Outcome of Patients Developing GVHD after DLI for CML Relapse from HLA-Identical Sibling or VUD HSCT.

Abstract Using data submitted to the EBMT registry, we analyzed outcome on 344 patients (pts) who had received donor lymphocyte infusions (DLI) for relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) in 31 centers. 113/344 pts (33%) developed acute graft-versus-host disease (aGVHD) a median of 50 days post DLI (max grade: I=42, II=30, III=31, IV=6)(60% grade II–IV). Organs involved (%): skin (88), liver (42), gut (30). Median age was 38 (4–59), 58% pts were male, 62 transplants were HLA-identical sibling and 51 unrelated. 74 were T-cell depleted, 92 transplanted in CP1, 21 beyond CP1. Relapse was molecular in 19 pts, cytogenetic in 31, hematological in 49, accelerated or blastic in 12. Median initial cell dose was 107CD3+ cells/kg (0.01–32), median number of DLI was 1 (1–10). aGvHD was treated with prednisone in 92% of pts, CSA in 52 %, ATG and monoclonal antibodies in 2% and other in 19%. aGVHD resolved in 53% of the pts within a median of 63 d (7–546). 82/344 pts (24%) had chronic GVHD (cGVHD)(30 limited, 50 extensive, 2 not specified), of those 46 (56%) following aGVHD post DLI. Organs involved (%): skin (75), liver (35), lungs (13), mouth (43), eyes (22) and gut (5). Median age was 35 (6–58), 51% were male, stem cell source was PB in 15% and marrow in 85%, 43 underwent HLA-identical sibling HSCT and 39 unrelated donor HSCT. Forty-three were T-cell depleted, 66 transplanted in CP1, 16 beyond CP1. Relapse was molecular in 21 pts, cytogenetic in 29, hematological in 22, accelerated or blastic in 7. Median initial cell dose was 107 CD3+ cells/kg (0.05–40), median number of DLI was 1 (1–7). 61 pts are alive with a median follow-up of 50 mth. Treatment was with steroids in 83% of pts, CSA in 58 %, MMF in 20%, thalidomide in 15%, photopheresis in 15%, PUVA in 10% and other in 17%. cGVHD resolved in 39% of the pts within a median of 354 d (44–1588). The estimated 5-y OS post-DLI was significantly lower in pts who developed aGVHD post-DLI, 61 ± 10% vs 74 ± 7% in the one that did not, p=0.007 and also a tendency to have a lower 5-y EFS, 58 ± 10% vs 65 ± 7%, p=0.19. Median duration of response to DLI in aGVHD pts was 4 y. aGVHD post-DLI did not influence the relapse rate (5 ± 5% vs 6 ± 5% in the absence of aGVHD). 5-y DLI related mortality was significantly higher in aGVHD pts, 31 ± 8% vs 4 ± 4%, p<0.00001. On the other hand, pts that developed cGVHD post-DLI had a tendency to have a better 5-y OS and EFS, 74 ± 11% and 71 ± 11% respectively vs 69 ± 6% and 62 ± 7% in those that did not, p=0.32 and 0.09. This was related to a tendency to lower incidence of relapse, 2 ± 3% in pts with cGVHD vs 9 ± 6% without, p=0.2. DLI related mortality was not different, 11 ± 8% vs 10 ± 5%, p=0.77. aGVHD post-DLI for CML relapse is mainly of advanced stage and negatively influence OS and EFS with a higher DLI related mortality. cGVHD post-DLI is mainly extensive, but pts with cGHVD tend to have better outcome with better 5-y OS, EFS and less relapse than those without, although this was not statistically significant.

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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 ◽

10.1182/blood.v126.23.4303.4303 ◽

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.

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HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia

Blood Advances ◽

10.1182/bloodadvances.2020003707 ◽

2021 ◽

Vol 5 (5) ◽

pp. 1333-1339

Author(s):

Luisa Strocchio ◽

Daria Pagliara ◽

Mattia Algeri ◽

Giuseppina Li Pira ◽

Francesca Rossi ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Fanconi Anemia ◽

Chronic Gvhd ◽

Prospective Trial ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Platelet Recovery

Abstract We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell–depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.

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

Blood ◽

10.1182/blood.v128.22.4594.4594 ◽

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.

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A Comparison of Stem Cell Source in Recipients of T-Cell Depleted Myeloablative Transplants for Leukaemia: No Difference in Mortality Using BM or PBSC.

