T- Cell Depleted Peripheral Blood Stem Cell (TCD-PBSC) Transplants Secure Consistent Engraftment with Low Risk of Acute or Chronic Gvhd and Favorable Disease Free Survival (DFS) and Overall Survival (OS) for Pediatric Patients (<21 years) with AML in CR1 or CR2 or MDS Including tMDS/AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5513-5513
Author(s):  
Nancy A. Kernan ◽  
Farid Boulad ◽  
Susan Prockop ◽  
Suzanne Wolden ◽  
Andromachi Scaradavou ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Pediatric Patients ◽  
Chronic Gvhd ◽  
Sheep Erythrocyte ◽  
Disease Free Survival ◽  
Low Risk ◽  
Phase Iii ◽  
Platelet Recovery ◽  
Entire Cohort

Abstract Higher cGVHD, TRM and treatment failure following sibling donor unmanipulated allogeneic PBSCT compared to BMT in children and adolescents has been reported by the IBMTR (Eapen M et al, J Clin Oncol, 2004). To determine the effect of T cell depletion (TCD) of PBSC on outcome for pediatric patients with AML or MDS, we reviewed our results with 49 patients (pts) with AML-1CR (n=18), AML-CR2 (n=11), MDS (n=10) and tAML/MDS (n=8/2) following allogeneic TCD-PBSCT transplanted between June 2003 and January 2015. Median age in this cohort was 13.9yrs (range 1.9 - 20.4) with 27 males and 19pts CMV seropositive at time of PBSCT. Donors were related HLA identical (14siblings, 1uncle), unrelated HLA 10/10 matched (n=14) or unrelated HLA mismatched (n=20: 9/10 n=12: 8/10 n=8). Cytoreduction consisted of a HFTBI containing regimen (n=14) with thiotepa and cyclophosphamide (n=12) or thiotepa and fludarabine (n=2). Alternatively, 35 pts received chemotherapy alone: BU/MEL/FLU (n=31) or other (n=4). ATG provided graft rejection prophylaxis for 43 pts either pre (n=37) or post (n=6) infusion. Six young pts with sibling donors did not receive ATG. No pt received additional GVHD prophylaxis. PBSC were CD34+ selected using ISOLEX 300i Magnetic Cell Selection System, followed by sheep erythrocyte rosetting (n=25) or CD34+ selected with Miltenyi CliniMACS device (n=24). The median CD34+ cells/Kg was 10.5x106 (range 3.3 - 33.4x106) and CD3+ cells/kg was 2.4x103 (range 0 - 29x103). All pts engrafted neutrophils and platelets at a median of 11 days (range 9 - 14 days) and 26 days (range 13 - 182 days), respectively. 42pts had platelet recovery by day 40. One patient who had late graft failure (GF) at 3.5 mos engrafted with a subsequent unmanipulated PBSCT. Seven pts developed Grade II or III aGVHD of skin or GI. No pt had Gr IV aGVHD. Six pts responded to treatment. Only 1pt developed limited cGVHD of the skin. No pt who was CMV seronegative developed CMV viremia. 7 of 19 CMV seropositive pts developed CMV viremia. Nine pts received rituximab for EBV viremia. No pt died of CMV disease or EBV-LPD. Five pts received defibrotide for treatment of VOD. Table 1.N1o GF2o GFaGVHD (Gr 2-3)cGVHD (limited)CMV-CTLEBV-CTLRelapseAlive in CR p2nd SCT for GF/rel3 yrs DFS3 yr OSEntire Cohort4901(2%)6(12%)1 (2%)1(2%)1(2%)11(22%)5(4rel,1GF)72.3%87.7%AML-CR11800210043(3rel)75.6%94.4AML-CR2110020114056.0%66.7MDS1001000022(1GF,1rel)78.8%100%tAML/MDS100020001080.0%88.9% With a median follow-up of 36.3 mos the DFS and OS at for the entire cohort at 3 yrs is 72.3% and 87.7%, respectively. Although the DFS for pts with AML-CR1 is 75.6%, 3 of 4 pts are in CR2 post a second BMT for OS of 94.4%. The 4 pts with AML-CR2 who relapsed died of disease. In this series of 49 pts, 6pts died of disease, 1 pt died of aGVHD and 1 pt (Down Syndrome) died of MOF (VOD). Thus, in young pts (< 21 yrs) TCD-PBSCT is associated with low risk of acute and chronic disease, no increment in relapse and a highly favorable DFS and OS. The data support the inclusion of pediatric pts in BMT CTN 1301 trial (NCT02345850): a Randomized, Multi-Center, Phase III Trial of Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus-Host Disease. Disclosures Kernan: Gentium S.p.A.: Research Funding. Hasan:Atara Biotherapeutics: Research Funding. O'Reilly:Atara Biotherapeutics: Research Funding.

scholarly journals Donor Genetic Determinant of Thymopoiesis rs2204985 Impacts Clinical Outcome after Single HLA Mismatched HSCT

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3903-3903
Author(s):  
Chrysanthi Tsamadou ◽  
Sowmya Gowdavally ◽  
Uwe Platzbecker ◽  
Elisa Sala ◽  
Thomas Valerius ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Genetic Variant ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Multivariate Models ◽  
Common Genetic Variant ◽  
Hematopoietic Stem ◽  
Genotype Frequencies ◽  
The Impact

