Bone marrow transplantation for chronic myeloid leukemia with volunteer unrelated donors using ex vivo or in vivo T-cell depletion: major prognostic impact of HLA class I identity between donor and recipient

Between August 1985 and July 1994, we performed 115 volunteer unrelated donor (VUD) bone marrow transplants (BMT) for first chronic phase (n = 86) or advanced phase (n = 29) chronic myeloid leukemia (CML). Standard serologic HLA typing of potential donors and recipients was supplemented with one-dimensional isoelectric focusing (IEF) for class I proteins, allogenotyping for DR and DQ alleles using DNA restriction fragment length polymorphism (RFLP) analysis, and the measurement of antirecipient major histocompatibility complex (MHC) cytotoxic T- lymphocyte precursor cells in the donors' blood (CTLp assay). Recipients were conditioned for transplantation with a combination of high-dose chemotherapy and total body irradiation (n = 103) or high- dose chemotherapy alone (n = 12). Twenty eight recipients received ex vivo T-cell-depleted marrow, and 84 underwent some form of in vivo T- cell depletion. The probability of severe (grades III or IV) acute graft-versus-host disease (aGVHD) was 24%, and that of extensive chronic graft-versus-host disease (cGVHD), 38%. Proportional hazards regression analysis showed an association between low frequency CTLp and a reduced incidence of severe aGVHD (relative risk [RR], 0.28; P = .0035). The probability of relapse at 3 years was 23%, with first chronic phase disease being independently associated with a lower risk of relapse (RR, 0.71; P = .01). The overall leukemia-free survival (LFS) at 3 years was 37%; the LFS for the first chronic phase and advanced phase recipients was 41% and 26%, respectively. First chronic phase disease (RR, 0.56; P = .063) and the combination of recipient cytomegalovirus (CMV) seronegativity and an IEF-matched donor (RR, 0.48; P = .011) were both associated with improved LFS. The probabilities of survival and LFS for patients under 40 years of age transplanted in first chronic phase from an IEF-matched donor were 73% and 50%, respectively. We conclude that VUD BMT is a reasonable option for patients with CML; when using ex vivo or in vivo T-cell depletion, optimal results are achieved in patients transplanted in chronic phase with marrow from donors without demonstrable class I HLA mismatch and a low CTLp frequency.

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Haploidentical transplantation of hematopoietic stem cells

Revista da Associação Médica Brasileira ◽

10.1590/1806-9282.62.suppl1.29 ◽

2016 ◽

Vol 62 (suppl 1) ◽

pp. 29-33 ◽

Cited By ~ 1

Author(s):

Nelson Hamerschlak

Keyword(s):

Stem Cell ◽

T Cell ◽

Hematopoietic Stem Cell ◽

Ex Vivo ◽

Cell Depletion ◽

Post Transplantation ◽

T Cell Depletion ◽

Hematopoietic Stem ◽

Increased Risk

SUMMARY Objective: To review and discuss the literature on hematopoietic stem cell transplantation (HSCT) with haploidentical donors in Brazil. Method: Literature review. Results: The haploidentical hematopoietic stem cell transplantations have become a safe option in hematology since the 80s, with the possibility of ex-vivo T-cell depletion. However, its broad use worldwide occurred with the advent of haploidentical nonmyeloablative transplants using in vivo T-cell depletion with the administration of post-transplant cyclophosphamide. The results were encouraging, despite the increased risk of infection and post-transplantation recurrence. Recent publications on acute myeloid leukemia, myelodysplastic syndrome and Hodgkin’s lymphoma have shown similar results among haploidentical, unrelated and related full-match transplants. Obviously, these findings of retrospective studies should be confirmed by clinical trials. Conclusions: Transplantation with haploidentical donor has shown to be feasible in Brazil and the first publications and results are showing encouraging results.

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Impact of HLA Class I and Class II DNA High-Resolution HLA Typing on Outcome in Adult Unrelated Stem Cell Transplantation after In Vivo T-Cell Depletion with CAMPATH 1H: A Single Centre Experience in 100 Patients.