Blood ◽

10.1182/blood.v110.11.46.46 ◽

2007 ◽

Vol 110 (11) ◽

pp. 46-46

Author(s):

B.E. Shaw ◽

Nigel H. Russell ◽

A. Pagliuca ◽

J. Apperley ◽

G. Cook ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Stem Cell Source ◽

Increased Risk ◽

Significant Difference ◽

Cell Source ◽

The Impact

Abstract The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in transplant related mortality (TRM) and decrease in survival (OS) in T-cell replete transplants. We sought to analyse the impact of PBSC compared to BM in a cohort of UD transplant recipients, where T-cell depleting agents (in-vivo campath in >90%) were included in the transplant conditioning. The study included 145 patients transplanted between January 2000 and March 2006: CML- 35 in 1CP; acute leukaemia (AML in 61, ALL in 49)-110 in CR1 or 2. All had myeloablative conditioning regimens and received grafts with 9–10/10 matched HLA alleles. 86 patients received BM and 59 PBSC. There were no associations between the stem cell source and any transplant variable (including disease and stage). There was a trend to an increased use of PBSC in patients with a single antigen mismatch (p=0.052). All evaluable patients achieved neutrophil engraftment, with a significantly faster time to engraft in recipients of PBSC compared to BM (16 vs 20 days; p=0.0003). The incidence of acute GvHD was 46% (grade I in 50%, II in 41%, III in 8%, IV in 2%). This was significantly higher in recipients of PBSC (60%) compared to BM (36%; p=0.006), however there was no increase in either II/IV (p=0.69) or III/IV (p=0.18) disease in PBSC recipients. In univariate analysis, the presence of a single HLA mismatch (p=0.026) was the only other variable to be associated with an increase in acute GvHD. In a logistic regression model including both these variables, the use of PBSC remained significantly associated with an increase in aGvHD (OR=2.3; 95% CI 1.1,4.7;p=0.020). The TRM was 14%, 27% and 39% at 100 days, 1 and 5 years respectively. At none of these time points was the stem cell source associated with a significant difference in TRM. The 5-year incidence of chronic GvHD was 58% (BM 55%, PBSC 60%; NS), extensive disease in one third, and of relapse was 61% (BM 60%, PBSC 62%; NS). The 5-years OS was 41% with a median follow-up of 3.4 years (0.5–7.1). This was 44% using PBSC and 40% using BM (NS). In conclusion, although we observed an increase in acute GVHD with PBSC this was only of grade 1 disease. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM, in recipients of T-cell depleted myeloablative transplants for leukaemia.

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Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Patients Aged 65 Years or Older with AML and MDS.

Blood ◽

10.1182/blood.v104.11.2301.2301 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2301-2301 ◽

Cited By ~ 2

Author(s):

Marcos de Lima ◽

Munir Shahjahan ◽

Jorge Alamo ◽

Patricia Williams ◽

Brigitte von Wolff ◽

...

Keyword(s):

Stem Cell ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Free Survival ◽

Allogeneic Hsct ◽

Stem Cell Source ◽

One Year ◽

Active Disease

Abstract Allogeneic HSCT is a potentially curative treatment for AML/MDS, but aging is generally associated with poorer outcomes. The incidence of AML/MDS, however, increases after the 7th decade of life, and there is limited data with transplantation in this age group. Here we review our experience treating such patients. Methods: Retrospective analysis of outcomes of patients aged 65 or older treated from 1996 to 2004 with allogeneic HSCT (n=40; median age 67 years, range 65–75 years). Diagnosis was MDS in 5 cases and AML in 35 patients. Cytogenetics were high-risk in 50% and intermediate risk in 50%; 80% of the patients had active disease at HSCT (n=32). All preparative regimens contained fludarabine 100–150 mg/m2, combined with cytarabine 4 gm/m2, and idarubicin 36 mg/m2 (n=12); or with busulfan (n=8); with melphalan 140 or 180 mg/m2 (n=12); and with melphalan 140 mg/m2 and Mylotarg 2 or 4 mg/m2 (n=8). ATG was added in unrelated donor (MUD) HSCT. All but 2 patients received tacrolimus and methotrexate for graft-versus host disease (GVHD) prophylaxis. Stem cell source was bone marrow in 11 cases and peripheral blood in the others. Donors were related in 27 cases and unrelated in 13 cases (33%). Results: 35 patients engrafted (88%); complete remission (CR) rate was 72%, 6 patients died early and 3 did not respond. Eleven patients are alive at a median of 12.5 mo (range, 2.6–59 mo), 10 of them in CR. One-year overall survival was 30% for the whole group, 26% for recipients of MUD and 32% for recipients of related donor HSCT (MUD x sibling, P=NS). One-year event-free survival was 28%. Median survival and disease-free survival was 4.5 and 2.5 mo, respectively; 42% of the patients in CR post HSCT have relapsed (n=13). Acute and chronic GVHD rates were 45% and 48%, respectively. Non-relapse mortality (NRM) was 40%. Figure shows survival of patients with and without circulating blasts at the time of transplant. Figure shows survival of patients with and without circulating blasts at the time of transplant. Conclusions: Here we expanded our previous observations indicating that allogeneic HSCT is a treatment option for selected patients in this age range. In this cohort with advanced stage disease (80% with active disease at transplant), NRM was high, but survival after sibling and unrelated donor transplants was similar.