Abstract Introduction: A common genetic variant within the TCRA-TCRD locus has been recently identified as a predictive factor of thymic function and T cell repertoire diversity (Clave et al., 2018). Specifically it was shown in a mouse model that transplantation of rs2204985 AA human hematopoietic stem cells (HSC) into immunodeficient mice led to lower thymocyte counts and poorer TCR diversity. T cell mediated pathways are known to play a significant role in immunological processes affecting HSCT outcome like GvL, GvH and infection. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient's outcome after unrelated HSCT. Methods: The study included 2,016 adult patients with hematologic malignancies who received their first unrelated (10/10 or 9/10 HLA matched) graft between 2000 and 2013 in a German transplant center. Patients with refractory disease at time of transplantation were excluded from the analysis. Both donors and patients were retrospectively genotyped for the TCRA-TCRD rs2204985 polymorphism by next generation sequencing using a validated protocol on an Illumina Miseq platform. Overall survival (OS), disease free survival (DFS), relapse (RI), non-relapse mortality (NRM), acute GvHD (aGvHD) and chronic GvHD (cGvHD) were evaluated; p&lt;0.05 was considered significant and donor rs2204985 GG/AG genotype was set as reference vs the AA genotype. Stratification for diagnosis was performed and a backward stepwise model finding approach was used to select variables related to a given outcome with a threshold of 0.10 for retention in the model. Results: The rs2204985 genotype frequencies found in both patients and donors were in line with those previously reported for Caucasian populations indicating a codominance of the two alleles (i.e. A and G). Regarding the impact of this genetic variation on outcome, multivariate analysis of the combined cohort indicated different risk estimates in 10/10 and 9/10 HLA matched transplantations, therefore subanalysis on account of HLA incompatibility was performed. Analysis in the subgroup of single HLA mismatched cases (n=624) revealed that donor AA genotype associated with markedly inferior OS (55.1% vs 70.6%, p=0.004, Fig. 1) and DFS (47.6% vs 63.4%, p=0.002, Fig. 2) one year after HSCT as compared to the donor AG/GG genotypes. These results were confirmed in the corresponding multivariate models (OS HR: 1.48, p=0.003; DFS HR: 1.50, p=0.001) which are visually displayed as forest plots in Fig. 3 and Fig 4, respectively. The adverse effect of donor AA genotype on survival appears to be driven by a combined higher risk of RI (1Y after HSCT: 29.3% vs 18.3%, p=0.048; HR: 1.38, p=0.035) and NRM (1Y after HSCT: 28.6% vs 19.9%, p=0.043; HR: 1.38, p=0.042) as shown by both the univariate and multivariate analyses for the two respective endpoints. No association was found between donor rs2204985 genotype and risk of acute or chronic GvHD. The donor rs2204985 genotype had also no significant impact on any outcome endpoint in the 10/10 HLA matched subgroup. Last, no significant interactions were observed between this variable and the other adjusted covariates in the multivariate models. Conclusion: To our knowledge this is the first study to date investigating the potential effect of donor's genotype regarding a common genetic variant within the TCRA-TCRD locus on the outcome of patients receiving unrelated HSC grafts. Our data suggest that donor rs2204985 AA genotype in combination with single HLA mismatches may adversely affect the outcome of HSC transplanted patients and should therefore be avoided. It is of note that one in four unrelated donors of Caucasian origin is expected to carry the AA genotype. A weaker relapse and -presumably- infection control, especially in the early post-transplantation period, due to compromised T cell reconstitution as a result of the unfavorable donor AA genotype may account for these findings. Confirmatory studies in larger independent cohorts are warranted before final conclusions are drawn. Figure 1 Figure 1. Disclosures Platzbecker: Geron: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria. Sala: Celgene/BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Wulf: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Kroeger: Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Gilead/Kite: Honoraria; AOP Pharma: Honoraria; Novartis: Honoraria; Jazz: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Hertenstein: Novartis: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; BMS: Honoraria. Schrezenmeier: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Travel support, Research Funding; Roche: Honoraria; Novartis: Honoraria; Apellis: Honoraria; Sanofi: Honoraria.

scholarly journals Itolizumab As a Potential Therapeutic for the Prevention and Treatment of Graft Vs Host Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5603-5603 ◽  
Author(s):  
Cherie Tracy Ng ◽  
Jeanette Ampudia ◽  
Robert J. Soiffer ◽  
Jerome Ritz ◽  
Stephen Connelly
Keyword(s):  
Weight Loss ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Vehicle Control ◽  
Control Group ◽  
Employment Equity ◽  
Equity Ownership

