pentostatin and Graft-vs-Host-Disease

To evaluate the treatment options in steroid-refractory acute graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation.. Literature was obtained by searching MEDLINE (1966-May 2007) and EMBASE (1980-May 2007).. All pertinent clinical trials, retrospective studies, case reports, and compassionate use studies were identified and evaluated for safety and efficacy of the pharmacologic agents.. Steroid-refractory acute GVHD is associated with high rates of morbidity and mortality. Although various pharmacologic agents have been studied in the treatment of steroid-refractory acute GVHD, no treatments have been established as a salvage therapy. Preliminary data on different pharmacologic agents have been identified and evaluated for their efficacy and tolerability in the treatment of steroid-refractory acute GVHD. The effects of the pharmacologic agents varied significantly among patients: severity of the disease, involvement of different organs, and the patient's age seem to be the major factors that affect an individual's response to drug therapy. In addition, the treatments are further challenged by the high incidence of potentially fatal opportunistic infections that occur during the therapy.. Selection of pharmacologic agents for the treatment of steroid-refractory acute GVHD should be based on the target organs, adverse drug reactions, and economic factors. Further studies with larger sample sizes are warranted to better understand the roles of these agents in the treatment of steroid-refractory acute GVHD.

Topics: Antibodies, Monoclonal; Antilymphocyte Serum; Cyclophosphamide; Diphtheria Toxin; Drug Resistance; Etanercept; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin G; Immunosuppressive Agents; Interleukin-2; Pentostatin; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Sirolimus; Steroids

Graft-versus-host disease is one of the commonest complications of allogeneic bone marrow or peripheral blood stem cell transplantation. This review will cover advances in the pathophysiology of graft-versus-host disease and new agents under investigation for the treatment of this disorder. Patients developing graft-versus-host disease who fail to respond to steroids have a poor prognosis. In this group of people, morbidity and mortality are very high.. Novel agents are currently under investigation for the treatment of such devastating disorders. Pentostatin, denileukin diftitox, mycophenolate mofetil, extracorporeal photopheresis, and several monoclonal antibodies have been used, some of them with encouraging results.. As supportive care improves and new agents are added to the armamentarium against steroid-refractory acute graft-versus-host disease, the prognosis of this entity may start to change. Patients with this complication after transplantation should be enrolled, whenever possible, in clinical trials to find effective therapies.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Bone Marrow Transplantation; Diphtheria Toxin; Drug Resistance; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-2; Mycophenolic Acid; Pentostatin; Photopheresis; Recombinant Fusion Proteins; Steroids

Pentostatin (deoxycoformycin), is one of a number of purine analogues. The drug was originally designed to mimic a form of severe combined immune deficiency, characterised by marked T lymphopenia but variable B cell function. Clinically, the drug has been used primarily to treat a rare type of leukaemia - hairy cell leukaemia. Recently, the drug has seen increasing attention as an immunosuppressant. This review will cover the basic pharmacology and immunological effects of pentostatin. The clinical use of this agent in prevention and treatment of graft-versus-host disease will be examined. Although many of these studies are ongoing, this agent has promise as a novel immunosuppressive agent with a new mechanism of action.

Topics: Bone Marrow Transplantation; Clinical Trials as Topic; Graft vs Host Disease; Humans; Immunologic Tests; Immunosuppressive Agents; Pentostatin

Bone marrow transplantation has become the modality of choice for a number of malignant conditions. One of the primary causes of morbidity and mortality following bone marrow transplantation is graft-versus-host disease (GVHD). Moderate to severe acute GVHD affects 9% to 35% of patients undergoing standard allogeneic bone marrow transplantation. The incidence of chronic GVHD is approximately 40% to 50%. In our experience at Johns Hopkins Oncology Center, patients with stages 2, 3, and 4 acute GVHD had median survivals of only 5.4, 3.6, and 2.5 months, respectively, despite treatment. Patients with chronic GVHD do not fare much better. Their overall 10-year mortality rate remains high at 42%. Significant failure rates and toxicities have been associated with all available therapeutic options for GVHD. Pentostatin (Nipent; SuperGen, San Ramon, CA) is currently used to treat a variety of hematologic malignancies. In addition to its antineoplastic effects, considerable immunosuppressive properties have been reported. Pentostatin affects the immune system by decreasing lymphocyte number and function. Its immunosuppressive effect has promise for the treatment of GVHD and warrants further study.

