Lymphodepleting effects and safety of pentostatin for nonmyeloablative allogeneic stem-cell transplantation1

Pavletić, Steven Z.; Bociek, R. Gregory; Foran, James M.; Rubocki, Ronald J.; Kuszynski, Charles; Wisecarver, James L.; Hatcher, Lori; Lucas, David M.; Byrd, John C.; Grever, Michael R.; Joshi, Shantaram S.; Hardiman, Penny; Smith, Lynette M.; McGuire, Timothy R.; Bierman, Philip J.; Vose, Julie M.; Armitage, Jamés O.; Talmadge, James E.

doi:10.1097/01.tp.0000084869.08639.a0

Cited by 18 publications

(14 citation statements)

References 9 publications

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“…Fludarabine is used in most RIT regimens, although pentostatin has also been associated with good results. 22 The addition of fludarabine to an immunosuppressive regimen of low-dose total body irradiation, coupled with post-transplant cyclosporine and mycophenolate mofetil, results in high rates of engraftment. 23 RIT regimens tend to be named for their city of origin.…”

Section: Does Rit Work?mentioning

confidence: 99%

The hope and the reality of reduced intensity transplants in children with malignant diseases

Stein

Dini

Yaniv

2005

Bone Marrow Transplant

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Summary:Reduced intensity preparative regimens are increasingly used for conditioning prior to allogeneic stem cell transplantation. As opposed to classical methods of pretransplant conditioning, patients receive predominantly immunosuppressive therapies that facilitate early engraftment, while cells within the graft itself promote continuation of the engraftment process. Despite early hopes that this form of transplant would be devoid of grade III and IV acute toxicities, there is a substantial amount of shortterm morbidity associated with the technique. Although long-term follow-up is not yet available, it is hoped that these regimens will spare young patients many of the late effects (cataracts, growth retardation, endocrine and reproductive problems) that are often associated with classical pre-transplant conditioning regimens. Reliable engraftment and leukemic control have been demonstrated in a large number of both adult and pediatric transplant recipients of these regimens, many of whom were deemed at high risk for standard conditioning because of serious co-morbidities, previous autologous transplantation or multiply relapsed disease. A brief review of the state of the art of this technology as it applies to pediatric transplantation is presented. Preliminary results of a survey of pediatric transplant centers indicate that a variety of protocols are used for a variety of indications. The use of standardized criteria for implementation of reduced intensity preparative regimens, the use of a limited number of regimens, and more extensive data collection will permit the elaboration of prospective comparative studies of this new and exciting modality. Bone Marrow Transplantation (2005) 35, S39-S43.

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Section: Does Rit Work?mentioning

confidence: 99%

The hope and the reality of reduced intensity transplants in children with malignant diseases

Stein

Dini

Yaniv

2005

Bone Marrow Transplant

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“…10 Fludarabine is used in most RIT regimens, although pentostatin has been used in some protocols with good results. 11 The addition of fludarabine to an immunosuppressive regimen of low-dose TBI coupled with posttransplant CsA and mycophenolate mofetil increased engraftment rates dramatically. 12 The most widely used RIT protocols with dose variations include:…”

Section: Resultsmentioning

confidence: 99%

Reduced-intensity conditioning in children: a reappraisal in 2008

Yaniv

Stein

2008

Bone Marrow Transplant

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Transplant-related mortality and morbidity (both short and long term) have limited the effectiveness of SCT in children with both malignant and nonmalignant diseases. Reducedintensity preparative regimens permit engraftment of allogeneic cells without many of the toxicities associated with standard TBI-and non-TBI-based conditioning. We review the concepts that underlie reduced-intensity transplantation (RIT) and highlight the experience of the technique in children. Although acute organ damage may be reduced after these transplants, the overall incidence of severe infections and of GvHD may be similar to that seen after standard-intensity transplantation. The relatively small numbers of children who have received RIT and the newness of the technique preclude long-term follow-up with which to monitor the incidence of associated long-term side effects and disease-free survival. Future refinements in RIT and appropriate patient selection for these procedures will hopefully extend its utility in the future.

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“…Pentostatin was used as transplant conditioning with neutropenia-inducing doses of total body irradiation(9, 10) or busulfan(11). Pentostatin plus bolus-dose Cy (600 mg/m 2 ) caused neutropenia(12); as such, we used low-dose Cy (200 mg/day) and allowed Cy reductions depending upon achievement of ALC reduction targets.…”

Section: Introductionmentioning

confidence: 99%

High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses

Mossoba

Halverson

Kurlander

et al. 2015

Clinical Cancer Research

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PURPOSE We hypothesized that lymphoid-selective host conditioning and subsequent adoptive transfer of sirolimus-resistant allogeneic T cells (T-Rapa), when combined with high-dose sirolimus drug therapy in vivo, would safely achieve anti-tumor effects while avoiding GVHD. EXPERIMENTAL DESIGN Patients (n=10) with metastatic renal cell carcinoma (RCC) were accrued because this disease is relatively refractory to high-dose conditioning yet may respond to high-dose sirolimus. A 21-day outpatient regimen of weekly pentostatin (P; 4 mg/m2/dose) combined with daily, dose-adjusted cyclophosphamide (C; ≤ 200 mg/day) was designed to deplete and suppress host T cells. After PC conditioning, patients received matched sibling, T cell-replete peripheral blood stem cell allografts and high-dose sirolimus (serum trough target, 20–30 ng/ml). To augment graft-versus-tumor (GVT) effects, multiple T-Rapa donor lymphocyte infusions (DLI) were administered (days 0, 14, and 45 post-transplant) and sirolimus was discontinued early (day 60 post-transplant). RESULTS PC conditioning depleted host T cells without neutropenia or infection and facilitated donor engraftment (10/10 cases). High-dose sirolimus therapy inhibited multiple T-Rapa DLI, as evidenced by stable mixed donor/host chimerism. No anti-tumor responses were detected by RECIST criteria and no significant classical acute GVHD was observed. CONCLUSIONS Immune-selective PC conditioning represents a new approach to safely achieve alloengraftment without neutropenia. However, allogeneic T cells generated ex vivo in sirolimus are not resistant to the tolerance-inducing effects of in vivo sirolimus drug therapy, thereby cautioning against use of this intervention in patients with refractory cancer.

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Lymphodepleting effects and safety of pentostatin for nonmyeloablative allogeneic stem-cell transplantation1

Cited by 18 publications

References 9 publications

The hope and the reality of reduced intensity transplants in children with malignant diseases

The hope and the reality of reduced intensity transplants in children with malignant diseases

Reduced-intensity conditioning in children: a reappraisal in 2008

High-Dose Sirolimus and Immune-Selective Pentostatin plus Cyclophosphamide Conditioning Yields Stable Mixed Chimerism and Insufficient Graft-versus-Tumor Responses

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