score: 0-1(n=232, 42.9%), 2-4 (n=267, 49.4%) and ≥5 (n=42, 7.8%). The HCT-CI was able to stratify patients in relation to aGSS (p=0.001): The 2 year aGSS rate was 72.0±3.9% in those with an HCT-CI of 0-1 (n=148), 53.6±4.4% with an HCT-CI of 2-4 (n=173), and 35.6±11.5% with an HCT-CI of ≥5 (n=25). In contrast, no correlation was found with cGSS among the 3 groups (p=0.355). The 2 year cGSS rate was 79.5±3.6% in patients with an HCT-CI of 0-1 (n=141), 70.5±4.3% with an HCT-CI of 2-4 (n=149), and 63.2±14.0% with an HCT-CI of ≥5 (n=24). A multivariable analysis was performed to confirm the HCT-CI score as an independent prognostic factor for GSS, accounting for the following covariates: age, donor type, source of stem cells, and severity of acute GVHD (grade 3-4 vs others) and chronic GVHD (NIH global score mild, moderate and severe). The HCT-CI was found to be an independent risk factor for aGSS (p=0.016, HR 1.15, 95% CI [1.03-1.3]), but not for cGSS (p=0.80, HR 1.02, 95% CI [0.84-1.2]). Conclusion : Patients undergoing allogeneic HCT with significant comorbidities prior to transplant demonstrated by a higher HCT-CI have a shorter GSS. This finding is only significant for survival following acute GVHD (i.e. acute GSS), but not for chronic GVHD. This study suggests that the HCT-CI score may provide additional prognostic information in the assessment of the risk of acute GVHD related outcomes but not chronic GVHD outcomes, and that the assessment of HCT-CI score prior to HCT may be useful in risk adaptive preventive and treatment strategies for GVHD. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparison of Post-Allogeneic Hematopoietic Cell Transplantation (HCT) Outcomes after Matched Related Donor Versus Matched Unrelated Donor HCT in Adults with Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2017-2017 ◽  
Author(s):  
Eric Segal ◽  
Michael Martens ◽  
Hai-Lin Wang ◽  
Ruta Brazauskas ◽  
Daniel Weisdorf ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Survival Outcomes ◽  
Unrelated Donor ◽  
Term Survival ◽  
Donor Source

Abstract Allogeneic hematopoietic cell transplantation (HCT) is a potentially life-saving treatment for patients with acute lymphoblastic leukemia (ALL). About one-third of patients have a human leukocyte antigen (HLA) matched related donor (MRD), while the remaining two-thirds have either a fully HLA-matched (HLA-A, -B, -C, -DRB1 [8/8]) unrelated donor (MUD) or a MUD with a single HLA mismatch (7/8). Previous analyses by the CIBMTR have shown that MRD and MUD transplants produce similar survival outcomes for patients with acute myelogenous leukemia (AML) (Blood 2012; 119(17):3908-16), while donor source was an important predictor of outcomes in patients with myelodysplastic syndrome (MDS) (Blood 2013; 122(11):1974-82). Given that ALL represents the second most common indication for HCT, and recognizing the disease-specific nature of the impact of donor source on post-HCT outcomes previously described, we performed an analysis of outcomes after MRD versus MUD HCT in 1458 patients with ALL who underwent allogeneic HCT from 2000-2011 (MRD n=440, 8/8 MUD n=729, 7/8 MUD n=289). Median age was 37 years (18-69). Thirty-four percent were Philadelphia chromosome positive.Ten percent received reduced intensity conditioning (RIC). Twenty-three percent were transplanted in second complete remission (CR2).Seventy-four percent received peripheral blood stem cells. At 100 days post-HCT, the incidence of acute GVHD Grade B-D was significantly lower in MRD recipients than in 8/8 MUD or 7/8 MUD recipients (26%, 45%, 50%, respectively; p<0.001). In multivariate analysis, 8/8 MUD recipients had similar rates of transplant-related mortality (TRM) and overall survival (OS) (hazard ratio [HR] 1.16, p=0.225and HR 1.01, p=0.93, respectively) compared to MRD recipients; 7/8 MUD recipients had inferior TRM and OS when compared to both MRD recipients (HR 1.92, p<0.001 and HR 1.29, p=0.01, respectively) and 8/8 MUD recipients (HR 1.66, p<0.001 and HR 1.28, p=0.008, respectively).Recipients of peripheral blood transplants had inferior long-term survival (>24 months post-HCT) (HR=2.13, p=0.003) compared to bone marrow transplants. Compared to MRD, 8/8 MUD recipients had superior relapse rates (HR 0.77, p=0.02), while 7/8 MUD recipients had no difference (HR 0.75, p=0.05). There were no differences in leukemia-free survival (LFS) comparing 8/8 MUD recipients (HR 0.95, p=0.55) and 7/8 MUD recipients (HR 1.20, p=0.07) to MRD recipients (Table 2, Figure 1).Differences in survival were likely due to higher rates of acute GVHD and TRM in the 7/8 MUD group. We conclude that MRD and 8/8 MUD recipients have similar survival outcomes post-HCT, while 7/8 MUD recipients suffer inferior survival, demonstrating that donor source plays a large role in the quality of outcomes. While MRD remains the ideal donor source due to its lower incidence of acute GVHD,HCT from an 8/8 MUD is a good alternative to MRD transplant, given its comparable long-term survival outcomes. Figure 1. 