Blood ◽

10.1182/blood.v106.11.1804.1804 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1804-1804 ◽

Cited By ~ 2

Author(s):

Jolanta B. Perz ◽

Ruhena Sergeant ◽

Richard Szydlo ◽

Nick Davey ◽

Eduardo Olavarria ◽

...

Keyword(s):

T Cell ◽

Risk Group ◽

Class Ii ◽

Hla Typing ◽

Cell Depletion ◽

Class I ◽

T Cell Depletion ◽

Poor Risk ◽

Impact On Survival

Abstract Aim: Outcome of unrelated donor stem cell transplantation (SCT) is influenced by matching for HLA class I and II. We investigated the effects of HLA typing on acute and chronic graft-versus-host disease (aGvHD and cGvHD) and overall survival (OS) in adult patients/donors typed for HLA-A, B, Cw, DRB1, DPB1 at high resolution (HR) and low resolution (LR). Patients: 100 patients (pts.)(median age 32 y, 17 – 54) were treated with allogenic SCT for diseases: 55 Ph-positive chronic myeloid leukaemia in first chronic phase (CML CP1), 21 CML in advanced phase (CML AP) and 24 acute leukaemias (AL). Pre-transplant conditioning consisted in 98 pts of total body irradiation (TBI) and cyclophosphamide (91) or etoposide (7) and in 2 pts of cyclophosphamide and busulphan. In all pts. GvHD prophylaxis was provided by cyclosporin A and short-term methotrexate with in vivo T-cell depletion (TCD) by CAMPATH 1H (Anti CD52). Results: With LR typing 68 pts./donors were fully matched but 32 had class I (31) or class II (1) mismatches (MisM). HR typing revealed 9 pts with additional class I (7) or II (7) MisM, thus 59 pts./donors were fully matched. AGvHD grade III–IV occured in 11 pts (11%) whilst extensive cGvHD was seen in 12 pts (14% out of 83). There was no statistical difference in the occurrence of aGvHD or cGvHD between fully matched and mismatched pts./donors at LR or HR. The probability of transplant-related mortality (TRM) of the whole cohort was 15% at day 100 and 23% at day 180 and engraftment failure 1%. The 3-year survival probabilities were significantly different (p=0.004) for pts. with CML CP1 at 63% (good risk group) when compared with CML AP and AL at 23% (poor risk group). In multivariate analysis patients age, diagnosis group and negative CMV status of patient and donor were the only significant predictors for survival. In the entire group the full compatibility at LR or HR for class I or class II or for a single HLA antigen or the KIR ligand mismatch in the GvHD direction did not have an impact on survival. In contrast to the CML CP1 group (n=55) we found that in the poor risk group (n=45) a MisM at HR had a negative impact on survival (p=0.03) and a trend towards worse survival was found for patients with HLA B HR mismatch. Patients with more than one HR MisM had a worse survival when the combination of HLA B and HLA D MisM was present (p=0.008). Conclusion: In 100 pts. treated with unrelated SCT and in vivo TCD with CAMPATH 1H the HR typing did have an impact on survival only in the poor risk group but not in pts with CML CP1. Thus, T-cell depletion with in vivo CAMPATH 1H permits the use of mismatched unrelated donors in patients with CML CP. The overall rates for aGvHD and cGvHD were low compared to published data in non TCD SCT. Further investigations on larger cohorts are needed to elucidate the impact of HR typing in unrelated SCT and the significance of HR MisM at single HLA loci in transplants T-cell depleted with in vivo CAMPATH 1H.

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Minimal HLA Disparity and KIR Ligand Compatibility in Host Versus Graft Direction May Facilitate Donor Engraftment Following In Vivo and Ex Vivo T Cell Depleted (TCD) Nonmyeloablative Haploidentical Stem Cell Transplantation for Hematologic Malignancies.