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Outcome of Hematopoietic Stem Cell Transplantation for Pediatric Acute Lymphoblastic Leukemia in Third Complete Remission (CR3): A Vital Role for Graft-Versus-Host-Disease/Graft-Versus-Leukemia Effect in Survival.

Blood ◽

10.1182/blood.v108.11.3667.3667 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3667-3667

Author(s):

Adam Gassas ◽

Kashif Ishaqi ◽

John Doyle

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Complete Remission ◽

Lymphoblastic Leukemia ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

Related Mortality

Abstract Children with acute lymphoblastic leukemia (ALL) who suffer 2 relapses could be salvaged by hematopoietic stem cell transplantation (HSCT) when a suitable stem cell source is available provided they respond to the pre HSCT chemotherapy and at least enter morphological remission. However, these patients are at very high risk for post HSCT relapse and also at a high risk for transplant related mortality (TRM). Our objective, herein, was to review the outcome of children (0–18years) with ALL who received allogeneic HSCT in third complete remission (CR3) at our institution. Between January 1994 – August 2005, twenty-two consecutive children in CR3 received HSCT in the Hospital for Sick Children, Toronto, Canada. Conditioning regimens included single dose of VP16 (60mg/kg infused over 4 hours) and fractionated total body irradiation (TBI; 1200cGy) in six fractions over 3 days (VP16/TBI) in 10 patients (1994–1998) and cyclophosphamide 50mg/kg infused over 1 hour daily for 4 days followed by the same dose of fractionated TBI (CY/TBI) in 12 patients (1999–2005). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A and a short course of methotrexate for the majority of patients, and all patients were in complete morphological remission prior to HSCT. Median age was 8.4 years (range 3–15.4). Donor source was as follows: matched sibling donor (MSD), 8; matched unrelated donor (MUD) 6; one antigen mismatch related donor (MMRD) 4; one antigen mismatched unrelated donor (MMUD) 3; and one patient received 1 antigen mismatched cord progenitor stem cells. White cell engraftment was successful in all patients at a median of 18 days (range 9–29). Ten patients died of TRM, seven relapsed, one died from other causes and four patients are long term survivors at a median follow up of 3.7 years (range 1–10.2). All patients who did not develop clinical acute or chronic GVHD relapsed and died. Event free survival was (EFS 19% ± 4%). Three out of the 4 survivors received MMUD and all 4 survivors had moderate to severe acute GVHD and three had chronic GVHD, limited in two and extensive in one. Conclusion: Children with ALL in CR3 receiving HSCT are extremely high risk for relapse and transplant related mortality. These children have already relapsed twice and demonstrated chemotherapy resistance and GVL/GVHD plays a key role in leukemia eradication. Although, TRM is high in such patients and GVHD could potentially increase TRM, there are no survivors without GVHD and exploring means of inducing GVHD by reduction of immunosuppressive medications or other means of immunotherapy should seriously be considered in these patients.

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A Comparison of Stem Cell Source in Adult and Paediatric Recipients of T-Cell Depleted Myeloablative Transplants for Standard Risk Leukaemia: No Difference in Mortality Using BM or PBSC.

