Use Of Pentostatin Research Articles

Renal Function Is Preserved after Hematopoietic Stem Cell Transplantation for Sickle Cell Disease

Chronic kidney disease (CKD) is a common complication and a significant contributor to morbidity and mortality for patients with sickle cell disease (SCD). Hematopoietic stem cell transplantation (HSCT) is a curative strategy for SCD and potentially life-saving therapy. Though HSCT can reverse the SCD phenotype, acute and chronic kidney dysfunction may be an unintended consequence. The incidence of acute kidney injury (AKI) and the effect of different HSCT regimens on progression or amelioration of CKD in adults with SCD have not previously been reported. This cohort study analyzes prospectively collected data from 106 patients transplanted for SCD at the National Institutes of Health (NIH) Clinical Center, including HLA-matched sibling (N=71) and haploidentical HSCT (N=26) where nonmyeloablative conditioning was given, as well as gene therapy (N=9), where a myeloablative regimen was employed. Patients' renal function was assessed at baseline and annually thereafter for up to 3-years. We sought to define 1) the prevalence of CKD before and after HSCT 2) the incidence of CKD after HSCT 3) estimated glomerular filtration rate (eGFR) trends after HSCT 4) urine albumin to creatinine ratio (UACR) change after HSCT and 5) the incidence of AKI within 100 days of HSCT. We defined and staged AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria (stage 1: 1.5-1.9 times baseline serum creatinine increase or ≥0.3 mg/dl increase; stage 2: 2-2.9 times baseline; stage 3: 3 times baseline, increase in creatinine to ≥4.0 mg/dl, or initiation of renal replacement therapy). The baseline prevalence of CKD was 6% when defined conservatively (eGFR <60 ml/min/1.73m2); this prevalence did not change significantly post-HSCT. When using a more comprehensive definition of CKD (urine albumin to creatinine ratio (UACR) ≥30 mg/g OR eGFR <60 ml/min/1.73m2), 48% had CKD at baseline, 62% at 1 year, 55% at 2 years, and 55% at 3 years (with p=0.02, 0.26, 0.54 for longitudinal model comparing post-HCST prevalence to baseline). The incidence of CKD any time after HSCT was 1% and 11% according to each of these CKD definitions, respectively. 25% of participants had follow-up of ≤2 years, median follow-up was 3 years. The median eGFR remained within the normal range throughout the follow-up period but declined annually: the baseline median eGFR was 139.7 ml/min/1.73m2 and declined by 7.6, 11.6, and 20.9 ml/min/1.73m2 each year post-HSCT (p<0.0001). In an adjusted regression analysis, there was no association of gender, engraftment status, transplant regimen, or conditioning agent- specifically use of pentostatin, total body irradiation, or post-transplant cyclophosphamide- with worsening eGFR (p>0.05 for each variable). This eGFR trend represents an improvement in renal function toward the normal range: there was a statistically significant decrease in hyperfiltration (eGFR ≥150 ml/min/1.73m2), which was present in 34% patients at baseline but steadily declined to 12% by 3 years post-HSCT (p = 0.0006 for adjusted longitudinal model). There was a corresponding increase in patients with normal eGFR (60-149 ml/min/1.73m2) from 60% at baseline to 80% at 3 years post-HSCT. UACR showed an increase in the year following transplant that subsequently dissipated. Median UACR at baseline was 24.3 mg/g with annual follow-up median values of 62.2, 38.9 and 36.2 mg/g (p-values of 0.007, 0.41, and 0.69 for comparison to baseline from regression model of log transformed UACR). In our cohort, 58% of patients experienced AKI in the first 100 days post-HSCT; which is consistent with previous data. 77% of those were mild, stage 1; 13% were moderate, stage 2; and 10% were severe, stage 3 AKI. This study demonstrates that HSCT in patients with SCD is not associated with a significant increase in CKD incidence or prevalence at 2 and 3 years post-HSCT. While there is a substantial decline in eGFR from baseline to each annual follow-up, the proportion of patients whose eGFR was in the normal range increased and the prevalence of hyperfiltration decreased. The stability of UACR after an initial increase at the 1-year time point further suggests that even more mild renal damage may stabilize after transplant. Finally, AKI occurred in over half of the patients in our cohort, though the preponderance developed mild AKI. Disclosures Diamantidis: United Health Group: Membership on an entity's Board of Directors or advisory committees.

