The Impact of Pre-Transplant Depression on Outcomes of Allogeneic and Autologous Hematopoietic Stem Cell Transplantation

Abstract Introduction: Depression is associated with increased mortality among healthy individuals and patients with various medical conditions including cardiovascular disease and cancer. The impact of an existing diagnosis of depression prior to autologous and allogeneic hematopoietic stem cell transplantation (HCT) on clinical outcomes including overall survival has not been studied. Methods: We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to compare overall survival and hospital-length-of-stay during the first 100 days after autologous (n= 3786) or allogeneic (n = 7433) HCT for adult (≥ 18 years) patients with hematologic malignancies with an existing diagnosis of pre-transplant depression requiring treatment vs. those without pre-transplant depression. Data regarding an existing diagnosis of pre-transplant depression requiring treatment were collected from medical chart reviews and reported to the CIBMTR. Data for autologous and allogeneic HCT were analyzed separately. Using Cox proportional hazards regression models adjusting for patient-, disease-(including the disease risk index for allogeneic HCT), donor-(for allogeneic HCT), and transplant-related variables, we compared overall survival between patients with or without pre-transplant depression. To account for early deaths, we compared the number of days alive and out of the hospital in the first 100 days post-transplantation using Poisson models adjusting for patient-, disease-, and transplant-related variables. Among patients undergoing allogeneic HCT, we also compared the risk of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD among patients with or without pre-transplant depression using Cox proportional hazard regression analyses controlling for significant confounders. Results: We included 1116 (15%) patients with pre-transplant depression and 6317 (85%) patients without pre-transplant depression who underwent allogeneic HCT between 2008 and 2012. Patients with pre-transplant depression were similar to those without pre-transplant depression with regards to age, disease distribution, disease risk index, time from diagnosis to transplant, conditioning regimen, receipt of total body irradiation, graft type, donor type, and donor source, but they were more likely to be female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. In multivariable analyses, pre-transplant depression was associated with higher overall mortality (HR 1.13, 95% CI 1.04-1.23, p = 0.004) and higher risk of grade II-IV acute GVHD (HR 1.25, 95%CI 1.14-1.37, p < 0.0001), but similar risk of chronic GVHD (HR 1.06, 95% CI 0.96-1.16, p = 0.26). Pre-transplant depression was associated with fewer days alive and out-of-the hospital (Means Ratio (MR) = 0.97, 95% CI 0.95-0.99, P = 0.004). Among patients undergoing autologous HCT, we included 512 (13.5%) patients with pre-transplant depression and 3274 (86.5%) patients without pre-transplant depression between 2007 and 2012. Patients with pre-transplant depression were similar to those without pre-transplant depression with regards to disease distribution, disease status prior to HCT, time from diagnosis to transplant, conditioning regimen, and year of transplant, but they were slightly younger, more likely be to female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. Pre-transplant depression in autologous HCT recipients was not associated with overall survival in multivariable analyses (HR 1.15, 95% CI 0.98-1.34, p = 0.096), but was significantly associated with fewer days alive and out of the hospital (MR = 0.98, 95% CI 0.97-0.99, p = 0.002). Conclusion: Pre-transplant depression was associated with higher mortality and higher risk of acute GVHD among patients undergoing allogeneic HCT. Moreover, pre-transplant depression is associated with a longer hospital-length-of stay during the first 100 days after autologous and allogeneic HCT. Therefore patients with pre-transplant depression represent a highly vulnerable population at risk for post-transplant mortality and complications, and they may benefit from more intensive interventions to mitigate the risk of depression on their post-transplant outcomes. Disclosures Chen: Bayer: Consultancy, Research Funding. Lee:Bristol-Myers Squibb: Consultancy; Kadmon: Consultancy. Hahn:Novartis: Equity Ownership; NIH/NHLBI: Research Funding.

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Impact Of Total Nucleated Cell and CD34+ Cell Dose On Transplant Related Outcomes In Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplants

Blood ◽

10.1182/blood.v122.21.2048.2048 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2048-2048 ◽

Cited By ~ 1

Author(s):

Paul Martin ◽

Shuli Li ◽

Edwin P. Alyea ◽

Vincent T. Ho ◽

Corey S. Cutler ◽

...

Keyword(s):

