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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2048-2048 ◽  
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.

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

Blood ◽  
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.

scholarly journals High Peripheral Blood Stem Cell (PBSC) CD34+ Cell Dose Increases the Risk of Chronic Gvhd after Human Leukocyte Antigen (HLA) Matched Sibling Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5877-5877 ◽  
Author(s):  
Ezzideen Barjes Alrawi ◽  
Erica D. Warlick ◽  
Qing Cao ◽  
Mukta Arora ◽  
Shernan G. Holtan ◽  
...  
Keyword(s):  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Blood Type ◽  
Platelet Recovery ◽  
Cell Dose ◽  
Matched Sibling

Abstract CD34+ cell dose is a critical determinant of outcomes after allogeneic PBSC transplantation, with a CD34 dose ≥2.0 x 10e6/kg shown to positively impact hematopoietic engraftment and survival. However, it is unknown whether additional benefits are observed with even higher CD34 cell doses. Therefore, we further explored the effect of intermediate, high and very high CD34 cell doses on the incidence of engraftment, acute and chronic graft-versus-host disease (GVHD) and transplant related mortality (TRM) and on probability of survival and GVHD-Relapse-free survival (GRFS). Three hundred and five consecutive patients transplanted with GCSF-mobilized PBSC from HLA-matched sibling donors (MSD) were evaluated. Patients were ≥16 years of age, had a hematological malignancy and received a myeloablative or a nonmyeloablative conditioning regimen between 2002 and 2012. The median recipient age was 52 years (r, 19-74 years) with most being male (n=194, 63.8%) diagnosed with leukemia (72%) or lymphoma (22%), and intermediate disease risk index (DRI, n=204, 67%). The median age for the donor were 49 years (r,17-76 years). In 159 patients (52%) the donor and recipient were sex matched with 89 male patients having a female door (29%). The ABO blood type was matched in 195 patients (64%), 153(50%) received a myeloablative (MA) conditioning regimen, and 37 (12%) received a reduce intensity conditioning regimen containing ATG. The median follow up of surviving patients was 793 days (r, 14-4562 days). Patients were divided in four CD34 dose quartiles: first quartile (QT1), ≤4.8 x10e6/kg, QT2 4.8-6.0 x10e6/kg, QT3 6.0-7.5 x10e6/kg, and QT4 ≥ 7.6 x 10e6/kg. Notably, the CD3 doses were similar for all quartiles: QT1 was 3.4 x 10e8/kg (r, 0.3-10.0), QT2 was 2.7 x 10e8/kg (r, 1.1-7.6), QT3 was 2.8 x 10e8/kg (r, 0.8-7.2) and QT4 was 2.8 x 10e8/kg (r, 1.4-7.7); there was no correlation between CD34 and CD3 cell doses. Patient and donor characteristics were similar in the four groups except for shorter median follow-up (P <0.01) in QT1, more sex mismatched grafts (P <0.01) in QT3, and lower median number of cell collections (P <0.01) and more female donor: male recipient pairs (P< 0.01) in QT4. Multivariate analysis results are summarized on the table. Higher CD34+ cell dose was associated with improved platelet recovery with trends toward lower TRM and improved overall survival. Chronic GVHD however was also higher. In summary, additional studies are needed to establish a survival benefit in recipients of higher cell doses >4.8 x 10e6 CD34 cells/kg. Unless survival is positively impacted, the higher risk of chronic GVHD would argue for assigning an upper CD34 cell dose limit to reduce this risk that can significantly impair quality of life. Table Table. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 265-265 ◽  
Author(s):  
Areej El-Jawahri ◽  
Yi-Bin Chen ◽  
Ruta Brazauskas ◽  
Naya He ◽  
Stephanie J. Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
Disease Risk ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hospital Length Of Stay ◽  
Full Time ◽  
Hematopoietic Stem ◽  
Allogeneic Hct ◽  
The Impact

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.

