Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation (HCT): A Single Center Analysis of 613 Adult HCT Recipients Using a Modified Composite Endpoint

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4574-4574
Author(s):  
Melhem Solh ◽  
Lawrence E. Morris ◽  
H. Kent Holland ◽  
Scott R. Solomon ◽  
Stacey Brown ◽  
...  
Keyword(s):  
Competing Risks ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Chronic Gvhd ◽  
Composite Endpoint ◽  
Allogeneic Hct ◽  
Kaplan Meier ◽  
Donor Type ◽  
Grade 3

Abstract Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation (HCT): A single Center Analysis of 613 Adult HCT Recipients Using a Modified Composite Endpoint Introduction The success of allogeneic HCT is based on long term survival, free of relapse or morbidity as commonly encountered when patients develop graft versus host disease (GVHD). The Bone marrow transplant clinical trials network (BMTCTN) recently incorporated a composite endpoint to determine success rate in ongoing clinical trials. The new composite endpoint of GVHD free, relapse free survival (GRFS) includes the factors of acute GVHD grade 3-4, relapse, death and chronic GVHD requiring systemic immunosuppression. As the decision to start patients on immunosuppression for chronic GVHD can be subjective and physician dependent, we elected to assess the success of allogeneic HCT using a more objective endpoint m-GRFS where the clinically significant negative events are acute GVHD grade 3-4, moderate-severe chronic GVHD, disease relapse and Death at 1 and 2-year post HCT. Methods Six hundreds and thirteen patients who underwent a first allogeneic HCT after a HLA-identical sibling (MRD, n=212), 10/10 matched unrelated donor (MUD, n=251) or T-replete haploidentical donor with post-transplant cyclophosphamide (HIDT, n=150) were included in this analysis. Patient, Disease and Transplant related variables were prospectively documented and obtained from our institutional database. The Kruksall-Wallis test was used to compare continuous variables and the Chi-squared test for categorical variables. OS, DFS and m-GRFS were estimated by the Kaplan-Meier (K-M) method. Log-log transformed confidence intervals for OS, DFS and GRFS were calculated. Comparison of m-GRFS between demographic subgroups and between clinical subgroups were evaluated using the log-rank test for the entire study period and using the Wald test for a select time point. Competing risks analysis was performed to disentangle the components of GRFS. Grade III/IV acute GVHD, mod-severe chronic GVHD, relapse and death were considered as competing risks and cumulative incidences of these endpoints were calculated. Patients were considered to have met the endpoint once any of the components occurred. Cox regression analysis was conducted to examine the impact of donor, demographic and clinical factors on the primary endpoint of modified GRFS. The proportional hazards assumption was checked by temporarily including and testing time-dependent variables and the variables in the final model passed the proportionality test. The adjusted GRFS for one characteristic was calculated as the average survival of the whole sample, assuming that everyone in the sample had this characteristic. Results The median follow-up was 50.2 months. Patients characteristics were as follows: median age 53 years (18-77), male 56%, reduced intensity/non-ablative 49%, AML 37%, ALL 13%, MDS/MPD 24%, bone marrow graft 19%, HCT-comorbidity index >=3 in 39%, and high/very high DRI 34%. The unadjusted Kaplan-Meier estimates for 1- and 2-year m-GRFS were 36% (95%CI 32%-40%) and 28% (95%CI 25%-32%). The 2-year m-GRFS for MRD recipients was 30% (24-36%), MUD 24% (19-30%) and HIDT 33% (26-41%). The most common event at 2 years post HCT was chronic GVHD (39%) followed by relapse (31%), acute GVHD 3-4(20%) and death (10%). After adjusting for age, gender, diagnosis, conditioning intensity, donor type, cell source, HCT-CI, DRI , donor-recipient gender mismatch and year of transplant, the multivariate cox model on m-GRFS showed donor type, DRI risk , donor recipient sex mismatch and year of transplant to be significant predictors of m-GRFS (table 1). Patients who received a MUD had worse GRFS compared to MRD (HR 1.39, p=0.003) whereas HIDT had similar GRFS to MRD (HR 1.10, p=0.43). HIDT had better GRFS than MUD (HR 0.79, p=0.046). The adjusted 1- and 2- year m-GRFS showed donor type (MUD vs MRD), DRI, donor-recipient sex mismatch and transplant year to be associated with worse GRFS (table 2). Conclusions m-GRFS is a useful measure of transplant success. It appears to be significantly impacted by several modifiable factors including donor type, donor-recipient sex match and also by DRI. Adjusting donor choice and early referral of patients for transplant evaluation to improve DRI can potentially overcome the negative impact of these factors. Disclosures No relevant conflicts of interest to declare.

scholarly journals What Predicts Success for a New Composite Endpoint: Graft–versus-Host Disease-Free and Relapse-Free Survival (GRFS) after Allogeneic Hematopoietic Cell Transplantation?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 429-429
Author(s):  
Shernan G. Holtan ◽  
Todd E. DeFor ◽  
Aleksandr Lazaryan ◽  
Nelli Bejanyan ◽  
Mukta Arora ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Composite Endpoint ◽  
Stem Cell Source ◽  
Kaplan Meier ◽  
Cell Source ◽  
Donor Type ◽  
Conditioning Intensity ◽  
Over Time

