T-Cell Depleted Unrelated Donor Stem Cell Transplants Appear to Be of Value for Adult Philadelphia Chromosome Negative ALL Patients and Should Be Evaluated Prospectively in New Large Group Studies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4413-4413
Author(s):  
B. R Patel ◽  
Keiren Kirkland ◽  
R. Pearce ◽  
Richard E Clark ◽  
Charles F. Craddock ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Chronic Gvhd ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
British Society ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donor

Abstract Matched sibling allogeneic haematopoietic stem cell transplantations (HSCT) in first complete remission (CR1) result in superior survival compared to standard chemotherapy in adult patients with acute lymphoblastic leukaemia (ALL). However, application is limited by donor availability. The role of unrelated donor (URD) transplantation in ALL in CR1 is not clearly delineated. We report a retrospective series of URD transplants in 55 adults with Philadelphia chromosome (Ph) negative acute lymphoblastic leukaemia (ALL) in CR1 reported to the British Society of Blood and Marrow Transplantation registry from 1993 to 2005. Median follow-up of survivors was 55.2 months (range 17–160). Median age was 25.5 years (range 15.7–50). Eighty nine percent of patients had at least one adverse prognostic feature. Sixty six percent of transplants were matched at 10 of 10 loci and 34% were mis-matched. T cell depletion (TCD) was carried out by in-vivo Campath administration in 96% of recipients with additional ex-vivo TCD in 21% of these patients. The estimated actuarial Overall survival (OS), Disease free survival (DFS) and non relapse mortality (NRM) were 59%, 57% and 19% at 5 years respectively. The overall incidence of Grade II–IV and III–IV GVHD was 25% and 7% respectively. The actuarial estimate of extensive chronic GVHD was 22 % at 5 years. HLA mismatching at 2 alleles or antigens was associated with poorer survival (RR=3.22, (1.08–9.64). T depleted URD HSCT can result in good OS and low TRM for adults with high risk ALL in CR1 and merits prospective comparison with other methods of GVHD prophylaxis.

scholarly journals Unrelated Transplants for High-risk Adult Acute Lymphoblastic Leukaemia

2009 ◽  
Vol 03 (01) ◽  
pp. 45
Author(s):  
Christelle Ferrà ◽  
Josep-Maria Ribera ◽  
◽  
Keyword(s):  
High Risk ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Adult Patients ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
High Incidence

Standard chemotherapy has a poor outcome in adult patients with high-risk acute lymphoblastic leukaemia (ALL). Allogeneic haematopoietic stem cell transplant (alloSCT) is the treatment of choice, and SCT with alternative progenitors should be considered in the absence of a matched sibling donor. There is great heterogeneity in the data on unrelated SCT for adult patients with high-risk ALL. Many studies include both paediatric and adult patients, or provide combined data from ALL and acute myeloid leukaemia (AML) patients. Moreover, the follow-up of the reported series is highly variable, and the definition of high-risk criteria varies from one study to another. The reported disease-free survival (DFS) for adult ALL patients ranges from 30 to 70%, and leukaemia relapse (14–47%) is an important cause of treatment failure. Despite great improvements in recent years, transplant-related mortality (TRM) from unrelated SCT (USCT) remains unacceptably high (29–36%). The human leukocyte antigen (HLA) disparity in the unrelated donor setting with a high incidence of graft-versus-host disease (GvHD) and delayed immunological reconstitution with a high incidence of infectious events in the unrelated cord blood SCT are the most important causes of morbidity and mortality in unrelated transplants. Disease status at transplant and the presence of acute and/or chronic GvHD are the most important factors determining relapse in high-risk ALL adult patients undergoing USCT.

scholarly journals Minimal Residual Disease Prior to and After Haematopoietic Stem Cell Transplantation in Children and Adolescents With Acute Lymphoblastic Leukaemia: What Level of Negativity Is Relevant?

2021 ◽  
Vol 9 ◽  
Author(s):  
Pietro Merli ◽  
Marianne Ifversen ◽  
Tony H. Truong ◽  
Hanne V. Marquart ◽  
Jochen Buechner ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Acute Lymphoblastic Leukaemia ◽  
Minimal Residual Disease ◽  
Lymphoblastic Leukaemia ◽  
Haematopoietic Stem Cell Transplantation ◽  
Residual Disease ◽  
Haematopoietic Stem Cell ◽  
Minimal Residual

