scholarly journals Late-occurring Venous Thromboembolism in Allogeneic Blood or Marrow Transplant Survivors - a BMTSS-HiGHS2 Risk Model

2021 ◽  
Author(s):  
Radhika Gangaraju ◽  
Yanjun Chen ◽  
Lindsey Hageman ◽  
Jessica Wu ◽  
Liton Francisco ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Venous Thromboembolism ◽  
Risk Model ◽  
Chronic Gvhd ◽  
Marrow Transplant ◽  
Allogeneic Bmt ◽  
Stem Cell Source ◽  
Cell Source ◽  
History Of

Background: Allogeneic blood or marrow transplant (BMT) recipients are at risk for venous-thromboembolism (VTE) because of high-intensity therapeutic exposures, comorbidities and a pro-inflammatory state due to chronic graft vs. host disease (GvHD). The long-term risk of VTE in allogeneic BMT survivors remains unstudied. Methods: Participants were drawn from the BMT Survivor Study (BMTSS), a retrospective cohort study that included patients who underwent transplantation between 1974 and 2014 and survived ≥2y after BMT. The BMTSS survey collected information on sociodemographics, health behaviors and chronic health conditions along with age at diagnosis. Details regarding primary cancer diagnosis, transplant preparative regimens, type of transplant and stem cell source were obtained from institutional databases and medical records. We analyzed the risk of VTE in 1,554 2y survivors of allogeneic BMT compared to 907 siblings. Using backward variable selection guided by minimizing Akaike's information criterion, we created a prediction model for risk of late-occurring VTE. Results: Allogeneic BMT survivors had a 7.3-fold higher risk of VTE compared to siblings (95%CI: 4.69-11.46, p<0.0001). After a median follow-up of 11y (inter-quartile range: 6-18y), and conditional on surviving the first 2y after BMT, the cumulative incidence of late-occurring VTE was 2.4% at 5y, 4.9% at 10y and 7.1% at 20y after BMT. Older age at BMT (hazard ratio [HR]=1.02/y, 95%CI=1.01-1.04, p=0.002), use of immunosuppressive medications (HR=2.28, 95%CI=1.41-3.38, p=0.0008), obesity (HR=1.06/unit increase in body mass index, 95%CI=1.02-1.10, p=0.002), history of stroke (HR=3.71, 95%CI=1.66-8.27, p=0.001), chronic GvHD (HR=1.62, 95%CI=1.00-2.60, p=0.049), and use of peripheral blood stem cells (PBSCs) as source of stem cells compared to bone marrow (HR=2.73, 95%CI=1.65-4.50, p<0.0001) were associated with increased VTE risk. The final model for VTE risk applied at 2y post-BMT ("HiGHS2") included History of stroke, chronic GvHD, Hypertension, Sex (male vs. female) and Stem cell source (PBSCs vs. other) (corrected C-statistics: 0.73; 95%CI=0.67-0.79), and was able to classify patients at high and low VTE risk (10y cumulative incidence 9.3% vs. 2.4%, p<0.0001). Conclusions: The BMTSS HiGHS2 risk model when applied at 2y post-BMT can be used to inform targeted prevention strategies for patients at high risk for late-occurring VTE.

scholarly journals Family Mismatched Donor Transplantation for Myelofibrosis: A Retrospective Analysis of the EBMT Chronic Leukaemia Working Party

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4655-4655 ◽  
Author(s):  
Kavita Raj ◽  
Eduardo Olavarria ◽  
Diderik-Jan Eikema ◽  
Liesbeth C de Wreede ◽  
Linda Koster ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Mismatched Donor