Incorporation of Posttransplant Cyclophosphamide (PCy) As Part of Standard Immunoprophylaxis (IP) for All Allogeneic Transplants: A Retrospective, Single Institution Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4485-4485
Author(s):  
Dennis Cooper ◽  
Jackie Manago ◽  
Vimal Patel ◽  
Dale Schaar ◽  
Tracy Krimmel ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Number Of Patients ◽  
One Year ◽  
Disease Free

Background: The incorporation of PCy in IP has allowed transplantation of stem cells from haploidentical (HI) family members such that nearly all patients have a potential donor. Thus far, HI stem cell transplantation with PCy appears to yield comparable results to matched unrelated (MUD) and matched sibling donors (MSD) who have been treated with conventional GVHD regimens, but with less chronic GVHD (cGVHD). Particularly in light of the low incidence of cGVHD, which has not been achieved with other IP strategies after T cell-replete products, PCy is being investigated after MUD and MSD transplantation where complications from cGVHD remain the major cause of non-relapse mortality. A recent study from the BMTCTN showed that in patients conditioned with reduced intensity regimens and who received MSD and MUD stem cells, the addition of PCy to standard IP (SIP) was superior to either bortezomib or maravoric in the composite endpoint of graft-versus-host disease-free, relapse-free survival (GRFS). However, this study did not include patients who received ablative conditioning regimens and did not report on the percentage of patients who were disease-free and off immunosuppression (DFOI) at 1 year after transplant. In the present study, we have compared our experience with the addition of PCy for essentially all allogeneic stem cell transplants treated over a 2 year period with the results of patients treated with SIP in the prior two year span. Outcomes of interest included one-year overall survival (OS) and one-year GRFS as well as the percentage of patients DFOI at one year. Methods: With the exception of patients receiving umbilical cord blood transplants, beginning in April 2016, all but two patients who received allogeneic transplants were given mobilized peripheral blood stem cells and then treated with PCy on days +3 and +4 followed by tacrolimus and mycophenolate on day 5. In the absence of GVHD, mycophenolate was stopped at days +35-50 and tacrolimus was tapered beginning after day +100 unless there was low donor chimerism or a suspicion of relapse in which case tacrolimus could be tapered sooner. In order to have at least one-year follow-up, the last patient included in the study was treated before April 2018. During this time period, MSD were prioritized over MUD which in turn were chosen over haploidentical donors. For comparison, we looked at the prior 2 year period (2014-2016) in which patients were treated with SIP (including ATG in patients who received MUD stem cells). Because of a higher percentage of patients with an advanced disease risk index (DRI) in the years 2014-2016, we restricted our analysis in the SIP cohort to those patients with low and intermediate risk disease but included all patients in the more recent period who received PCy. Results: There were 68 patients treated in the PCy group, including 2 patients who received PCy after HI transplants in the years 2014 and 2015. After eliminating patients with high DRI there were 40 patients in the earlier SIP cohort of patients. The resulting patient groups were similar with respect to median age (53) and diagnosis (approximately 80% of patients with AML and ALL). There was a slightly higher percentage of patients in the SIP group with hematopoietic cell transplantation-comorbidity index scores of 3 or more (52.5 vs 48.5). In the PCy group the number of patients with early, intermediate and advanced DRI were 2, 53 and 13, whereas in the (modified) SIP category 2 patients had a low DRI and 38 had intermediate DRI. In the PCy group, HI donors comprised 26.5% of the total compared to 19.1% MSD and 54.4% MUD donors. In the SIP group, MSD and MUD donors accounted for 30% and 70% of the donors. One-year percentages of OS, GRFS and DFOI were 79.4, 47.1 and 44.1 in the PCy group compared to 72, 45 and 35 in the SIP cohort. If the analysis of the PCy group is limited to the 50 patients with MSD and MUD donors (as in the SIP cohort), the one-year OS, GRFS and DFOI are 88, 52 and 52. Conclusions: PCy in combination with SIP resulted in at least comparable results as SIP despite the inclusion of 19% of patients with a high DRI and 26.5% HI donors. The results with the addition of PCy are excellent in patients with MSD and MUD donors with more than half of the patients GRFS and DFOI at one year. Future studies on GVHD prophylaxis should report DFOI as the latter status may be the best platform for posttransplant strategies aimed at eliminating minimal residual disease and for improving QOL. 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.