Pentotstatin/TBI Conditioning Is Well-Tolerated and Permits Engraftment of a Second Allogeneic Stem Cell Transplant Following Primary or Secondary Rejection of an Allogeneic Hematopoietic Stem Graft

Introduction: Graft failure remains a major obstacle to the success of allo-HSCT. Rates of graft failure are reported to be 2% in recipients of HLA identical grafts, 9% in those with an unrelated donor, and up to 12.3% in those with an HLA-mismatched related donor (0-3 antigen mismatched). Graft failure is associated with high mortality due to prolonged cytopenia's leading to significant anemia, bleeding, and infection. Successful management of graft failure usually requires a second transplant to restore normal hematopoiesis. The selection of a preparative regimen presents a challenge in these patients who have recently undergone myelosuppressive therapy prior to the failed transplant maneuver. We have employed the use of a minimally myelosuppressive regimen consisting of a single dose of pentostatin with a low dose of total body irradiation (TBI) as conditioning prior to a second allogeneic transplant for patients who experienced primary graft rejection. Methods: Under an IRB-approved retrospective study, we describe 4 consecutive patients with graft failure after allogeneic stem cell transplantation, who received a re-conditioning regimen consisting of pentostatin and low-dose TBI prior to second allo-HSCT. The median age of patients was 38 years (23-51). The conditioning regimens of the first transplant were myeloablative doses of cyclophosphamide/rabbit ATG; busulfan/fludarabine rabbit ATG/; busulfan/fludarabine; and fludarabine/melphalan (Table 1). Median cell doses for the first transplant were 7.7 x 10E6 CD34+ cells/kg and 104 x 10E6 CD3+ cells/kg. Two patients had primary graft rejection and 2 patients had secondary graft rejection. Patients with secondary graft rejection had initial hematopoietic engraftment of neutrophils on a median of 21 days and platelets on a median 61 of days post-transplant with subsequent declines in peripheral blood counts and chimerism studies showing loss of donor cell engraftment. The donor for the second transplant was the same in one patient and different in three patients and included a HLA-matched sibling in 2/4 patients and HLA-matched unrelated donor (URD) in 2/4 patients. One patient had two transplants from the same donor followed by a third transplant from a different HLA matched sibling donor. Conditioning for the second transplant in these cases consisted of pentostatin 4 mg/m2 as a single dose on day -3 and two fractions of 200 cGy TBI on days -2 and -1 as shown in Table 2. Results: Patients underwent the second (or third) donor allogeneic transplant at a median of 99 days following the first transplant. The second donor allograft contained a median of 9.6 x 10E6 CD34+ cells/kg and 390 x 10E6 CD3+ cells/kg. All recipients of the pentostatin-TBI conditioning regimen engrafted following transplantation of allogeneic stem cells (Table 2). Engraftment following the second transplant (or third transplant, in patient #1) occurred at a median of 22 days for neutrophils and 54 days for platelets, and all patients achieved 100% myeloid and lymphoid chimerism. Patients did not experience VOD/SOS or have severe mucositis, enteritis, or pulmonary toxicity, and were hospitalized a median of 39 days from the second transplant. All four patients achieved normal blood counts following the second transplant. One patient died unexpectedly of an apparent infection following full donor hematopoietic reconstitution. Three of the four patients undergoing a second transplant using pentostatin/TBI conditioning are alive without evidence for disease relapse or graft rejection at a median follow-up of 3.5 years, with none of these patients experiencing severe acute or chronic GvHD. Conclusion: Single dose pentostatin combined with low-dose TBI represents an effective and well-tolerated conditioning regimen that facilitates engraftment of a second allogeneic transplant in patients who experienced primary or secondary graft rejection. The enhanced therapeutic efficacy of this reduced-intensity regimen that allowed consistent donor-derived hematopoietic engraftment after initial allo-graft rejection warrants further study. Disclosures Langston: Astellas Pharma: Other: Research Support; Incyte: Other: Research Support; Jazz Pharmaceuticals: Other: Research Support; Chimerix: Other: Research Support; Takeda: Other: Research Support; Kadmon Corporation: Other: Research Support; Novartis: Other: Research Support; Bristol Myers Squibb: Other: Research Support. Waller:Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: the use of pentostatin as part of a conditioning regimen

Randomized Phase II Trial of Pentostatin, Cyclophosphamide, and Rituximab with or without Concurrent Avastin for Previously Untreated B-Chronic Lymphocytic Leukemia (CLL)