Abstract Background: Allogeneic stem cell transplantation is a treatment option for patients with advanced myelofibrosis. Problems encountered include an increased risk of delayed or poor engraftment and in the mismatched unrelated donor setting a higher rate of GVHD and particularly poor outcomes. As for other indications for allogeneic stem cell transplants, patients for whom either a matched sibling or matched unrelated donor is not available are considered for either a double umbilical cord blood, a mismatched unrelated donor or haploidentical stem cell transplant. Data on the latter option are limited and we reviewed registry data on all family mismatched donor transplants performed between 2001 and 2015 and reported to the EBMT registry. Results: Records retrieved 69 patients with myelofibrosis transplanted between November 2001 and November 2015. 44 (64%) were male. 50 (74%) had primary myelofibrosis,18 (27%) had secondary myelofibrosis (6 from ET, 5 from PRV and 7 others) and unknown 1(2%). Of 25 patients for whom the JAK2 V617F mutation status was known, 15 (22%) harboured the mutation. Patient Karnofsky performance status was > 70% in 98%. Of the mismatched family donors, 47 (68%) were male and 22 (31%) female. Donors were HLA mismatched at 1 locus in 12 (17%) and 2 or more loci in 48 (69%). Donor-recipient serology combinations were CMV -/- in 8 (12%), +/- in 4 (6%), -/+ in 15 (22%) and +/+ in 34 (49%) missing 8 (12%). Bone marrow was the stem cell source in 34 (49%) and peripheral blood in 35 (51%). The median total nucleated cell count (TNC) infused was 7.5x108/kg (range 2.3-21x108/kg) from data available in 17 patients. The median CD34+ cell dose was 6.9x106/kg (range 1.9-18.18x106/kg) from data available in 19 patients. Conditioning was myeloablative in 48 (70%) and RIC in 21 (30%) The conditioning regimes were varied but the predominant ones were Fludarabine, Busulphan, ATG (FBATG) and Thiotepa, Busulphan, Fludarabine (TBF). TBI was administered in 8 (12%) and in vivo T cell depletion in 22 (32%), ex-vivo T cell depletion in 5 (7%) patients. GVHD prophylaxis varied with post transplant Cyclophosphamide administered in 34/67 (49%) and ATG in 19/67 patients (28%). Neutrophil engraftment was established in 53 (82%) at a median of 20 days (range 11-83). Primary graft failure occurred in 8 (12%) and secondary graft failure in 4 (6%). This occurred at a median of 12 months (range 4.5-35 months). Eleven of these patients had a second allograft at a mean interval of 6.4 months. Responses to the first allograft (censoring for patients who had a second allograft) with data available in 45 patients, showed that complete remission was achieved in 35 patients (78%), 6 (13%) were never in CR and 4 (9%) were not evaluable. The cumulative incidence of grade II-IV acute GvHD at 100 days was 12% (95% CI 4-21%) and for grade III-IV acute GvHD at 100 days it was 5% (95% CI 3-11%). Data for chronic GVHD was valid in 49 patients. The cumulative incidence of chronic GvHD at 2 years was 62% (95% CI 47-76%). The cumulative incidence of limited cGvHD was 45% (95% CI 31-59%) whereas the cumulative incidence of extensive cGvHD was 10% (95% CI 2-19%). The median follow up was 24 months (95% CI 13-35 months). The 2-year OS was 51% (95% CI 37-76%) and the 5-year OS was 38% (95% CI 21-55%). The 2-year RFS was 44% (95% CI 30-59%) and the 5-year RFS was 31% (95% CI 15-48%). The 2 year cumulative incidence of relapse was 14% (95% CI 5-24%). The 2 year NRM was 41% (95% CI 28-55%), which increased to 54% (95% CI 37-72%) at 5 years. The main causes of death were infection (16, 24%), GVHD (7, 10%) organ damage or failure (3, 5%), relapse/disease progression (1, 2%) and secondary malignancy or PTLD (1, 2%). On univariate analysis there was no significant effect of recipient gender, donor gender, degree of HLA mismatch 1 vs >1 Ag MM, CMV matching between donor and recipient, primary or secondary MF, disease stage at transplant (chronic versus advanced phase), conditioning intensity, conditioning regimen, GVHD prophylaxis with ATG or post transplant cyclophosphamide or stem cell source on overall survival. Conclusion: Concerns regarding engraftment and secondary graft failure have excluded patients with myelofibrosis from clinical trials of mismatched related donor transplant. The data suggest that engraftment is feasible, and PFS and OS can be attained with limited severe chronic GVHD with family mismatched donors in this setting. Disclosures Ciceri: MolMed SpA: Consultancy.

Effects of Chemical and Physical Shear-Stress Stimulation of Human Placenta-Derived Multipotent Stem Cells in Microchannel

2013 ◽  
Author(s):  
Chia-Wen Tsao ◽  
Meng-Zhi Chiang ◽  
Yu-Che Cheng
Keyword(s):  
Stem Cells ◽  
Shear Stress ◽  
Stem Cell ◽  
Human Placenta ◽  
Multipotent Stem Cells ◽  
Term Placenta ◽  
Stem Cell Source ◽  
Multipotent Cells ◽  
Cell Source ◽  
Stimulation Of

Multipotent cells obtain from human postpartum term placenta is an ethically conductive, easily accessible and high-yielding stem cell source. In this conference presentation, we demonstrate using microchannel platform to culture and differentiate the human placenta-derived stem cells. Both chemical and shear stress stimulation effects were investigated.