100-day Cumulative Incidence of Acute GVHD; 5-year Cumulative Incidence of chronic GVHD, relapse, and TRM; 5-year Probabilities of LFS and OS in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011 *Overall point-wise comparison † Point-wise pair-wise comparison Figure 1. 100-day Cumulative Incidence of Acute GVHD; 5-year Cumulative Incidence of chronic GVHD, relapse, and TRM; 5-year Probabilities of LFS and OS in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011 *Overall point-wise comparison † Point-wise pair-wise comparison Figure 2. Multivariate Analysis for Relapse, TRM, Treatment Failure (Inverse of LFS), and All-Cause Mortality (Inverse of Overall Survival) in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011. Figure 2. Multivariate Analysis for Relapse, TRM, Treatment Failure (Inverse of LFS), and All-Cause Mortality (Inverse of Overall Survival) in Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT from 2000-2011. Figure 3. Adjusted Overall Survival Estimatesfor Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT Figure 3. Adjusted Overall Survival Estimatesfor Adult ALL Patients Receiving MRD, 8/8 MUD, or 7/8 MUD HCT Disclosures Sandmaier: Gilliad: Honoraria; ArevaMed: Honoraria; Jazz Pharmaceutical: Honoraria; Seattle Genetics: Honoraria; Abmit: Research Funding; Bellicum: Research Funding.

scholarly journals Killer Cell Immunoglobulin-like Receptor Ligand Matching Determines the Post-Transplant High Risk Groups Among Patients with Permissive HLA Mismatch in Unrelated Donor Hematopoietic Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4566-4566
Author(s):  
Yoo Jin Lee ◽  
Joon Ho Moon ◽  
In Hee Lee ◽  
Jae-Ho Yoon ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Killer Cell ◽  
Risk Groups ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells

Abstract Background: Human leukocyte antigen (HLA) matching between donor and recipient is a key part of successful allogeneic hematopoietic cell transplantation (allo-HCT). The HCT from the unrelated donor (UD) with one allele/antigen mismatch (MM) can be as beneficial as HCT from perfectly matched donor. For the remaining patients, the donors with permissive mismatches may be the option. In HLA-mismatched transplantation, the patient and donor can also be mismatched for their killer cell immunoglobulin-like receptor (KIR) ligands that recognize allotypic determinants shared by certain HLA class I allele groups. Recent research has accumulated evidence of the role of each HLA locus and KIR ligand MM on clinical outcomes for UD-HCT. However, HCT outcomes of the patients with permissive MM depending on KIR ligand MM (KIR-L-MM) status remain obscure in UD-HCT. In the current study, we identified permissive and nonpermissive MM allele combinations and analyzed the effects of these mismatches in combination of KIR ligand mismatches in patients with acute myeloid leukemia (AML). Methods: A total of 438 patients with AML who underwent allo-HCT from UD from 2007 to 2014 were analyzed. Alleles of patients and donors at the HLA-A, -B, -C, and -DRB1 loci were identified by the high resolution DNA typing. Nonpermissive HLA allele combinations were defined as a significant HLA risk factor for severe acute graft-versus-host disease (aGVHD). KIR-L-MM among patient-donor pairs were searched in the Immuno Polymorphism Database available at www.ebi.ac.uk/ipd/kir. Results: Median age of the patients was 45 (range 15-60) years and 117 patients (40.4%) were female. Eighty-five (19.4%) patients were high risk at the time of HCT. Reduced intensity conditioning was performed in 131 patients (29.9%) and anti-thymocyte globulin was used in 324 patients (74.0%). Primary graft source was peripheral blood stem cells (n=369, 84.2%) and median 6.0 x 106/kg cells were infused. Severe aGVDH occurred in 43 patients (9.8%) and chronic GVHD (cGVHD) in 193 (44.1%). With median follow-up duration of 19 (range, 2-96) months, treatment-related mortality (TRM) occurred in 111 patients (25.3%), relapse in 119 (27.2%) and death in 214 (48.9%). Two-hundred sixty-four patients (60.3%) were HLA full matched in the 4 loci. Mismatches in HLA-A loci observed in 64 patients, HLA-B in 35, HLA-C in 98, and HLA-DRB1 in 60. Five nonpermissive MM pairs in 33 patients were identified as donor/patient pair: A*02:06/A*02:01, C*03:03/C*08:01, C*08:01/C03:04, C*08:01/C*15:02, and