BACKGROUND: Although chemoimmunotherapy (CIT) has improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 40-50% of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays. Interactions with nurturing environments can enhance CLL B-cell resistance to apoptosis. These interactions include cytokine mediated prosurvival signals by angiogenic molecules, such as VEGF and bFGF that nurture CLL B-cells in an autocrine fashion and promote CLL cell survival partly through up regulation of anti-apoptotic proteins. These findings provide a strong rationale for testing anti-VEGF therapy in combination with a purine nucleoside analogue CIT regimen for upfront treatment. We conducted a randomized phase 2 CIT trial using pentostatin, cyclophosphamide, and rituximab with (PCR-B) or without (PCR) bevacizumab (B), an anti-VEGF monoclonal anti-body.METHODS: Eligible patients were previously untreated and had CLL in need of treatment by NCI-WG criteria (Blood 111:5446). Patients were randomized using a dynamic allocation procedure stratifying for stage (0-II vs. III-IV) and FISH (17p or 11q deletion vs. other) to receive either 6 cycles of rituximab (100 mg on day 1 of cycle 1; 375 mg/m2on day 2 of cycle 1 and day 1 of cycles 2-6) followed by pentostatin (2 mg/m2) and cyclophosphamide (600 mg/m2) (PCR) administered every 21 days. Patients in the PCR-B cohort also received bevacizumab 15mg/kg on day 1 of cycles 1-5 and days 1, 22, & 43 of cycle 6. All patients underwent complete response evaluation 3 months after day 1 of cycle 6 (or last cycle of treatment for those completing < 6 cycles). MRD was assessed using 6-color flow cytometry (Leukemia 21:956) at the completion of treatment.RESULTS: 68 patients were enrolled through the Mayo Clinic Cancer Research Consortium between 1/2009 and 1/2013. Three patients were excluded from analysis: 1 patient canceled prior to treatment, 1 was dosed incorrectly, and 1 was ineligible due to immunophenotyping inconsistent with CLL. Median age of eligible patients was 63 years (range 43-81) and 43 (66%) were men. With respect to disease stage, 3 (5%), 38 (58%), and 24 (37%) had low, intermediate and high Rai stage disease. Eleven (17%) patients had deletion 17p or 11q & 29 (45%) had unmutated IGHV. No statistically significant differences were observed in these variables by treatment arm.All 65 evaluable patients have completed active treatment, with 54 (83.1%) completing the intended 6 cycles (PCR group 27/32 [84.4%] and PCR-B 27/33 [81.8%]). Hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 10 (31.3%) patients on PCR and 12 (36.4%) on PCR-B (p=0.79).Non-hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 9 (28.1%) patients on PCR and 18 (54.4%) on PCR-B (p=0.04). The most common such events were hypertension (PCR: 3.1% vs. PCR-B: 21.2%), proteinuria (0% vs. 6.1%) and creatinine increase (3.1% vs. 6.1%).Across both arms, 64/65 (98.5%) patients achieved a response including 31/32 (96.9%) treated with PCR and 33/33 (100%) treated with PCR-B (p=0.49). CR/CRi was achieved in 10/32 (31.3%) patients treated with PCR & 18/33 (54.5%) treated with PCR-B (p=0.08). Of the 28 who achieved a CR/CRi, MRD analysis was completed on 26, of whom 12 (46%) were MRD negative. With respect to treatment arm, 5/32 (16%) patients on PCR and 7/33 (21%) on PCR-B achieved an MRD negative CR.Median time to retreatment for all 65 patients was 44.8 (95% CI: 34.6 – NA) months. Median overall survival has not yet been reached. With current follow-up no differences between treatment-free survival (p=0.38), progression-free survival (p=0.23), or overall survival (p=0.45) are observed by treatment arm.Plasma levels of angiogenic cytokines VEGF, bFGF, thrombospondin (TSP) and the chemokines CCL3 and CCL4 were measured prior to treatment and at the time of the post treatment response evaluation. Correlations of these cytokines with clinical outcome will be presented.CONCLUSION: The addition of bevacizumab to purine analogue-based CIT was generally well-tolerated and may increase complete remission rates in patients with CLL. No clear improvement in treatment free survival has been observed to date. DisclosuresShanafelt:Hospiria: Research Funding; Pharmacyclics/Jannsen: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; glaxoSmithKline: Research Funding; Genetech: Research Funding; Polyphenon E Int’l: Research Funding. Off Label Use: Off label use of pentostatin for treatment of CLL. Off label use of bevacizumab for treatment of CLL. . Kay:Genetech: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees; Gilead: Membership on an entity’s Board of Directors or advisory committees.

Ofatumumab Based Chemoimmunotherapy (CIT) for Patients with Previously Untreated CLL,