Abstract The success of allogeneic hematopoietic cell transplantation (HCT) is typically assessed by the rates of individual complications of graft–versus-host disease (GVHD), relapse, or death, yet each of these add to overall morbidity. We examined a novel composite endpoint of GVHD-free/relapse-free survival (GRFS) where events include grade III-IV acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death in the first year after HCT. GRFS measures freedom from ongoing morbidity and therefore represents full recovery following HCT. In this analysis, we examined clinical factors influencing GRFS, including year of HCT, age, disease, conditioning regimen intensity, donor type, and graft source. In 907 consecutive University of Minnesota pediatric and adult allogeneic HCT recipients treated from 2000 to 2012, 1-year GRFS was 31% (95% CI 28-34%), but significantly improved over time (2008-2012 relative risk [RR] 0.7, 95% CI 0.6 – 0.9, p<0.01, vs. 2000-2007). Regression analyses modeled over time demonstrated that age, disease risk, and donor type significantly impacted GRFS (Table). Adults age 21+ had a two-fold worsening of GRFS (RR 2.2, 95% CI 1.7 – 2.8, p<0.01) vs. children, but no fall in GRFS from age 21-50+ years was noted (1 year GRFS 20-27%). Standard risk hematologic malignancies had 35% 1 year GRFS; high risk were 30% worse (22%, RR 1.3, 95% CI 1.1 – 1.5, p<0.01). Adjusted for conditioning intensity, stem cell source, disease risk, age, and year of transplant, HLA-matched sibling donor (MSD) marrow grafts resulted in the best GRFS (Figure 1) while peripheral blood stem cells (PBSC) from MSD were significantly worse. GRFS after umbilical cord blood (UCB) and marrow from matched unrelated donors ([URD] were similar to each other, but worse than MSD marrow. Conditioning intensity did not impact GRFS (29% myeloablative, 33% reduced intensity, p=0.5). Among factors that impact GRFS, the stem cell source is potentially modifiable. The improved GRFS with MSD marrow grafts predominantly reflects less morbidity of GVHD (Figure 2). For patients without a MSD, grafts from UCB are equivalent to marrow from URD. GVHD prophylaxis is also a modifiable factor that could impact GRFS, although the choice of prophylaxis regimen was linked to underlying disease and stem cell source and thus not an independent factor in this series. The use of GRFS as a novel endpoint used to capture overall morbidity after HCT may provide a better global comparison of outcomes across different HCT platforms. GRFS has improved over time, although not by any single type of adverse failure event. Using this new GRFS endpoint, 31% of all patients, and only 24% of adults over age 50, survived to 1 year without experiencing one of these major complications. With less than one-third of HCT recipients achieving GRFS, these findings highlight the importance of identifying novel methods of improving upon all these adverse failure events. Each reason for failure can be studied, and all can be improved. Table Multiple regression analysis on overall survival Factors N RR of GRFS (95% CI) Overall P P-Value Conditioning MA 494 1.0 RIC 413 0.9 (0.8-1.1) 0.53 Donor Type Marrow MSD 53 1.0 0.01 Reference PBSC MSD 269 1.8 (1.1-2.9) 0.02 Marrow/PBSC URD 73 1.8 (1.1-3.1) 0.03 UCB 512 1.8 (1.2-2.9) 0.01 Age 0-20 220 1.0 21+ 687 2.2 (1.7-2.8) <0.01 Disease Risk Standard risk 590 1.0 High risk 317 1.3 (1.1-1.5) <0.01 Year of HCT 2000-2007 558 1.0 Reference 2008-2012 349 0.7 (0.6-0.9) <0.01 Figure 1 Kaplan-Meier estimate of GRFS based upon donor type, adjusted for conditioning intensity, stem cell source, disease risk, age, and year of transplant. Figure 1. Kaplan-Meier estimate of GRFS based upon donor type, adjusted for conditioning intensity, stem cell source, disease risk, age, and year of transplant. Figure 2 Reasons for GRFS events by stem cell source. Figure 2. Reasons for GRFS events by stem cell source. Disclosures No relevant conflicts of interest to declare.

scholarly journals Graft-versus-Tumor Effects after Allogeneic Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 184-184
Author(s):  
Frederic Baron ◽  
Michael B. Maris ◽  
Brenda M. Sandmaier ◽  
Barry E. Storer ◽  
Mohamed Sorror ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Disease Risk ◽  
Chronic Gvhd ◽  
Allogeneic Hct ◽  
Risk Of Progression ◽  
Grade Ii