Disease Risk ◽

Conflicts Of Interest ◽

Risk Index ◽

Chronic Gvhd ◽

Multivariable Analysis ◽

Reduced Intensity Conditioning ◽

Allogeneic Hct ◽

Cell Dose ◽

The Impact ◽

Reduced Intensity

Abstract Background Mobilized peripheral blood (PB) is the most common graft source for allogeneic hematopoietic transplantation (HCT) following reduced intensity conditioning (RIC). The impact, if any, of donor PB graft composition on major transplant outcomes in the RIC allogeneic HCT setting remains incompletely understood. Existing studies have focused primarily on CD34+ cell dose and report conflicting results, especially in relation to survival. The impact of total nucleated cell (TNC) dose has been less frequently evaluated, but limited studies with relatively small cohort sizes have reported higher TNC dose to be associated with improved survival. Methods In order to further explore the relationship between PB donor CD34+ cell dose, TNC dose and RIC HCT outcomes, we assessed 705 adult patients with hematological malignancies who underwent RIC allogeneic HCT at Dana Farber Cancer Institute/ Brigham and Women's Hospital (DFCI/BWH) between 2000 and 2010. The vast majority received a RIC regimen of fludarabine and busulfan (n=698). GVHD prophylaxis was tacrolimus based with or without sirolimus (524 vs. 171, respectively). Recipients of in vivo T-cell depletion (TCD) with antithymocyte globulin or ex-vivo TCD were excluded. The median age was 57 years (range,18-74). Patient's disease risk index (DRI) was categorized as low (n=164), intermediate (n=350), high (n=170) or very high (n=21) per Armand, et al (Blood, 2012). Transplants were categorized as matched (MRD n=273, MUD n=374) or mismatched (MMRD n=4, MMUD n=58). Results There was weak correlation between CD34+ cell dose and TNC (Spearman coefficient 0.25 [0.18-0.32]), and between CD34+/kg and TNC/kg with coefficient 0.25 [0.26, 0.39]. Cell doses for TNC effects were evaluated by quartiles. On multivariable analysis including age, DRI, donor source, gender, and CMV serostatus, higher TNC dose (top quartile, ≥10.8 x 10^10 cells) was independently associated with increased chronic GVHD (HR 1.33 [1.06-1.67], p=0.015) as well as decreased relapse (HR 0.74 [0.58-0.94], p=0.015). There was no effect on acute GVHD, engraftment, or non-relapse mortality. Importantly, higher TNC dose was associated with improved overall survival (HR 0.74 [0.59-0.94], p=0.014, Figure 1) and progression free survival, PFS (HR 0.76 [0.61-0.94], p=0.014). In contrast, although higher doses of CD34+ cells (> 10 x 10^6/kg vs. < 5 x10^6/kg) resulted in faster engraftment for both platelets and neutrophils (data not shown) and a decrease in non-relapse mortality ( HR 0.53 [0.30-0.93], p=0.027), there was no significant effect on acute or chronic GVHD incidence, relapse, PFS or survival. Conclusions These data suggest TNC dose is an important prognostic variable in T-replete RIC HCT with significant impact on survival and should, like CD34+ cell dose, be taken into consideration when planning donor graft infusions. Further studies are needed to confirm these data, and characterize the components of the PB graft that influence survival. Disclosures: No relevant conflicts of interest to declare.

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Impact of Cytopenia Following Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Using Post-Transplant Cyclophoshamide

Blood ◽

10.1182/blood.v128.22.2281.2281 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2281-2281

Author(s):

Villetard Ferdinand ◽

Stefania Bramanti ◽

Samia Harbi ◽

Sabine Fürst ◽

Catherine Faucher ◽

...

Keyword(s):

Bone Marrow ◽

Cell Transplantation ◽

Disease Risk ◽

Conflicts Of Interest ◽

Risk Index ◽

Conditioning Regimen ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Cell Dose ◽

The Impact

Abstract Introduction Allogeneic transplantation from a haploidentical donor (HaploSCT) is an alternative strategy in the treatment of hematologic malignancies in absence of HLA-identical donor. Recent studies reported similar outcome after HaploSCT compared to HLA-identical transplantation in different settings (Bashey, JCO 2013; Wang, Blood 2015; Gosh, JCO 2016). Although survivals seemed promising after HaploSCT, hematopoietic recovery following such a mismatched transplantation could represent a limitation. Thus, our series aims to evaluate hematological recovery after HaploSCT using a post transplantation cyclophosphamide (PT-Cy) platform. Methods This retrospective monocentric study included consecutive patients with following criteria: adults with hematological malignancies; bone marrow or peripheral blood T-replete HaploSCT from 2011 to 2015; non-myeloablative (Baltimore approach) or reduced intensity conditioning (busulfan-based) regimen; PT-Cy as part of GVHD prophylaxis. Patients with primary graft failure were excluded. Absolute neutrophil count (ANC), red cells (RCT) or platelet transfusion (PT) requirements on day 30 (D30) and day 100 (D100) were analyzed among disease-free patients. We first separately evaluated the rate of patients with significant cytopenia in each lineage (defined by ANC < 1 G/L, RCT need, PT need) and searched for impact of pre-transplantation factors on cytopenia (multivariate analyses by binary logistic regression). Then, we evaluated outcome by D30- and D100-landmark analyses according to cytopenia. Results One hundred and forty six patients with a median age of 56 years (range: 19-73) were analyzed: 142 and 117 were evaluable at D30 (4 early deaths) and D100 (17 deaths, 11 relapses), respectively. At D30, 20% of patients had ANC<1G/L, 67% needed RCT and 63% needed PT. Corresponding values at D100 were 20%, 42% and 28%, respectively (Figure 1). At D30: the use of PBSC (HR 9.5, p=0.002) was significantly associated with ANC>1G/L at D30; the use of NMAC Baltimore schema (HR 0.3, p=0.012) and CD34+ cell dose > median (HR 0.4, p=0.041) decreased PT needs while hematopoietic cell transplantation comorbidity index (HCT-CI)≥3 (HR 3.3, p=0.004) was associated with PT needs; no factor was found to significantly influence RCT. At D100: Age>60 years (HR 2.4, p=0.045), female to male HaploSCT (HR 3.3, p=0.020) and HCT-CI≥3 (HR 3.7, p=0.006) were significantly associated with higher risk of RCT need; female to male HaploSCT (HR 3.6, p=0.015) and HCT-CI≥3 (HR 6.9, p=0.001) were associated with PT needs; no factor was found to significantly influence ANC. With a median follow up of 25 months (range: 5-55), cox multivariate model with adjustment by age (continuous), disease risk index (low/intermediate vs high/very high), HCT-CI (0-2 vs ≥3), conditioning regimen (baltimore vs. busulfan-based) and graft source (bone marrow vs PBSC) showed that ANC<1 G/L was strongly associated with higher NRM (HR 2.9, p=0.011) and shorter OS (HR 3.4, p<0.001), overcoming the impact of RCT and PT needs (Figure 2A and 2B). In contrast, D100 analysis showed that PT need was the most determinant factor of increased NRM (HR 13.7, p=0.013) and poor OS (HR 7.3, p=0.003), while both D100 ANC and RCT needs did not impact outcome (Figure 2C and 2D). Discussion We found that cytopenia remain a concern after HaploSCT, leading to increased NRM and OS. The absence of ANC>1G/L at D30 as well as the need of PT at D100 may be considered as a strong post transplantation factor predicting poor outcome. Some pre-transplantation factors of cytopenia have been identified, such as CD34+ cell dose, sex mismatch and graft source. Among them, some may help for donor selection while the optimal donor for HaploSCT is still unknown. Moreover, better neutrophil recovery at D30 is achieved with the use of PBSC. CD34+ optimal cell dose in this setting remains also to be determined. In addition, post transplantation events such GVHD and/or infections should be evaluate to explore their interactions with such cytopenia, aiming to develop early therapeutic interventions. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Outcome of Allogeneic Hematopoietic Stem-Cell Transplantation for Acute Myeloid Leukemia (AML) with 11q23 (MLL) Rearrangement (MLL-r AML). A Retrospective Analysis From the Acute Leukemia Working Party of EBMT

