T-Cell Depletion Plus Salvage Immunotherapy With Donor Leukocyte Infusions as a Strategy to Treat Chronic-Phase Chronic Myelogenous Leukemia Patients Undergoing HLA-Identical Sibling Marrow Transplantation

Drobyski, William R.; Hessner, Martin J.; Klein, John P.; Kabler-Babbitt, Claudia; Keever-Taylor, Carolyn A.

doi:10.1182/blood.v94.2.434.414k42_434_441

Cited by 14 publications

(13 citation statements)

References 38 publications

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“…We recently reported a low relapse rate in high risk AML patients in remission or good partial remission receiving T cell depleted PBSC grafts after intensified conditioning with radioimmunotherapy(Bunjes, 2002), and some of these patients are included in the present study. Preemptive and prophylactic DLI are highly effective in patients with CML and MM receiving TCD stem cell grafts (Lokhorst et al , 1997; Drobyski et al , 1999; Alyea et al , 2001).…”

Section: Discussionmentioning

confidence: 99%

CD34⁺ cell selection of peripheral blood progenitor cells using the CliniMACS device for allogeneic transplantation: clinical results in 102 patients

Ringhoffer¹,

Wiesneth

Harsdorf³

et al. 2004

Br J Haematol

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SummaryThe present study investigated the effects of CD34 + cell selection in 102 patients using the CliniMACS device. Patients were at high risk for the development of graft versus host disease (GvHD) because of age, or the use of a haploidentical, mismatched or unrelated donor (UD). The median age of the patients was 44 years. The CliniMACS procedure yielded 8AE0 · 10 6 CD34 + cells/kg and the number of residual T cells was 1AE3 · 10 4 /kg (median). The median follow up was 20AE6 months. The probability of graft failure was 7%. The rate of acute GvHD was low (compatible family donors 10%, UDs 17%, and haploidentical donors 26%) with no patient enduring more than grade II disease. The cumulative incidence of chronic GvHD at the median follow up after transplant was 15% for the compatible family donor group, 40% for the UD group and 78% in the group transplanted from a haploidentical donor Treatment failure was mainly because of transplantrelated mortality, especially aspergillus infection, and not due to relapse. The probability of disease-free survival, stratified for the risk of treatment failure, was 27% for the high risk, 46% for the intermediate risk and 83% for the low risk group.

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Section: Discussionmentioning

confidence: 99%

CD34⁺ cell selection of peripheral blood progenitor cells using the CliniMACS device for allogeneic transplantation: clinical results in 102 patients

Ringhoffer¹,

Wiesneth

Harsdorf³

et al. 2004

Br J Haematol

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“…[580][581][582][583][584][585] In the early studies some of the donor cell infusions caused an appreciable incidence of GVHD, which was sometimes severe or even fatal, and marrow aplasia was also reported. [586][587][588] More recently, improved results have been obtained with (CD8+-depleted) CD4+ donor lymphocyte infusions (CD4+ DLI), which may act by inducing host-reactive cytolytic CD8+ donor T cells to directly or indirectly inhibit the Ph+ progenitors or stem cells. 589,590 The survival of patients who lack HLA-matched siblings and who receive transplants from unrelated HLA-matched donors identified by bone marrow registries is generally substantially lower than recipients of related donor transplants, 591,592 although certain immunologically distinct HLA subtypes fare better than others.…”

Section: Bone Marrow Transplantationmentioning

confidence: 99%

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies

et al. 2003

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The chronological history of the important discoveries leading to our present understanding of the essential clinical, biological, biochemical, and molecular features of chronic myelogenous leukemia (CML) are first reviewed, focusing in particular on abnormalities that are responsible for the massive myeloid expansion. CML is an excellent target for the development of selective treatment because of its highly consistent genetic abnormality and qualitatively different fusion gene product, p210(bcr-abl). It is likely that the multiple signaling pathways dysregulated by p210(bcr-abl) are sufficient to explain all the initial manifestations of the chronic phase of the disease, although understanding of the circuitry is still very incomplete. Evidence is presented that the signaling pathways that are constitutively activated in CML stem cells and primitive progenitors cooperate with cytokines to increase the proportion of stem cells that are activated and thereby increase recruitment into the committed progenitor cell pool, and that this increased activation is probably the primary cause of the massive myeloid expansion in CML. The cooperative interactions between Bcr-Abl and cytokine-activated pathways interfere with the synergistic interactions between multiple cytokines that are normally required for the activation of stem cells, while at the same time causing numerous subtle biochemical and functional abnormalities in the later progenitors and precursor cells. The committed CML progenitors have discordant maturation and reduced proliferative capacity compared to normal committed progenitors, and like them, are destined to die after a limited number of divisions. Thus, the primary goal of any curative strategy must be to eliminate all Philadelphia positive (Ph+) primitive cells that are capable of symmetric division and thereby able to expand the Ph+ stem cell pool and recreate the disease. Several highly potent and moderately selective inhibitors of Bcr-Abl kinase have recently been discovered that are capable of killing the majority of actively proliferating early CML progenitors with minimal effects on normal progenitors. However, like their normal counterparts, most of the CML primitive stem cells are quiescent at any given time and are relatively invulnerable to the Bcr-Abl kinase inhibitors as well as other drugs. We propose that survival of dormant Ph+ stem cells may be the most important reason for the inability to cure the disease during initial treatment, while resistance to the inhibitors and other drugs becomes increasingly important later. An outline of a possible curative strategy is presented that attempts to take advantage of the subtle differences in the proliferative behavior of normal and Ph+ stem cells and the newly discovered selective inhibitors of Bcr-Abl. Leukemia (2003) 17, 1211-1262. doi:10.1038/sj.leu.2402912