Abstract We have used a nonmyeloablative conditioning regimen consisting of 2 Gy total body irradiation +/− fludarabine, 30 mg/m²/day x 3 days, to condition elderly or ill patients (pts) with hematological malignancies for allogeneic hematopoietic cell transplantation (HCT). This approach relies almost exclusively on graft-versus-tumor (GVT) effects for control of malignancy. Here, we analyzed GVT effects in 322 pts with hematological malignancies given grafts from HLA-matched related (n=192) or unrelated (n=130) donors. Grades I, II, III and IV acute GVHD were seen in 26 (8.1%), 141 (43.8%), 34 (10.6%) and 11 (3.4%) pts, respectively. Extensive chronic GVHD was seen in 181 (56.2%) pts and of these, 64 (19.9%) cases had de novo chronic GVHD. Putative GVT effects were evaluated using time-dependent Cox regression models. Of the 221 pts with measurable disease at HCT, 126 (57%) achieved complete (n=98) or partial (n=28) remissions. Multivariate analysis identified chemosensitivity for B-cell malignancies (p=.02), and tandem autologous/allogeneic HCT (p=.04) as pre-transplant factors associated with higher probabilities of achieving complete remissions (CR) after HCT. After adjusting for these factors, acute GVHD of any grade was not found to be associated with an increased probability of achieving CR. There was a trend for a higher probability of achieving CR in pts with chronic GVHD (p=.07). Progression/relapse was observed in 108 pts. Multivariate analysis identified that lower disease-risk (p=.0004), tandem autologous/allogeneic HCT (p=.02) and adapted Charlson comorbidity index (CCI) score at transplant < 3 (p=.002) resulted in significantly decreased risk of progression/relapse. After correcting for these factors, extensive chronic GVHD was associated with a decreased risk of progression/relapse (p=.006). Pts with grade 1 acute GVHD tended to have less progression/relapse (p=.07). Conversely, grade II–IV acute GVHD did not significantly affect the risk of progression/relapse. Nonrelapse mortality was observed in 70 pts. Multivariate analysis showed that lower disease-risk (p=. 001), tandem autologous/allogeneic HCT (p=.002) and CCI score at transplant < 3 (p<.0001) significantly decreased nonrelapse mortality. After adjusting for these variables, grade II (p=.04) and grade III–IV (p<.0001) acute GVHD increased nonrelapse mortality while extensive chronic GVHD did not. The 3-year probability of progression-free survival (PFS) was 38.5%. In multivariate analysis, lower disease-risk (p<.0001), tandem autologous/allogeneic HCT (p=.0008) and CCI score at transplant < 3 (p<.0001) resulted in significantly better PFS. After adjusting for theses variables, grade 1 acute GVHD (p=.02) and chronic extensive GVHD (p=.003) were both associated with significantly better PFS, while grade III–IV acute GVHD (p<.0001) was associated with decreased PFS. In summary, chronic GVHD in pts given nonmyeloablative conditioning was associated with substantial GVT effects which led to improved PFS. Conversely, any potential GVT benefits from grade II–IV acute GVHD were offset by higher nonrelapse mortality resulting in worse PFS. Efforts should be directed at reducing the risk of grade II–IV acute GVHD while allowing de novo chronic GVHD for best PFS after allogeneic HCT with nonmyeloablative conditioning.

The PTPN22 1858C/T Polymorphism Is Associated with the Development of Grade 3 to 4 Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation Following Nonmyeloablative Conditioning.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1969-1969
Author(s):  
Brian Kornblit ◽  
Tania Masmas ◽  
Soren L. Petersen ◽  
Hans O. Madsen ◽  
Peter Garred ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Factor ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Graft Versus Host ◽  
Allogeneic Hct ◽  
Significant Difference ◽  
Grade 3 ◽  
Related Mortality

Abstract Graft-versus-host disease (GVHD) is a cause of considerable morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning. Genetic polymorphisms in various genes, associated with the immune system have been implicated in the development of GVHD. The PTPN22 gene encodes a lymphoid tyrosine phosphatase (LYP), which is involved in suppression of T-cell receptor signalling. The 1858 C→T polymorphism in PTPN22 entails an amino acid substitution that disrupts the suppressive function of LYP, rendering T-cells hyperresponsive. The 1858 T allele has been implicated in conferring increased susceptibility to various autoimmune diseases. As in autoimmunity, T-cell activation plays a key role in the development of GVHD. To asses the influence of the protein tyrosine phospatase N22 (PTPN22) 1858 C→T polymorphism on development of GVHD after allogeneic HCT following nonmyeloablative conditioning, 100 consecutive patient-donor pairs receiving allogeneic HCT with related (n=66) or unrelated (n=34) donors for hematological malignancies (HD=13, MM=14, CLL=12, NHL=17, MDS=18, AML=24, CML=2), between March 2000 and December 2005 at Rigshospitalet, Denmark, were genotyped. With a mean follow-up of 534 days (range 38–2324 days) the overall survival (OS), progression free survival (PFS), treatment related mortality (TRM) and relapse related mortality (RRM) were 59%, 50%, 25% and 17%. The C/T and T/T genotypes were present in 16% and 1% of the recipients, respectively, and in 17% and 1% of the donors. The overall cumulative incidence of grade 2–4 acute GVHD, grade 3–4 acute GVHD and extensive chronic GVHD was 67%, 24%, and 49%, with no significant difference between patients carrying the C/C or C/T and T/T genotype or donors carrying the C/C or C/T and T/T genotype. To assess a possible gene-dosage effect, the number of T-alleles in each recipient-donor pair was cumulated, and the cumulative incidence of grade 3–4 acute GVHD increased from 20% in recipient-donor pairs carrying no or one T-allele to 50% in recipient-donor pairs carrying two or more T alleles (p=0.04), while there was no significant difference in grade 2–4 acute GVHD (66% versus 80%; p=0.47) and extensive chronic GVHD (50% versus 42%; p=0,8) between groups. In the competing risk regression analysis, the recipient-donor pair genotype with 2 or more T-alleles was an independent risk factor (hazard ratio 3.0; 95% CI 1.2–7.5; p=0.022) for development of grade 3–4 acute GVHD, even after adjusting for baseline variables known to affect GVHD rates (donor type and sex-mismatch, patient and donor age, CD34+ cell dose, single HLA locus mismatch). Overall survival, PFS, TRM or RRM were not significantly different for recipient-donor pairs for any given combination of alleles. Furthermore, patients from recipient-donor pairs carrying two or more T-alleles were hospitalized for significantly more days (p=0.01) due to GVHD (median=15 days; range 0–63 d), than patients from recipient-donor pairs with no or one T-allele (median=0 days; range 0–104 d). Collectively, our data suggest, that the PTPN22 1858 C→T polymorphism, when present in both recipient and donor, is a risk factor for development of grade 3–4 acute GVHD after nonmyeloablative conditioning allogeneic HCT.