Topics: Acute Disease; Bone Marrow Transplantation; Chronic Disease; Graft vs Host Disease; Humans; Immunosuppressive Agents; Incidence; Lymphocytes; Pentostatin; Survival Rate; Transplantation, Homologous; Treatment Outcome

Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cyclophosphamide; Disease-Free Survival; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Lymphocyte Transfusion; Male; Middle Aged; Pentostatin; Primary Immunodeficiency Diseases; Prospective Studies; Survival Rate; Transplantation Conditioning

Extracorporeal photopheresis (ECP) is an immunomodulatory cellular therapy which has been shown to induce a tolerogenic state in patients with acute and chronic graft-vs-host disease. ECOG-ACRIN explored the activity of ECP as a part of a reduced intensity conditioning regimen in two multicenter trials in patients with MDS (E1902) and lymphomas (E1402). While both studies closed before completing accrual, we report results in 23 patients (17 MDS and 6 lymphoma).. Patients received 2 days of ECP followed by pentostatin 4 mg/m2 /day for two consecutive days, followed by 600 cGy of total body irradiation prior to stem cell infusion. Immunosuppression for aGVHD was infusional cyclosporine A or tacrolimus and methotrexate on day +1, +3, with mycophenolate mofetil starting on day 100 for chronic GVHD prophylaxis.. All patients engrafted, with median time to neutrophil and platelet engraftment of 15-18 days and 10-18 days respectively. Grade 3 or 4 aGVHD occurred in 13% and chronic extensive GVHD in 30%.. These studies demonstrate that ECP/pentostatin/TBI is well tolerated and associated with adequate engraftment of neutrophils and platelets in patients with lymphomas and MDS.

Topics: Adult; Allografts; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Pentostatin; Photopheresis; Tacrolimus; Transplantation Conditioning; Whole-Body Irradiation

Pentostatin is an irreversible inhibitor of adenosine deaminase and has been used to prevent graft-versus-host disease (GVHD) and to treat both acute and chronic GVHD. Dose reduction equations for patients with renal insufficiency are based on few patients with limited pharmacokinetic and clinical results. This phase II study (NCT00201786) was conducted to assess pentostatin efficacy and infectious complications seen from our previous phase I study in steroid-refractory acute GVHD (aGVHD).. Hospitalized patients with steroid-refractory aGVHD were given pentostatin 1.5 mg/m(2)/day intravenously on days 1-3 of each 14-day cycle. Prior to each dose, dose modifications were based on Cockcroft-Gault estimated creatinine clearance (eCrCL) with 30-50 mL/min/1.73 m(2) leading to a 50 % dose reduction and eCrCL less than 30 mL/min/1.73 m(2) leading to study removal. Plasma pentostatin area under the concentration-time curve (AUC) and incidence of infectious complications were evaluated.. Two of the eight patients treated demonstrated excessive pentostatin exposure as determined by measurement of AUC. One of these patients had renal impairment, whereas the other patient demonstrated borderline renal function. Despite dose reduction to 0.75 mg/m(2), AUCs were significantly increased compared to the other patients in this study. Seven of eight patients treated with pentostatin had cytomegalovirus (CMV) viremia after pentostatin treatment; however none developed proven CMV disease.. A 50 % dose reduction in patients with eCrCL 30-50 mL/min/1.73 m(2) seems reasonable. However, the eCrCL should be interpreted with extreme caution in patients who are critically ill and/or with poor performance status. Renal function assessment based on the Cockcroft-Gault method could be significantly overestimated thus risking pentostatin overdosing. These results imply a need to closely monitor pentostatin exposure in patients with renal insufficiency.

Topics: Adenosine Deaminase Inhibitors; Adult; Antibodies, Monoclonal; Area Under Curve; Blood Transfusion, Autologous; Creatinine; Cyclosporine; Drug Resistance; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infliximab; Lymphocyte Transfusion; Male; Methotrexate; Methylprednisolone; Middle Aged; Pentostatin; Renal Insufficiency; Stem Cell Transplantation; Tacrolimus; Young Adult

One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ≥50% CD3(+) donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m(2) i.v. on days -28, -21, and -14 when the CD4(+) cell count was >100 cells/μL and on days -4 and -3 regardless of CD4(+) level. Rituximab 375 mg/m(2) was administered to patients with CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan 200 mg/m(2) i.v. was administered on days -4 and -2 at a dose to target a cumulative AUC dose of 16,000 (±10%) μmol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4(+) cell count decrease from baseline (day -28) was 52% to day -21, 66% to day -14, 62% to day -7, and 91% to day 0. At day +28, all 42 patients (100%) had ≥50% CD3(+) donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.