DRB1*04:03/DRB1*04:05. Among 98 patients with HLA-C loci MM, 16 patients showed KIR ligand MM (KIR-L-MM) as GvH direction, which was observed in the permissive MM group. Severe aGVHD occurred in 30.4%, 22.4%, 13.4%, and 10.8% in nonpermissive, permissive MM and KIR-L-MM, permissive MM and KIR-L-M, and full match group, respectively (p=0.003). The 3-year overall survival (OS) rate was inferior in permissive MM and KIR-L-MM group (30.0%) compared to full match (53.5%), permissive MM and KIR-L-M (51.8%), and nonpermissive (42.4%) group (p=0.067). The 3-year TRM was higher in permissive MM and KIR-L-MM group (57.5%) than full match (21.0%), permissive MM and KIR-L-M (27.7%), and nonpermissive (33.3%) group (p=0.006). In the multivariate analysis, high risk at HCT (HR 2.087, p<0.001), severe aGVHD (HR 3.851, p<0.001), and cGVHD (HR 0.321, p<0.001) were identified as variables affecting the OS. The following variables adversely affected on TRM: permissive MM and KIR-L-MM group (HR 2.699, p=0.007), severe aGVDH (HR 2.204, p=0.001), and cGVHD (HR 2.052, p<0.001). Non-permissive MM (HR 7.487, p=0.001) and CD34+ cells >6x106/kg (HR 4.113, p=0.017) were high risk factors on severe aGVHD. Conclusion: Permissive MM for HLA could be further classified into high risk groups with regard to TRM by KIR-L matching in UD-HCT. The evaluation of KIR-L matching is warranted to reduce unfavorable outcomes among the patients with permissive MM in UD-HCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Extramedullary Disease at Diagnosis of Acute Myeloid Leukemia Does Not Influence Outcome of Patients Undergoing Allogeneic Hematopoietic Cell Transplant in First Complete Remission

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2020-2020
Author(s):  
Fotios V. Michelis ◽  
Hans A. Messner ◽  
Naheed Alam ◽  
Vikas Gupta ◽  
Dennis Dong Hwan Kim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Hematopoietic Cell ◽  
First Complete Remission ◽  
Acute Myeloid

Abstract Occurrence of extramedullary (EM) disease at diagnosis of acute myeloid leukemia (AML) has been associated with increased risk of relapse and worse outcomes post-chemotherapy. There is minimal data in the literature concerning the association with outcomes following allogeneic hematopoietic cell transplantation (HCT). The purpose of this single-centre study was to retrospectively investigate the impact of EM disease at diagnosis on the outcome of 303 patients with AML in first complete remission (CR1) that underwent HCT during the time period 2000-2013. Median age at HCT was 51 years (range 18-71), 151 (50%) patients were female. Myeloablative conditioning (MAC) was used in 202 (67%) patients, reduced-intensity (RIC) in 101 (33%) patients. Donors were related for 194 (64%) patients, unrelated for 109 (36%) patients. Grafts were peripheral blood stem cells (PBSC) in 253 (83%) patients and bone marrow in 50 (17%) patients. Median follow-up of patients alive was 63 months (range 12-168). Cytogenetics at diagnosis were available for 263 (87%) of patients, of which 16 (5%) were favorable, 185 (61%) were intermediate and 62 (20%) were unfavorable risk (MRC classification). Primary induction failure prior to achievement of CR was seen in 67 (22%) patients. In vivo T-cell depletion was performed in 71 (23%) patients. A total of 124 patients (41%) underwent HCT during the years 2000-2006 and 179 patients (59%) during the years 2007-2013. EM disease at diagnosis was seen in 39 patients (13%), of whom 11 patients had CSF disease, 7 patients had gingival infiltration and 5 patients had leukemia cutis. Univariate analysis for overall survival (OS) demonstrated that EM disease at diagnosis had no influence (HR=0.96 for EM, 95%CI=0.60-1.51, p=0.85, Figure 1). Multivariable analysis for OS including the previously described variables verified this observation. EM disease did not influence cumulative incidence of relapse (CIR) on univariate analysis (HR=0.94 for EM, 95%CI=0.45-1.96, p=0.86, Figure 2), and this also was confirmed on multivariable analysis. Moreover, EM disease did not influence cumulative incidence of non-relapse mortality on both univariate (HR=0.94 for EM, 95%CI=0.53-1.66, p=0.83) and multivariable analysis. In conclusion, EM disease at diagnosis of AML in patients achieving CR1, does not seem to influence outcomes post allogeneic HCT. This is significant in the consideration of allogeneic HCT for the treatment of this unfavorable subtype of AML. We are unable to comment on whether a similar percentage of patients with EM disease versus without EM disease, achieve CR1. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Kim: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding.