Outcomes of c Hematopoietic Stem Cell Transplantation (HCT) after Non-Myeloablative Conditioning in Relapsed, Refractory, or Transformed Indolent Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3124-3124 ◽  
Author(s):  
Andrew R. Rezvani ◽  
Brenda M. Sandmaier ◽  
Barry Storer ◽  
Michael Maris ◽  
Edward Agura ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Aggressive Lymphoma ◽  
Optimal Timing ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Allogeneic Hct ◽  
Grade 3

Abstract Sixty-two patients (pts) with chemotherapy-refractory indolent or transformed NHL were treated at 10 centers with allogeneic HCT from related (n=34) and unrelated (n=28) donors after 2 Gy total body irradiation with or without fludarabine. Diagnoses included follicular lymphoma (FL) (n=54, including 10 with grade 3 FL), small lymphocytic lymphoma (n=6), and marginal zone lymphoma (n=2). Median age was 54 years (range 33–66 years), and median time from diagnosis to HCT was 4.4 years (range 0.5–18.5 years). Sixteen pts had histologically documented transformation to diffuse aggressive lymphoma prior to HCT. Twenty-seven pts (44%) had failed autologous HCT. Disease status at the time of HCT was complete response (CR, n=16), partial response (PR, n=22), refractory (n=13), untested relapse (n=9), or unknown (n=2). Eleven of the 28 unrelated donor/recipient pairs (39%) had HLA mismatches: 2 at a single allele, 7 at a single antigen, and 2 at an antigen and an allele. One pt had non-fatal graft rejection from a 1-antigen-mismatched unrelated donor. Median follow-up of survivors after HCT was 36.6 months (range 2.3–60 months). Responses (CR [n=18] and PR [n=7]) were seen in 25 of 44 (57%) pts with evaluable disease prior to HCT, while 5 had stable disease, 9 progressed, and 5 were not evaluable due to early non-relapse mortality (NRM) on d27–d108. Two of 16 pts (13%) transplanted in CR relapsed; one was treated with donor lymphocyte infusion and achieved a persistent CR. The incidences of acute GVHD grades II–IV, III–IV, and chronic GVHD were 63%, 19%, and 53%, respectively. At 3 years, the risks of relapse/progression and NRM were 19% and 42%, respectively. There was a trend toward increased mortality with unrelated donors (HR 1.87 [0.9–3.7, p=0.08]). Progression-free and overall survival (PFS and OS) were significantly better in the non-transformed group (see tables 1 and 2). Table 1. Outcomes Non-transformed Transformed Relapse 6/46 (13%) 6/16 (38%) NRM 20/46 (43%) 6/16 (38%) 3-year OS 24/46 (52%) 4/16 (25%) 3-year PFS 20/46 (43%) 4/16 (25%) Table 2. Hazard Ratios (HR) for Transformed vs. Non-Transformed Pts HR (95% CI) p All-cause Mortality 2.39 (1.2–4.9) 0.02 Relapse/progression 4.75 (1.5–15) 0.01 Grade 3+ acute GVHD 1.84 (0.5–6.3) 0.35 Extensive chronic GVHD 1.96 (0.8–5.0) 0.18 Figure Figure Allogeneic HCT after non-myeloablative conditioning can produce durable responses and prolonged survival in pts with refractory indolent or transformed NHL. Pts transplanted before histologic transformation had significantly better outcomes. Future efforts will focus on reducing NRM and identifying optimal timing of HCT.

A Randomized 3-Arm Phase II Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute Graft-Versus-Host Disease (GVHD) After Unrelated Donor Hematopoietic Cell Transplantation (HCT) Using Nonmyeloablative Conditioning for Patients with Hematologic Malignancies: A Multi-Center Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 348-348 ◽  
Author(s):  
Brenda M. Sandmaier ◽  
Michael Maris ◽  
Barry Storer ◽  
Lars Vindelov ◽  
Amelia Langston ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Phase Ii ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Sequential Trials