Topics: Acute Disease; Adult; Aged; Antineoplastic Agents; Busulfan; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Chronic Disease; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Depletion; Male; Middle Aged; Molecular Targeted Therapy; Pentostatin; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous

Although significant strides have been made in understanding the biology of graft-versus-host disease (GVHD) and its prevention over the last 4 decades, little is known about the different populations of lymphocytes and the changes in response to treatment for this condition. BMT-CTN 0302 was a randomized phase II clinical trial in the Blood and Marrow Transplant Clinical Trials Network that assessed the efficacy of combination therapy with steroids plus pentostatin, mycophenolate mofetil, etanercept, or denileukin diftitox in patients with acute GVHD. Patients enrolled in the study underwent blood analysis by flow cytometry on days 0, 14, and 28 of therapy to enumerate the number of total lymphocytes, T cells, B cells, and lymphocytes expressing activation markers. Baseline total lymphocyte counts and subpopulations were similar in the 4 treatment arms. Responding patients had a smaller decrease in total CD45(+) cell count (P = .005) compared with nonresponding patients at day 28. On univariate analysis, those who developed chronic GVHD had significantly higher CD8(+) cell counts at day 14 compared with those without it (P = .005). There was no significant association between baseline lymphocyte count and survival. On univariate analysis, among the patients with higher lymphocyte counts at days 14 and 28, there was a trend toward better survival at day 180, although this trend did not reach the predetermined threshold for significance. We found no significant differences in lymphocyte total or subpopulation counts among the 4 treatment arms, and no notable influence on outcomes.

Topics: Acute Disease; Adult; Antigens, CD; Antineoplastic Agents; B-Lymphocyte Subsets; Bone Marrow Transplantation; Diphtheria Toxin; Etanercept; Female; Graft vs Host Disease; Humans; Immunoglobulin G; Immunophenotyping; Immunosuppressive Agents; Interleukin-2; Lymphocyte Count; Male; Middle Aged; Mycophenolic Acid; Pentostatin; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Survival Analysis; T-Lymphocyte Subsets; Transplantation, Homologous

Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after matched unrelated, related, or mismatched related donor hematopoietic stem-cell transplantation (HSCT). Improved GVHD prevention methods are needed. Pentostatin, an adenosine deaminase inhibitor, leads to lymphocyte depletion with low risk of myelosuppression. We hypothesized that addition of pentostatin to GVHD prophylaxis with tacrolimus and mini-methotrexate may improve outcomes, and we conducted a Bayesian adaptively randomized, controlled, dose-finding study, taking into account toxicity and efficacy.. Success was defined as the patient being alive, engrafted, in remission, without GVHD 100 days post-HSCT and no grade ≥ 3 GVHD at any time. Patients were randomly assigned to pentostatin doses of 0, 0.5, 1.0, 1.5, and 2.0 mg/m(2) with drug administered on HSCT days 8, 15, 22, and 30. Eligible patients were recipients of mismatched related (n = 10) or unrelated (n = 137) donor HSCT.. Median age was 47 years. Thirty-seven, 10, 29, 61, and 10 patients were assigned to the control and four treatment groups, respectively, with comparable baseline characteristics. Pentostatin doses of 1.0 and 1.5 mg/m(2) had the highest success rates (69.0% and 70.5%) versus control (54.1%). The posterior probabilities that the success rates were greater with 1.5 mg/m(2) or 1.0 mg/m(2) versus control are 0.944 and 0.821, respectively. Hepatic aGVHD rates were 0%, 17.2%, and 11.1%, respectively, for 1.5 mg/m(2), 1.0 mg/m(2), and control groups. No grades 3 to 4 aGVHD occurred in 11 HLA-mismatched recipients in the 1.5 mg/m(2) group.. Pentostatin increased the likelihood of success as defined here, and should be further investigated in larger randomized, confirmatory studies.

Topics: Adenosine Deaminase Inhibitors; Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Intention to Treat Analysis; Male; Methotrexate; Middle Aged; Pentostatin; Survival Analysis; Tacrolimus; Transplantation Conditioning

Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplant (HCT) is the major reason for nonrelapse mortality (NRM), and thus is a major determinant of long-term survival. Clinical trials of new aGVHD treatments are needed to identify approaches that will ultimately improve upon HCT survival. At present, it is not clear how quickly response to GVHD treatment needs to be established to reliably categorize patients at high risk for death or to promptly identify those who might benefit from alternate treatment. Therefore, we analyzed time to response from onset of aGVHD treatment in 180 patients who were enrolled on a national, randomized, phase II aGVHD treatment clinical trial whose initial treatment of GVHD consisted of high-dose steroids plus a second immunosuppressive agent. The aim of this analysis was to determine whether time to aGVHD treatment response predicts patient outcomes, especially survival. We used response at 14, 28, and 56 days from initiation of aGVHD treatment to categorize patients for NRM and survival. Multivariate analyses and specificity/sensitivity analyses identified that day 28 response (complete or partial response) best categorized patients by NRM and survival at 9 months from start of aGVHD treatment. If verified as a reliable predictor of late outcomes following other aGVHD treatment approaches, day 28 response should serve as a standard early endpoint for future trials of aGVHD therapy.