Radiation Dose Determines Degree of Donor Chimerism after Nonmyeloablative Hematopoietic Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1828-1828 ◽  
Author(s):  
Christoph Kahl ◽  
Marco Mielcarek ◽  
Mineo Iwata ◽  
Michael Harkey ◽  
Barry Storer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Radiation Dose ◽  
Low Dose ◽  
Donor Chimerism ◽  
Stem Cell Source ◽  
Cd34 Cells ◽  
Cell Source ◽  
Total Body

Abstract Efforts to replace total body irradiation (TBI) used for transplant conditioning with agents that have less acute and long-term toxicities require a better understanding of the biological effects of low dose TBI. We therefore retrospectively analyzed the role of radiation dose, stem cell source, and type of immunosuppression on both the stability and degree of donor chimerism in canine recipients of matched littermate hematopoietic cell transplants. Recipients were prepared with 200 cGy (n=26), 100 cGy (n=76) or 50 cGy (n=19) total body irradiation (TBI) at 7 cGy/min. Stem cell sources included bone marrow (BM) alone (n=58), BM plus G-CSF mobilized peripheral blood mononuclear cells (G-PBMC) (n=42), BM and CD14-depleted G-PBMC (n=13), or BM and T-cell-depleted G-PBMC (n=8). Posttransplant immunosuppression consisted of cyclosporin (CSP) only (n=53), CSP plus mycophenolate mofetil (MMF) (n=23), CSP and rapamycin (n=12), CSP, MMF and rapamycin (n=5); or CSP and MMF in combination with pretransplant immunosuppression (n=28). The percentage of donor granulocytes in the peripheral blood, as determined by PCR amplification of variable numbers of tandem repeats (VNTR), served as a marker for engraftment. TBI dose and stem cell source were both significantly associated with long-term (>26 weeks) stable engraftment in multivariate analysis (p=0.0001 and p=0.004, respectively). Among the 39 dogs with stable engraftment, however, TBI dose was the only factor examined that was associated with the degree of donor chimerism (mean % of donor granulocytes after 200 cGy, 100 cGy and 50 cGy of TBI: 65%, 52%, and 24%, respectively; p=0.008). To determine whether low-dose irradiation directly affected recipient stem/progenitor cell numbers and thereby conferred a competitive disadvantage to donor cells, CD34+ cells were isolated from two normal human donors. One preparation of CD34 cells was ex vivo irradiated (=200 cGy) and then injected into NOD/SCID beta2m-/- mice in combination with an equal number of unirradiated CD34 cells from the second donor. The contributions of each donor to human engraftment were assessed at 10 weeks by VNTR. After 200 cGy, the irradiated population contributed 74% less than expected, 24% less after 100 cGy, but only 6% less after 50 cGy. Flow analysis of Caspase-3 activation indicated that a significant percentage of cells irradiated with 200 cGy were apoptotic, and that this was associated with the loss of L-selectin and P-selectin glycoprotein ligand-1. In conclusion, our findings suggest that TBI, in addition to its well-characterized immunosuppressive effects, determines the degree of donor cell engraftment by directly compromising recipient stem cells, thereby providing a competitive advantage to donor stem cells.

Allogeneic Stem Cell Transplantation (allo-SCT) in 192 Acute Myeloid Leukemias (AML): A Single Center Experience From 1982 to 2010

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4498-4498
Author(s):  
Carmen Montes-Gaisan ◽  
Jorge Monge ◽  
Clara Martin ◽  
Zurie Diez ◽  
Johny Alberto Hinostroza ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Multivariable Analysis ◽  
The Other ◽  
Univariable Analysis ◽  
Stem Cell Source ◽  
Significant Difference ◽  
Cell Source