Background: CD6 is a co-stimulatory receptor, predominantly expressed on T cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presentation cells and various epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation, proliferation, differentiation and trafficking and is central to inflammation. While effector T cell (Teff) are CD6hi and upregulate expression upon activation, regulatory T cells (Treg) remain CD6lo/-, making this an attractive target to modulate Teff activity while preserving Treg activity. Early studies by Soiffer and colleagues demonstrated using T12, an anti-CD6 monoclonal antibody (mAb) that ex-vivo depletion of CD6+ donor cells prior to transplantation decreased the incidence of both acute and chronic GVHD, highlighting the importance of CD6+ cells in GVHD pathogenesis and validating it as a therapeutic target. However, it remains to be shown whether modulating the CD6-ALCAM pathway in vivo can attenuate GVHD. We investigated the use of itolizumab, a humanized anti-CD6 mAb that has demonstrated clinical efficacy in other autoimmune diseases, as both a preventive and therapeutic treatment for GVHD, using a humanized xenograft mouse model. Methods: Humanized xenograft mice were generated by intravenous transfer of 2x10^7 human PBMCs into 6-8 weeks old NOD/SCID IL2rγ-null (NSG). To investigate the ability of itolizumab to prevent GVHD, mice were dosed with either 60μg or 300μg of itolizumab, 150μg of abatacept (CTLA4-Ig), or vehicle, starting one day prior to PBMC transplantation. To investigate the therapeutic effect of itolizumab, mice were dosed with either 150μg of itolizumab or vehicle, starting at Day 5 post-PBMC transfer, when transplanted T cells are already activated. All treatments were administered IP every other day. Weight and disease scores were monitored throughout the study. At Days 18 and 35, peripheral blood was evaluated by flow cytometry to examine T cell prevalence, and tissues were collected for histological examination of pathology and T cell infiltration. Results: When administered as prevention (Day -1), treatment with either 60μg or 300μg of itolizumab significantly decreased mortality compared to the vehicle control (100% vs. 10%); this decrease was similar to the positive control group treated with abatacept (Figure 1). At 60μg, itolizumab-treated mice demonstrated significant reductions in the prevalence of human T cells in peripheral blood vs. vehicle-treated mice at Day 18 (<0.2% vs. 74.5%; p < 0.001). The reduction in peripheral T cells was accompanied by reductions in tissue-infiltrating T cells in lung (85-fold) and gut (9.5-fold), as well as reductions in disease scores and weight loss. When administered therapeutically, treatment with itolizumab was associated with a survival rate of 50% compared to 10% in the control group (Figure 2). Similarly, peripheral T cell prevalence (34.3% vs. 65.1%; p < 0.001), weight loss, and disease scores were inhibited by itolizumab compared to vehicle control mice. Conclusions: These data suggest that systemic treatment with itolizumab can modulate pathogenic Teff cell activity, establishing this antibody as a potential therapeutic for patents with GvHD. A phase I/II study using itolizumab as first line treatment in combination with steroids for patients with aGVHD is currently ongoing (NCT03763318). Disclosures Ng: Equillium: Employment, Equity Ownership. Ampudia:Equillium: Employment. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Cugene: Consultancy; Jazz: Consultancy. Ritz:Equillium: Research Funding; Merck: Research Funding; Avrobio: Consultancy; TScan Therapeutics: Consultancy; Talaris Therapeutics: Consultancy; Draper Labs: Consultancy; LifeVault Bio: Consultancy; Celgene: Consultancy; Aleta Biotherapeutics: Consultancy; Kite Pharma: Research Funding. Connelly:Equillium: Employment, Equity Ownership.

scholarly journals A Systematic Review and Meta-Analysis of Luspatercept for Anemia Treatment in Low Risk Myelodysplastic Syndrome with Ring Sideroblast Subtype in Phase II and Phase III Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-41
Author(s):  
Arshia Akbar ◽  
Waqas Khan ◽  
Zunairah Shah ◽  
Muhammad Yasir Anwar ◽  
Muhammad Ali Aziz ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Pooled Analysis ◽  
Low Risk ◽  
Phase Iii ◽  
Erythroid Response ◽  
Transfusion Independence ◽  
Line Of Therapy ◽  
Erythropoietin Stimulating Agents ◽  
Anemia Treatment