Topics: Adrenal Cortex Hormones; Adult; Diphtheria Toxin; Etanercept; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin G; Interleukin-2; Methylprednisolone; Middle Aged; Pentostatin; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Survival Analysis; Treatment Outcome

One of the obstacles to chronic GVHD research is the lack of standardized response criteria. The National Institute of Health (NIH) has recommended response criteria at a Consensus Conference. These need to be validated. We recently completed and reported a trial of pentostatin in treating steroid-refractory chronic GVHD. During the trial, we prospectively collected percent body-surface-area (BSA) involvement of rash, superficial sclerosis and deep sclerosis. Here, we compare cutaneous responses using the NIH scale and the Hopkins scale. The two scales produced similar overall response rates but different domain response rates. There was 80% agreement in overall response at the final treatment evaluation, but only a 64% agreement for fasciitis/non-moveable sclerosis. There was more disparity in the measurement of sclerosis than in that of erythema, which highlights the difficulty of quantifying sclerosis. For sclerosis, the Hopkins scale, which used skin softening, was more predictive of early response as compared with the NIH scale, which focused on percent BSA. Early assessment of skin softening may be important if trying to detect the activity of a particular agent in chronic GVHD. Further validation of the NIH scale is ongoing, which should produce a clinically useful and predictive scale.

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Chronic Disease; Consensus Development Conferences, NIH as Topic; Drug Resistance; Erythema; Female; Graft vs Host Disease; Humans; Lichen Sclerosus et Atrophicus; Male; Pentostatin; Prospective Studies; Skin; United States

Acute graft-versus-host disease (aGVHD) is the primary limitation of allogeneic hematopoietic cell transplantation. Corticosteroids remain the standard initial therapy, yet only 25% to 41% of patients completely respond. This randomized, 4-arm, phase 2 trial was designed to identify the most promising agent(s) for initial therapy for aGVHD. Patients were randomized to receive methylprednisolone 2 mg/kg per day plus etanercept, mycophenolate mofetil (MMF), denileukin diftitox (denileukin), or pentostatin. Patients (n = 180) were randomized; their median age was 50 years (range, 7.5-70 years). Myeloablative conditioning represented 66% of transplants. Grafts were peripheral blood (61%), bone marrow (25%), or umbilical cord blood (14%); 53% were from unrelated donors. Patients who received MMF for prophylaxis (24%) were randomized to a non-MMF arm. At randomization, aGVHD was grade I to II (68%), III to IV (32%), and (53%) had visceral organ involvement. Day 28 complete response rates were etanercept 26%, MMF 60%, denileukin 53%, and pentostatin 38%. Corresponding 9-month overall survival was 47%, 64%, 49%, and 47%, respectively. Cumulative incidences of severe infections were as follows: etanercept 48%, MMF 44%, denileukin 62%, and pentostatin 57%. Efficacy and toxicity data suggest the use of MMF plus corticosteroids is the most promising regimen to compare against corticosteroids alone in a definitive phase 3 trial. This study is registered at http://www.clinicaltrials.gov as NCT00224874.

Topics: Acute Disease; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Child; Diphtheria Toxin; Drug Therapy, Combination; Etanercept; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin G; Infections; Interleukin-2; Methylprednisolone; Middle Aged; Mycophenolic Acid; Pentostatin; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Survival Rate; Treatment Outcome

There is no standard therapy for steroid-refractory chronic graft-versus-host disease (GVHD). This problem is particularly daunting in children with chronic GVHD, whereby the effects of the disease and its treatment may impair normal growth and development. Children are also particularly vulnerable to failure and/or toxicity of therapy; for example, joint contractures or joint damage may result in life-long disability. The Pediatric Blood and Marrow Transplant Consortium performed a phase 2 trial of pentostatin for steroid-refractory chronic GVHD in 51 children (median age, 9.8 years) from 24 institutions. Overall response was 53% (95% confidence interval, 40%-64%), with a response of 59% (95% confidence interval, 42%-75%) in sclerosis. Thirteen subjects (25%) had toxicity requiring them to stop pentostatin. The drug had a significant steroid-sparing effect in those that responded. A trend was also observed toward increased survival at 3 years in responders versus nonresponders (69% vs 50%; P = .06). The intravenous administration of the drug ensures compliance in a patient group in which oral therapy is difficult to monitor. Pentostatin has activity in refractory chronic GVHD in children, and future studies, including treatment of children newly diagnosed with high-risk chronic GVHD, are warranted. The trial was registered at www.Clinicaltrials.gov as #NCT00144430.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Chronic Disease; Female; Graft vs Host Disease; Humans; Infant; Male; Neoplasms; Pentostatin; Stem Cell Transplantation; Young Adult