Abstract Abstract 4498 Background: Giving the fact that allo- SCT currently offers patients with high risk AML the best chance of cure, we`ve aimed to investigate the outcome of AML patients who have undergone allo-SCT in our center, considered as one of spanish reference hospital in SCT, and the parameters that have been able to influence in relapse rate (RR), overall survival (OS) and relapse free survival (RFS). Methods: Retrospective study in 192 AML patients who have undergone allo-SCT between 1982 and 2010. The analysis has been performed in 171 patients (85 male and 86 female) by excluding 21 acute promyelocitic leukemias (APL): 65 patients until 1999 and 106 since 2000. Median age was 37 1874 and median lecocyte count, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(13400/\hbox{ L }\frac{470}{250000}\) \end{document}. 82 were de novo AML and 87 were in morfologic complete remission (70 in first CR). 14 patients had received a previous SCT. Cytogenetic risk was as follows: 55 intermediate, 34 high and 11 low. Conditioning regimen was ablative in 162 patients: CyTBI (36), BuCy (31), BuFlu (30) and others (3). 130 patients (76) underwent a related allo-SCT (95 of them were matched) and 41 patients (24), an unrelated allo-SCT (64 of them were matched). Stem cell source was bone marrow (BM) in 146 patients (85) and only 3 patients received umbilical cord (UC). Graft versus host disease (GvHD) prophilaxis was based on Ciclosporine in 150 patients (88). Median time from last treatment was 73 days 12268. Results: The median follow-up of this study was 61 months 1317. OS at 1, 3 and 5 years were 57, 44 and 40. RFS at 1, 3 and 5 years were 62, 50 and 45. Early mortality (before day 100) was 26 (43 until 1999 and 15 since 2000, p0,0001): 18 patients because of infections, 10 because of toxicity, 9 because of disease and 7 because of EICH. Late mortality was 27 (more than the half because of relapse, with no significant difference between 19881999 and 20002010). Cumulative relapse incidence at 5 years was 35, with a median time of relapse of 4 months. Secondary malignancies incidence was 5. Multivariable analysis showed that Transplantation Related Mortality (TRM) was influenced by: year of allo-SCT (OS at 5 years of 49 if 20002010 vs 28 if 19821999, p0,0001), late engraftment (p0,002) and severe acute GvHD (OS at 5 years of 45 if no evidence/grade I-II vs 25 if grade III-IV, p0,071). The other important parameters which lost its univariable analysis significance were donor type, recipient age and conditioning regimen. No difference was found in case of HLA and ABO discordance or donor/recipient CMV status. Multivariable analysis also showed that RR and RFS at 5 years was influenced by: disease status at allo-SCT (50 if 1CR vs 0 if 2CR/PR/refractory disease, p0,002), chronic GvHD (67 if present vs 41 if absent, p0,035) and leucocyte count at diagnosis (54 if 20000/ L vs 37 if 20000/ L, p0,038). The other important parameters which lost its univariable analysis significance were cytogenetic risk, initial induction response and positive minimal residual disease (MRD) before allo-SCT. No diference was found in case of ethiologic classification or stem cell source. Conclusions: Allo-SCT is a curative procedure in AML patients (global RFS of 50 at 3 years), specially when disease is under control and patient develops chronic GvHD. In the last decade, there have been important improvements in the procedure which have led to a significant decrease in TRM, and consequently, a significant increase in OS. Disclosures: No relevant conflicts of interest to declare.

Pre-/Post-HSCT Imatinib Improves Survival of Childhood with BCR/ABL+ Acute and Chronic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5248-5248
Author(s):  
Fuyu Pei ◽  
Qi Li ◽  
Wenfeng Xu ◽  
Zhiyong Peng ◽  
Xuedong Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Stem Cell Source ◽  
Significant Difference ◽  
Cell Source