Abstract 3898 Background:Although chemoimmunotherapy (CIT) has substantially improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 4050 of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays. There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a humanized anti-CD20 monoclonal antibody that is approved for patients with relapsed CLL refractory to fludarabine and alemtuzumab. The single agent activity of ofatumumab in patients with refractory CLL suggests it may have greater efficacy than rituximab in patients with CLL. To explore the efficacy of ofatumumab based CIT, we initiated a clinical trial studying the effect of ofatumumab in combination with pentostatin and cyclophosphamide (PCO) for patients with previously untreated CLL. METHODS:Eligible patients were previously untreated and had CLL in need of treatment according to the NCI-WG criteria (Blood 111:5446). The treatment schema included 6 cycles of ofatumuamb (300 mg on day 1 of cycle 1;1000 mg on day 2 of cycle 1 and day 1 of cycles 26) followed by pentostatin (2 mg/m2) and cyclophosphamide (600 mg/m2) administered every 21 days. All patients underwent complete response evaluation including evaluation for MRD using sensitive flow cytometry (Leukemia 21:956) at the completion of treatment. RESULTS:33 patients were enrolled at Mayo Clinic and Duke University between 3/2010 and 9/2010. All patients were eligible for treatment and have completed active treatment. Clinical characteristics included: 76 male, median age 63 (range: 5083); intermediate Rai risk 27; and high Rai risk 73. On prognostic testing 33 were CD38, 48 Zap-70, 58 IGHV unmutated, and 6 had high risk FISH (del 17p13; del 11q22).26 of 33 eligible patients (79) completed all 6 cycles of PCO induction. Seven patients went off treatment early (toxicity: n5; refusal: n1; progression: n1). Adverse events deemed at least possibly related to PCO induction included 8 (24) patients with grade 3 hematologic toxicity and 5 (15) with grade 3 non-hematologic toxicity.The overall response rate to PCO induction was 94 (31/33) with 15 (45) CR/CRi, 5 (15) CCR, 9 (27) nPR, and 2 (6) PR. 2/10 (20) patients with CR's tested for MRD were also MRD negative by 6 color flow cytometry analysis.Finally, we compared this cohort of patients treated with ofatumuamb-based CIT to our prior 108 patient cohort of patients treated with rituximab-based CIT both of which used an identical chemotherapy backbone (pentostatin and cyclophosphamide). Although the age, gender, ALC, and prognostic profile (CD38, ZAP-70, and IGHV mutation status) of treated patients were similar (all p0.3), the ofatumumab cohort included more advanced stage patients (Rai stage III/IV: 73 vs. 41 p0.002). Ofatumumab-based CIT appeared to be better tolerated than our previous experience with rituximab-based CIT (grade 3 hematologic toxicity ofatumumab-CIT 24 ▪ vs. rituximab-CIT51 ▪, p0.009; grade 3 non-hematologic toxicity ofatumumab-CIT 15 ▪ vs. rituximab-CIT 24 ▪, p0.34). Despite a higher proportion of Rai Stage III/IV patients in the ofatumumab cohort, the efficacy of ofatumumab-based CIT also compared favorably to our previous experience with rituximab based CIT (Table). CONCLUSION:Front-line ofatumumab-based CIT appears to be well-tolerated in patients with CLL. Compared to our historic experience with rituximab based CIT, ofatumumab-based CIT appeared to have less hematologic toxicity and improved efficacy. This trial has been expanded to provide a larger experience with ofatumumab-based CIT.ofatumumab-CITTFU1-1 n33 N ()rituximab-CITTFU1-1 n108 N ()ORR31 (94)99 (92)CR/CRi15 (45)40 (37)CCRTFU1-25 (15)4 (4)nPR9 (27)30 (28)PR2 (6)25 (23)SD/PROG2 (6)9 (8)CR/CRi/CCR20 (61)44 (41)TFU1-1both CIT cohorts included an identical chemotherapy platform of pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2) on day 1 of every cycleTFU1-2response bone marrows pending/unavailable Disclosures:Shanafelt:Hospira: Research Funding; Glaxo-Smith-Kine: Research Funding; Genentech: Research Funding. Off Label Use: Off label use of pentostatin and Ofatumumab. Lanasa:GlaxoSmithKline: Consultancy, Speakers Bureau. Zent:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding. Tun:Celgene: Research Funding. Kay:Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity's Board of Directors or advisory committees.

Lenalidomide Consolidation Appears to Prolong Time to Retreatment After First-Line Chemoimmunotherapy for Patients with Previously Untreated CLL,