Therapy for patients with chronic graft-versus-host disease (cGVHD) is based on prolonged immunosuppression with corticosteroids. There is no standard therapy for patients whose cGVHD does not resolve with corticosteroid treatment. Pentostatin, a potent inhibitor of adenosine deaminase, has activity in acute GVHD. We examined the toxicity and efficacy of pentostatin in a prospective phase II trial in corticosteroid-refractory cGVHD.. Patients of any age were eligible. Patients received pentostatin 4 mg/m2 intravenously every 2 weeks for 12 doses, and continued therapy as long as benefit was documented. Corticosteroid taper was begun after three doses of pentostatin. Responses were graded in real time in the skin, mouth, and liver using objective response criteria.. Fifty-eight heavily pretreated (median, four prior regimens) patients (median age, 33 years) were enrolled. Results are shown as an intent-to-treat analysis. Of the 58 patients, a total of 32 (55%; 95% CI, 42% to 68%) had an objective response, as evaluated by use of a new grading scale. Infection was the most significant toxicity, with 11 grade 3 to 4 infectious events. The survival at 1 and 2 years was 78% (95% CI, 64% to 86%) and 70% (95% CI, 57% to 80%), with cGVHD with/without infection accounting for the majority of deaths.. Pentostatin has immunosuppressive effects that are currently being explored further for treatment of cGVHD.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Drug Resistance; Graft vs Host Disease; HLA Antigens; Humans; Immunosuppressive Agents; Leukemia; Middle Aged; Pentostatin; Treatment Outcome

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic bone marrow transplantation. In steroid-refractory aGVHD, mortality is very high. Pentostatin, a potent inhibitor of adenosine deaminase, induces lymphocyte apoptosis and may be useful in the treatment of this condition.. We have conducted a phase I dose escalation study of pentostatin in patients with steroid-refractory aGVHD. Twenty-three patients were enrolled. Starting dose was 1 mg/m2/d by intravenous injection for 3 days.. The maximum tolerated dose was found to be 1.5 mg/m2/d. Late infections at the 2-mg/m2/d dose level were believed to be dose limiting toxicities. Lymphopenia was universal, but the neutrophil count was generally not affected. Fevers associated with neutropenia were not observed. Otherwise, the drug was well tolerated, with only modest elevations of liver function tests and thrombocytopenia, each being observed in a single patient. Twenty-two patients were assessable for response, including 14 complete responses (63%) and three partial responses (13%). Median survival after therapy for the group was 85 days (range, 5 to 1,258 days).. The suggested intravenous dose for a phase II study will be 1.5 mg/m2/d for 3 days. Pentostatin has activity in patients with steroid-refractory aGVHD that is worth exploring in future trials.

Topics: Acute Disease; Adolescent; Adult; Apoptosis; Bone Marrow Transplantation; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Graft vs Host Disease; Hematologic Neoplasms; History, 16th Century; Humans; Immunosuppressive Agents; Infant; Infusions, Intravenous; Lymphocytes; Male; Maximum Tolerated Dose; Middle Aged; Pentostatin; Transplantation, Homologous; Treatment Outcome

In all, 55 patients at high risk or ineligible for a conventional allogeneic hematopoietic stem cell transplant (HSCT) received a regimen consisting of extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation. The median age was 49 years (18-70 years); 44 received a sibling and 11 an unrelated HSCT; 44% were over the age of 50 years and 31% had undergone a prior HSCT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Full donor chimerism was documented in 98% by day +100. The 1000-day nonrelapse mortality was 11%. The median follow-up is 502 days (154-1104 days). The 1- and 2-year overall survival (OS) and event-free survival (EFS) are 67, 58 and 55%, and 47%, respectively. Patients who had not received a prior HSCT or had less than three prior chemotherapy regimens had a 71% OS and 67% EFS at 1 year. Greater than grade II aGVHD developed in 9% and chronic GVHD (cGVHD) in 43%, and extensive in 12% and limited in 31%. Of the patients, 86% who engrafted had a disease response, 72% had complete and 14% partial responses. This novel reduced intensity preparative regimen was well tolerated and associated with a low incidence of transplant-related mortality and serious acute and cGVHD.

Topics: Adolescent; Adult; Aged; Cyclosporine; Disease-Free Survival; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Methotrexate; Middle Aged; Pentostatin; Time Factors; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

Topics: Carcinoma, Renal Cell; Cyclosporine; Graft Survival; Graft vs Host Disease; Humans; Leukocyte Transfusion; Pentostatin; Peripheral Blood Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Homologous