Abstract Objective:To evaluate the effect of hematopoietic stem cell transplantation (HSCT) for children with leukemia in our center in recent years. Methods: We retrospectively analyzed data of 87 patients with leukemia underwent HSCT at a median age of 8 years from February 2006 to December 2013 in our center. The median follow-up time was 28 months (range, 2-96), the ratio of male to female patients was 59:28. Conditioning regimen included cyclophosphamide, fludarabine, busulfan with or without (w/o) thiotepa. Anti-thymocyte globulin and cytarabine were individually used for the patients with lymphoid leukemia and myeloid leukemia. GVHD prophylaxis included tacrolimus, mycophenolate mofetil w/o post-transplant cyclophosphamide. Median nucleated cells: 3.75 (1.16`7.56) × 107/Kg. Patients with BCR/ABL+ acute lymphoblastic leukemia (ALL) received imatinib before and after transplant over 6 months per each one. Twenty-six patients received transplant from sibling donors, 31 from haploidentical donor, 30 from unrelated donors; Status before transplant were grouped as CR1 (n= 57), CR 2 (n=13), CR 3 (n=1) and NR (n=16). Source of stem cells included PBSC in 40 cases, UCB in 3 cases, BM in 24 cases, BM+PBSC in 9 cases, and mixed stem cells (BM /PBSC+ UCB) in 11 cases. Results: The estimated 5-year overall survival (OS) was 56.8 ± 5.8% in total.Among them, OS was 54.3 ± 8.0% in 45 patients with ALL; 85.7 ± 13.2% in 8 patients with BCR/ABL+ALL; 48.6 ± 8.7% in 37 patients with BCR/ABL-ALL. 32.8 ± 15% in 29 patients with acute myeloid leukemia and 82.5 ± 11.3% in 13 patients with chronic myelogenous leukemia, respectively. Single factor analysis showed there was no significant difference for OS in comparison of BCR/ABL+ALL, BCR/ABL-ALL, AML and CML (P=0.057), but patients with BCR/ABL+ALL had higher OS compared to those with BCR/ABL-ALL (P=0.048) and to AML (P=0.040). In comparison of difference status before transplant, OS were 55.2 ± 11.6%, 54.9 ± 15.6%, 0,and 27.5 ± 11.6% in CR1, CR2, CR3 and NR, respectively (P=0.025). OS was higher in CR1 than NR (P=0.005). When comparing stem cell source, OS was 65.5 ± 8.5%, 0%, 41.7 ± 11.4%, 33.3 ± 15.7%, and 72 ± 17.8% in PBSC, unrelated CB (UCB), BM, BM+PBSC, and BM/PBSC+UCB transplants, respectively (P=0.003); PBSC transplant associated with higher OS than BM (P=0.049) and BM+PBSC (P=0.009); and BM/PBSC+UCB mixed transplant had highest OS (P=0.026). Multivariate analysis showed Risk factors for OS only remained stem cell source (P=0.046) and status before transplantation (P=0.048). the transplant types (P=0.023), and follow up time(P=0.017). Conclusion: Comparing with data reported in literature we have similar outcomesin total for childhood with leukemia. Use of imatinib pre-/post-transplant for patients with BCR/ABL+ALL conduces to the highest OS in current study. Stem cell sources and the status before transplant have a significant effect on OS. Disclosures No relevant conflicts of interest to declare.

The Best of Both? Megadose Stem Cells with CD34 Selection and T-Cell Addback Enables Engraftment from Mismatched Unrelated Donors Using Reduced Toxicity Conditioning in Primary Immunodeficiency

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4303-4303
Author(s):  
Juliana Montibeller Silva ◽  
Kanchan Rao ◽  
Robert Chiesa ◽  
Stuart Adams ◽  
Margaret Brocklesby ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
T Cell ◽  
Primary Immunodeficiency ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Stem Cell Source ◽  
Reduced Toxicity

Abstract Background: The optimal approach for transplanting patients with primary immunodeficiency from a mismatched unrelated donor (MMUD) remains unclear. With reduced intensity conditioning, when bone marrow (BM) was used as the stem cell source in such patients we have previously observed a high rate of very low level donor chimerism (4 of 12 patients) requiring a second transplant procedure. The use of peripheral blood stem cells (PBSC) can overcome this but results in a high incidence of acute (≥ Gde II 10/21, Gde III-IV 5/21) and chronic (10/21, extensive 7/21) graft-versus-host disease (GVHD) (Rao et al in press). We hypothesized that the use of megadose CD34 selected stem cells from PB with addback of a T-cell dose akin to BM might facilitate engraftment through improved competition for the stem cell niche without severe GVHD. Methods: We prospectively analysed outcomes on 20 consecutive patients with primary immunodeficiency (SCID n=5, HLH n=3, Other PID n=12) transplanted from 8/10 (n=4) or 9/10 (n=16) HLA MMUD at our institution between 2011-2015. The mean age at transplant was 5.1 years. All patients received reduced toxicity conditioning regimens (12/20 Fludarabine/Melphalan/Alemtuzumab; 8/20 Fludarabine/Treosulphan/Alemtuzumab) with Cyclosporin (CsA) and mycophenolate mofetil (MMF) GvHD prophylaxis. CD34 selection of donor PBSC was performed using CliniMACs and the mean CD34+ dose was 20.1x106/kg. At day 0 either 108 CD3/kg (cohort 1, n=6) or 3x108 CD3/kg (cohort 2, n=14) T-cells from the CD34- fraction were infused with the graft. Mean follow up was 31.9 months. Results: In cohort 1, all patients engrafted and 2 developed high level donor mixed chimerism (both curative) in the myeloid and lymphoid lineages at last follow up. Two patients had Grade II acute GvHD and 1 had moderate chronic GvHD. In view of the slow immune reconstitution in this cohort, the T-cell addback dose was increased to 3x108/Kg in subsequent patients. In cohort 2, all patients achieved full donor haemopoiesis initially, 6/14 developed high levels of donor chimerism in both myeloid and lymphoid lineages later and 1/14 progressed with 10% donor T-cell engraftment but remains disease-free. The incidence of significant aGVHD was low (grade II n=4, no grade III or IV) and no patient developed cGvHD. Overall across both cohorts, 10 patients had viral reactivations and there were 5 deaths (3 viral complications, 1 pulmonary vasculopathy, 1 cGVHD lungs). The disease free survival at 2 years 7 months follow up was 70% which compares favorably with a previous cohort transplanted with unmanipulated BM as the stem cell source (Fig 1). Immune reconstitution was delayed (mean CD3 and CD19 counts at day 100 post-transplant was 245 x 109/L and 315 x 109/L) with similar kinetics in both cohorts (Fig 2), comparable to RIC transplant using unmanipulated BM. By 1 year post transplant 11/14 evaluable patients achieved normal CD3+T-cell numbers and 8/14 normal CD19+ B-cell counts. Conclusion: The use of megadose peripheral blood stem cells with T-cell addback in the mismatched unrelated donor transplant setting results in high rates of curative engraftment and a low incidence of acute and chronic GvHD following reduced toxicity conditioning. However, T-cell reconstitution remains delayed (presumably reflecting the effect of Alemtuzumab on the infused T-cells) with a high incidence of viral complications. Disclosures No relevant conflicts of interest to declare.