The Combination of Siromilus Plus Tacrolimus (SiTac) Improves the Results of Cyclosporine Plus Mycophenolate Mofetil (CsAMMF) After Reduced Intensity Conditioning (RIC) Unrelated Donor Allogeneic Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 890-890
Author(s):  
Jose Antonio Perez-Simón ◽  
Rodrigo Martino ◽  
Rocio Parody ◽  
M. Cabrero ◽  
Lucía López-Corral ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cumulative Incidence ◽  
Sequential Analysis ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Multicenter Trial ◽  
Antifungal Prophylaxis ◽  
Unrelated Donor ◽  
Multicenter Studies ◽  
Gvhd Prophylaxis

Abstract Abstract 890 Background: One of the most extensively used approaches to prevent GVHD in the RIC setting is the combination of CsAMMF. Other strategies have been described such as SiTac, mostly as single center experiences, with promising results. Nevertheless, data from multicenter studies are lacking using the latter approach and, furthermore, no studies have been performed comparing both approaches. Aim: in the current study we describe the results of the prospective multicenter trial 2007–006416-32 by GEL-TAMO/GETH using SiTac as GVHD prophylaxis and compare this approach to the combination of CsAMMF in a sequential analysis. Material and Methods: from May 2002, 90 patients were included. All of them received an URD transplantation after RIC based on fludarabine (150 mg/m2) plus busulphan (10 mg/kg) or melphalan (140 mg/m2). 45 transplanted between 2002 a 2007 received CsAMMF as GVHD prophylaxis while the remaining 45 patients undergoing transplantation from 2008 received SiTac. 41% of the patients were in CR, 30% were in PR and 29% had active disease at the time of transplantation. No differences were observed in terms of disease status. Patients in the SiTac trial had a higher median age (49 versus 43 years, p=0.02) while a higher percentage of patients in the CsAMMF were diagnosed with acute leukemia (10 versus 19 patients, p=0.05). Supportive care was similar in both subgroups except for the use of azols as antifungal prophylaxis which was not allowed in the SiTac. Results: 12% of patients receiving SiTac developed mycroangiopathy which required to modify immunesuppresive treatment although it did not increase the mortality of the procedure. No VOD was reported. No significant differences were observed neither in terms of hematopoietic recovery nor in the cumulative incidence of grades 2–4 or 3–4 aGVHD (49% versus 50% grades 2–4 and 15% versus 26% grades 3–4 for patients receiving SiTac versus CsAMMF, respectively). By contrast 18% of patients receiving SiTac versus 55% of those receiving CsAMMF developed gut aGVHD ≥ grade 2, p=0.007. Cumulative incidence of cGVHD was 55% versus 88% for SiTac versus CsAMMF, respectively, p=0.0002 while the incidence of extensive cGVHD was 27% versus 52%, respectively, p=0.03. Non relapse mortality was 10% versus 20% at 100 days and 19% versus 40% at 1 year, for patients receiving Si-Tac versus CsAMMF, respectively (p=0.028). Event free and overall survival at 2 years were 59% versus 35%, p=0.008 and 72 versus 48%, p=0.018, for patients receiving Si-Tac versus CsAMMF, respectively. Conclusions: the current study confirms in a multicenter trial the promising results of the combination Sirolimus plus Tacrolimus among patients undergoing RIC URD transplantation. The current is the first study comparing in a sequential study SiTac versus CsAMMF and confirms that the prior decreases the risk of chronic GVHD and the non-relapse mortality of the procedure which translates into a better event free and overall survival. Disclosures: No relevant conflicts of interest to declare.