Abstract 3899 BACKGROUND:Although chemoimmunotherapy (CIT) has substantially improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 40–50% of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays for minimal residual disease (MRD). While these facts generated interest in consolidation strategies for patients with residual disease, previous trials of alemtuzumab-based consolidation found excess morbidity/mortality. In 2008 we began a trial of lenalidomide-based consolidation for patients with previously untreated CLL who had received 6 cycles of CIT induction. Preliminary analysis suggested that lenalidomide consolidation may improve the quality of response and prolong time to retreatment (Shanafelt; ASH 2010), although follow-up was short (median 16 months). METHODS:Eligible patients were previously untreated and had CLL in need of treatment according to the NCI-WG criteria (Blood 111:5446). Treatment schema consisted of 6 cycles of pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2) and rituximab (375 mg/m2) given every 21 days (Blood 109:405). All patients completing 6 cycles of PCR induction, underwent complete restaging including evaluation for MRD using sensitive flow cytometry. Patients subsequently received 6 months of lenalidomide consolidation by daily administration with a starting lenalidomide dose of 5 mg/day and escalation to 10 mg/day after the first cycle as tolerated. Patients again underwent complete restaging including MRD evaluation after 6 months of lenalidomide. At the time of restaging, MRD negative patients entered observation. Those with residual disease continued on lenalidomide and underwent repeat MRD assessment every 3 months until an MRD negative state was achieved. RESULTS:45 patients were enrolled at Mayo Clinic between 3/2008 and 12/2009 of whom 44 were eligible. Median age was 65 (range: 44–78) and 71% of patients were male. 61% of patients had intermediate Rai risk and 39% high Rai risk. On prognostic testing 32% were CD38+, 52% Zap-70+, 52% IGHV unmutated, and 16% had high risk FISH (del 17p13; del 11q22). Of the 38 eligible patients who completed 6 cycles of PCR induction, 34 (89%) initiated lenalidomide consolidation. Thus by intent to treat analysis, 34/44 (77%) patients starting CIT with PCR were able to receive consolidation therapy.Among the 34 patients who initiated consolidation, the median number of cycles of lenalidomide received was 6 (range: 1–29). Nine of 34 (26%) patients had the lenalidomide dose increased to 10 mg daily while 18 (53%) required a reduction to 5 mg every other day. Five patients are still on lenalidomide at the time of this report. No cases of tumor lysis syndrome or tumor flare reaction were observed. Adverse events deemed at least possibly related to lenalidomide consolidation included 23 (68%) patients with grade 3+ hematologic toxicity and 5 (15%) with grade 3+ non-hematologic toxicity.Among the 34 patients who received at least 1 cycle of lendalidomide, 6 patients have improved the quality of their response including 3 patients who converted from having residual disease to a MRD- state. After a median follow-up of 29 months, 39/44 patients are alive and the median duration of response has not been reached. To date 8/44 (18%) patients have progressed to require additional treatment.Finally, since the eligibility criteria were nearly identical to our historic trial of PCR without lenalidomide consolidation, we conducted an intent to treat analysis that compared all 44 patients in the present trial (i.e. regardless of whether they received lenalidomide consolidation) to the 64 patients previously treated on our PCR trial (Blood 109:405). The demographic and prognostic characteristics of patients in the two studies were similar. With the caveat it represents a comparison across phase II trials, the proportion of patients free of retreatment at 30 months was 79% (95% CI:67–93) for PCR followed by lenalidomide consolidation vs 66% (95% CI: 54–80) for PCR alone (Figure 1). [Display omitted] CONCLUSION:Lenalidomide-based consolidation for CLL patients receiving first-line CIT induction appears to improve the quality of response and prolong time to retreatment. Randomized clinical testing of lenalidomide-based consolidation appears warranted. Disclosures:Shanafelt:Celgene: Research Funding; Hospira: Research Funding; Genentech: Research Funding. Off Label Use: PCR-Lenalidomide (off label use of pentostatin and lenalidomide). Tun:Celgene: Research Funding. Kay:Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity's Board of Directors or advisory committees.

Long term outcome of patients with steroid‐refractory acute intestinal graft versus host disease after treatment with pentostatin

Long term outcome of patients with steroid‐refractory acute intestinal graft versus host disease after treatment with pentostatin

The Pentostatin Plus Cyclophosphamide Nonmyeloablative Regimen Induces Durable Host T Cell Functional Deficits and Prevents Murine Marrow Allograft Rejection

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.

Pentostatin for First-Line Salvage Therapy of Steroid-Refractory Intestinal Acute Graft-Versus-Host Disease; a Dual Center Retrospective Analysis

AbstractAbstract 1274Acute graft-versus-host disease (aGvHD) of the gastrointestinal (GI) tract remains a major complication after allogeneic stem cell transplantation. The outcome of patients who fail first-line therapy with steroids is poor. There is no standard therapy for steroid-refractory aGvHD. A promising strategy is the use of pentostatin, an inhibitor of adenosine deaminase. The capacity of this purine analogue to inhibit proliferation and to induce apoptosis of T-cells in combination with its mild toxicity resulted in the approach to use pentostatin in steroid-refractory aGvHD. Here we report on our experience with pentostatin in steroid-refractory aGvHD at the universities of Frankfurt (F) and Heidelberg (H). Patients:From 2000 to 2009 (F) and from 2005 to 2009 (H) a total number of 72 (F: n=39; H: n=33) consecutive patients who had undergone first-line salvage treatment of histologically proven severe steroid-refractory aGvHD of the GI-tract with pentostatin were retrospectively analyzed. Steroid-refractory aGvHD was defined as progression or no improvement of diarrhea despite a treatment with prednisolone (≥2mg/kg/d) for ≥ 3 days. In steroid-refractory aGvHD pentostatin was infused at a dose of 1mg/m2 for 3 consecutive days. Patients received 1–4 cycles. Response after therapy with pentostatin was classified as complete (CR, no ongoing symptoms of GvHD), very good partial (VGPR, residual symptoms only) or no response (NR). 31 females and 41 males with a median age of 48 (range: 20–68) years were included. The underlying diseases were AML (n=43), ALL (n=10), CML (n=1), lymphoma (n=7), MDS (n=6), and multiple myeloma (n=5). The conditioning regimen was myeloablative in 25 patients and reduced intensity in 47 patients. Patients were transplanted with peripheral blood stem cells (except one bone marrow transplantation) from matched siblings (n=26), matched unrelated (n=27) or mismatched donors (n=19). All patients suffered from severe steroid-refractory intestinal aGvHD overall grade III (n=39) or IV (n=33). Results:39 patients (54%) responded to pentostatin. 30 patients (42%) achieved CR, 9 patients (12%) VGPR. Clinical improvement occurred within a median of 13 (range: 5–58) days after the first infusion of pentostatin. 33 patients (46%) did not respond. After a median follow up of 27 (range 10 to 108) months 23 patients (32%) are alive. 49 patients (68%) died (53% therapy related, 15% due to relapse of the malignant disease). 59% of the 39 responding patients versus 0% of the non-responders survived. 10 patients without response to pentostatin received further salvage therapies including alemtuzumab, infliximab, rituximab, tacrolimus, etanercept or mesenchymal stem cells (MSC). All these patients died without response. 26 patients (36%) achieved CR or VGPR after one cycle of pentostatin. 24 patients without CR or VGPR after one cycle were treated with 1–3 further cycles. The probability of survival was significantly higher for patients who responded after one cycle in comparison with patients without response and further pentostatin treatment (73% versus 13%, p<0.01). Thus, further immunosuppressive therapy beyond one cycle of pentostatin has almost no positive impact on survival. Except one patient who died 4 years after pentostatin due to relapse of lymphoma all one-year-survivors stayed alive. Conclusions:In the critical clinical situation of severe steroid-refractory intestinal aGvHD pentostatin conferred encouraging rates of response and overall survival. In comparison with other treatment options such as MSC or immunosuppressive monoclonal antibodies pentostatin has some favorable characteristics: Its effect is sustainable; the majority of responding patients survived. Costs for pentostatin are relatively low and toxicity is moderate. However, despite therapy with pentostatin mortality in steroid-refractory aGvHD is still unacceptably high. Since response rates and survival after other therapies are even less convincing we suggest using pentostatin as salvage therapy in severe steroid-refractory intestinal aGvHD. Disclosures:Klein:Hospira: Honoraria.