Blood ◽

10.1182/blood.v106.11.3668.3668 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3668-3668

Author(s):

Andrew J. Yee ◽

Thomas R. Spitzer ◽

Susan L. Saidman ◽

Juanita Shaffer ◽

Karen A. Power ◽

...

Keyword(s):

T Cell ◽

Ex Vivo ◽

Hematologic Malignancies ◽

Cell Depletion ◽

Lower Percentage ◽

T Cell Depletion ◽

Exact Test ◽

Fisher's Exact Test ◽

Fisher’S Exact Test

Abstract Mixed chimerism (MC) can be induced in mice across MHC barriers using nonmyeloablative conditioning and T cell depletion. Delayed donor lymphocyte infusions (DLI) convert this MC state to full donor hematopoiesis and impart a powerful graft versus tumor effect without inducing GVHD. Based on this principle, we developed a clinical trial with a goal of inducing a GVH-free mixed chimeric platform for delayed cellular immunotherapy via DLI following nonmyeloablative haploidentical HSCT. This study analyzed graft outcomes in 13 patients who received in vivo and ex vivo TCD, haploidentical (HLA 1–3 Ag mismatched) HSCT for refractory hematologic malignancies (NHL, n=7; CLL, n=1; HD, n=3; CML, n=1; MDS, n=1). Conditioning consisted of MEDI-507 (siplizumab, an anti-CD2 mAb) for in vivo T cell depletion of both the host and donor, cyclophosphamide, fludarabine, thymic irradiation, and a brief course of cyclosporine. An earlier cohort of 4 patients did not receive fludarabine. All patients received ex vivo TCD of G-CSF-mobilized peripheral blood stem cells using a CD34+ cell-selection device. A median of 7.38 x 106 (3.19 x 106 to 1.49 x 107) CD 34+ cells/kg and a median of 5.24 x 104 (6.31 x 102 to 1.61 x 105) CD3+ cells/kg were given. DLI was given as early as 5 weeks in patients without evidence of GVHD. Inhibitory killer immunoglobulin-like receptor (KIR)-HLA epitope mismatches (missing ligand) in the GVH and HVG (host versus graft) directions were assessed based on HLA and KIR genotyping of patients and their donors. Natural killer (NK) cells recovered relatively early, despite the presence of circulating MEDI-507. Split lineage MC was observed in each case, with a predominance of early donor myeloid chimerism and a lower percentage of donor T cell chimerism. Four of the 13 patients eventually lost their grafts despite DLI, including 2 who were not conditioned with fludarabine. Five patients spontaneously achieved full donor chimerism (FDC) and 4 converted to FDC following DLI. The spontaneous chimerism group had significantly fewer HLA mismatches in the HVG direction. Four out of the 5 had only one mismatch, whereas the patients who had graft loss or required DLI had at least two mismatches (p=0.007 by Fisher’s exact test). This finding remained significant when the subgroup of patients not conditioned with fludarabine was excluded from the analysis (p=0.048). Spontaneous FDC was also associated with the presence of graft HLA-C group 1 (HLA-CAsn80) ligand for host NK cell inhibitory receptor KIR2DL2/3 (KIR-L match/compatible, 4 out of 4 evaluable patients) while this graft HLA ligand tended to be absent in the group that lost the graft or required DLI to achieve chimerism (KIR-L mismatch, 5 out of 8 patients) (p=0.08 by Fisher’s exact test). There was no significant relationship between donor KIR and host HLA types in the GVH direction for predicting engraftment. While these observations are preliminary given the heterogeneity of the conditioning regimens and the small number of patients, the data suggest that the lesser degree of HLA mismatching and the presence of KIR ligand compatibility in the HVG direction may influence donor engraftment following nonmyeloablative TCD haploidentical HSCT and warrant further study.

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Haploidentical Transplant with High Dose of Unmanipulated CD34, in Vivo T Cell Depletion with Alemtuzumab and Ric Regimen. Good Engraftment Rate, Low GVHD Incidence and Encouraging Survival. Single Center Experience in Colombia

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2011.12.382 ◽

2012 ◽

Vol 18 (2) ◽

pp. S349

Author(s):

A.J. Karduss ◽

Y. Coll ◽

J. Alejo ◽

G.L. Rodolfo ◽

R. Pedro ◽

...