Background: Low-risk Myelodysplastic Syndromes (MDS) patients commonly present with anemia and may become blood transfusions dependent upon progression. Luspatercept, a targeted drug for an activin receptor ligand has emerged as new anemia treatment in MDS for patients with ring sideroblasts and the patients with SF3B1 mutation. This systemic review highlights the efficacy of luspatercept in MDS patients whom erythropoietin stimulating agents (ESA) are not effective. Methods: We conducted a comprehensive literature search using PubMed, Clinical trial.gov, Embase, Cochrane, and Web of science. Our search strategy included MeSH (Medical Subject Headings) terms and keywords for MDS and luspatercept including trade names and generic names from inception to 29 April 2020. Studies were selected according to PRISMA guidelines. The initial screening revealed 240 articles. After excluding review articles, duplicates, and non-relevant articles, finally we included two clinical trials, which reported transfusion independence (TI), an erythroid response (HI-E) in MDS patients with luspatercept. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.0.2) to report the efficacy of luspatercept. We pooled the results of the experimental arms of the two trials using the inverse variance method and logit transformation. Between studies, variance was calculated using DerSimonian-Laird Estimator. Results: A total of 287 patients were enrolled and evaluated in two phases II/III trials. Platzbecker et al and Fenaux et al reported Erythropoietin stimulating agents (ESA) with one median prior line of therapy (n= 148, n=46). Fenaux et al. also reported iron chelation therapy (n=71) as a prior line of therapy. Patients having ring sideroblast positive &lt;15% (n=172) and SF3B mutation were present in 169 evaluable patients. Low-risk MDS (LR-MDS) patients are classified according to IPSS-R criteria, defined as being of very low (n=19), low (n=135), or intermediate-risk (n=44). Platzbecker et al. (2017) studied luspatercept in MDS patients (n=58) in the PACE phase II trial. Fenaux et al. (2020) studied the efficacy of luspatercept in MDS pts (n=219) in the MEDALIST phase III trial. The baseline Erythropoietin (EPO) levels were: levels &lt;200: n=191, level 200-500: n= 81, level &gt;500: n=57 for both studies. The baseline means hemoglobin (Hb) levels were eight before therapy. TI for more than eight weeks was observed in 38% of patients in both the MEDALIST trial and PACE trial. The erythroid response was 53% and 63% in both trials respectively. In a Phase II study, for LR-MDS patients, the overall erythroid response was higher among patients (n= 69%) having ringed sideroblast status (&gt;15% ring sideroblast) and SF3B mutation (n=77%). The mean increase of Hb was observed in 29 out of 46 and 32 out of 41 pts in MEDALIST and PACE trial, respectively. Luspatercept proved to be efficacious in the pooled analysis i.e transfusion independence (TI): 38%, 95% CI 0.31-0.45; p =0.98, I2 = 0%), and erythroid response (HI-E): 54%, 95% CI 0.48-0.62; p=0.22, I2 = 32%) with an increase in mean Hb of 70% 95%: CI 0.59-0.78; I2 = 56%) (Figure 1). CONCLUSION: In patients with low risk MDS positive ringed sideroblast or SF3B1 mutation status shows good responses with luspatercept treatment, with reduced transfusion dependence, and higher erythroid response. Disclosures Anwer: Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Millennium Pharmaceuticals: Research Funding; Celgene: Research Funding; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; AbbVie Pharmaceuticals: Research Funding.

scholarly journals Effect of T-cell depletion as graft-versus-host disease prophylaxis on engraftment, relapse, and disease-free survival in unrelated marrow transplantation for chronic myelogenous leukemia

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1980-1987 ◽  
Author(s):  
WR Drobyski ◽  
RC Ash ◽  
JT Casper ◽  
T McAuliffe ◽  
MM Horowitz ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Free Survival ◽  
Entire Cohort ◽  
Graft Versus Host ◽  
Disease Free

Abstract Between January 1988 and March 1993, 48 patients received T-cell- depleted marrow grafts from unrelated donors as treatment for chronic myelogenous leukemia (CML). The median age of the population was 31.7 years (range 5.4 to 53) with 17 of 48 patients greater than 40 years of age. Twenty-seven patients were transplanted in chronic phase, 17 in accelerated phase, and 4 in blast crisis. All patients received a standardized preparative regimen of cyclophosphamide, high-dose cytosine arabinoside, methylprednisolone, and total body irradiation. Marrow grafts were depleted of mature T cells with the alpha beta T- cell receptor antibody T10B9 as graft-versus-host disease (GVHD) prophylaxis. All patients also received posttransplant cyclosporine therapy. Twenty-eight of 48 patients were mismatched with their donors for one or more HLA-A, B, DR, or DQ loci by either serology or high- resolution oligonucleotide genotyping. Nine of 28 were mismatched at multiple HLA loci. Durable engraftment was achieved in 94% (45/48) of patients. The actuarial probability of developing grades II to IV and grades III to IV acute GVHD were 39.6% (95% confidence interval (CI) 26.9 to 53.0) and 8.3% (95% CI 6.1 to 10.9) for the entire cohort. There was no difference in the incidence of grades II to IV acute GVHD between patients receiving matched (36.8%) or mismatched (41.4%) marrow grafts (P = .77). The actuarial probability of relapse at 2 years was 8.8% (95% CI 2.1 to 21.6) for the entire cohort and 18% (95% CI 4 to 41) for patients transplanted in either the accelerated or blast crisis phase (advanced disease). One cytogenetic relapse has occurred among patients transplanted in the chronic phase. The probability of disease- free survival at 2 years was 52% (95% CI 24 to 70) for patients transplanted in chronic phase and 46% (95% CI 25 to 73) for patients transplanted with advanced disease. No difference in disease-free survival was observed between patients receiving matched (49%) or mismatched (51%) marrow grafts (P = .90). This study shows that patients receiving unrelated T-cell-depleted marrow grafts for CML can achieve durable engraftment with a low incidence of severe GVHD and apparent preservation of graft-versus-leukemia reactivity. These data also suggest that T-cell depletion may allow patients who might otherwise experience unacceptable toxicity from GVHD-related complications caused by older age or increased HLA disparity to benefit from unrelated marrow grafts.