Blood ◽

10.1182/blood.v118.21.498.498 ◽

2011 ◽

Vol 118 (21) ◽

pp. 498-498

Author(s):

Arnaud Pigneux ◽

Myriam Labopin ◽

Johann Maertens ◽

Ulrike Bacher ◽

Gérard Socié ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Good Prognosis ◽

Hematopoietic Stem ◽

Long Term Outcome ◽

The Impact ◽

Acute Myeloid

Abstract Abstract 498 Acute myeloid leukemia (AML) with 11q23 (MLL) rearrangement (MLL-r AML) belongs to the intermediate or high risk cytogenetic classification. It prognosis is known to depend on the translocation partner. Data from multicenter studies suggest that most patients with t(11q23) achieve complete remission after induction chemotherapy. However, the impact of different t(11q23) on long-term outcome is less clear, with overall survival (OS) rates at 5 years ranging from 0% to 45%. A more favourable outcome has been reported in patients receiving an alloHSCT in an early phase. To investigate the potential role of alloHSCT for the management of t(11q23) AML we analyzed the outcome of the cases reported to the ALWP between 2000 and 2010 (median year of transplant: 2007). Overall, we identified 172 patients (median age: 41, 18–70; 43% male) allografted. The following rearrangements were identified: t(9;11) in 82 patients, t(11;19) in 20, t(6;11) in 21, t(10;11) in 17, t(4;11) in 5, t(11;17) in 5 and others in 22. Most transplants were performed in complete response (CR1=148, 86%; CR2=21, 12%, CR3=3, 2%). Donor was an HLA-identical sibling in 84 transplants (49%), and an unrelated in 88 (51%). Conditioning regimen consisted of a myeloablative regimen in most patients (n=113, 65%), and source of stem-cells was peripheral blood in 110 (64%), bone marrow in 49 (28%), and cord blood in 13 (8%). One hundred sixty-six patients engrafted and 57 presented an acute GVHD ≥ 2. After a median follow-up of 24 months (2–123), 2-year overall survival (OS) was 56 ± 4%, 2-year leukemia-free survival (LFS) was 52 ± 4%, CI of relapse incidence (RI) was 35±3%, non-relapse mortality (NRM) was 16±4% and the rate of chronic GVHD was 47±4%. The outcome was significantly different (p<10−4) according to the rearrangement with a 2-year LFS for patients with t(9;11) of 61±6%, t(11;19) of 65±11%, t(6;11) of 12±10%, t(10;11) of 34±12%. LFS was improved by CR status with a 2-y LFS for CR1 patients of 56 ± 5% and only 23 ± 9% for patients in more advanced disease. We subsequently restricted our analysis on the population of 148 patients in first CR in which the 2-year LFS was for patients with t(9;11) of 64±6%, t(11;19) of 68±12%, t(6;11) of 16±10%, t(10;11) of 40±13%, the 2-year RI was for patients with t(9;11) of 23±5%, t(11;19) of 26±11%, t(6;11) of 55±15%, t(10;11) of 36±14%, the 2-year NRM was for patients with t(9;11) of 24±13%, t(11;19) of 6±5%, t(6;11) of 29±13%, t(10;11) of 24±13%. Multivariate analysis on LFS identified as poor prognostic factors: the presence of a t(6;11)(p<0.0001) or t(10,11) (p = 0.034) and an interval from diagnosis to CR1 greater than 43 days (p=0.008). This preliminary study confirms the known good prognosis of t(9;11) and poor outcome of t(6;11), while it highlights the good prognosis of t(11;19) AML patients submitted to alloHSCT in CR1, suggesting that this procedure might overcome the adverse prognosis associated to this entity. Disclosures: No relevant conflicts of interest to declare.