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“…While T cell‐depleted marrow transplants lower the incidence of acute and chronic GVHD, they increase the risk of leukaemia relapse, graft failure and prolonged immunosuppression (Apperley et al , 1986; Butturini & Gale, 1988; Horowitz et al , 1990; Marmont et al , 1991); there are little data on the performance of T cell‐depleted PBSCT. In an attempt to reduce the risk of GVHD from T‐cell depletion, while conserving useful donor immune function, we and colleagues have performed T cell‐depleted transplantation followed by delayed add‐back of donor T cells (Slavin et al , 1996; Barrett et al , 1998; Drobyski et al , 1999). Using cyclosporine prophylaxis, we showed that the risk of acute GVHD from donor lymphocyte infusions (DLI) was low following substantial T‐cell doses given 45 d or more after marrow transplant (Barrett et al , 1998).…”

mentioning

confidence: 99%

Transplant dose of CD34⁺ and CD3⁺ cells predicts outcome in patients with haematological malignancies undergoing T cell‐depleted peripheral blood stem cell transplants with delayed donor lymphocyte add‐back

et al. 2001

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Summary. We sought to optimize and standardize stem cell and lymphocyte doses of T cell-depleted peripheral blood stem cell transplants (T-PBSCT), using delayed add-back of donor T cells (DLI) to prevent relapse and enhance donor immune recovery. Fifty-one patients with haematological malignancies received a T-PBSCT from an HLA-identical sibling, followed by DLI of 1 Â 10 7 and 5 Â 10 7 CD31 cells/kg on d 145 and 1100 respectively. Twenty-four patients were designated as standard risk and twenty-seven patients with more advanced leukaemia were designated as high risk. Median recipient age was 38 years (range 10± 56). Median (range) of CD34 1 and CD3 1 cell transplant doses were 4´6 (2´3±10´9) Â 10 6 /kg and 0´83 (0´38± 2) Â 10 5 /kg respectively. The cumulative probability of acute GVHD was 39%. No patient died from GVHD or its consequences. The probability of developing chronic GVHD was 54% (18% extensive). The probability of relapse was 12% for the standard-risk patients and 66% for high-risk patients. In multivariate analysis, the risk factors for lower disease-free survival and overall survival were high-risk disease, CD341 dose , 4´6 Â 10 6 /kg and CD3 1 dose , 0´83 Â 10 5 /kg. Predictive factors for chronic GVHD were a T-cell dose at transplant . 0´83 Â 10 5 CD3 1 cells/ kg. These results further define the impact of CD34 and CD3 cell dose on transplant outcome and show that careful dosing of stem cells and lymphocytes may permit the control and optimization of transplant outcome.

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T-Cell Depletion Plus Salvage Immunotherapy With Donor Leukocyte Infusions as a Strategy to Treat Chronic-Phase Chronic Myelogenous Leukemia Patients Undergoing HLA-Identical Sibling Marrow Transplantation

Cited by 14 publications

References 38 publications

CD34⁺ cell selection of peripheral blood progenitor cells using the CliniMACS device for allogeneic transplantation: clinical results in 102 patients

CD34⁺ cell selection of peripheral blood progenitor cells using the CliniMACS device for allogeneic transplantation: clinical results in 102 patients

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies

Transplant dose of CD34⁺ and CD3⁺ cells predicts outcome in patients with haematological malignancies undergoing T cell‐depleted peripheral blood stem cell transplants with delayed donor lymphocyte add‐back

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T-Cell Depletion Plus Salvage Immunotherapy With Donor Leukocyte Infusions as a Strategy to Treat Chronic-Phase Chronic Myelogenous Leukemia Patients Undergoing HLA-Identical Sibling Marrow Transplantation

Cited by 14 publications

References 38 publications

CD34+ cell selection of peripheral blood progenitor cells using the CliniMACS device for allogeneic transplantation: clinical results in 102 patients

CD34+ cell selection of peripheral blood progenitor cells using the CliniMACS device for allogeneic transplantation: clinical results in 102 patients

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies

Transplant dose of CD34+ and CD3+ cells predicts outcome in patients with haematological malignancies undergoing T cell‐depleted peripheral blood stem cell transplants with delayed donor lymphocyte add‐back

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CD34⁺ cell selection of peripheral blood progenitor cells using the CliniMACS device for allogeneic transplantation: clinical results in 102 patients

CD34⁺ cell selection of peripheral blood progenitor cells using the CliniMACS device for allogeneic transplantation: clinical results in 102 patients

Transplant dose of CD34⁺ and CD3⁺ cells predicts outcome in patients with haematological malignancies undergoing T cell‐depleted peripheral blood stem cell transplants with delayed donor lymphocyte add‐back