Use Of Unrelated Donors In Elderly Patients (age >60 years) Undergoing Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation For Hematologic Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5544-5544
Author(s):  
El-Cheikh Jean ◽  
Devillier Raynier ◽  
Fürst Sabine ◽  
Crocchiolo Roberto ◽  
Granata Angela ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Objectives The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. However, there are only limited data on the feasibility and outcomes of URD HCT in elderly patients.The aim of the study was to compare the outcome in OS and PFS for patients transplanted using unrelated donor (URD) in patients age 60 or older. Patients and methods We retrospectively analyzed outcomes in 62 consecutive hematologic malignancy patients aged > or =60 years (median, 62 years; range: 60-70 years) undergoing reduced intensity conditioning regimens (RIC) from URD. In this study, URD was used only when a MRD was not available. Then we compared the outcome of 17 elderly patients (age >65 years) with 44 younger patients aged between 60 and 65 years. Patient, disease and transplant characteristics are shown in Table 1. Results No patients experienced graft rejection. The median HCT comorbidity index score was 2 (range, 0 to 6). With a median follow up of 36 months (range, 5-74), the cumulative incidence of grades II to IV acute GVHD was 28% and of grades III to IV acute GVHD, 13%. At 2 years, the cumulative incidence of chronic GVHD was 27%, progression-free survival (PFS) was 62%, overall survival (OS) was 63%, and relapse was 14%. Non relapse mortality (NRM) was 24% at 2 years. The cumulative incidence of grade II–IV Acute GVHD was 43% for the younger group and 17% for the older group (P = 0.056). The cumulative incidence of chronic GVHD was not different between the two groups (23% vs. 45% (p=0.3), respectively). Two-year OS and PFS was 57% versus 86% (P = 0.059) and 55% versus 86% (P = 0.03), in the younger and the older group respectively. The 2-year NRM and relapse was 26% versus 14% (P = 0.4) and 19% versus 0% (P = 0.04), in the younger and older group respectively. Conclusions This retrospective study suggest that RIC HCT from URD is a safe and effective option for patients aged > or =60 years or older, and in the absence of suitable related donors, well-matched URD may offer a very reasonable alternative, and that does not appear to be associated with a detrimental outcome. However these results are encouraging showing once again that with an adequate selection, age is not a definitive limitation. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation (Allo-SCT) Following a Reduced-Intensity Conditioning (RIC) Regimen in Relapsed Peripheral T-Cell Lymphomas (PTCL): Results at 4 Year of Median Follow-up.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 875-875
Author(s):  
Anna Dodero ◽  
Francesco Spina ◽  
Franco Narni ◽  
Francesca Patriarca ◽  
Sergio Cortelazzo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Number Of Patients ◽  
Significant Difference

Abstract Abstract 875 Conventional therapies and autologous stem cell transplantation lead to disappointing results in relapsed PTCL, therefore allo-SCT has been investigated in the last years. There are evidence supporting the existence of a “graft-versus-PTCL” effect, but the majority of the studies have a limited number of patients with a short follow-up. We conducted a retrospective analysis on 53 patients (pts) affected by relapsed/refractory PTCL who received a RIC regimen followed by allo-SCT. The main histopathological subtypes were PTCL-not otherwise specified (PTCL-NOS, n=24), anaplastic large-cell lymphoma (ALCL, n=11), and angioimmunoblastic (AILD, n=6). The remaining cases were rare subtypes (n=12). Median age was 47 years (range, 15-64 years). Patients were allografted from matched related siblings (n=34, 64%) or alternative donors (n=19, 36%). The majority of pts had chemosensitive disease (n=39, 74%), received allo-SCT more than 12 months from diagnosis (n=38, 72%) and were treated with only 1 or 2 lines of therapy before transplantation (n= 37, 70%). At last follow-up (median 49 months, range 6-118), 29 pts are alive (55%, 26 in CR) and 24 died [n=20 for disease progression, n=4 for non-relapse mortality (NRM)]. The majority of relapsing patients (20 of 25, 80%) died at median time of 7 months after allo-SCT. The crude cumulative incidence (CCI) of relapse was 32% and 50% at 6 months and at 4-year after allo-SCT. The CCI of relapse was influenced by status of disease [chemosensitive versus chemorefractory: 41% versus 77% at 