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Comparison of Peripheral Blood Stem Cells (PBSC) to Bone Marrow (BM) for T-Replete HLA-Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood.v128.22.683.683 ◽

2016 ◽

Vol 128 (22) ◽

pp. 683-683 ◽

Cited By ~ 3

Author(s):

Asad Bashey ◽

MeiJie Zhang ◽

Shannon R. McCurdy ◽

Stefan O. Ciurea ◽

Andrew St. Martin ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Disease Risk ◽

Risk Index ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Committees ◽

Mortality Risks ◽

Post Transplant

Abstract T cell-replete haploidentical donor transplants (HAPLO-HCT) using post-transplant cyclophosphamide for control of alloreactivity is now being increasingly utilized. HAPLO-HCTs were originally performed using BM grafts. However, recently, a few single center studies have reported good outcomes using G-CSF mobilized PBSC grafts for HAPLO-HCT. No prospective randomized comparisons of BM to PBSC grafts for HAPLO-HCT have been performed. Therefore, we analyzed outcomes for 687 adults (496 BM, 191 PBSC) who received HAPLO-HCT for hematologic malignancies using post-transplant cyclophosphamide + mycophenolate + calcineurin inhibitor for GVHD prophylaxis between 2009 and 2014 in the United States. The primary outcome was overall survival. The characteristics of recipients of BM and PBSC were similar except BM recipients were older, more likely to have a performance score ≥90, HCT-CI index ≤2, be CMV seronegative, have a lymphoid malignancy and receive reduced-intensity conditioning. Most PBSC transplants occurred between 2012 and 2014. The median follow-up was 35 and 20 months for recipients of BM and PBSC grafts, respectively. Cox regression models were built to study the effect of graft type adjusted for other significant factors on overall mortality, non-relapse mortality, relapse and graft-versus-host disease (GVHD) and outcomes censored at 2-years to accommodate differential follow-up between treatment groups (Table 1). After adjusting for age, CMV serostatus, disease risk index (disease type/disease status for myeloid and lymphoid malignancy and cytogenetic risk for acute leukemia and myelodysplastic syndrome) and transplant conditioning regimen there were no significant differences in risks for overall mortality (HR 1.00, p= 0.98; 2-year overall survival: 54% and 57%) or non-relapse mortality (HR 0.92, p=0.74; 2-year non-relapse mortality: 17% and 16%) after transplantation of BM compared to PBSC, respectively. However, relapse risks were higher after transplantation of BM compared to PBSC (HR 1.49, p=0.009; 2-year relapse: 45% and 28%). Subset analyses explored the effect of graft type separately for myeloablative and reduced intensity conditioning regimen adjusting for age, CMV serostatus and disease risk index. Consistent with the main analysis there were no differences in overall or non-relapse mortality risks and relapse risks were higher with BM compared to PBSC with myeloablative regimens (Table 1). Although this may in part be explained by lower chronic GVHD risks with transplantation of BM grafts, chronic GVHD was not significantly predictive of relapse risk when modeled as a time-dependent covariate (HR= 0.73, p=0.49). Grade II-IV acute GVHD risks (HR 0.45, p<0.001; 22% and 37%), adjusted for conditioning regimen were lower after transplantation of BM compared to PBSC. Chronic GVHD risks adjusted for age and performance score were also lower after transplantation of BM compared to PBSC (HR 0.35, p<0.001; 20% and 41%) but rates of moderate and severe chronic GVHD were not significantly different (28% and 32%). There were no differences in incidence of hematopoietic recovery by graft type. In conclusion, compared to BM grafts HAPLO-HCT with PBSC are associated with similar overall survival and non-relapse mortality risks but lower relapse risks with myeloablative conditioning regimens. Longer follow up is needed to ascertain whether survival differences may occur later. The observed adverse effect of BM grafts on relapse with myeloablative regimens must be studied further in the setting of carefully controlled trials. Table 1. Table 1. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board. Hamadani:Takeda: Research Funding. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees. Wingard:Ansun: Consultancy; Gilead: Consultancy; Astellas: Consultancy; Fate Therapeutics: Consultancy; Merck: Consultancy.

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No Improvement of Overall-Survival in Children with High-Risk Acute Myeloid Leukemia by Stem Cell Transplantation in 1st Complete Remission.

Blood ◽

10.1182/blood.v108.11.320.320 ◽

2006 ◽

Vol 108 (11) ◽

pp. 320-320 ◽

Cited By ~ 2

Author(s):

Dirk Reinhardt ◽

Bernhard Kremens ◽

Martin Zimmermann ◽

Josef Vormoor ◽

Michael Dworzak ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Complete Remission ◽

Children And Adolescents ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Hla Typing ◽

Unrelated Donor ◽

The Impact

Abstract One aim of the AML-BFM 98 study was to evaluate prospectively the impact of matched sibling donor (MSD)-SCT in 1st complete remission (CR) in children with high-risk (HR)-AML. Patients: Between 7/1998 and 3/2004 494 children and adolescents were enrolled in the studies AML-BFM 98 and the AML-BFM 98 Interim 2003. Patients with favorable cytogenetics [t(8;21), inv(16), t(15;17)], corresponding morphology (AML FAB M1/2 with Auer rods, M4eo, M3) and < 5% blasts on day 15 were defined as standard risk (SR)-group (n=177). All others were stratified to HR-group (n=317) and eligible for SCT in 1st CR. Out of 275 patients achieving 1st CR (87%) 63 patients had a MSD and 188 had no MSD (intent-to-treat group, ITT) while 24 patients had to be excluded due to missing HLA typing or initial refusal to SCT. Thirty-six patients received MSD-SCT (=as-treated group), another two children were transplanted from a matched unrelated donor (MUD) although an MSD was available. The reasons not performing SCT in 1st CR in the remaining 25 children with a donor available were early relapse (n=7), death in CR (n=2), clinical reasons (n=8), or refusal of SCT (n=8). Chemotherapy (CHT) only was given in 192 patients (n=167 without MSD, n=25 with a MSD). Another 21 children were transplanted from an unrelated donor (n=18), family donor (n=1), haploidentical donor (n=2). The reasons were slow response, very poor cytogenetics or other clinical reasons. Treatment: All patients received double induction and consolidation. MSD-SCT in 1st was scheduled after 4 blocs of treatment. Children who were not transplanted in 1st CR received intensification and a 1-year maintenance therapy. The recommended conditioning regimen consisted in busulfan and cyclophosphamide. Results ITT analysis revealed no significant differences in of 5 year disease-free survival (DFS) and overall survival (OS) between children with or without a donor (no donor vs. donor: DFS 43±4% vs. 47±7% plog rank 0.52; OS 56±4% vs. 58±9%, plog rank 0.16). The as-treated analysis gave similar results: CHT only vs. MSD-SCT: DFS 35±11% vs. 59±9% p Mantel-byar 0.13; OS 59±13% vs. 62±12%, p Mantel-byar 0.51). The major reasons of treatment failures were relapses in all groups [CHT only n=100 (52%), MSD-SCT n=13 (34%), MUD-SCT n=9 (50%)]. A 2nd CR was achieved in 71% of the CHT only group (n=74). After SCT in 2nd CR, OS was 40±6%. By contrast, only two children (9%) of 22 children after relapse following SCT in 1st CR could be salvaged. Severe late adverse events (e.g. severe chronic GvHD CTC grade IV, destruction of big joints, intracerebral bleedings) were more frequent in children transplanted in 1st CR (15%) than in those with CHT only (including SCT in 2nd CR; 5%, p×2< 0.05). Conclusion: In the population-based, prospective multi-center study AML-BFM 98 allogeneic MSD-SCT in 1st CR showed no advantage in children and adolescents with HR-AML. Considering the higher toxicity of allogeneic SCT, in the ongoing trial AML-BFM 2004, this SCT (MSD or MUD) is restricted to patients in 2nd CR and refractory AML.