We report outcomes of 60 patients with steroid-refractory (SR)-aGVHD treated with pentostatin. Almost half (47%) of patients had grade 4 GVHD-22% had stage 3-4 liver GVHD and 51% had stage 3-4 lower gastrointestinal tract (LGI) GVHD. Patients received a median of 3 courses (range, 1-9) of pentostatin. Day 28 overall response rate (ORR) was 33% (n = 20) (complete response 18% (n = 11), partial response 15% (n = 9)). Non-relapse mortality was 72% (95% confidence interval (CI) 61-84%) and overall survival (OS) was 21% (95% CI 12-32%) at 18 months. On univariate analysis, age >60 years (HR 1.9, 95% CI 1.01-3.7, p = 0.045) and presence of liver GVHD (HR 1.9, 95% CI 1.9, 95% CI 1.5-3.3, p = 0.03) were significant predictors of poor OS while patients with LGI GVHD had superior OS than those without (HR 0.4, 95% CI 0.2-0.8, p = 0.01). On stratified analysis, patients <60 years with isolated LGI GVHD had the best outcomes with an ORR of 48% and OS of 42% at 18 months. Among older patients, OS was 14% in those with isolated LGI aGVHD and 0% in others. Pentostatin remains a viable treatment option for SR-aGVHD, especially in patients 60 years or younger with isolated LGI involvement.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Child; Child, Preschool; Female; Gastrointestinal Diseases; Graft vs Host Disease; Humans; Liver Diseases; Male; Middle Aged; Patient Selection; Pentostatin; Prognosis; Risk Factors; Salvage Therapy; Steroids; Survival Analysis; Young Adult

Patients who undergo allogeneic stem cell transplantation and subsequent radiation therapy uncommonly develop graft-versus-host disease within the irradiated area. We quantified the incidence of this complication, which is a novel contribution to the field. From 2010 to 2014, 1849 patients underwent allogeneic stem cell transplantation, and 41 (2 %) received radiation therapy afterward. Of these, two patients (5 %) developed graft-versus-host disease within the irradiated tissues during or immediately after radiation therapy.. The first patient is a 37-year-old white man who had Hodgkin lymphoma; he underwent allogeneic stem cell transplantation from a matched unrelated donor and received radiation therapy for an abdominal and pelvic nodal recurrence. After 28.8 Gy, he developed grade 4 gastrointestinal graft-versus-host disease, refractory to tacrolimus and steroids, but responsive to pentostatin and photopheresis. The other patient is a 24-year-old white man who had acute leukemia; he underwent allogeneic stem cell transplantation from a matched related donor and received craniospinal irradiation for a central nervous system relapse. After 24 cobalt Gy equivalent, he developed severe cutaneous graft-versus-host disease, sharply delineated within the radiation therapy field, which was responsive to tacrolimus and methylprednisolone.. We conclude that graft-versus-host disease within irradiated tissues is an uncommon but potentially serious complication that may follow radiation therapy in patients who have undergone allogeneic stem cell transplantation. Clinicians must be aware of this complication and prepared with strategies to mitigate risk. Patients who have undergone allogeneic stem cell transplantation represent a unique population that may offer novel insight into the pathways involved in radiation-related inflammation.

Topics: Adult; Anti-Inflammatory Agents; Antineoplastic Agents; Fatal Outcome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Immunosuppressive Agents; Leukemia, Biphenotypic, Acute; Male; Methylprednisolone; Pentostatin; Photopheresis; Radiotherapy, Adjuvant; Tacrolimus; Transplantation, Homologous; Young Adult

Extracorporeal photopheresis (ECP) and the purine analog pentostatin exert potent immunomodulatory effects. We evaluated the use of these treatment modalities to prevent GVHD in a canine model of unrelated dog leukocyte Ag-mismatched hematopoietic cell transplantation, after conditioning with 920 cGy TBI. We have shown previously in this model that 36/40 dogs given MTX alone as postgrafting immunosuppression engrafted and that 25 of 40 dogs had severe GVHD and median survival of 21 days. In the current study, nine dogs received conditioning with 920 cGy TBI and postgrafting MTX either with ECP on days -2 to -1 alone (n=5) or ECP on days -6 and -5 combined with two doses of pentostatin (days -4 to -3) (n=4). Seven of nine dogs achieved engraftment. Six dogs developed severe acute GVHD (four in the group with ECP alone and two with pentostatin and ECP). We failed to demonstrate a positive impact of ECP and pentostatin for the prevention of GVHD compared with historical control dogs.

Topics: Animals; Antineoplastic Agents; Dog Diseases; Dogs; Flow Cytometry; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Pentostatin; Photopheresis; Transplantation Chimera; Transplantation Conditioning

Topics: Acute Disease; Bone Marrow Transplantation; Boronic Acids; Bortezomib; Chronic Disease; Clinical Trials as Topic; Cyclohexanes; Cyclophosphamide; Cyclosporine; Evidence-Based Medicine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hydroxamic Acids; Immunosuppressive Agents; Maraviroc; Methotrexate; Pentostatin; Peripheral Blood Stem Cell Transplantation; Pyrazines; Quality of Life; Tacrolimus; Triazoles; Vorinostat