Induction of Remission Prior to Transplantation Improves the Disease-Free Survival (DFS) of Patients with Advanced Myelodysplastic Syndromes (MDS) Treated with Myeloablative T-Cell Depleted (TCD) Stem Cell Transplants (SCT) from HLA Identical Siblings.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5426-5426
Author(s):  
H.R. Castro-Malaspina ◽  
Ann A. Jakubowski ◽  
Esperanza B. Papadopoulos ◽  
Farid Boulad ◽  
James W. Young ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Peripheral Blood ◽  
Marrow Cell ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Untreated Group ◽  
Refractory Anemia ◽  
Marrow Graft ◽  
Failure Group

Abstract Posttransplant relapse is a major limitation to the success of allogeneic SCT in patients with advanced MDS (refractory anemia with excess blasts (RAEB I and II), refractory anemia in transformation (RAEB-t), and acute myeloid leukemia transformed from MDS). The use of induction chemotherapy prior to transplant to induce remission and thereby to reduce posttransplant relapse in these patients remains controversial. From 1985 to 2004, 47 patients with advanced MDS underwent bone marrow or peripheral blood SCT from HLA identical siblings after myeloablative conditioning with total body irradiation (TBI) and cyclophosphamide alone or in some combined with thiotepa, carboplatinum, diaziquone, or etoposide, or TBI combined with thiotepa and fludarabine. Thirty-six patients received low dose (3 patients) or full induction (33 patients) chemotherapy before conditioning, and 11 patients did not receive any chemotherapy. Prior to transplant, 22 of the 36 treated patients were in hematologic remission (CR) and 4 achieved a second refractory cytopenia phase (RCy2) for a total of 26 responders, and 10 had failed to respond to chemotherapy. Marrow grafts were depleted of T cells using soybean lectin agglutination and then sheep RBC-rosetting (n=32 patients). G-CSF-mobilized peripheral blood stem cell (PBSC) grafts underwent positive CD34 selection and T-cell depletion by sheep RBC-rosetting (n=10 patients). Five patients received a marrow graft followed by a PBSC allograft from the same donor because of low marrow cell dose. Rejection prophylaxis with anti-thymocyte globulin was used in 33 patients. No posttransplant pharmacologic prophylaxis for GvHD was given. The median age was 48 years (range 13–61). Forty-three of the 47 patients in this series engrafted, and 2 had primary graft failure. Two patients died before engraftment. Only 3 patients developed acute GvHD (grades 1 and 3) and 1 chronic GvHD. At 5 years posttransplant, the DFS was 44% for the patients in CR and RCy2 at time of transplant, but no patients in the untreated group or in the chemotherapy failure group survived (p=0.0004). The cumulative incidence (CI) of relapse at 2-years posttransplant for the responders was 27.0%, for the failures 50%, and for the untreated group 45%. The CI for non-relapse mortality at 2-years posttransplant was 19% for the responders, 40% for the failures, and 36% for the untreated patients. All survivors have achieved ≥KPS 90%. These results indicate that patients with advanced MDS who achieve remission or a second refractory anemia phase with chemotherapy before TCD allogeneic SCT can achieve successful long-term remisions. In contrast, the high incidence of posttransplant relapse mitigates against the use of TCD SCT in patients with advanced MDS with active disease (≥5% blasts) prior to transplant. Prospective multicenter randomized studies are needed to validate the value of pre-transplant chemotherapy in patients with advanced MDS undergoing allogeneic SCT.

The Role of In Vivo T-Cell Depletion On Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation From HLA-Identical Siblings in Patients with Follicular Lymphoma: An European Blood and Marrow Transplantation Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3375-3375
Author(s):  
Julio Delgado ◽  
Carme Canals ◽  
Michel Attal ◽  
Kirsty Thomson ◽  
Antonio Campos ◽  
...  
Keyword(s):  
T Cell ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Alkylating Agent ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Off Label ◽  
Reduced Intensity

Abstract Abstract 3375 Poster Board III-263 Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (Allo-HCT) has become a feasible and effective therapeutic approach for younger patients with relapsed or refractory follicular lymphoma (FL). However, there is still much debate regarding the most appropriate conditioning regimen or whether the use of in vivo T-cell depletion (TCD) is beneficial or not for these patients. We analyzed the outcome of 164 patients with advanced FL reported to the EBMT from 1999 to 2007, who underwent RIC Allo-HCT conditioned with fludarabine plus an alkylating agent. Donors were HLA-matched siblings in all cases. Patients receiving transplants from alternative donors or conditioned with other agents were specifically excluded. The alkylating agent was melfalan in 48% of cases, busulfan in 32% and cyclophosphamide in 20%. Forty-six patients (28%) received anti-thymocyte globulin (ATG), 41 (25%) received alemtuzumab and 77 (47%) did not receive TCD in vivo. Median age at transplantation was 50 (range 29-64) years, and patients receiving alemtuzumab were significantly younger [45 (33-63)] than those receiving ATG [52 (29-64)] or no TCD [50 (32-64)], P = 0.05. There were no other differences among groups in terms of disease stage or presence of bulky masses at diagnosis, interval from diagnosis to HCT, number of prior therapies, or disease status at HCT. Engraftment was observed in 161 (98%) patients, with no significant differences among groups. Median follow-up was 43 (1–110) months for survivors. At three years, non-relapse mortality (NRM), relapse rate (RR), progression-free survival (PFS) and overall survival (OS) were 17% (95% CI 12-24%), 23% (17-31%), 60% (52-68%) and 75% (67-82%), respectively, for the entire cohort. The incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly higher for patients not receiving any TCD (31%) compared to TCD patients (18%), P = 0.05, and the incidence of chronic GVHD at one year was also significantly higher for the former compared to the latter group (68% vs. 25%, P < 0.001). There were no significant differences in NRM among groups, but there was a trend towards a higher RR in patients receiving alemtuzumab (40%) or ATG (24%) compared to patients receiving no TCD (16%) (P = 0.15), which translated into a trend towards a significantly shorter 3-year PFS for the alemtuzumab group (42% vs. 69%; P = 0.18). However, there were no differences in the 3-year OS among groups, which was 77% for patients receiving alemtuzumab, 73% for those receiving ATG and 77% for patients not receiving any TCD. In conclusion, results with RIC Allo-HCT from HLA-identical siblings were very promising for patients with advanced FL. Both alemtuzumab and ATG were effective in reducing acute and chronic GVHD, but had no significant impact on NRM. There was a trend towards a shorter PFS for patients receiving alemtuzumab, which did not translate into a significantly different OS. Disclosures: Delgado: Bayer Schering Pharma: Consultancy, Research Funding; Genzyme: Research Funding. Off Label Use: The use of alemtuzumab as a T-cell depleting agent in the context of hematopoietic transplantation is considered off-label.