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Increased Disease Progression in HLA-a, -B, -C, -DRB1 and -DBP1 Matched Recipients of Unrelated Donor Transplants with Peripheral Blood Is Independent of Risk Groups By Disease Risk Index

Blood ◽

10.1182/blood.v126.23.2005.2005 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2005-2005

Author(s):

Betul Oran ◽

Rima M Saliba ◽

Yudith Carmazzi ◽

Elizabeth J. Shpall ◽

Katayoun Rezvani ◽

...

Keyword(s):

Disease Progression ◽

Peripheral Blood ◽

Disease Risk ◽

Risk Group ◽

Risk Index ◽

Risk Groups ◽

Study Cohort ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

The Impact

Abstract The use of unrelated donors matched in all alleles of HLA-A, -B, -C, and -DRB1 loci has been associated with superior outcomes compared with those having 1 or more mismatches. Recent studies showed increased transplant-related mortality (TRM) with the use of HLA-DPB1 mismatched donors supporting the notion that the ideal volunteer unrelated donor should fully match at HLA-A, -B, -C, and -DRB1 and lack -DPB1 mismatches. The issue of the effect of HLA-DPB1 mismatch on the disease progression rate is still controversial and we aimed to investigate the impact of HLA-DPB1 mismatch in the graft versus host direction on transplant outcomes in patients categorized according to the recently defined disease risk index (DRI) for disease risk classification. Our study cohort included 1,211 transplant patients with hematological malignancies whohave received an hematopoietic stem cell transplant (HSCT) from an unrelated HLA-A, -B, -C,-DRB1 matched donor by high resolution typing (8/8 matched) after 2005 through 2014. The study cohort had a median age of 55 (range, 19-77); the hematopoietic stem cell source was peripheral blood (PB) in 698 and bone marrow (BM) in 513 patients. Disease risk index (DRI) at HSCT was high or very high in 382 (33%), intermediate in 598 (51%), low in 185 (16%) patients. Of the pairs, 1,154 (95%) were matched atHLA-DQB1 and 1,116 (92%) at HLA- DRB3/4/5 by high resolution testing. However, 633 (52%) had mismatch at one of the DPB1 alleles and 208 (17%) had two mismatches. There was association between matching for DPB1and matching for DRB3/4/5 (p=0.002) but not with DQB1. In PB recipients, there was a highly significant decreaseof disease progression in DPB1 mismatched pairs (one and two allele; HR=0.7, p=0.01 and HR=0.6, p=0.01 respectively) as compared tothose pairs with DPB1 matched. The impact of mismatches at one or two alleles were not different on disease progression (HR=1.2, p=0.4). However, the impact of DPB1 mismatch on disease progression was not uniform in different disease risk groups by DRI. Mismatch at DPB1 significantly decreased disease progression only in the intermediate risk group (HR=0.5, p=0.002) but not in low risk and high/very high disease groups by DRI (HR=0.9, p=0.8 and HR=0.7, p=0.1 respectively) (Figure 1a-c). In BM recipients, increasing number of DPB1 incompatibilities decreased disease progression (HR=0.9, p=0.4 and HR=0.6, p=0.1 for 1 and 2 allele mismatches respectively) but did not reach significance. Mismatches at HLA-DQB1 and -DRB3/4/5 had no impact on disease progression in both PB and BM recipients. Pairs with one or two allele-level DPB1 mismatches increased TRM compared with DPB1 matched pairs in PB (HR=1.5, p=0.04 and HR=1.9, p=0.006 respectively) and BM recipients (HR=1.8, p=0.03 and HR=1.9, p=0.05). There was no difference between two and one allele DPB1 mismatched for TRM in PB and BM recipients. Multivariate analyses revealed that the negative impact of DPB1 mismatch on TRM was not uniform in younger or (?) older patients. Interestingly, DPB1 mismatches increased TRM only in younger (aged<55) patients (HR=2.3, p=0.02) if they were PB recipients but only in older patients (HR=2.03, p=0.046) if they were BM recipients. We next analyzed the impact of DPB1 matching on progression free survival (PFS) and did not observe any impact of DPB1 mismatches on PFS in PB (HR=0.9, p=0.9) and BM (HR=1.12, p=0.6) recipients. Subgroup analyses by DRI to identify a specific risk group that the use of HLA-A, -B, -C and -DRB1 matched but DPB1 mismatched unrelated donor might lead to improved PFS did not reveal any particular risk group in both PB and BM recipients. Thus, in recipients of HLA-A, -B-C and DRB1 allele-level matched unrelated donors a mismatch for DPB1 is associated with a significantlydecreased risk of disease progression with no impact on PFS in intermediate risk group by DRI. Further analysis permissive vs. non-permissive DPB1 mismatches would be warranted. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Disclosures No relevant conflicts of interest to declare.