Blood ◽

10.1182/blood.v114.22.1205.1205 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1205-1205

Author(s):

Bronwen E Shaw ◽

Jane Apperley ◽

Nigel H. Russell ◽

Charles F. Craddock ◽

Effie Liakopoulou ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Stem Cell Source ◽

Significant Difference ◽

Cell Source ◽

Standard Risk

Abstract Abstract 1205 Poster Board I-227 The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in non relapse mortality (NRM) and decrease in survival (OS) in T-cell replete transplants. We have previously reported outcome data in 145 patients who received an unrelated donor transplant for leukaemia. In that study we reported an increase in mild acute GvHD using PBSC, but no other significant differences in outcome. We have now doubled the cohort and report our findings on 320 patients here. In this group all of the patients received pre-transplant serotherapy (Alemtuzumab = 306, ATG = 14) as part of myeloablative conditioning prior to an HLA-matched UD allograft. Patients were transplanted between January 2000 and August 2007: CML in 1CP (n=102) and acute leukaemia in CR1/2 (AML in 105, ALL in 144). 190 patients received BM and 130 PBSC. The median age of the recipients was 28.9 years (10months - 58years). There was no significant difference in age between those receiving BM or PBSC.98% and 96% of patients receiving PBSC and BM achieved neutrophil engraftment (NS), with a significantly faster time to engraftment in recipients of PBSC compared to BM (14 vs 20 days; p<0.001). The incidence of acute GvHD was significantly higher in recipients of PBSC (64%) compared to BM (51%; p=0.022), however there was no increase in grade III/IV (p=0.420) disease in PBSC recipients. The incidence of chronic GvHD at 6 years was 61% in the BM recipients and 55% in the PBSC recipients (NS), with no difference in the incidence of extensive disease. The 5-years OS was 55% in BM recipients, with a median follow-up of 59 months, compared to 54% in PBSC recipients at a median follow-up of 38 months (NS). The incidence of neither disease relapse nor NRM was significantly different between groups (relapse at 5 years: BM 44%, PBSC 36%; p=0.112, and NRM at 5 years: BM 22%, PBSC 24%; p=0.751). In view of the fact that there were more CML patients in the BM group and more AML patients who received PBSC (the distribution of ALL patients was similar) (p=0.051), we performed a subgroup analysis. The pattern of results for each outcome, dependant on the use of BM or PBSC, in patients with CML and those with acute leukaemia were similar to those reported in the group overall. In conclusion, we have confirmed the results of our previous smaller study, showing the only significant difference in clinical outcome between PBSC and BM to be a higher incidence in the occurrence (but not grade) of acute GvHD. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM. We suggest that either stem cell source can be used with a similar outcome in adult and paediatric recipients of T-cell depleted allografts for standard risk leukaemia. Disclosures: Apperley: Novartis: Consultancy, Honoraria.

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Influence of Stem Cell Source On GvH and NRM: Comparison of 10/10 HLA-Matched Unrelated Donor (MUD) with 9/10 HLA-Mismatched Unrelated Donor (MMUD) and Unrelated Cord Blood (UCB) Transplants.

Blood ◽

10.1182/blood.v120.21.3135.3135 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3135-3135

Author(s):

Clémence Granier ◽

Emeline Masson ◽

Lucie Biard ◽

Raphael Porcher ◽

Regis Peffault de la Tour ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hla Typing ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Significant Difference ◽