Treatment of AML in First Remission (CR1) with Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Using Unrelated Donors (UD).

Introduction/Methods: A key component of improving the success rate of allogeneic HSCT for AML in CR1 is to reduce non-relapse mortality (NRM), which, if excessive, will deny the benefit of the graft-versus-leukemia effect. UD HSCT has traditionally been associated with high NRM rates. We reported previously on the significant reduction of NRM using the conditioning regimen of fludarabine 40mg/m2, IV busulfan 130 mg/m2 for 4 days and thymoglobulin. Here we analyze the outcomes of all patients (n=37) with AML in CR1 treated with this regimen and UD HSCT in our institution from January 2002 to December 2007. High-resolution allele level HLA typing was performed for all donorrecipient pairs for HLA-A, -B, -C, DRB1 and DQB1; up to one mismatch was allowed (9/10). Median follow up is 30 months (range, 9–72).Results: Median age was 48 years (range, 13–68); 30% (n=11) were older than 54 years and 51% (n=19) were male. Eleven patients (30%) had secondary AML. Prognostic cytogenetics classification was poor and intermediate in 53% and 47% of the cases, respectively. Stem cell source was bone marrow (BM) in 68% (n=25) and peripheral blood (PB) in 32% (n=12). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methotrexate with and without pentostatin (1 or 1.5 mg/m2 on days 8, 15, 22 and 30) in 46% (n=17) and 54% of the cases (n=20), respectively. Donor-recipient HLA match was 9/10 and 10/10 in 14% and 86% of the cases. Median infused total nucleated and CD34+ cells was 3.72 x 108 (range, 0.57 – 11.78) and 3.77 x 106 (range, 0.45 – 12.4), respectively. Median time to neutrophil and platelet engraftment was 12 days (range, 8–18) and 14 days (range, 8–101), respectively. All but one patient engrafted. Grade II–IV acute (a) GVHD rate was 13% (n=2) and 50% (n=10) for patients that received and not received pentostatin-based prophylaxis. Grade III–IV aGVHD rate was 0% versus 15% (n=3) for patients receiving and not receiving pentostatin. Chronic GVHD was diagnosed in 55% (n=18) of all patients (extensive in 10). 100-day and 3-year NRM rate was 11% (n=4) and 20% (n=4), respectively, and was due to engraftment failure (n=1) and aGVHD (n=3). Eight patients (22%) have relapsed, and 8 (22%) have died (4 of relapse, and 4 of NRM causes). Relapse rate was 18% (3/17) and 25% (5/20) for patients that received and not received pentostatin as part of GVHD prophylaxis. Actuarial 3-year event-free and overall survival (figure) is 68% and 78%, respectively. Actuarial 3-year overall survival for patients receiving BM and PB is 80% and 75%, respectively.Conclusion: Long-term disease control can be achieved in a significant fraction of high-risk AML patients undergoing UD transplants as described in this abstract. Use of pentostatin in this context deserves further prospective evaluation. [Display omitted]