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Post-transplant cyclophosphamide in matched and haploidentical transplant recipients receiving myeloablative timed sequential busulfan conditioning regimen: Results of a phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7007 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7007-7007

Author(s):

Uday R. Popat ◽

Rohtesh S. Mehta ◽

Roland Bassett ◽

Amanda Leigh Olson ◽

Amin Majid Alousi ◽

...

Keyword(s):

Phase Ii ◽

Disease Risk ◽

Phase Ii Study ◽

Risk Index ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Area Under The Curve ◽

Pharmacokinetic Studies ◽

Target Area ◽

Post Transplant

7007 Background: Myeloablative stem cell transplants have a lower rate of relapse than reduced intensity regimens. Timed sequential busulfan (TSB) with fludarabine (Flu) is a promising myeloablative regimen for patients undergoing matched sibling (MSD) or unrelated (MUD) donor transplantation (HCT) with low non-relapse mortality (NRM) (Popat et al Lancet Haematology 2018), but was not tested in haploidentical (haplo). Also, whether this approach can be used with post-transplant cyclophosphamide (PTCy) in MSD, MUD and haplo HCT is unknown. To address these issues, we conducted a prospective phase II study. Methods: Patients with hematological malignancies with MSD, MUD or haplo donor were eligible. They received fixed doses of Busulfan(BU) 80mg/m2 either on day -13 and -12 (n=45) or on -20 and -13 (n=10). Then, Flu 40mg/m2 was given on day -6 to -2 followed by Bu dosed to achieve target area under the curve (AUC) of 20,000 umol/min for the whole course based on pharmacokinetic studies. Thiotepa 5mg/kg was given on day -7 to haplo group. GVHD prophylaxis was PTCy 50mg/kg on day 3 and 4 and tacrolimus. Haplo and later MUD recipients also received mycophenolate mofetil. Results: 55 patients with a median age of 47 (15-65) years were enrolled. 30 patients had AML or MDS, 9 CML or MPD, 5 lymphoma, 5 myeloma and 6 ALL. About half had haplo 26 (47%); others had MUD 18 (33%) or MSD 11(20%). Disease risk index was high in 18 (32%), intermediate in 32 (58%), and low in 5 (9%) patients. Comorbidity score was ≥3 in 22 (40%) patients. With a median follow up of 17 months (5-28), 1-year OS, PFS, NRM and relapse rates were 71% (60-84%), 63% (51-77%), 20% (9-31%), and 17% (7-27%), respectively [Table]. There were no graft failures. Day 100 grade II-IV and III-IV acute GVHD rates were 38% (25-51%) and 9% (95% CI 1-17%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 10% (2-28%) and 8% (0-15%), respectively. 1-year OS in MSD, MUD and haplo groups were 91% (75-100%), 72% (54-96%), and 62% (45-83%) respectively (P=0.11). Conclusions: Myeloablative TSB with PTCy is feasible in MSD, MUD and haplo HCT. It lowers the incidence of severe acute and chronic GVHD without apparent increase in relapse. Clinical trial information: NCT02861417. [Table: see text]

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Updated Analysis of Hematopoietic Stem Cell Transplantations after Reduced Intensity Conditioning Regimen (RIC HSCT) for Hematological Malignancies from the Société Française de Greffe de Moelle Osseuse et de Thérapie Cellulaire (SFGM-TC) Registry.

Blood ◽

10.1182/blood.v106.11.45.45 ◽

2005 ◽

Vol 106 (11) ◽

pp. 45-45 ◽

Cited By ~ 1

Author(s):

Mauricette Michallet ◽

Quoc-Hung Le ◽

Thomas Prebet ◽

Mohamad Mohty ◽

Jean Michel Boiron ◽

...

Keyword(s):

Hematological Malignancies ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Status ◽