Post Transplant Cyclophosphamide (PTCy) with Anti-Thymocyte Globulin (ATG) Effectively Reduces the Severe (Grade III-IV) Acute Graft-Versus-Host Disease (GVHD) When Compared to ATG Alone in Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplants

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3430-3430 ◽  
Author(s):  
Uday Deotare ◽  
David Loach ◽  
Fotios V. Michelis ◽  
Dennis D. Kim ◽  
Santhosh Thyagu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Historical Cohort ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Grade Iii ◽  
Severe Grade

Abstract Introduction: Acute Graft-versus-Host Disease (aGVHD) is a frequent complication of Allogeneic Hematopoietic cell transplants (allo-HCT). It can be lethal with increased morbidity and mortality and can occur in upto 40-50% of allo-HCT. Various agents such as calcineurin inhibitors, anti-metabolites and anti T cell antibodies, have been variably used for GVHD prophylaxis. Use of Post-transplant Cyclophosphamide (PTCy) has recently been used extensively in haplo-identical transplant setting with promising results, but has mainly been used in patients with BM as a stem cell source. In those patients receiving PBSC as a stem cell source, PTCy alone could reduce the risk of acute and chronic GVHD significantly. Anti-Thymocyte Globulin (ATG) has been associated with decrease in chronic but not acute GVHD. As most of our patients use PBSC as a graft source, we hypothesized that combination of ATG and PTCy can reduce the incidence of both acute and chronic GVHD. Since we had also used ATG for GVHD prophylaxis in a historical cohort, we compared the results of this approach with the current GVHD prophylaxis regimen. Methods: A total of 28 patients with hematological malignancies, who had an unrelated donor underwent allo-HCT at our center from 1 Oct 2015 to 31 Mar 2016. After interim analysis, when increased non-hematological toxicity was observed with myeloablative conditioning, all patients subsequently received reduced intensity conditioning. Peripheral blood was used as a stem cell source in all patients. The GVHD prophylaxis consisted of a combination of ATG-PTCy-CsA, with rabbit ATG administered on Days -3 (0.5 mg/Kg), -2 (2 mg/Kg) and -1 (2 mg/Kg), PTCy at dose of 50 mg/kg on Days +3 and +4 and CsA from Day+5 onwards. Filgrastim was used from day +7 onwards for 13 patients. Emphasis was given to incidence of acute GVHD, especially Steroid Refractory (SR-GVHD). Results: Out of total of 28 patients, aGVHD was seen in 6 (21.4%) patients, five of which had skin involvement (Grade I- II) and one suspected liver involvement (Grade III), all of which responded rapidly to steroids with no cases of SR-GVHD. Secondary graft failure and EBV reactivations; each were seen in 10% of cases. Primary disease relapse was seen in 3 patients, two of which had minimal residual disease prior to transplantation. These results were then compared to the historical cohort of 27 patients who received a combination of ATG-CsA plus Mycophenolate Mofetil (MMf) (Table 1). The incidence of acute GVHD was 26% vs 22% (p=0.99), with severe Grade III-IV aGVHD of 4% vs 20% (p=0.085) in the ATG-PTCy-CsA and ATG-CsA-MMf cohorts, respectively; both were statistically not signifcant. There were five patients with SR-GVHD in the ATG-CsA-MMf cohort and none in the current GVHD prophylaxis arm. In the historical cohort, the main cause of death in 7 out of 11 patients was severe GVHD as compared to 1 out of 9 in the ATG-PTCy-CsA cohort. Conclusions: Combination of ATG-PTCy-CsA is an effective strategy to reduce aGVHD; especially severe Grade III-IV and doesnot increase the risk of SR-GVHD, in unrelated donor transplants as compared to ATG-CsA-MMf. However, a long term follow up is needed to assess relapse and cGVHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Low Incidence of Chronic Gvhd after Haploidentical T-Cell Replete Peripheral Blood Stem Cell Transplantation with Post Transplantation Cyclophosphamide (PT-Cy)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4594-4594
Author(s):  
Angela Granata ◽  
Sabine Furst ◽  
Jean marie Boher ◽  
Luca Castagna ◽  
Patrice Chevallier ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Neutrophil Recovery ◽  
Stem Cell Source ◽  
Cell Source ◽  
Low Incidence