Cell Source

Abstract Abstract 3135 Background: When an HLA-matched donor is not available for allogeneic Hematopoietic Stem Cell Transplantation (HSCT), the use of an alternative HLA-mismatched stem cell source may be considered. In Europe, HLA compatibility for HSCT is calculated for 10 alleles (HLA-A, -B, -C, -DRB1, -DQB1). The aim of this study was to retrospectively compare outcomes after transplantation from 10/10 HLA-MUD, 9/10 HLA-MMUD and UCB performed at the Hospital Saint Louis (Paris, Fr). Methods: Patients receiving a first allogeneic transplantation from a 10/10, 9/10 UD or UCB from 2000 to 2011 were included. High resolution HLA typing was performed by PCR SSO and SSP for HLA loci: A, B, C, DRB1 and DQB1. The following variables were studied as risk factors for transplant outcomes: disease, disease risk (standard/high risk), age at transplant, gender, donor/recipient sex-matching, ABO matching, donor/recipient CMV status, conditioning regimen, and use of anti-thymoglobulin (ATG). Results: 355 consecutive patients with hematologic malignancies were analyzed. One hundred and ninety-six were transplanted with MUD, 84 with MMUD (mismatches for HLA-A: 16%, -B: 16%, -C: 39%, -DRB1: 8%, -DQB1: 21%) and 75 with UCB (52% with single and 48% with two UCB unit; 87% of all UCB transplants were 4–6/6 HLA-matched). Median patient age was 31 (range: 5–55). Patient characteristics differed between the 3 groups: (i) median age at transplant: 36 in MUD, 31 in MMUD, 22 in UCB (p<0.0001), (ii) high risk disease: 37%, 51%, 68% (p<0.0001), (iii) CMV negative donor/positive recipient: 31%, 36%, 60% (p<0.0001), (iv) use of ATG: 37%, 64%, 55% (p<0.0001). Cumulative incidences of grade II-IV and grade III-IV acute GvHD disease (aGvHD) were 61% (66% for MUD, 60% for MMUD and 48% for UCB) and 17% (17%, 24% and 15%), respectively. Three-year cumulative incidence of chronic GvHD (cGvHD) was 46% (51% for MUD, 49% for MMUD and 29% for UCB). Three-year NRM was 34% (28% for MUD, 31% for MMUD and 51% for UCB). Graft failure occurred in 15% of UCB patient, 8% in MMUD group and 3% in MUD group (significant difference between UCB and MUD: OR=5.44, 95%CI 1.93–15.3, p=0.001). Multivariate analysis is summarized in table 1. It showed that MMUD tented to have a higher incidence of aGvHD III-IV than MUD and UCB. UCB had a lower incidence of cGvHD than MMUD. No significant effect of HSCT source on NRM was demonstrated. Conclusion: Compared to MMUD, UCB-HSCT induces less cGvHD and non significantly increased NRM. Compared to MUD, MMUD and UCB-HSCT did not result in a clear increase of NRM. UCB and 9/10 HLA-MMUD are both suitable stem cell sources for patients who cannot benefit from 10/10 HLA-MUD transplant. Disclosures: No relevant conflicts of interest to declare.

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HLA-DRB4 Mismatch Is Associated with Worse Outcomes in Unrelated Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

Blood ◽

10.1182/blood.v120.21.4540.4540 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4540-4540 ◽

Cited By ~ 1

Author(s):

Marie Y. Detrait ◽

Ibrahim Yakoub-Agha ◽

Valerie Dubois ◽

Françoise Dufossé ◽

Myriam Labalette ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Stem Cell Source ◽

Cell Source

Abstract Abstract 4540 Introduction The impact of HLA DRB3 and DRB4 allele mismatch after allogeneic HSCT using unrelated donors is unclear. We therefore examined retrospectively the outcome of 35 patients who received HLA-10/10 unrelated hematopoietic stem cell transplantation with a DRB3 or DRB4 mismatch between 2005 and 2011. This cohort of 35 patients was a part of a cohort of 132 consecutive patients who underwent allogeneic HSCT between 2005–2011 with a 10/10-HLA matched donor. There were 18 males (51.4%) and 17 females (48.6%) with a median age of 48 years (range, 6–64), there were 13 (37%) AML, 9 (26%) ALL, 4 (11.5%) MDS, 3 (8.5%) multiple myeloma and 6 (5.7%) other (CML, CLL, NHL). Twenty patients (57%) received a myeloablative conditioning (MAC) and 15 (43%) received a reduced intensity conditioning (RIC). At transplantation, 21 patients (60%) were in complete remission (CR), 4 patients (11.5%) in partial remission (PR) and 10 (28.5%) in relapse; 13 (37%) patients received peripheral blood stem cell (PBSC) and 22 (63%) received bone marrow (BM). Twelve (34%) patients had a mismatched DRB4 donor and 23 (66%) patients had a mismatched DRB3 donor. In the remains of 97 patients, there were 55 male (57%) and 42 female (43%), 28 (29%) patients received a MAC and 69 (71%) a RIC as regimen before allogeneic HSCT. The stem cell source was BM for 32 (34%) patients and PBSC for 65 (66%). At transplantation, 34 (35%) patients are in CR and 63 (65%) were in PR. The distribution of diagnosis was acute leukaemia and MDS for 44 (45%), CLL for 2 (2.5%) and other diagnosis (aplastic anemia, NHL, CML, MPS) for 51 patients (52.5%). Results After HSCT, 124 (94%) patients engrafted. After a median follow-up of 11.5 months (range, 0–76), the cumulative incidence of acute GvHD≥2 at 3 months was 20% (95%CI,16.5–24) and the cumulative incidence of chronic GvHD at one year was 19 % (95%CI, 15–22). In univariate analysis, the mismatch DRB3 or DRB4 had no effect on engraftment and no effect on acute GvHD (p=0.08) or chronic GvHD (p=0.63). There was no impact of DRB3 or DRB4 mismatch on relapse (p=0.33 and p=0.53, respectively) and on PFS (p=0.63 and p=0.07, respectively). We found an impact of the DRB4 mismatching (p=0.016) on overall survival. The median survival for patient without DRB3 or DRB4 mismatch was 23 months (14-NR), for patients with DRB3 mismatch 32 months (12-NR), and for DRB4 mismatched patients 5 months (3-NR). The probability of survival at 24 months, for patients without mismatch DRB3 or DRB4 is 47% (36–61), for patients with DRB3 mismatch 51% (32–82) and for DRB4 mismatched patients 19% (6–66%). (figure1). The multivariate analysis that studied age, type of disease, DRB3 or DRB4 mismatch, sexmatching, TBI, ATG, disease status at transplantation and type of conditioning and stem cell source showed a significant impact of mismatch DRB4 on survival (HR= 2.5 [95%CI, 1.2–5.5] p=0.019); there was no impact for DRB3 mismatch (HR= 1.3 (95%CI,0.5–3.9 p=0.58). We found also an impact of the DRB4 mismatch on TRM (HR= 3.5; [95%CI, 1.6 –8] p= 0.026). The incidence of TRM at 24 months for patients without DRB3 or DRB4 mismatch is 29% (24–34), for patients with DRB3 mismatch 17% (9–26%) and for DRB4 mismatched patients 50% (34–66%). (figure 2). Conclusion The HLA DRB4 matching donor is relevant for survival of patients who undergo allo-HSCT from unrelated donor in the HLA-10/10 matching settings. In view of the important impact of these loci mismatches on clinical outcome, it seems to be important to consider this matching loci in the unrelated donor selection. Disclosures: No relevant conflicts of interest to declare.