Acute GVHD (aGVHD) remains a major cause of mortality in patients undergoing allo-SCT. In particular, the outcome of those patients who fail first-line therapy with glucocorticosteroids is poor. Preliminary reports suggested that the purine analogue pentostatin might be effective for treatment of steroid-refractory aGVHD. Here, we report on our single-center experience with pentostatin in this condition. From 2005 to 2008, a total of 24 consecutive patients, who had undergone first-line salvage treatment for steroid-refractory aGVHD of the gastrointestinal tract with pentostatin, were identified from 301 patients allografted during that period and retrospectively analyzed. Response to treatment, defined as CR or very good PR (VGPR), was observed in nine patients (38%), with a median time to response of 10 days. Although pentostatin was associated with only moderate myelosuppressive toxicity, if any, 2-year survival was only 17% with five of the nine responders dying from infection (four patients) or recurrent GVHD (one patient). We conclude that pentostatin is a moderately effective therapy for steroid-refractory aGVHD, showing response and outcome rates similar to other clinically used regimens.

Topics: Adult; Antineoplastic Agents; Female; Gastrointestinal Diseases; Graft vs Host Disease; Humans; Male; Middle Aged; Pentostatin; Remission Induction; Retrospective Studies; Salvage Therapy; Steroids; Treatment Outcome; Young Adult

We describe a novel animal model of nonmyeloablative bone marrow transplantation (BMT) using the purine analog pentostatin. Other cohorts of mice received another purine analog, fludarabine, which we and others have previously evaluated in nonmyeloablative murine models. We evaluated pentostatin for its ability to (1) operate synergistically with cyclophosphamide to induce host T cell depletion; (2) induce host T cell suppression, as defined by modulation of cytokine secretion in vitro and abrogation of host-versus-graft reactivity in vivo; (3) constrain host T cell recovery post-therapy; and (4) prevent the rejection of T cell-depleted, fully major histocompatibility complex-mismatched bone marrow allografts. Relative to single-agent regimens, combination regimens with pentostatin and cyclophosphamide (PC) and with fludarabine and cyclophosphamide (FC) worked synergistically to deplete host CD4(+) and CD8(+) T cells. PC and FC regimens were developed that yielded similar levels of host T cell and myeloid cell depletion. In the setting of these generally comparable states of host T cell and myeloid cell depletion, the PC regimen was found to be highly immunosuppressive, as evidenced by a reduced host T cell capacity to secrete interleukin-2 and interferon-γ in vitro, to mediate host-versus-graft reactivity in vivo, and to recover numerically and functionally during a 2-week observation period after chemotherapy. Finally, using B6 hosts treated with the 14-day chemotherapy regimens, the PC regimen more consistently prevented the rejection of BALB/c T cell-depleted allografts compared with the FC regimen (rate of alloengraftment, 14/15 [93%] of PC-treated recipients vs 8/14 [57%] of FC-treated recipients; P < .05); similar results were observed using an 8-day conditioning regimen. These data suggest that host T cell suppression, distinct from T cell depletion, may be a critical determinant of engraftment after purine analog-based regimens and also may be preferentially attained by the use of pentostatin.

Topics: Animals; Antineoplastic Agents; Bone Marrow Transplantation; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclophosphamide; Drug Synergism; Female; Graft Survival; Graft vs Host Disease; Immunosuppressive Agents; Interferon-gamma; Interleukin-2; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Pentostatin; Transplantation Chimera; Transplantation, Homologous; Vidarabine

Topics: Acute Disease; Adenosine Deaminase Inhibitors; Adult; Female; Graft vs Host Disease; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Pentostatin; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Treatment Outcome; Young Adult

We present an adaptive Bayesian method for dose-finding in phase I/II clinical trials based on trade-offs between the probabilities of treatment efficacy and toxicity. The method accommodates either trinary or bivariate binary outcomes, as well as efficacy probabilities that possibly are nonmonotone in dose. Doses are selected for successive patient cohorts based on a set of efficacy-toxicity trade-off contours that partition the two-dimensional outcome probability domain. Priors are established by solving for hyperparameters that optimize the fit of the model to elicited mean outcome probabilities. For trinary outcomes, the new algorithm is compared to the method of Thall and Russell (1998, Biometrics 54, 251-264) by application to a trial of rapid treatment for ischemic stroke. The bivariate binary outcome case is illustrated by a trial of graft-versus-host disease treatment in allogeneic bone marrow transplantation. Computer simulations show that, under a wide rage of dose-outcome scenarios, the new method has high probabilities of making correct decisions and treats most patients at doses with desirable efficacy-toxicity trade-offs.