Important Prognostic Impact of Early Monocytes Recovery after Reduced Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5923-5923
Author(s):  
Amandine Le Bourgeois ◽  
Thierry Guillaume ◽  
Jacques Delaunay ◽  
Pierre Peterlin ◽  
Viviane Dubruille ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Older Age ◽  
Reduced Intensity Conditioning ◽  
The Impact ◽  
Reduced Intensity ◽  
Grade Iii

Abstract Introduction: Little is known regarding the impact of hematopoietic and immune recoveries after double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT), especially after the TCF (low dose 2 Grays total body irradiation + cyclophosphamide 50 mg/Kg 1 day + fludarabine 200 mg/m² 5 days) reduced-intensity conditioning (RIC) regimen, which is considered as a standard RIC regimen for dUCB allo-SCT in adults Patients and Methods: Here we considered a homogeneous cohort of 47 patients (males: n=24; median age: 55.5 years (range: 17.5-69) who engrafted after a dUCB TCF allo-SCT performed between November 2006 and April 2013 in our department. Fifty-three percent of the patients had myeloid disease. The majority of cases were in complete remission at time of transplant (72.3%). GVHD prophylaxis consisted of cyclosporine + mycophenolate mofetyl in all cases. All patients received G-CSF from day 1 until neutrophils recovery. The median nucleated cells dose infused was 4.17 107/kg. The aim of the study was to investigate the impact on outcomes of the recovery of the following cellular subsets: leucocytes, monocytes, lymphocytes, neutrophils at day +30 and day +42, and CD4+, CD8+ T cells, B and NK cells at day+100. Results: Median times for neutrophils and platelets recoveries were 17 days (range: 6-59) and 37 days (range: 0-164), respectively. With a median follow-up of 30.4 months (range: 2.8-77.5), the 3-year overall and relapse-free survivals (OS, RFS), relapse incidence (RI), and non-relapse mortality (NRM) were 65.7%, 57.2%, 27.1% and 19%, respectively. The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 38.3% and 10.6%, respectively, while, 3-year incidence of chronic GVHD was 53.5% (limited 42%, extensive 11.5%). In univariate analysis, 3-year OS was significantly higher in case of lymphoid disease (80.9% vs 51.9%, p=0.05) or when achieving at day+30 or day +42 higher counts of leucocytes (> median: 2760/mm3; 79% vs 51%, p=0.05; median > 4250/mm3; 78.6% vs 55.4%, p=0.04) or monocytes (> median: 615/mm3; 87.5% vs 45.8 %, p=0.02; median > 830/mm3, 86.2% vs 54.1%, p=0.03). Older age (>median: 55 years) and higher monocytes count at day +42 (> median: 830/mm3) were significantly associated with higher 3-year RFS (63.6% vs 49.1 %, p=0.046; and 75.7 vs 44.4%, p=0.014). Higher leucocytes count at day +42 (>median: 4250/mm3) was the only factor associated with significant 3-year lower NRM (7.1% vs 31.7%, p=0.04), while younger age was associated with higher risk of grade 3-4 acute GVHD (16.7% vs 4.4 %, p=0.05). No factor was predictive of chronic GVHD in this series. In multivariate analysis, older age and early higher monocytes count after transplant were the two independent factors associated with a significantly higher OS (>55 years, HR: 0.21; 95%CI: 0.05-0.85, p=0.028; >615/mm3 at day +30, HR: 0.05; 95%CI: 0.01-0.43, p=0.006) while only older age remained independently associated with better RFS (>55 years, HR: 0.25, 95%CI: 0.08-0.78, p=0.017). No factor was predictive of NRM, grade 2-4 GVHD, grade III-IV acute or chronic GVHD. Conclusion: These results suggest that higher early monocytes recovery is predictive of outcome after dUCB TCF RIC allo-SCT in adults. Immune recovery seems to have no impact on survivals in this series while influence of age has to be confirmed by other studies. Our results pave the way for future studies aiming to closely and prospectively monitor the kinetics of hematopoietic and immune recoveries after this type of graft. As all patients received G-CSF after transplant, other immunostimulatory cytokines should be tested to ensure sufficient hematopoietic recovery in the setting of adult dUCB TCF RIC allo-SCT. Disclosures No relevant conflicts of interest to declare.