Efficacy and Safety of Eculizumab in Children and Adolescents with Paroxysmal Nocturnal Hemoglobinuria

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1034-1034
Author(s):  
Ulrike M. Reiss ◽  
Jeffrey Schwartz ◽  
Kathleen M Sakamoto ◽  
Geetha Puthenveetil ◽  
Masayo Ogawa ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Pediatric Patients ◽  
Phase Iii ◽  
Intravascular Hemolysis ◽  
Short Term ◽  
Clone Size ◽  
Sustained Reduction ◽  
Life Threatening

Abstract Abstract 1034 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive, life-threatening disease characterized by chronic intravascular hemolysis caused by uncontrolled complement activation. The cellular abnormality in PNH originates from a somatic mutation in the PIG-A gene resulting in a deficiency of the glycosylphosphatidyl-inositol (GPI) anchored complement regulatory proteins, CD55 and CD59. Featuring a complex pathophysiology, PNH is associated with hemolysis, cytopenia, thromboembolism (TE), multi-organ damage, bone marrow failure, and death. Patients with PNH also experience a range of debilitating symptoms including fatigue, shortness of breath, erectile dysfunction, and abdominal pain that significantly reduce quality of life (QoL). The terminal complement inhibitor eculizumab has been shown to provide a rapid and sustained reduction in intravascular hemolysis, leading to significant reductions in TE events, pulmonary hypertension and improvements in renal disease, QoL and anemia. In a single center study of long term eculizumab treatment (up to 8 years), eculizumab was shown to normalize the survival of adult PNH patients compared to age and sex-matched controls. In contrast, systematic research focused on pediatric PNH patients has been limited, largely due to small patient numbers. However, pediatric PNH patients experience many of the same clinical features and life-threatening complications as adult patients. The current study assessed the safety, pharmacokinetics, and efficacy of short-term eculizumab treatment in children and adolescents with PNH. Methods: The study began in May 2009, and is no longer recruiting as the enrollment targets have been met. In this 12-week, open-label, multicenter study, children and adolescents (aged 2 to 17 years) were eligible with a diagnosis of PNH, ≥5% GPI-deficient red blood cells (RBC) or granulocytes, and serum lactate dehydrogenase (LDH) levels > upper limit of normal (ULN) or those who had received ≥1 transfusion during the previous 2 years for anemia or anemia-related symptoms. Eculizumab was administered using weight-based dosing (300–900 mg IV) at pre-determined regular 7–14 day intervals throughout the treatment period. In addition to pharmacokinetic (PK) and pharmacodynamic (PD) parameters, safety and efficacy parameters included adverse events (AEs), LDH and hemoglobin levels, platelet counts, and granulocyte and RBC type III clone size. Results: Seven pediatric patients with PNH ranging in age from 11 to 17 years participated in this study (4 females, 3 males). One patient also had aplastic anemia at study enrollment. At baseline, patients had elevated LDH (normal range 100–275 U/L), thrombocytopenia and anemia, and a median PNH granulocyte clone size of 79%. Eculizumab was well-tolerated; common AE's included headache, fever, and nasal congestion, all mild to moderate in severity. All 7 patients completed the 12-week trial and are currently alive; the safety and AE profile of eculizumab was consistent with that previously reported in adults participating in Phase III PNH clinical trials. Eculizumab treatment led to a rapid and sustained reduction in LDH levels, from a mean of 1,020 U/L at baseline to 256 U/L at 12 weeks (Table 1). PK-PD analysis is ongoing. Conclusions: Consistent with results in adults, pediatric patients with PNH tolerate short-term eculizumab infusions well and have reduced intravascular hemolysis. These results highlight the potential of eculizumab for the treatment of children and adolescents with PNH. Disclosures: Sakamoto: Abbott: Research Funding; Genentech: Research Funding. Puthenveetil:Novartis Pharmaceuticals Corporation: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau. Ogawa:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership.