4 years (p<0.001)] and number of lines [≤ 2 versus > 2: 40% versus 70% at 4 years (p<0.02)] received before allo-SCT and not by hystotype and time from diagnosis to allograft. The CCI of NRM were 4% and 10% at 6 months and 4-year, respectively; type of donor and previous auto had no significant impact on NRM. The CCI of acute (grade II-IV) and chronic GVHD were 21% and 44%, respectively. The 4-year OS and PFS were 50% (95% CI, 35% to 63%) and 47% (95% CI, 32% to 60%) for all the population, 62% (95% CI, 44% to 76%) and 15% (95% CI, 3% to 38%) as OS, 58% (95% CI, 40% to 72%) and 13% (95% CI, 1% to 41%)as PFS, for chemosensitive and chemorefractory pts, respectively. According to the histopathological subtypes, the OS and PFS were 42% and 40% for PTCL-NOS, 50% and 44% for ALCL, 67% and 80% for AILD, 58% and 48% for rare subtypes, respectively (p=ns). At multivariable analysis of OS and PFS, refractory disease prior to alloSCT and age more than 45 years were independent adverse prognostic factors [hazard ratio (HR)= 5.3, p<0.001, HR=4.8, p<0.003 for OS; HR=5.4, p<0.0007, HR=2.7, p<0.02 for PFS]. Six-teen pts received donor lymphocytes infusions (DLIs) for disease progression (n=12) or to accelerate immune reconstitution (n=4): 7 out of 12 responded to DLIs (n=3 CR, n=4 PR). In conclusion, our long-term data with a median 4-year follow-up shows that: i) only patients with chemosensitive had advantage from allo-SCT; ii) transplantation should be performed early because pts receiving less lines of therapy had a better outcome; iii) we did not observe a significant difference in outcome between the different histopathological subtypes; iv) response to DLI supports the notion of an immune mediated effect. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Consolidation Chemotherapy Is Not Beneficial for Adult Acute Lymphoblastic Leukemia Patients with Available Donor Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation in First Complete Remission: A CIBMTR Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 684-684
Author(s):  
Nelli Bejanyan ◽  
Aleksandr Lazaryan ◽  
Mei-Jie Zhang ◽  
Hai-Lin Wang ◽  
Marcos de Lima ◽  
...  
Keyword(s):  
Complete Remission ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Consolidation Chemotherapy ◽  
P Values

Abstract Allogeneic hematopoietic cell transplantation (alloHCT) is potentially curative for patients with ALL who achieve complete remission with upfront chemotherapy (CR1). However, the necessity of consolidation chemotherapy remains uncertain in patients with an available donor undergoing alloHCT, even if the goal is to reduce the detectable disease burden prior to alloHCT. We therefore compared clinical outcomes of 524 adult patients with ALL in CR1 who received ≥2 cycles (n=109) vs. 1 cycle (n=93) vs. no (n=322) consolidation chemotherapy prior to myeloabalative alloHCT from 2008-2012. The median follow up of survivors was 59 (6-78) months. All three consolidation groups had similar patient, disease and transplant characteristics, but no consolidation patients were older, took longer to achieve CR1 and less frequently received CNS prophylaxis or maintenance chemotherapy prior to alloHCT. In contrast, fewer with 1 cycle consolidation had prior comorbidities. Time to alloHCT was longer with increasing cycles of consolidation. Only a minority had either cytogenetic or molecular detectable disease in their pre-HCT CR1 assessment; and it was similar in each consolidation cohort. For ≥2 cycles, 1-cycle, no consolidation groups, the adjusted 3-year cumulative incidence of relapse was 20%, 27% and 22% and 1-year transplant-related mortality (TRM) was 16%, 18% and 23%, respectively (all p-values > 0.4). Similarly, adjusted 3-year leukemia-free survival (LFS) was 54%, 48% and 47% (Figure), while overall survival (OS) was 63%, 59% and 54%, respectively (all p-values > 0.3). Consolidation did not influence acute or chronic GVHD risks. Multivariable regression analysis adjusted for recipient age, Karnofsky performance status, time to CR1, graft source, donor type and recipient CMV serostatus, confirmed that consolidation chemotherapy was not prognostic of LFS (RR=1.20, 95% CI 0.86-1.67; p=0.28 for no consolidation; RR=1.18, 95% CI 0.79-1.76; p=0.41 for 1 cycle; ≥2 cycles=reference). Similarly, consolidation was not associated with OS, relapse, TRM or GVHD. We conclude that consolidation chemotherapy does not benefit adult ALL patients with readily available donor who undergo myeloablative alloHCT in CR1. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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