Pentostatin in chronic lymphocytic leukemia

Background: Chronic lymphocytic leukemia (CLL) is a disease that typically afflicts older individuals with a median age of diagnosis in the eighth decade of life for which treatments available now are not curative. Although purine analogue based combinations produce complete responses (CRs) in many patients, the use of these combinations has been limited by toxicity including myelosuppression and an increased risk of infectious complications. Objective: To identify the role of pentostatin, a specific inhibitor of adenosine deaminase (ADA), in the treatment of CLL. We compare pentostatin to other purine analogues, most notably fludarabine, with regard to safety and efficacy. Finally, we review the use of pentostatin in other diseases. Methods: The scope of this review encompasses the history of treatment for CLL as well as the genesis of modern combination chemoimmunotherapy and the advantages of pentostatin within such a treatment program. Results: Combination therapy with pentostatin seems to provide response frequencies comparable to fludarabine based combinations but with less toxicity and with greater ease of administration.

Pulmonary Nocardia and Aspergillus co‐infection in a patient with chronic graft‐versus‐host disease

Immunosuppression and chronic graft-versus-host disease (GVHD) are major risk factors for the development of invasive pulmonary aspergillosis in bone marrow transplant patients. Although nocardial infections are well described in hematopoietic stem cell transplantation (HSCT) recipients, little information is available about the incidence of nocardiosis in patients with chronic GVHD after HSCT. Coexistence of invasive pulmonary aspergillosis and nocardiosis following non-myeloablative HSCT has not been reported previously. With the increasing use of pentostatin in the treatment of chronic GVHD in future and other nucleoside analogues as preparative regimens in patients undergoing reduced-intensity conditioning transplantation, the possibility of co-infection with rare organisms should be kept in mind while assessing at-risk patients.

Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia

AbstractBuilding on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (> 70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.

Long Term Outcome of Patients with Steroid Refractory Acute Intestinal Graft Versus Host Disease after Treatment with Pentostatin.

Steroid refractory intestinal acute Graft versus Host Disease (aGvHD) is a mayor complication after allogeneic hematopoietic cell transplantation. Survival rate of severe intestinal aGvHD is low. No therapy has been proven to increase the survival rate in steroid refractory aGvHD so far. A promising strategy is the use of pentostatin, a purine nucleotide analogue and inhibitor of adenosine deaminase, which is known to decrease function and number of lymphocytes. Here we report the six year follow-up of a pilot study on salvage therapy of aGvHD by pentostatin. We treated 18 patients with steroid refractory intestinal aGvHD stage III or IV with Pentostatin (8 female and 10 male patients). The mean age was 45 (range: 25–61 years). The underlying diseases were ALL (4), AML (10), Multiple Myeloma (2), Hodgkin's Disease (1) and CML (1). Eight patients were allografted with HLA-identical sibling donors, three with related donors with a single HLA class I mismatch, seven with matched unrelated donors. All patients were allografted with peripheral blood stem cells. As GvHD prophylaxis ciclosporine A in combination with mycophenolate mofetil or methotrexate were used. Eleven patients had aGvHD stage III, seven stage IV. All patients had a severe gastrointestinal-tract involvement (grade III or IV). After failure of steroid treatment (prednisolone >2 mg/kg for at least 3 days) pentostatin was applied as a salvage therapy (1 mg/m2 for three consecutive days). Eight patients received between one and three further courses of pentostatin every three to four weeks. Therapy was well tolerated. No severe neutropenia was observed. Except one case of hemolytic uremic syndrome (HUS) no impairment of renal function was observed. Eleven patients achieved a complete, five a partial remission of aGvHD. Time until a clinical improvement could be observed was 12–14 days. Two patients died before day 12 without improvement of GvHD symptoms. Seven patients (39%) are alive (510–2060 days post first cycle of pentostatin), two with extensive chronic GvHD. All one-year-survivors stayed alive. Eleven patients died (two due to relapse of leukemia, nine transplant related [1 x interstitial pneumonitis, 1 x pneumonia, 1 x chronic GvHD, 4 x aGvHD and multiple organ failure (MOF), 1 x parvo B19 infection and MOF, 1 x HUS and MOF]). In conclusion, in this pilot study pentostatin has been demonstrated to be a highly effective and well tolerated drug for salvage therapy of steroid refractory acute GvHD with intestinal involvement. Moreover, compared with earlier studies on steroid refractory aGvHD a high rate of long term survivors could be observed. By a multicenter prospective randomised study we are currently investigating whether pentostatin can improve the outcome in steroid refractory intestinal aGvHD.

Influence of Allele Level HLA Typing on Unrelated Donor (UD) Transplantation for High Risk Myeloid Leukemias.