A Phase II Prospective Feasibility Study of Clofarabine Cytoreduction Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Relapsed or Refractory Acute Leukemias and Advanced Myelodysplastic Syndromes

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 496-496
Author(s):  
Rajiv Agarwal ◽  
Frederick L Locke ◽  
Rangesh Kunnavakkam ◽  
Koen van Besien ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Acute Leukemias ◽  
T Cell Depletion ◽  
Kaplan Meier ◽  
One Year

Abstract Abstract 496 HCT may provide long-term disease control for patients (pts) with relapsed and/or refractory acute leukemias (AL) and advanced myelodysplastic syndromes (MDS). Active disease burden at HCT is associated with high relapse rates and poor long-term outcomes. We hypothesized tolerable intensification would be achieved safely by clofarabine cytoreduction followed by HCT conditioning at the nadir and would result in improved outcomes. We performed a prospective study (3/08 – 9/10) to examine the feasibility and efficacy of clofarabine (Clo) cytoreduction prior to HCT for relapsed or refractory AL and MDS with > 5% marrow blasts. Clo was administered at 30mg/m2/day IV over 2 hours for 5 consecutive days. On Day 12 post Clo initiation, a bone marrow (BM) biopsy determined cytoreduction, followed by HCT conditioning by day 21 post-Clo. Our primary endpoint was to assess the proportion of pts who achieved effective cytoreduction, defined as BM cellularity <20% and BM blasts<10% on Day 12 post Clo initiation. Our secondary endpoints included (a) the proportion of pts able to proceed to HCT within 21 days of initiating Clo bridge, (b) Clo-related toxicities, and (c) disease free (DFS) and overall survival (OS) on Day 100 post HCT. 29 pts were enrolled and evaluable; 11 AML, 7 MDS, 3 t-MN, 4 secondary AML, 2 CML, 2 ALL; median age was 51 years (range 23–69); sex: 16 M, 13 F. 16 pts had high risk and 13 had intermediate risk cytogenetic profiles. 3 of 12 pts evaluated showed a FLT3 ITD mutation. 18 of 23 evaluable pts had high C-reactive protein levels at study entry (>5mg/L). All pts had ECOG performance status of 0 to 1. The median Charlson co-morbidity index was 1 (range 0–8). Effective cytoreduction was achieved in 15/29 pts (52%). Clo bridge therapy was well tolerated with mild toxicities (CTCAE v.3) prior to HCT as follows: 7% with grade (gr.) 1 creatinine elevation; 46% gr.1–2 and 7% gr.3 bilirubin elevation; 50% gr.1–2 and 25% gr.3 SGOT elevation, which were reversible. There were no hand-foot syndrome, cardiac, or CNS toxicities. All 29 pts (100%) successfully proceeded to HCT conditioning after clofarabine bridge – one pt with refractory AML, who achieved cytoreduction and conditioning, died one day before HCT due to sepsis. Median time from Clo initiation to HCT was 21 days (range 18–77). Two pts were delayed due to infection and/or failure to cytoreduce; both received second bridge with HiDAC mitoxantrone and achieved cytoreduction followed by HCT. 25 of 29 underwent reduced intensity conditioning (flu-mel-campath-17, clo-mel-campath 3, flu-mel-atg 5) and 26 of 28 received T-cell depletion (campath 22, ATG 5). Among the 28 transplanted pts, graft sources included: 23 PBSC (11 matched related, 12 matched unrelated), and 5 haploidentical PBSC plus a cord blood unit. With a median follow up 343 days after HCT, the median PFS = 353 days (95% CI 229–573) and the median OS = 381 days (95% CI 229–649). One year PFS is 65% by Kaplan-Meier estimate for cytoreduced pts compared to 33% in non-cytoreduced pts. Of the 28 pts who received transplant, 3 pts died before Day 100 – one due to sepsis before Day 28 post HCT, and two due to disease progression. At Day 28 post HCT, 26/27 pts (96%) had BM biopsies showing no evidence of residual disease – one pt had residual AML. The cumulative incidence of gr.2–3 acute GVHD by Day 100 was 9/27 pts, and 2/25 pts developed mild or moderate chronic GVHD within the first year. The Kaplan Meier estimate for one year survival is 65% (95% CI 35–84%) for the cytoreduced pt group and 41% (95% CI 16–65%) for the non-cytoreduced pt group. In summary, clofarabine bridge achieved cytoreduction in 52% of very high risk pts with advanced hematologic malignancies with low toxicity. Cytoreduction was associated with prolonged PFS, but late relapse remains problematic. Despite RIC and T-cell depletion, most pts achieved remission post-HCT with low rates of acute and chronic GVHD. This bridging approach provides a platform for testing novel post-transplant interventions. Disclosures: Off Label Use: Clofarabine is being used for treatment of advanced leukemia for cytoreduction prior to HCT. Locke:Genzyme: Honoraria. van Besien:Genzyme: Research Funding. Odenike:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Genzyme: Research Funding.