Results of a Two-Arm Phase II Clinical Trial Using Post-Transplantation Cyclophosphamide for Prevention of Graft-Versus-Host Disease in Haploidentical and Mismatched Unrelated Donors Hematopoietic Stem-Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 152-152 ◽  
Author(s):  
Sameh Gaballa ◽  
Isabell Ge ◽  
Riad O. El Fakih ◽  
Jonathan E. Brammer ◽  
Sa A. Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Disease Risk ◽  
Risk Index ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Equity Ownership ◽  
Reduced Intensity

Abstract Allogeneic stem cell transplantation offers curative therapy for many patients (pts) with high-risk hematologic malignancies. Donor availability remains a major limitation for many pts. The introduction of high-dose post-transplant cyclophosphamide (PTCy) has significantly improved the outcomes of pts undergoing haploidentical (HAPLO) stem cell transplants. The choice between a HAPLO or a one-antigen HLA mismatched unrelated donor (9/10 MUD) for pts lacking an HLA-matched donor remains unclear. Methods: We conducted a prospective non-randomized phase 2 clinical trial with two parallel arms, HAPLO (n=60) and 9/10 MUD (n=46) transplants, for pts with advanced hematologic malignancies or aplastic anemia who lacked an HLA-matched unrelated donor type at 10 loci (HLA-A, -B, -C, -DRB1, and -DQB1) using a MEL-based reduced-intensity conditioning regimen. The regimen included a single intravenous dose of MEL 140 mg/m2 (day -7), thiotepa 5 mg/kg (day -6), and four daily IV doses of fludarabine 40 mg/m2 (day -5 to day -2) (FM140). Thiotepa was intermittently available and was replaced by total body irradiation at a dose of 2 Gy on day -1. Pts >55 years (yr) old or with significant comorbidities received a lower MEL dose (100 mg/m2) (FM100). All pts with CD20-positive lymphoma received rituximab (375 mg/m2) on days -13, -6, +1 and +8. GVHD prophylaxis consisted of PTCy 50 mg/kg on day +3 and +4, and tacrolimus and mycophenolate for 6 and 3 months (mo), respectively. The stem cell source was unmodified bone marrow for both arms. Results: Patient characteristics are shown in Table 1. The median follow-up duration was 24 mo in the HAPLO arm and 29 mo in the 9/10 MUD arm. The cumulative incidence (CI) of neutrophil (ANC) recovery at day 45 was 95% and 98% in the HAPLO and 9/10 MUD arm, respectively. The median time to ANC recovery was 18 days in both arms; the median time to platelet recovery was 25 days in the HAPLO arm and 28 