Peripheral Blood Stem Cells ◽

Hematopoietic Stem ◽

Grade Ii ◽

The Impact ◽

Global Population

Abstract This report updates a retrospective study from SFGM-TC registry concerning 738 patients who underwent RIC HSCT for hematological malignancies [280 F, 458 M, median age: 51 years (1–72)] between 1997 and 2004. The diagnosis were 173 AML, 40 ALL, 68 MDS, 152 NHL, 36 HD, 45 CLL, 70 CML, 154 MM; 332 patients have been previously transplanted. At time of conditioning, 261 patients were in CR, 224 in PR and 253 in progressive disease (PD). Peripheral blood stem cells (PBSC) were used in 574 patients and bone marrow in 164 patients from 655 HLA related donors and 83 unrelated donors. As conditioning, 152 patients received fludarabine and TBI (2 grays), 300 patients fludarabine, busulfan and anti-thymocyte globulins (FBS) (ATG 1d: 57, 2 d: 84, 3 d: 58, 4 d: 18, 5 d: 83) and 286 patients an other regimen. As GVHD prophylaxis, 722 patients received a cyclosporine A (CsA) based regimen. After transplant, 252 patients (35%) in the global population developed an acute GVHD ≥ grade II (grades III and IV: 116) and 208 patients (37%) in the PBSCT population (grades III and IV: 100). A chronic GVHD was present in 258 patients (38%) in the global population (115 limited and 143 extensive) and 221 patients (42%) in the PBSCT population (95 limited and 126 extensive). With a median follow-up of 27 months, the 3-year probability of overall survival (OS) and event-free survival (EFS) for the global population was 38% (33–44) and 28%(24–34) and for PBSC SCT patients 39%(33–46) and 32%(27–39) respectively. The 3-year probability of OS varied according to diagnosis (CLL: 62%, NHL:50%, CML:44%, MM:41%, MDS:37%, AML:26%, ALL:20%) and cGVHD (no:28%, yes:61%). The cumulative TRM incidence was 12% at 1 year and 13% at 3 years. A multivariate analysis was performed studying pre and post transplant factors for OS, EFS and GVHD:. Table 1 summarizes all variables showing a significant impact on OS and EFS. Furthermore, analyses showed the impact of one variable on AGVHD and cGVHD for PBSCT population: FBS with ATG 1day vs 2 days [HR:1.56(1.19–2.04) p=0.001, HR:1.50(1.14–1.97) p=0.003]. In conclusion, besides the influence of known factors on OS and EFS after RIC HSCT, this study pointed out, on a large series with a long-term follow-up, the major impact of disease status, acute and chronic GVHD and demonstrated the important role of ATG duration on GVHD incidence. Table 1: Multivariate analyses OS/EFS Variables OS (HR) p EFS (HR) p Conditionning :FBS ATG 1d vs 2 d Global 1.47 (1–2.2) 0,05 NS PBSC 1.6 (1.03–2.49) 0,04 NS FBS ATG 5d vs 2 d PBSC NS 1.13(1.04–1,24) < 0.01 PD vs CR Global 1.22 (1.1–1.32) < 0.01 1.15 (1.07–1.25) < 0.01 PBSC 1.2 (1.1–1,3) < 0.01 1.14 (1.05–1.24) < 0.01 Previous HSCT: yes vs no Global 1.27 (1.02–1,59) 0,04 1.25 (1.01–1.55) 0.04 AGVHD : Grade II vs 0-I PBSC 1.21 (1–1.47) 0,05 NS AGVHD : Grade III-IV vs 0-I Global 1,28 (1,14–1,43) < 0.01 1.12 (1–1.25) 0.04 PBSC 1.3 (1.14–1.47) < 0.01 1.13 (1–1.28) 0.05 cGVHD : yes vs no Global 0.2 (0.14–0.28) < 0.01 0.25 (0.19–0.35) < 0.01 PBSC 0.19 (0.13–0.28) < 0.01 0.25 (0.18–0.34) < 0.01

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Treatment of AML in First Remission (CR1) with Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Using Unrelated Donors (UD).

Blood ◽

10.1182/blood.v112.11.976.976 ◽

2008 ◽

Vol 112 (11) ◽

pp. 976-976

Author(s):

Leandro de Padua Silva ◽

Borje S. Andersson ◽

Uday Popat ◽

Lori Griffin ◽

Michele Alvarez ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hla Typing ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Unrelated Donors ◽

Engraftment Failure

Abstract Introduction/Methods: A key component of improving the success rate of allogeneic HSCT for AML in CR1 is to reduce non-relapse mortality (NRM), which, if excessive, will deny the benefit of the graft-versus-leukemia effect. UD HSCT has traditionally been associated with high NRM rates. We reported previously on the significant reduction of NRM using the conditioning regimen of fludarabine 40mg/m2, IV busulfan 130 mg/m2 for 4 days and thymoglobulin. Here we analyze the outcomes of all patients (n=37) with AML in CR1 treated with this regimen and UD HSCT in our institution from January 2002 to December 2007. High-resolution allele level HLA typing was performed for all donorrecipient pairs for HLA-A, -B, -C, DRB1 and DQB1; up to one mismatch was allowed (9/10). Median follow up is 30 months (range, 9–72). Results: Median age was 48 years (range, 13–68); 30% (n=11) were older than 54 years and 51% (n=19) were male. Eleven patients (30%) had secondary AML. Prognostic cytogenetics classification was poor and intermediate in 53% and 47% of the cases, respectively. Stem cell source was bone marrow (BM) in 68% (n=25) and peripheral blood (PB) in 32% (n=12). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methotrexate with and without pentostatin (1 or 1.5 mg/m2 on days 8, 15, 22 and 30) in 46% (n=17) and 54% of the cases (n=20), respectively. Donor-recipient HLA match was 9/10 and 10/10 in 14% and 86% of the cases. Median infused total nucleated and CD34+ cells was 3.72 x 108 (range, 0.57 – 11.78) and 3.77 x 106 (range, 0.45 – 12.4), respectively. Median time to neutrophil and platelet engraftment was 12 days (range, 8–18) and 14 days (range, 8–101), respectively. All but one patient engrafted. Grade II–IV acute (a) GVHD rate was 13% (n=2) and 50% (n=10) for patients that received and not received pentostatin-based prophylaxis. Grade III–IV aGVHD rate was 0% versus 15% (n=3) for patients receiving and not receiving pentostatin. Chronic GVHD was diagnosed in 55% (n=18) of all patients (extensive in 10). 100-day and 3-year NRM rate was 11% (n=4) and 20% (n=4), respectively, and was due to engraftment failure (n=1) and aGVHD (n=3). Eight patients (22%) have relapsed, and 8 (22%) have died (4 of relapse, and 4 of NRM causes). Relapse rate was 18% (3/17) and 25% (5/20) for patients that received and not received pentostatin as part of GVHD prophylaxis. Actuarial 3-year event-free and overall survival (figure) is 68% and 78%, respectively. Actuarial 3-year overall survival for patients receiving BM and PB is 80% and 75%, respectively. Conclusion: Long-term disease control can be achieved in a significant fraction of high-risk AML patients undergoing UD transplants as described in this abstract. Use of pentostatin in this context deserves further prospective evaluation. Figure Figure

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Single Center Experience of Allogenic Hematopoietic Stem Cell Transplantation in 100 Patients with Myelodysplasia: The Impact of Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v126.23.5537.5537 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5537-5537

Author(s):

Colombe Saillard ◽

Raynier Devillier ◽

Sabine Furst ◽

Jérome Rey ◽

Angela Granata ◽

...