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Is Initial CD3+ T Cell Dose in Donor Lymphocyte Infusion for Relapsed Hematological Malignancies a Prognostic Determinant?

Blood ◽

10.1182/blood.v126.23.5483.5483 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5483-5483

Author(s):

Erden Atilla ◽

Pinar Ataca ◽

Selami Kocak Toprak ◽

Meltem Kurt Yuksel ◽

Pervin Topcuoglu ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

T Cell ◽

Hematological Malignancies ◽

Donor Lymphocyte Infusion ◽

Time Interval ◽

Hematopoietic Stem ◽

Cell Dose ◽

Stem Cell Source ◽

Cell Source

Abstract Introduction: Patients after relapsing allogeneic hematopoietic stem cell transplantation (AHSCT) have a treatment option of donor lymphocyte infusion (DLI). DLI is a form of adoptive immunotherapy which induces graft versus leukemia effect. Severe forms of graft versus host disease (GVHD) and marrow aplasia are known complications. In this study, we aimed to detect the effect of the infused CD3+ T cell dose on response, GVHD and overall survival (OS) of hematological malignancies after AHSCT. Methods: We retrospectively evaluated 78 DLI procedures in 57 patients with different hematological malignancies for relapse after AHSCT from June 2000 through June 2015. Initial DLI CD3+ cell dose/kg recipient body weight was ≤ 1x10^7 (n=20; Group 1), >1.0 to ≤ 5 x10^7 (n=29; Group 2), 5-10 x10^7 (n=29; Group 3). Chi-square test was used in comparison between groups. P<.05 was considered statistically significant. Results: The median age during DLI was 33,8 ± 13,2 (range 16-67 years) in 57 patients (38M/19F). The median time interval from HCT to DLI was 8.08 (2-69) months. Ten patients (18%) had bone marrow while 47 patients (82%) had peripheral blood as stem cell source. All patients received transplants from HLA-matched related siblings. There was no difference found between the three groups according to age, diagnosis, stem cell source and conditioning regimen. Achieving complete remission after DLI was detected in thirty two (56%) patients. Disease status after DLI, acute and chronic GVHD rates were not statistically different between the groups. Overall survival which was not statistically significant according to initial DLI cell dose at 2 years were 25%, 38% and 24%, respectively. Conclusion: An initial DLI CD3+ cell dose of 10 x10e7 or higher has been shown improve overall survival but increase GVHD rates with no effect on risk of relapse in previous reports. Response rate, GVHD and survival outcomes were found to be similar in comparison of three different DLI dose groups in our study. Disclosures No relevant conflicts of interest to declare.

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