days in the 9/10 MUD arm. Primary graft failure developed in two pts in the HAPLO arm (one due to anti-donor HLA antibodies) and one patient in the 9/10 MUD arm. One pt in both arms developed mixed donor chimerism at day 100; otherwise, all pts in both arms achieved full (>95%) donor chimerism. Bone marrow was the graft source in all pts except 2 in the HAPLO arm and 8 in the 9/10 MUD arm who received a peripheral blood graft. The 1-yr overall and progression free survival were 70% and 60%, respectively, in the HAPLO arm (Fig. 1A) and 60% and 47%, respectively, in the 9/10 MUD arm (Fig. 1B). Day 100 CI of grade II-IV aGVHD and III-IV aGVHD were 28% and 3%, respectively, in the HAPLO arm versus 33% and 13%, respectively, in the 9/10 MUD arm; the 2-yr CI of chronic extensive GVHD was 13% and 14% in the two groups, respectively. The 1-yr CI of non-relapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, while the 1-yr relapse rate was 19% and 25% in the two groups, respectively. Conclusions: This study establishes PTCy, tacrolimus, and mycophenolate as an effective regimen for GVHD prevention in mismatched transplantation using both haploidentical and mismatched unrelated donor sources. Melphalan-based reduced-intensity conditioning is an effective regimen for a broad range of hematologic malignancies. Prospective randomized studies comparing haploidentical and unrelated donor sources are needed. Table 1. HAPLO (n=60) 9/10 MUD (n=46) Median Age, years (Range) 45 (20-63) 51 (20-64) Sex (M/F) 29/31 23/23 KPS ³90 53 (88%) 40 (87%) <90 7 (12%) 6 (13%) HCT-CI 0-3 50 (83%) 38 (83%) >3 10 (17%) 8 (17%) Disease Risk Index* Very high 5 (8%) 3 (7%) High 18 (30%) 15 (33%) Intermediate 29 (48%) 12 (26%) Low 8 (13%) 12 (26%) NA 0 4 (9%)** Conditioning Regimen FM100 20 (33) 18 (39%) FM140 40 (67%) 28 (61%) Diagnosis AML/MDS 33 (55%) 18 (39%) ALL 7 (11%) 5 (11%) Lymphoma 10 (17%) 13 (28%) Others 10 (17%) 10 (22%) Disease Stage Acute Leukemia CR1/CR2 24 (66%) 9 (56%) CR3 or higher/ CRpx 6 (17%) 5 (31%) Active disease 6 (17%) 2 (13%) Lymphoma CR 3 (30%) 8 (62%) PR 5 (50%) 3 (23%) Chemoresistant 2 (20%) 2 (15%) *Disease Risk Index by Armand et al; xCRp: Complete Remission with incomplete count recovery; **Patients had aplastic anemia. Figure 1. Figure 1. Disclosures Brammer: Celgene: Research Funding. Lee:Ziopharm: Equity Ownership; Cyto-Sen: Equity Ownership; Intrexon: Equity Ownership. Rezvani:Pharmacyclics: Research Funding. Alousi:Therakos, Inc: Research Funding.