Abstract Abstract 348 We previously reported results of 3 sequential trials of GVHD prophylaxis with mycophenolate mofetil (MMF) BID/TID and cyclosporine (CSP) BID with various taper schedules in patients (pts) with advanced hematologic malignancies given unrelated G-CSF-mobilized peripheral blood stem cell (PBSC) grafts after fludarabine 90 mg/m2 and 2 Gray total body irradiation. Cumulative incidences of grades II-IV acute GVHD in the 3 trials were 52, 53 and 77%, respectively. The goal of the current protocol was to evaluate, in a phase II randomized 3-arm study, which drug combination or schedule was most promising in preventing acute GVHD. Tacrolimus (Tac) was used in place of CSP and each of the 3 arms used MMF TID until day 30 and then BID, but the subsequent duration of MMF varied. In Arm1, pts received Tac until day 180 and MMF until day 96. In Arm2, Tac was given until day 150 and MMF until day 180. In Arm3, Tac was given until day 150 and MMF until day 180 with the addition of rapamycin from days -3 through 80. One hundred seventy-five pts ineligible for myeloablative conditioning were enrolled on this multi-institutional study between Jan/05 and Aug/09, and results on the first 159 pts (Arm1 n=56; Arm2 n=51; Arm3 n=52) are reported here with a median follow-up of 18.4 months for surviving pts. The median age of pts was 60 (range 13-75) yrs. Sixty-six (42%) had previous autologous (n=55) or allogeneic (n=11) HCT. All pts were matched for HLA-DRB1 and -DQB1 at the allele level: 16 had single allele mismatches at HLA-A, -B or –C and the remainder (n=143) were fully HLA-matched. Diagnoses included AML (n=72), NHL (n=36), MM (n=19), ALL (n=10), CLL (n=9), MDS (n=8), HL (n=4), and CML (n=1). Randomization was based upon transplant center (FHCRC vs other), number of prior chemotherapy treatments (0-2 vs 3+), and age (<55 vs 55+ years). The pts received PBSC grafts containing a median of 7.9 ×106 CD34 and 2.8 × 108 CD3 cells/kg. Sustained donor engraftment occurred in 99.4% of pts. The day-150 cumulative incidences of grades II-IV (figure 1) and III-IV acute GVHD were as follows: Arm1: 56%, 9%; Arm2: 52%, 12%; and Arm3: 45%, 10%, respectively. Chronic GVHD requiring therapy was as follows: Arm1: 44%, Arm2: 35%, and Arm3: 55% of pts. The 6-month nonrelapse mortality was 6% in Arm1, 8% in Arm2, and 2% Arm3. The 2-year Kaplan-Meier estimates of relapse and nonrelapse mortality (figure 2) were as follows: Arm1: 27%, 24%; Arm2: 39%, 19%; and Arm3: 30%, 15%, respectively (overall 32% and 20%, respectively). The 2-year overall and progression-free survivals were as follows: Arm1: 49%, 41%; Arm2: 42%, 37%; Arm3: 55%, 41%, respectively (overall 48% and 40%, respectively). The addition of rapamycin to MMF and Tac (Arm3) resulted in the lowest incidence of grades II-IV acute GVHD (p=0.09 compared to reference Arm1), without a significant difference in chronic GVHD. While the phase II design of the study was not powered to show statistical differences between the 3 arms, the lower incidence of grades II-IV acute GVHD combined with the low morbidity and nonrelapse mortality in Arm3 using MMF, Tac and rapamycin is encouraging and warrants further study. Disclosures: Off Label Use: Fludarabine - conditioning prior to HCT. Mycophenolate mofetil - immunosuppression after HCT. Tacrolimus - immunosuppression after HCT. Rapamycin - immunosuppression after HCT..

Prophylactic Rituximab After Allogeneic Stem Cell Transplantation Prevents Steroid-Requiring Chronic Graft-Vs.Host Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 214-214 ◽  
Author(s):  
Corey Cutler ◽  
Lixian Sun ◽  
Haesook Kim ◽  
Stefanie Sarantopoulos ◽  
Bhavjot Bindra ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
First Year ◽  
Cell Recovery ◽  
Systemic Corticosteroids ◽  
Gvhd Prophylaxis ◽  
Donor Type ◽  
Grade 3