Immunomodulation of Both Donors and Recipients with Atorvastatin As a Strategy for the Prevention of Acute Graft-Versus-Host Disease (aGVHD): Results of Two Parallel Prospective Trials in Recipients of Matched Sibling Allogeneic Hematopoietic Cell Transplantation (alloHCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1942-1942
Author(s):  
Mehdi Hamadani ◽  
Michael Craig ◽  
Scot Remick ◽  
Laura Gibson ◽  
William Petros ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Fungal Infections ◽  
Chronic Gvhd ◽  
Off Label Use ◽  
Phase Ii Trials ◽  
Off Label ◽  
Gvhd Prophylaxis ◽  
Matched Sibling ◽  
Label Use

Abstract Abstract 1942 Introduction: Acute GVHD is a leading cause of morbidity and mortality following alloHCT. Atorvastatin (a statin drug) is a potent immunomodulatory agent capable of suppressing T cell–dependent immune responses that holds promise as a novel and safe agent for the prophylaxis of aGVHD. In murine models atorvastatin administration to both donor and recipient mice (compared to prophylaxis in either donors or recipients alone), prevented aGVHD by inhibiting donor T-cell proliferation, inducing T-helper 2 polarization, and by inhibiting recipient antigen presenting cell function (Zeiser et al. Blood, 2007). Several retrospective studies also suggest statins as potential prophylactic agents for aGVHD. Methods: We report here the results of two parallel, ongoing, prospective, phase II trials (NCT01175148 & NCT01491958) evaluating the safety and efficacy of a ‘two-pronged’ strategy of atorvastatin administration as aGVHD prophylaxis, to both adult (age ≥18yrs) donors and recipients of matched sibling alloHCT. The approach was identical in both protocols. Subjects with a history of atorvastatin allergy/intolerance were not eligible. As GVHD prophylaxis, atorvastatin at 40mg/day orally was administered to sibling donors, starting 14–28 days before the anticipated 1st day of stem cell collection. In alloHCT recipients GVHD prophylaxis consisted of atorvastatin (40mg/day) administered from day -14 to day +180 (or until stopping immunosuppression, toxicity, development of grade [Gr] II-IV aGVHD, or severe chronic GVHD [cGVHD]). In addition all recipients received standard GVHD prophylaxis with tacrolimus and methotrexate. Ex vivo CD34+ cell selection or in vivo T-cell depletion was not permitted. Primary outcomes were rate of Gr II-IV aGVHD at day +100 and safety of atorvastatin administration to alloHCT donor/recipient pairs. Both trials tested the null hypothesis H0: p≥35%, vs. the alternate H1: p≤15%, where p is probability of Gr II-IV aGVHD at day 100. Secondary outcomes included rates of late-onset aGVHD, cGVHD, relapse, progression-free survival (PFS), and overall survival (OS). Results: Between September 2010 and June 2012, 34 donor/recipient pairs were enrolled at WVU (n=24) and OSU (n=10). Median donor age was 50.5 yrs (range 24–69). Median duration of atorvastatin prophylaxis in donors was 15 days (range 7–26). No atorvastatin related Gr 3–4 toxicities were seen in the healthy donors. Table 1 shows baseline patient (pt) characteristics. At transplantation 16 pts (47%) had high-risk disease, 12 (35%) were chemorefractory, 11 (32%) had HCT-CI of ≥3, 14 (41%) were female to male allografts, and 12 (35%) pts had ABO mismatched transplants. Median follow up of survivors is 158 days (range 31 – 658). Atorvastatin was well tolerated with no Gr 2–4 adverse events. All pts engrafted. The median time to ANC ≥500/μL was 18 days (range 5–25) and to platelets ≥20k/μL was 15 days (range 11–51). The median day 100 chimerism was 85.5% (55–100%) for T-cells and 100% (26–100%) for myeloid cells. Respective numbers at day 180 are 99.5% and 100%. Among 34 evaluable pts, the cumulative incidences (CI) of Gr II-IV and Gr III–IV aGVHD at day 100 were 6.0 ± 4.2% and 0% respectively. Respective CI rates at day 180 are 16.7 ± 8.3% and 10.2 ± 7%. CI of mild/moderate and severe cGVHD at 1 year are 15.8 ± 8.9% and 18.3 ± 10.2%, respectively. Infectious complications were infrequent, with no fungal infections or EBV reactivations and few CMV reactivations (n=3). Non-relapse mortality was 0% at day 100 and 4.5% at day 180. CI of relapse at day 180 was 27.6 ± 9.2%. One year PFS and OS estimates are 54% and 66%, respectively. Conclusions: A two-pronged immunomodulatory strategy of atorvastatin administration to alloHCT donors/recipients appears to be a feasible, safe and potentially effective modality for aGVHD prophylaxis. Final results of NCT01175148 & updated results of NCT01491958 will be presented at the meeting. Disclosures: Hamadani: Celgene Corp: Speakers Bureau; American Cancer Society 116837-IRG-09-061-01: Research Funding; ASBMT & Millennium New Investigator Award: Research Funding; Conquer Cancer Foundation of ASCO: Research Funding. Off Label Use: Off Label use of atorvastatin for GVHD prophylaxis. Efebera:(NIA) K12 CA1333250: Research Funding; Leukemia and Lymphoma Society: Research Funding.

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