A Phase I Dose Escalation Study of Lenalidomide Following Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3954-3954 ◽  
Author(s):  
Leslie A. Andritsos ◽  
William Blum ◽  
Rebecca B. Klisovic ◽  
Sumithira Vasu ◽  
Sam Penza ◽  
...  
Keyword(s):  
Skin Rash ◽  
Dose Escalation ◽  
Acute Gvhd ◽  
Disease Risk ◽  
Risk Index ◽  
Reduced Intensity Conditioning ◽  
Dose Escalation Study ◽  
Elevated Creatinine ◽  
Very High ◽  
Reduced Intensity

Abstract Lenalidomide is an immunomodulatory drug that is FDA approved for treatment of 5q- myelodysplastic syndrome (MDS) and myeloma. It has also been tested as a salvage therapy of refractory/relapsed AML with encouraging activity, especially in patients (pts) who relapsed post allogeneic transplant (alloSCT). In this setting, it has been postulated that lenalidomide may re-activate donor immune system and enhance a graft-versus-leukemia effect. This hypothesis is also supported by evidence of increase graft-versus-disease (GVHD) observed in pts treated with lenalidomide post-alloSCT. Therefore, in order to prospectively study the safety, feasibility, and early impact on risk of disease relapse we performed a phase 1 dose escalation study of lenalidomide administered orally daily following reduced intensity conditioning (RIC) alloSCT in pts with leukemia and lymphoma eligible for transplant. Methods: Pts were enrolled on a two-step process, with initial enrollment prior to transplant followed by a re-registration evaluation post-transplant at day +60 (+/- 7 days) to ensure eligibility. At this screening, pts were required to demonstrate engraftment with ANC >1000/uL, platelet count ³50,000/uL, and T-cell chimerism ³40% by day +30. Pts were required to have a creatinine clearance ³50 mL/min, AST ²3 x ULN, and ECOG PS of 0-2. Grades 1 or 2 acute GVHD (aGVHD) were allowed if controlled on ² 20 mg of prednisone daily; pts with a history of grades 3 or 4 aGVHD were excluded. Lenalidomide was given orally daily for 28 days/cycle. Dosing escalation was performed using a standard 3 x 3 design, with dose level (DL) 1 = 5 mg , DL 2 = 10 mg, and DL 3 = 15 mg. Results: From 6/2011 to 10/2012, 17 pts with AML (n=13), CLL (n=1), and DLBCL (n=3) were enrolled (Table 1) and underwent RIC alloSCT. The majority of patients had a Disease Risk Index (Armand et al. Blood, 2014) of high or very high. Of enrolled pts, only 3 received lenalidomide. Of the pts who did not proceed to treatment at re-registration, 4 were ineligible due to relapse, 3 were ineligible due to elevated creatinine, 3 were ineligible due to GVHD, 2 declined, and 2 were not treated due to study closure. All pts who received lenalidomide were treated at DL 1. The first pt treated (00-06) received cycle 1 without toxicity. On cycle 2 day 9 he developed a skin rash consistent with acute GVHD and discontinued therapy. The second pt treated (00-11) developed skin rash and diarrhea on cycle 1 day 3 and was diagnosed with steroid refractory aGVHD of the GI tract. He expired from complications of treatment. The third pt treated (00-12) developed a skin rash and diarrhea on cycle 1 day 6. Lenalidomide was discontinued. Based on these outcomes, the study was closed due to concerns regarding the risk of severe aGVHD caused by lenalidomide. However, patients 00-06 and 00-12 remain alive and in CR days 958 and 751 post transplant, respectively. In the entire cohort, the median PFS was 103 days (range = 15-992) with median OS 103 days (range = 30-1085). Conclusion: Early administration of low-dose lenalidomide following alloSCT is not feasible due to potential increased risk of severe aGVHD and likelihood of elevated creatinine at this time point. However, 2 of 3 pts who received lenalidomide and responded to treatment for aGVHD remain in CR from their high-risk AML. Thus, an amended approach with lower/fewer dose of lenalidomide/cycle or alternatively, use in transplants that do not utilize calcineurin phosphatase inhibitors (such as T-cell depletion based approaches) warrants additional consideration. Abstract 3954. Table 1 PT Age Sex Diagnosis Disease Risk Index Comorbidity Index Lena Treatment Progression free survival (days) Overall survival (days) Cause of death 01 64 F AML High 3 Ineligible1 592 979 Relapse 02 64 M AML Very high 1 Ineligible1 140 229 Relapse 03 26 F AML High 6 Ineligible2 35 121 Relapse 04 39 M DLBCL Intermediate 0 Declined 789 1085 05 64 M DLBCL Intermediate 1 Declined 108 121 Relapse 06 36 M AML High 3 Yes 958 958 07 60 M AML High 3 Ineligible3 992 992 08 61 M CLL Low 0 Ineligible3 101 101 Acute GVHD 09 71 M AML High 1 Ineligible1 957 957 10 57 M AML High 5 Ineligible2 30 30 Regimen Related Toxicity 11 32 M AML Very High 2 Yes 103 103 Acute GVHD 12 50 F AML Very High 4 Yes 751 751 13 61 F AML Very High 4 Ineligible2 42 242 Relapse 14 60 M AML Very High 0 Ineligible2 15 160 Relapse 15 63 F AML High 3 Ineligible3 61 61 Acute GVHD 16 66 M AML High 3 Study closure 706 706 17 68 M DLBCL High 5 Study closure 72 72 Pneumonia 1 = elevated creatinine 2 = relapse 3 = GVHD Disclosures Off Label Use: Lenalidomide administration following allogeneic transplantation.. Blum:Celgene: Consultancy.