Abstract Abstract 214 There are no standard methods for the pharmacologic prevention of chronic GVHD (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Based on compelling biology implicating B cells in the pathophysiology of cGVHD and the utility of rituximab as therapy for established cGVHD, we performed a phase II trial of rituximab for the prevention of cGVHD after HSCT. Methods: 64 patients in remission without active GVHD received rituximab (375 mg/m2) at 3, 6, 9 and 12 months after HSCT. Related and unrelated donor recipients of 5/6 or 6/6 HLA-matched PBSCs were eligible. Prophylactic IVIG infusions were permitted at investigator discretion. Chronic GVHD severity was assessed by the requirement for systemic corticosteroids, with a historical rate of steroid-requiring cGVHD within 1 year of transplantation of approximately 60% at our institution. Results: 56 patients have been followed for at least 12 months from HSCT. One patient had a hypersensitivity reaction requiring treatment discontinuation and one patient was lost to follow-up, leaving 54 evaluable patients. The median patient age was 55 years (range 19 – 74); 25 were MRD recipients and 31 were URD recipients. 21 underwent myeloablative and 35 underwent reduced-intensity HSCT. Prior grade II-IV acute GVHD occurred in 6 patients (10.7%). Primary GVHD prophylaxis was sirolimus+tacrolimus (67.9%) or calcineurin inhibitor+methotrexate (32.1%), both without ATG. Overall, in the first year after HSCT there were 18 episodes of grade 3 toxicity and 8 episodes of grade IV toxicity without clear relationships to rituximab. There were 15 documented bacterial infections. Transient grade 3–4 neutropenia occurred in 11 subjects. 12 patients relapsed during the year after HSCT and 2 subjects died of non-relapse causes (pneumonitis and sepsis). The cumulative incidence of any cGVHD at 1 year from HSCT was 44.6%, however, the cumulative incidence of cGVHD requiring initiation of systemic corticosteroids was only 31.2%. When stratified by donor type, the incidence of all cGVHD and steroid-requiring cGVHD was 33.6 and 22.9% (MRD) and 52.3 and 37.0% (URD). Donor type, age, conditioning intensity, GVHD prophylaxis, donor gender or malignancy did not impact the incidence of cGVHD in a multivariable model. 8 additional patients required corticosteroids during the first post-transplant year for treatment of anorexia, pneumocystis pneumonia, pneumonitis or late acute GVHD. At 12 months, 50% of all patients had successfully discontinued all immunosuppressants and only 22.4% of all patients were on corticosteroids. Since anecdotally, myofascial and sclerodermatous cGVHD are treated effectively with rituximab, it is notable that only 1 patient had this subtype of cGVHD in contrast to the expected frequency of this manifestation of cGVHD in individuals not given rituximab. At 12 months from HSCT, relapse-free survival was 71.1% and overall survival was 88.6%. CD19+ B cells were very low during the first year post-HSCT, however patients without cGVHD demonstrated a trend toward enhanced B cell recovery at 6, 9 and 12 months from HSCT (6 months 0.58 vs. 0.28 × 106/L; 9 months 1.10 vs. 0.66 × 106/L; 12 months 1.09 vs. 0.76 × 106/L, all p=NS). Similarly, there was a trend for BAFF levels to be higher throughout the first year in patients without cGVHD (6 months 13.64 vs. 11.81; 9 months 12.30 vs. 9.57; 12 months 12.25 vs. 9.79, all p=NS). Among patients with cGVHD, there was a trend for BAFF levels to be higher in those who did not require systemic corticosteroids when compared to those that required steroids at 9 and 12 months (9 months 15.09 vs. 5.89 p=0.045; 12 months 11.86 vs. 7.14, p=0.25). 18 month B cell and BAFF data will be available at ASH. Conclusions. The use of rituximab at 3, 6, 9 and 12 months after allogeneic HSCT can reduce the rate of steroid-requiring cGVHD by up to 50% when compared with historical control data. The presence of enhanced B cell recovery, potentially related to higher BAFF levels found during the first year after HSCT, predicts freedom from cGVHD and a reduction in the severity of cGVHD among those affected. These data provide additional support for the hypothesis that B cells contribute to the development of cGVHD. A randomized trial should be performed to confirm these findings. Disclosures: No relevant conflicts of interest to declare.

Outcome of Patients Aged ≥60 After Allogeneic Hematopoietec Cell Transplantation: Age Has No Impact on Survival

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3540-3540 ◽  
Author(s):  
Birgit Federmann ◽  
Christoph Faul ◽  
Wichard Vogel ◽  
Lothar Kanz ◽  
Wolfgang A. Bethge
Keyword(s):  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Allogeneic Hct ◽  
Kaplan Meier ◽  
Group 2 ◽  
The Impact ◽  
Group 1