Abstract Background: Since the first publication at the John Hopkins Hospital, (Luznik et al. BBMT 2008), Haploidentical T-cell replete Stem Cell Transplantation (HaploSCT) with post transplantation cyclophosphamide (PT-Cy) has become a reproducible and feasibility therapeutic option for many patients (pts) with hematologic malignancies , notably because of the low incidence of GVHD and infections, without increased graft failure. Initially, bone marrow (BM) was considered as the favorite source of hematopoietic stem cells in order to minimize the risk of GVHD. In a retrospective study, we previously showed no difference in terms of increased events (GVHD, NRM), regardless of the hematopoietic stem cell source (PBSC or BM) (Castagna et al. BMT 2014). Some recent publication seems to confirm this observation (Sugita J. BBMT 2015 , Solomon R. Adv in Hem. 2016), although no randomized study so far has been conducted. Here, we retrospectively analyze the incidence and the characteristics of GVHD in the setting of HaploSCT using PT-Cy, after infusion of PBSC. Methods: Inclusion criteria were: adult pts with hematologic malignancies receiving a PBSC HaploSCT from 2012 to 2015 in 4 centers (3 in France and 1 in Italy) with PT-Cy as part of the GVHD prophylaxis. PBSC infusion at day 0 was followed by PT-Cy 50 mg/kg on days +3 and +4 in association with calcineurin inhibitors (cyclosporine A or Tacrolimus) and mycophenolate mofetil (MMF), started at day +5. All patients received G-CSF support from day+5 until neutrophil recovery. Study end points were the cumulative incidences of acute (a) and chronic (c) GVHD, with a specific organ grading evaluation, non-relapse mortality (NRM), relapse (CIR) as well as progression free (PFS) and overall survival (OS). Additionally, we analyzed the composite endpoint "GVHD and relapse free survival" (GFRS) for which the occurrence of relapse, death or severe chronic GVHD was considered as relevant events. Correlation between CD 34+ and CD 3+ and the incidence of aGVHD and cGVHD was studied by a linear continuous variable. Results: Between March 2012 and December 2015, 192 pts with a median age of 57 years (range: 16-73) received T-cell replete PBSC HaploSCT for hematologic malignancies (myeloid: n= 55%; lymphoid: n=45%) in 4 centers. Patient's characteristics are shown in table 1. Pts received non myeloablative (according to Baltimore regimen) or busulfan-based reduced intensity conditioning, in 56% and 44% of cases, respectively. All, but 3 pts, engrafted, with a median time of 19 days (range, 14-47) to neutrophil recovery (ANC >500 x106/L) and 22 days (range, 14-252) to platelet recovery (PLT > 20 G x 109/L). The median CD34+ x 106/Kg and CD3+ x 106/Kg cells infused were 5.5 (range, 1.5-14.8) and 404 (range, 38-704), respectively. No relevant correlation was observed between the CD34+ and CD3+ infused cells and the incidence of GVHD, studied by linear continues variable. We noted only a trend to develop severe cGVHD with an increasing number of CD3+ cells infused. This result has to be considered with caution, because of the small events (6 pts affected by severe cGVHD). Complete donor T cell chimerisme was evaluable in 162 pts (83%) and achieved by day +30. The incidence of aGVHD was 38% at 100 days (all grades), whereas grade II-IV and III-IV were 24% and 10%, respectively. Concerning patients with aGVHD grade 2-4, the most affected organ was skin (19%), followed by gut (9%) and liver (2%). The incidence of 3-year cGVHD according to NIH classification was 15% (all grades). Three percent of pts developed severe cGVHD (lung n=1; liver, n=1). The most frequent involved organs were skin and mucosae (70%). No patient showed gut cGVHD. Finally, in univariate analysis, busulfan-based conditioning seems to negatively impact on severe cGVHD (p = 0.03; HR=3.37 [1.09 -10.46]) After a median follow up of 20 (range, 4 - 52) months, NRM at 100 days and 1 year was 10% and 20%, respectively. Three-year OS, PFS, CIR and GRFS were 63%, 55%, 25% and 49%, respectively. Conclusion: This retrospective study shows a very low incidence of severe cGVHD after HaploSCT even with PBSC as stem cell source, suggesting that the use of PT-Cy may overcome the anticipated increased incidence of cGVHD, contrary to as previously reported in the HLA identical setting (Mohty et al. Leukemia 2003). Similar to HLA identical sibling and unrelated donor transplantation, the most frequent organs involved are skin and mucosae Disclosures No relevant conflicts of interest to declare.