Minimal residual disease (MRD) assessment plays a central role in risk stratification and treatment guidance in paediatric patients with acute lymphoblastic leukaemia (ALL). As such, MRD prior to haematopoietic stem cell transplantation (HSCT) is a major factor that is independently correlated with outcome. High burden of MRD is negatively correlated with post-transplant survival, as both the risk of leukaemia recurrence and non-relapse mortality increase with greater levels of MRD. Despite growing evidence supporting these findings, controversies still exist. In particular, it is still not clear whether multiparameter flow cytometry and real-time quantitative polymerase chain reaction, which is used to recognise immunoglobulin and T-cell receptor gene rearrangements, can be employed interchangeably. Moreover, the higher sensitivity in MRD quantification offered by next-generation sequencing techniques may further refine the ability to stratify transplant-associated risks. While MRD quantification from bone marrow prior to HSCT remains the state of the art, heavily pre-treated patients may benefit from additional staging, such as using 18F-fluorodeoxyglucose positron emission tomography/computed tomography to detect focal residues of disease. Additionally, the timing of MRD detection (i.e., immediately before administration of the conditioning regimen or weeks before) is a matter of debate. Pre-transplant MRD negativity has previously been associated with superior outcomes; however, in the recent For Omitting Radiation Under Majority age (FORUM) study, pre-HSCT MRD positivity was associated with neither relapse risk nor survival. In this review, we discuss the level of MRD that may require pre-transplant therapy intensification, risking time delay and complications (as well as losing the window for HSCT if disease progression occurs), as opposed to an adapted post-transplant strategy to achieve long-term remission. Indeed, MRD monitoring may be a valuable tool to guide individualised treatment decisions, including tapering of immunosuppression, cellular therapies (such as donor lymphocyte infusions) or additional immunotherapy (such as bispecific T-cell engagers or chimeric antigen receptor T-cell therapy).

scholarly journals T-Cell-Replete Versus ex vivo T-Cell-Depleted Haploidentical Haematopoietic Stem Cell Transplantation in Children With Acute Lymphoblastic Leukaemia and Other Haematological Malignancies

2021 ◽  
Vol 9 ◽  
Author(s):  
Katharina Kleinschmidt ◽  
Meng Lv ◽  
Asaf Yanir ◽  
Julia Palma ◽  
Peter Lang ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Haematopoietic Stem Cell Transplantation ◽  
Ex Vivo ◽  
Haematopoietic Stem Cell

Allogeneic haematopoietic stem cell transplantation (HSCT) represents a potentially curative option for children with high-risk or refractory/relapsed leukaemias. Traditional donor hierarchy favours a human leukocyte antigen (HLA)-matched sibling donor (MSD) over an HLA-matched unrelated donor (MUD), followed by alternative donors such as haploidentical donors or unrelated cord blood. However, haploidentical HSCT (hHSCT) may be entailed with significant advantages: besides a potentially increased graft-vs.-leukaemia effect, the immediate availability of a relative as well as the possibility of a second donation for additional cellular therapies may impact on outcome. The key question in hHSCT is how, and how deeply, to deplete donor T-cells. More T cells in the graft confer faster immune reconstitution with consecutively lower infection rates, however, greater numbers of T-cells might be associated with higher rates of graft-vs.-host disease (GvHD). Two different methods for reduction of alloreactivity have been established: in vivo T-cell suppression and ex vivo T-cell depletion (TCD). Ex vivo TCD of the graft uses either positive selection or negative depletion of graft cells before infusion. In contrast, T-cell-repleted grafts consisting of non-manipulated bone marrow or peripheral blood grafts require intense in vivo GvHD prophylaxis. There are two major T-cell replete protocols: one is based on post-transplantation cyclophosphamide (PTCy), while the other is based on anti-thymocyte globulin (ATG; Beijing protocol). Published data do not show an unequivocal benefit for one of these three platforms in terms of overall survival, non-relapse mortality or disease recurrence. In this review, we discuss the pros and cons of these three different approaches to hHSCT with an emphasis on the significance of the existing data for children with acute lymphoblastic leukaemia.

T-cell acute lymphoblastic leukaemia with late developing Philadelphia chromosome

1984 ◽  
Vol 56 (1) ◽  
pp. 139-146 ◽  
Author(s):  
Barbara A. Miller ◽  
Michael M. Reid ◽  
Marilyn Nell ◽  
Jeffrey M. Lipton ◽  
Stephen E. Sallan ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Philadelphia Chromosome

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

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1817-1817
Author(s):  
Yves Chalandon ◽  
Christoph Schmid ◽  
Kimmo Porkka ◽  
Alvaro Urbano-Ispizua ◽  
Bernd Hertenstein ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Chronic Gvhd ◽  
Median Number ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Initial Cell ◽  
Cell Dose ◽  
Stem Cell Source ◽  
Related Mortality

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.

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.

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