Topics: Abciximab; Algorithms; Antibodies, Monoclonal; Bayes Theorem; Biometry; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Graft vs Host Disease; Humans; Immunoglobulin Fab Fragments; Models, Statistical; Pentostatin; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Stroke; Tissue Plasminogen Activator

Chronic graft-versus-host disease (cGVHD) is a major barrier to successful allogeneic stem cell transplantation. Pentostatin has been used to treat cGVHD in a small series of pediatric patients. The authors report the results of the first five pediatric patients receiving pentostatin for refractory cGVHD at Johns Hopkins Hospital. In this early experience, the authors saw considerable symptom response in their patients. Every patient in this series demonstrated a significant improvement in skin and oral symptoms. An increased incidence of infection secondary to pentostatin was not observed. No patient was permanently discontinued from pentostatin subsequent to side effects. If these promising results continue, a trial of pentostatin as a first-line therapy for cGVHD should be considered to potentially reduce our dependence on high-dose steroids for its treatment.

Topics: beta-Thalassemia; Bone Marrow Transplantation; Child; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Male; Pentostatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Stem Cell Transplantation

Conditioning regimens have been intensified to a level at which organ toxicties are dose-limiting, which restricts the application of hematopoietic stem cell transplants to relatively young patients in otherwise good clinical condition. Studies done in a canine model have demonstrated that stable allogeneic mixed donor/host hematopoietic chimerism can be established by the administration of a sublethal dose of 2.0 Gy total body irradiation followed by immunosuppression with mycophenolate mofetil and cyclosporine after major histocompatibility complex-identical marrow transplantation. Both host-versus-graft and graft-versus-host reactions are controlled with mycophenolate mofetil and cyclosporine, which results in a stable state of graft/host tolerance manifested by stable mixed donor/ host hematopoietic chimerism. Current efforts are directed at replacing pretransplant radiation by anti-T-cell reagents, such as antibodies to T cells, or by purine antagonists, such as pentostatin (Nipent; SuperGen, San Ramon, CA). Given the minimal toxicity of this approach in dogs, a clinical study was initiated that uses an almost identical conditioning regimen. Thus far, 26 patients have been treated. Results to date indicate that this is a well-tolerated procedure that can be performed entirely in an outpatient setting. All patients have shown primary engraftment with persistence of mixed or full donor chimerism present through at least 2 months after transplant. Three patients experienced nonfatal graft rejection between 2 and 3 months after transplant, with a return to baseline peripheral counts over the subsequent 1 to 2 months. Acute graft-versus-host disease developed in 10 of 24 evaluable patients, occurring only after discontinuation of mycophenolate mofetil, and was controlled with additional immunosuppression in all cases. Overall, this novel nonmyeloablative conditioning regimen has been well tolerated and has encouraged us to investigate these transplants in other clinical settings, including using HLA-matched unrelated donors.

Topics: Animals; Bone Marrow Transplantation; Cyclosporine; Dogs; Follow-Up Studies; Graft Rejection; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; HLA Antigens; Host vs Graft Reaction; Humans; Immunosuppressive Agents; Mycophenolic Acid; Pentostatin; Purine Nucleosides; Radiation Chimera; Transplantation Chimera; Transplantation Conditioning; Whole-Body Irradiation

The combination of deoxycoformycin and deoxyadenosine was investigated for its capability to deplete T-cells from bone marrow and spleen cells and for its effect on GVHD in MHC-mismatched transplantation in rats. In vitro incubation with DCF/dADO for 18-20 hours resulted in significant but incomplete T-cell depletion without toxicity towards CFU-M. This corresponded with a lower incidence and a modification of GVHD following transplantation of such treated cells into MHC-incompatible recipient rats. However, GVHD could not be completely prevented by the in vitro treatment of donor cells.

Topics: Animals; Bone Marrow Transplantation; Coformycin; Deoxyadenosines; Dose-Response Relationship, Drug; Graft vs Host Disease; Immunosuppressive Agents; Pentostatin; Rats; Ribonucleosides; Spleen; T-Lymphocytes

Germ-free mice were used as a model for acute graft-versus-host disease (GVHD) in allogeneic bone marrow transplantation (BMT). C3H/He recipients of DBA/2 cells showed typical symptoms of acute GVHD and died within 8 days. Incubation of the cells with 10 microM 2'-deoxycoformycin (2dCF) + 100 microM deoxyadenosine (dAdo) for 1 h inhibited all T-cell functions as well as T-cell-dependent B-cell functions, but had no effect on B-cell functions that are T-cell independent, nor on the hemopoietic stem cells (CFU-S). Recipients of allogeneic cells that had been incubated with 2dCF + dAdo for 1 h prior to inoculation showed no signs, gross or histological, of acute or chronic GVHD up to 15 months after transplantation. The recovery patterns of the blood and bone marrow were not affected by the treatment, and were similar to those of recipients of treated and untreated syngeneic cells.

Topics: Animals; Bone Marrow Transplantation; Chimera; Coformycin; Deoxyadenosines; Graft vs Host Disease; Lymphocyte Culture Test, Mixed; Mice; Mice, Inbred C3H; Mice, Inbred DBA; Pentostatin; Premedication; Ribonucleosides; T-Lymphocytes; Transplantation, Homologous