Keyword(s):

T Cell ◽

Cell Depletion ◽

High Dose ◽

Single Center ◽

T Cell Depletion ◽

Single Center Experience

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Differential Outcomes for Ex Vivo Versus In Vivo Alloreactive T-Cell Depletion Strategies in Haploidentical HSCT

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2018.12.283 ◽

2019 ◽

Vol 25 (3) ◽

pp. S207

Author(s):

Steve M. Devine ◽

Stephan Mielke ◽

Eduardo Olavarria ◽

Bert Tuk ◽

Kees Meewisse ◽

...

Keyword(s):

T Cell ◽

Ex Vivo ◽

Cell Depletion ◽

T Cell Depletion ◽

Differential Outcomes ◽

Alloreactive T Cell

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Humanized anti-CD25 monoclonal antibody for prophylaxis of graft-vs-host disease (GVHD) in haploidentical bone marrow transplantation without ex vivo T-cell depletion

Experimental Hematology ◽

10.1016/s0301-472x(03)00228-5 ◽

2003 ◽

Vol 31 (11) ◽

pp. 1019-1025 ◽

Cited By ~ 26

Author(s):

Hui-Ren Chen ◽

Shu-Quan Ji ◽

Heng-Xiang Wang ◽

Hong-Ming Yan ◽

Ling Zhu ◽

...

Keyword(s):

Monoclonal Antibody ◽

Bone Marrow ◽

Bone Marrow Transplantation ◽

T Cell ◽

Marrow Transplantation ◽

Ex Vivo ◽

Cell Depletion ◽

T Cell Depletion ◽

Host Disease ◽

Graft Vs Host Disease

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T-cell depletion of HLA-identical transplants in leukemia

Blood ◽

10.1182/blood.v78.8.2120.bloodjournal7882120 ◽

1991 ◽

Vol 78 (8) ◽

pp. 2120-2130 ◽

Cited By ~ 15

Author(s):

AM Marmont ◽

MM Horowitz ◽

RP Gale ◽

K Sobocinski ◽

RC Ash ◽

...

Keyword(s):

T Cell ◽

Treatment Failure ◽

Chronic Gvhd ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Cell Depletion ◽

T Cell Depletion ◽

Free Survival ◽

Dose Rates ◽

Leukemia Relapse

We analyzed the effects of T-cell depletion on the outcome of HLA- identical sibling bone marrow transplants for leukemia by comparing 731 T-cell-depleted transplants with 2,480 non-T-cell-depleted transplants. T-cell depletion decreased acute graft-versus-host disease (GVHD) (relative risk [RR] 0.45; P less than .0001) and chronic (GVHD) (RR 0.56; P less than .0001). However, it increased graft failure (RR 9.29; P less than .0001). Leukemia relapse also was increased. In first remission acute leukemia or chronic phase chronic myelogenous leukemia, leukemia relapse was 2.75 times more likely after T-cell-depleted transplants (P less than .0001). T-cell depletion increased the risk of treatment failure (RR 1.35; P less than .0003) and decreased leukemia- free survival. We also studied controllable variables associated with outcome of T-cell-depleted transplants. The unique findings were that among recipients of T-cell-depleted transplants for early leukemia, radiation doses greater than or equal to 11 Gy (RR 0.54; P less than .01), dose rates greater than 14 cGy/min (RR 0.56; P less than .002), and additional posttransplant immune suppression with cyclosporine alone (RR 0.53; P less than .0006) or cyclosporine plus methotrexate (RR 0.36; P less than .01) were associated with fewer treatment failures. Use of monoclonal antibodies rather than physical techniques for T-cell depletion (RR 2.01; P less than .03) and fractionated radiation (RR 1.69; P less than .05) were associated with increased treatment failure and lower leukemia-free survival. These data may be useful in designing strategies to improve results of T-cell-depleted transplants.

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