Keyword(s):

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Donor Type ◽

The Impact ◽

Disease Free

Abstract Introduction Allogenic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for patients with myelodysplasia (MDS). However, because of age, MDS patients represent a challenging population for such an intensive treatment. Additionally, the low rate of HLA-identical donor has represented a major limitation in this strategy. Recently, reduced-intensity conditioning (RIC) regimens have made feasible Allo-HSCT in the elderly, although relapse rate might be increased. Additionally, the development of HSCT using alternative donors overcomes HLA-compatibility limitations. Graft-versus-host disease (GVHD) is a major post-transplant event, graft-versus-leukemia effect being counterbalanced by toxicity and impaired quality of life. The aim of this retrospective study was to report outcome of patients with MDS who underwent Allo-HSCT and to study the impact of GVHD. Methods Between 2003 and 2014, 100 consecutive patients presenting with MDS, or MDS-secondary AML, underwent Allo-HSCT in our institution. At diagnosis, 58 patients had ≥ 2 cytopenias. IPPS was low/intermediate-1 in 46% and intermediate-2/high in 54%, R-IPSS was very low/low in 25%, intermediate in 20% and high/very high in 55%. Cytogenetics, according to Disease Risk Index (DRI), was intermediate in 79% and adverse in 21%. Secondary MDS represented 27% of our cohort. Before Allo-HSCT, 42% received 5-Azacytidine, 27% intensive chemotherapy and 9% were transplanted upfront. At the time of Allo-HSCT, the median recipient age was 61 (19-71) years. Median time between diagnosis and Allo-HSCT was 12 months (1-131). After excluding patients transplanted upfront, 31 patients still had ≥5% blasts after treatment. Donors were HLA-matched in 70% (41% related, 29% unrelated), 30% were not HLA-matched (10% unrelated, 7% cord blood, 13% T-repleted haplo-HSCT). Stem cell source was peripheral blood stem cells in 90%. Twelve percent of patients received non-myeloablative (NMA) conditioning regimen, 75% RIC and 13% reduced-toxicity conditioning (RTC) regimens. Post-graft immunosuppression consisted in cyclosporine A (CSA) in 58%, CSA-Mycophenolate Mofetil (MMF) in 15%, CSA-Methotrexate in 14% and CSA-MMF-Cyclophosphamide for haplo-HSCT (13%). Results Median follow-up was 37 months (3-197). The incidence of 3-4 acute GVHD at day 100 was 7% (95% CI = 2-12). The incidence of severe chronic GVHD at 3 years was 19% (95% CI = 11-27). One and 3-year non-relapse mortality (NRM) were 23 and 29% respectively. The cumulative incidence of relapse (CIR) at 1 year and 3 years 24% and 33% respectively. One and 3-year progression-free survival (PFS) were 52% (95% CI = 43-63) and 37% (95% CI = 28-49). One and 3-year overall survival (OS) were 60% (95% CI = 51-71) and 48% (95% CI = 39-60). At one year, 51 patients were alive and disease-free, including 61% (n=31) without immunosuppression. At the end of follow-up, 39 patients were alive and disease-free, including 85% (n=33) without immunosuppression and 77% (n=30) GVHD-free. Time-dependent analysis of GVHD impact (Table 1), adjusted on age, donor-type, DRI and conditioning regimen, revealed that acute GVHD strongly impacts on OS (HR 3.8, 95% IC = 2-7, p<0.01), PFS (HR 3.1, 95% CI = 1.7-5.6, p<0.01) and NRM (HR 12, 95% CI = 5.2-28, p<0.01). Chronic GVHD was statistically significant on CIR (HR 0.16, 95% CI = 0.04-0.7, p=0.02) and NRM (HR 2.8, 95% CI = 1-8, p=0.05). Pre-transplant disease characteristics did not have any impact by univariate analysis. Multivariate analysis did not find any impact of age, donor type, DRI and conditioning regimen in terms of OS, PFS, NRM and CIR. Conclusion Our results suggest that GVHD highly influences outcome, regardless of MDS and Allo-HSCT characteristics. It should be quoted that a significant number of patients are alive, long-term survivors, disease-free and GVHD-free suggesting good quality of life. These results invite defining better strategies of GVHD prevention while retaining disease control magnifying the existing graft-versus-leukemia effect. Table 1. Time-dependent analysis of the impact of acute and chronic GVHD, adjusted on age (< or > 60), donor-type (HLA-matched or not matched), DRI and conditioning regimen (NMA, RIC or RTC). HR 95% CI p Acute GVHD OS PFS NRM CIR 3.8 3.1 12 0.4 2-7 1.7-5.6 5.2-28 0.09-1.7 <0.01 <0.01 <0.01 0.2 Chronic GVHD OS PFS NRM CIR 0.7 0.8 2.8 0.2 0.3-1.5 0.4-1.8 1.01-8 0.04-0.8 0.4 0.6 0.050.02 Disclosures Vey: Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria.

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