Abstract Abstract 3540 Historically, allogeneic hematopoietic cell transplantation (HCT) has been offered only to patients with good performance status and below the age of 60. However, the peak incidence of most hematologic malignancies is above 60 years of age. The introduction of reduced intensity conditioning (RIC) regimens enabled successful allogeneic HCT in patients with considerable comorbidities and older than 60 years. The impact of age on outcome of allogeneic HCT in patients ≥60 years has not been evaluated extensively. We retrospectively analyzed 109 consecutive patients (f=43, m=66) aged≥60 who received allogeneic HCT 2000–2010 at our institution. Median age of the patients was 65 years (range, 60–76). Patients were grouped in two cohorts depending on age: group 1 aged 60–65 years (n=60, median age=63) and group 2 aged 66–76 years (n=49, median age=68). Diagnoses were acute leukemia (AML n=65, ALL n=1), myelodysplastic syndrome (n=14), osteomyelofibrosis (n=7), non-Hodgkin lymphoma (n=9), multiple myeloma (n=8), aplastic anemia (n=1), chronic myeloid leukemia (n=2) and chronic lymphatic leukemia (n=2). At time of HCT, 41 of the patients were in complete remission (CR), 68 in partial remission (PR) (group 1: CR 21, PR 39; group 2: CR 20, PR 29) and 18 patients had a preceding HCT, 14 in group 1. Conditioning regimens were grouped in high (TBI/Bu+Cy, n=5, all group 1), intermediate (FLAMSA, Flu/Mel/BCNU, n=28, group 1=11, group 2=17), low (FLU+alkylans, n=48, group 1=32, group 2=16) and minimal (2GyTBI/Flu, n=28, group 1=12, group 2=16) intensity. Intermediate intensity conditioning was particularly used for high risk patients in PR (25/28). 22 patients were transplanted from matched related (MRD), 46 from matched unrelated (MUD) and 41 from mismatched unrelated donors (MMUD). Kaplan-Meier-estimated 3-year overall survival (OS) was 45% for all patients, 32% for group 1 and 62%, for group 2, respectively (p=0.02), with more patients with high risk constellation in group 1. 3-year OS for patients transplanted with MUD was 57%, with MMUD 46% vs. with MRD 0% (p=0.01). Non-relapse-mortality was 28% for all patients, 40% in group 1 and 12% in group 2, probably due to the higher intensity in conditioning in group 1. The outcomes with intermediate, low and minimal intensity conditioning were comparable, while all patients after high intensity conditioning died. Table 1 describes Kaplan-Meier estimated 3-year-OS and statistical univariate analysis by log-rank test in the different subgroups. Table 1. 3-year OS (in%) All Group 1 Age 60–65 Group 2 Age 66–76 Remission CR 52 p=0.25 31 p=0.76 77 p=0.15 PR 40 32 50 Conditioning high 0 p=0.5 0 p=0.08 – p=0.38 intermediate 52 50 53 low 48 43 57 minimal 45 17 67 Donor MRD 0 p=0.01 0 p=0.06 73 p=0.45 MUD 57 53 65 MMUD 46 40 33 GVHD acute no 18 p=0.003 13 p=0.008 33 p=0.27 ≥II 43 53 58 chronic no 39 p=0.25 36 p=0.70 52 p=0.08 limited 52 30 100 extensive 50 30 67 In group 1 the outcome of minimal conditioning was inferior compared to intermediate and low conditioning while patients in group 2 had a better outcome with minimal vs. low and intermediate conditioning. Incidences of acute GVHD ≥II, limited and extensive chronic GVHD (cGVHD) were 10%, 28% and 13%, respectively. In group 1, acute GVHD ≥II occurred in 13% and cGVHD in 35%, in group 2 in 5% and 41% of the patients, respectively. Acute GVHD ≥II was associated with inferior outcome (3-year OS of 18% vs. 43%, p=0.003) while cGVHD had a positive impact on OS. In group 2 patients with limited cGVHD showed better 3-year OS than patients without cGVHD (67% vs. 52%, p=0.12). Age alone had no major impact on outcome of allogeneic HCT. Patients aged ≥60 seemed to benefit from the use of MUD rather than an older MRD. Chronic GVHD had a positive influence on survival. Our data indicate that the regimen used should be tailored to disease risk and patient performance status. Disclosures: No relevant conflicts of interest to declare.

Relationship of Epidermal Growth Factor to Cyclosporine-Assocated Magnesium Wasting and Clinical Outcomes Post-Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3914-3914
Author(s):  
Fiona C. He ◽  
Michael R. Verneris ◽  
Sarah A. Cooley ◽  
Bruce R. Blazar ◽  
Margaret L. MacMillan ◽  
...  
Keyword(s):  
T Cells ◽  
Serum Creatinine ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Allogeneic Hct ◽  
Upper Gi ◽  
Donor Type ◽  
Daily Dose ◽  
Epidermal Growth ◽  
Grade Iii

Background: Hypomagnesemia is a frequent complication of allogeneic hematopoietic cell transplantation (HCT) and is related to cyclosporine-induced renal magnesium (Mg) loss. The importance of epidermal growth factor (EGF) in renal Mg reabsorption was suggested after identification of EGF mutation in isolated autosomal recessive hypomagnesemia (IRH). Mg wasting is also associated with EGFR tyrosine kinase inhibitors used in oncologic treatment. Recently, a link between EGF, Mg, and cyclosporine (CSA) in renal transplant recipients has been proposed through downregulation of EGF leading to inhibition of the Mg channel TRMP6 in the distal convoluted tubule, but similar associations have not been investigated post-allogeneic HCT. We hypothesized that lower serum EGF would be associated with higher CSA levels, acute graft versus host disease (GVHD) status, and more severe Mg wasting after allogeneic HCT. Patients and Methods: 107 adult allogeneic HCT recipients from the University of Minnesota enrolled on an immune monitoring study had EGF levels measured by magnetic bead array at day +100 post-allogeneic HCT. Clinical variables collected for analysis included patient age, sex, underlying diagnosis, donor type, HCT conditioning regimen, maximum acute GVHD overall grade and organ involvement prior to day +100, use of oral and intravenous supplemental Mg including cumulative requirements over 2 weeks, and concurrent immunosuppressive drug therapy including cyclosporine (N=66), tacrolimus (N=13), mycophenolate mofetil (N=5), sirolimus (N=22), and prednisone (N=40). Lab variables analyzed included serum creatinine and estimated glomerular filtration rate (GFR), immune suppressive drug levels, Mg levels, and lymphocyte subsets including absolute counts and percentages of NK cells, B cells, CD4+ T cells, CD8+ T cells, and regulatory T cells. Results: 54 patients had acute GVHD (grade I-II n= 34, grade III-IV n =20) and 53 patients did not have acute GVHD prior to the day +100 serum sample collection. The median serum EGF in this cohort was 101 pg/mL (not detectable in 5 samples). Levels of EGF at day +100 showed no relationship with age, underlying diagnosis, donor type, or conditioning intensity. EGF was significantly lower in patients who had acute GVHD grade III-IV prior to day +100 (Figure 1) and nearly 3-fold lower in those with upper GI GVHD involvement versus no upper GI GVHD involvement (median 43 pg/mL versus 119 pg/ml, p=0.007). Serum EGF negatively correlated with CSA level (Spearman's rho = -0.34, p=0.007), but not with tacrolimus levels, sirolimus levels, prednisone dose, or serum creatinine. Mg requirements, measured as either daily dose or cumulative dose over 2 weeks prior to the EGF sampling, were not associated with serum EGF overall, but those with EGF > 100 pg/mL showed higher magnesium requirements (average daily dose (1060 ± 142 mg/day versus 600 ± 85 mg mg/day, p=0.02) and average cumulative dose over 2 weeks (14.6 ± 2 grams versus 9 ± 1.3 grams, p=0.04) prior to the blood draw. Patients with or without acute GVHD required similar Mg supplementation. EGF levels showed a modest correlation with overall lymphocyte percentage in the peripheral blood (Spearman's rho = 0.24, p=0.01), but not with specific lymphocyte subsets at day +100. Serum EGF levels > 100 pg/mL at day +100 were associated with improved 2-year survival (RR 0.46, 95% CI 0.22–0.94, p=0.03, Figure 2). Conclusions: Patients with prior grade III-IV acute GVHD, and in particular upper GI GVHD, had lower EGF levels at day +100. This may be due in part to decreased EGF production from Brunner's glands in the duodenum versus excess EGF losses. The inverse relationship between CSA and EGF may be direct or may represent patients with more severe acute GVHD being maintained with higher drug levels. Serum EGF was negatively correlated with CSA levels but not Mg requirements or serum creatinine/estimated GFR. While studies in renal transplantation identified a connection between urinary EGF, Mg wasting, and diminished renal function, circulating levels of EGF in allogeneic HCT did not show a similar correlation. Differences in EGF post-allogeneic HCT are predominantly due to grade III-IV GVHD status, although a potential contribution from CSA effect on the kidney cannot be ruled out. The role of circulating EGF in the long-term outcomes of allogeneic HCT should be further studied. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Busulfan Fludarabine Vs. Busulfan Cyclophosphamide As a Preparative Regimen Prior to Allogeneic Hematopoietic Cell Transplantation – Systematic Review and Meta-analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3872-3872
Author(s):  
Sharon Ben Barouch ◽  
Omri Cohen ◽  
Liat Vidal ◽  
Irit Avivi ◽  
Ron Ram
Keyword(s):  
Systematic Review ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Meta Analysis ◽  
Chronic Gvhd ◽  
All Cause Mortality ◽  
Preparative Regimen ◽  
Grade 3 ◽  
Neutrophil Engraftment