Novel Conditioning Regimen for Haploidentical Hematopoietic Cell Transplant for Severe Aplastic Anemia in Children

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5651-5651 ◽  
Author(s):  
Hasan Hashem ◽  
Rawad Rihani ◽  
Eman Khattab ◽  
Mayada Abu Shanap ◽  
Abdelghani Tbakhi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Stem Cell Source ◽  
Cell Source

New hematopoietic cell transplant (HCT) approaches are urgently needed for patients with severe aplastic anemia (SAA) who lack an HLA-identical donor. Haploidentical HCT with post transplant cyclophosphamide (PTCy) represent a potential universal available option for almost all children with SAA. We present a novel conditioning regimen for haploidentical HCT in children with SAA in a center where horse ATG is not available. Conditioning regimen consists of rabbit ATG 2.5 mg/kg/day from day -9 to -7, Fludarabine 30 mg/kg/day from day -6 to -2, Cyclophosphamide 14.5 mg/kg/day from day -6 to -5, Thiotepa 5 mg/kg/day from day -4 to -3, and 4 Gy TBI on day -1 in in two fractions. GvHD prophylaxis consist of PTCy 50 mg/kg/day on days +3 and +4 along with Cyclosporine A and Mycophenolate mofetil (MMF) starting on day +5. Four consecutive children with SAA referred to our center for haploidentical HCT starting in 2018. Median age at HCT was 9 years (5-16) with 3 males and 1 female. All patients were heavily transfused with both blood and platelets prior to referral for HCT. Two patients had strong and one had weak positive anti-HLA antibodies (DSAs) and received desensitization with IVIG, Rituximab and plasmapheresis. One patient received buffy coat infusion on day -1 due to persistent strong DSAs despite desensitization. Median CD34+ dose received was 12 x 10e6, and median CD3+ dose was 29 x 10e6. Donors were all same blood group to patients. All patients successfully engrafted neutrophils at median of 13 days (12-14). Platelets engraftment in 3/4 patients at median of 7 days (5-10). All patients received peripheral blood as stem cell source. Three of four patients survived and doing well at last follow up. One patient had toxic death on day +38 due to chemotherapy related toxicity causing multi-organ failure. Chimerism analysis was full donor in all four patients at median follow up time of 11 months (2-12). Patients were sent home at median of 24 days post HCT. None developed grade 2-4 acute GvHD nor chronic GvHD. Acute GvHD of skin grade 1 stage 1 developed in 2 patient and managed with topical steroids. Viral reactivations consisted of CMV viremia and BK hemorrhagic cystitis in all patients, and have all resolved. No post transplant autoimmune complications. Haploidentical HCT with PTCy represents a quick and first line approach in heavily transfused children with SAA. Although yet limited number of patients, this regimen is feasible and appears to be safe. A great advantage of this regimen is the rapid engraftment of both neutrophils and platelets. Moreover, although using peripheral blood as a stem cell source, there was no severe acute or chronic GvHD. Disclosures No relevant conflicts of interest to declare.

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