A Single Institution Study of Allogeneic Hematopoietic Stem Cell Transplant for MDS and AML in Patients 60 Years of Age and Older: Impact of Disease Risk Index and Secondary Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5532-5532
Author(s):  
Eva Gupta ◽  
Randi Hoffman ◽  
Thomas Colleen ◽  
William J Hogan ◽  
Mark R Litzow ◽  
...  
Keyword(s):  
Overall Survival ◽  
Older Patients ◽  
De Novo ◽  
Disease Risk ◽  
Risk Index ◽  
Cell Transplant ◽  
Reduced Intensity Conditioning ◽  
Secondary Disease ◽  
Kaplan Meier ◽  
Reduced Intensity

Abstract Background: Allogeneic Hematopoietic cell transplantation (HCT) is potentially curative therapy for MDS and AML. Although the median age at presentation is >65 years, most patients receiving HCT for these disorders are young (<60years). With the availability of Reduced Intensity Conditioning (RIC) many older patients are able to undergo HCT. The older age group is the most rapidly increasing cohort in CIBMTR registry. We analyzed the outcomes of AML and MDS patients' ≥ 60 years who received allogeneic sibling or unrelated donor HCT at our institution between 2009 and 2014. We also evaluated the influence of patient-, disease-, and transplant related factors on outcomes. Methods: Prospectively collected data available in the BMT databases at Mayo Clinic Florida, Arizona and Rochester as well as individual patient charts were reviewed after IRB approval. Patients with MDS or AML in complete remission at the time of transplant were included; those with active disease, induction failure, or prior transplant were excluded. HCT-specific comorbidity index (HCT-CI) and the disease risk index (DRI- Armand et al. Blood 2012) was noted. Survival estimates were calculated using the Kaplan Meier method. Associations with survival were explored using single variable Cox-regression modeling and log-rank tests. Results: 80 patients were included; 68 AML and 12 MDS. 31 (39%) were male. Median age 66 years (range 60-75). 33%, 52%, and 13% patients had ECOG status of 0, 1, >2, respectively. Thirty-seven patients (46%) had low or intermediate DRI and 43(54%) had high DRI. Twenty-two (28%), 24 (30%), and 34 (43%) patients had HCT-CI of 0, 1, or >2. There were equal number of sibling and unrelated donors; 85% were full HLA match and 15% with 1 or 2 mismatches; mean age of the donors was 52years (range18-74). Transplant conditioning was fludarabine-containing reduced intensity regimens in 78 (97%), 2 patients received myeloablative conditioning. The source of stem cells was peripheral blood in all patients. A median of 5.87 x10^6 CD34/kg donor cells were infused (range 1.58-10.92 X10^6). All patients received calcineurin inhibitor based GVHD prophylaxis (tacrolimus 56%, cyclosporine 44%); 6 patients also received ATG. The median follow up of survivors was 13 months. Kaplan Meier estimate of overall survival at 100 days, 1 year, and 2 years was 90%, 64%, and 55%. Cumulative incidence of relapse at 6 months, 1 year, and 2 years was 19.5%, 22.3%, and 27.1%. Relapse free survival at 2 years was 50%. The non-relapse/ treatment related mortality at 6 months, 1 year and 2 years was 11.7%, 15.9% and 15.9%. The rate of acute grade 2-4 GVHD was 30% and chronic GVHD was 39%. Univariate analysis identified secondary disease (compared to de novo) and high DRI(compared to low/intermediate) to be associated with worse mortality - HR 2.54 (1.31-4.93; P = 0.006), and 2.31 (1.13-4.73; P = 0.021), respectively. Probability of overall survival at 6 months, 1 year, and 2 years for patients with de novo disease (n=57) vs. secondary disease (n=23) was 87.1% vs. 64.5%, 71.1 vs. 45.6%, and 63.2 vs. 32.6%, respectively; P= 0.006. There was no effect of donor age, donor type or degree of mis-match on the survival. Conclusion: Allogeneic HCT is feasible in older patients with MDS and AML utilizing reduced intensity conditioning regimens with acceptable outcomes that are comparable to published results in younger patients. Patients with high DRI and secondary disease have poorer overall survival as compared to those with de novo disease and low/intermediate disease risk index. These data support other studies that age alone does not negatively influence transplant outcomes. Disclosures No relevant conflicts of interest to declare.

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