Abstract Background: Both busulfan-cyclophosphamide (BuCy) and the reduced toxicity regimen busulfan-fludarabine (BuFlu) are considered myeloablative preparative regimens given prior to allogeneic hematopoietic cell transplantation (HCT). A comprehensive literature evaluation of BuFlu vs. BuCy is lacking and the question of the preferable regimen is still debatable. Objectives: We aimed to compare the efficacy and safety of BuFlu (intervention arm) vs. BuCy (comparable arm) as preparative regimens in patients given allografts. Methods: Systematic review and meta-analysis of all randomized controlled trials (RCTs) and non-randomized comparative trials of patients given BuFlu vs. BuCy as preparative regimens prior to allografts. Electronic search in the Cochrane Library, MEDLINE and conference proceedings was conducted up-to July 2014. Primary outcomes were all-cause mortality at 100 days and at the end of study. Secondary outcomes were time to neutrophil engraftment, primary & secondary rejection, risk for grade 3-4 mucositis, sinusoidal obstruction syndrome (SOS), microbiology documented infection, overall and grade 3-4 acute graft vs. host disease (GVHD), overall and extensive chronic GVHD, non-relapse mortality at 100 day and at the end of study, and relapse risk. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. For continuous variables we calculated weighted mean difference (WMD). Results: Our search yielded 14 trials recruiting 1578 patients. Three trials were RCTs and 11 were either one arm intervention trials compared to historical controls or retrospective studies. There were no differences in all-cause mortality at 100 days and end of study ( RR 0.85; 95% CI 0.56-1.30, 9 trials and RR 0.77; 95% CI 0.59-1.02, 12 trials, respectively), Figure, with similar results in sensitivity analyses including only RCTs and only studies in which patients' age and status of disease at HCT were well matched. Both primary and secondary rejections were comparable between the two regimens. Time to neutrophil engraftment was 1-day longer in patients given the BuCy regimen (WMD 0.84; 95% CI 0.37-1.31, 6 trials). Both the risks for SOS and microbiology documented infections were lower in the BuFlu patients (RR 0.34; 95% CI 0.19-0.62, 8 trials and RR 0.79; 95% CI 0.64-0.97, 2 trials, respectively). Grade 3-4 mucositis was comparable between the two groups. There was a lower incidence of grade 2-4 acute GVHD in patients given FluBu (RR 0.67; 95% CI 0.46-0.99, 10 trials), however this was no longer true in sensitivity analysis including only RCTs. There were no differences between the two arms in grade 3-4 acute GVHD, overall and extensive chronic GVHD, non-relapse mortality at 100 days and at the end of study and relapse risk. Conclusions: While toxicity profile of BuFlu regimen is safer than the classic BuCy regimen, this does not translate into composite transplantation outcomes. Patients at higher risk for SOS may benefit from the BuFlu regimen; however additional RCTs are required to identify other subgroups of patients who will benefit from a tailored-preparative regimen approach. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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