Donor-recipient histocompatibility is a major determinant of outcome after UD HSCT, and matching pairs by high-resolution (Hi-res) HLA typing is likely to improve results.Methods: We studied 66 pts with myeloid leukemias in complete remission (CR) transplanted with UD bone marrow (n=58) or peripheral blood (n=8) from 01/02 to 12/04. Preparative regimens were ablative [Busulfan (Bu)/Cyclophosphamide (Cy)(n=13), Cy/TBI (n=2), Fludarabine (Flu)/Bu 130 mg/m2x4 doses (n=33)] and reduced intensity [Flu/Bu 130 mg/m2x2 doses+Gleevec (n=7), Flu/Melphalan 140mg/m2 (n=11)]. ATG was given in 61 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate, with additional pentostatin in 24 pts. Hi-res typing of HLA-A, B, DRB1 and DQB1 loci was done prospectively; HLA-DPB1 and C loci were typed prospectively in 50% of cases and retrospectively in 50%. Hi-res typing was sequencing-based for HLA-A, B, DRB1, SSP-based for DRB3/4/5, DQB1 and DPB1; and SBT/SSOP-based for HLA-C. A Cox's proportional hazards regression model was used to study overall (S), event-free (EFS) and aGVHD-free survival. Variables with a p-value <0.25 by univariate analysis were included in the multivariate model (MV). Variables were age, conditioning regimen, use of pentostatin, diagnosis, cytogenetics, SC source, ABO typing, infused total nucleated cell (TNC) dose, HLA matching and GVHD.Results: Median age was 45yrs (21–72). Diagnoses were MDS (n=5), AML (n=39), and CML (n=22). 21 pts were in 1st CR, 23 pts in 2nd or 3rd CR, 22 pts in 2nd or greater chronic phase (CP) CML. 45 pts were 10/10 HLA match (HLA-A, B, C, DRB1, DQB1), and 21 had one or more mismatches. All pts engrafted neutrophils at a median of 13 days; 32 pts (48%) had gd. II–IV aGVHD and 33 pts (57%) had cGVHD. With a median follow-up of 9 mo, 44 pts are alive; 11 pts have relapsed. There were no regimen-related deaths; 100-day mortality was 13% due to aGVHD (n=7), relapse (n=1) and infection (n=1). Median S and aGVHD-free survival in 10/10 pts have not been reached. Median EFS for 10/10 pts vs others is 34 vs.9.66 mos. MV for S: age ≥60yrs (P=0.02; HR 4.17 (95%CI 1.24–14), Flu-based regimen (P=0.0004; HR 0.14 (95%CI 0.05–0.41), use of pentostatin (P=0.02; HR 0.27 (95%CI 0.09–0.78) and grade II–IV aGVHD (P=0.02; HR 3.25 (95%CI 1.19–8.88). MV for EFS: age ≥60yrs (P=0.046; HR 3.06 (95%CI 1.02–9.18), Flu-based regimen (P=0.001; HR 0.21 (95%CI 0.08–0.54) and use of pentostatin (P=0.02; HR 0.34 (95%CI 0.13–0.85). MV for aGVHD-free survival: age ≥60yrs (P=0.039; HR 3.43 (95%CI 1.06–11.1), Flu-based regimen (P=0.0027; HR 0.09 (95%CI 0.02–0.43), use of pentostatin (P=0.003; HR 0.22 (95%CI 0.08–0.6) and CP CML (P=0.004; HR 0.06 (95%CI 0.01–0.41). S and EFS for 10/10 matched pts were improved with Flu-based regimen (p=0.01), and higher infused TNC dose (p=0.02). aGVHD-free survival was improved by using reduced intensity regimens (p=0.004) and worsened by presence of 2 DPB1 mismatches (1.18 mo vs not reached; HR=3.43; p=0.08).Conclusion: A combination of donor selection by high-resolution typing, less toxic preparative regimens and improved GVHD prophylaxis can optimize outcomes in this high-risk disease context. [Display omitted]

DLA-Haploidentical Stem Cell Allografts after Anti-CD44 Therapy and Nonmyeloablative Conditioning: The Impact of Donor Lymphocyte Infusion (DLI), Pentostatin and Graft Composition on Donor Chimerism and Rejection.

Background: We previously reported that engraftment across a dog leukocyte antigen (DLA) haplotype-mismatched barrier could be achieved after nonmyeloablative conditioning with 200 cGy total body irradiation (TBI) plus post-grafting mycophenolate mofetil (MMF) /cyclosporine (CSP) when anti-CD44 monoclonal antibody (MAb), S5, is added to the regimen. However, 50% of dogs rejected their grafts after discontinuation of MMF/CSP. Here, we studied the influence of donor lymphocyte infusion (DLI), pentostatin, and graft composition in achievement of sustained full donor chimerism and prevention of rejection.Methods: Twenty-nine dogs were administered MAb S5 (0.2 mg/kg/day) from days -7 to -2, before 200 cGy TBI. Unmodified G-CSF-mobilized peripheral blood stem cells (PBSC) from DLA-haploidentical donors were infused followed by immunosuppression with MMF (5-10 mg/kg BID SQ) and CSP (15 mg/kg BID PO). Dogs in group 1 (n=8) were not given DLI and dogs in group 2 (n=5) were given 6 doses of pentostatin (4 mg/m2/dose) before TBI and no DLI. Dogs in group 3 (n=10) and 4 (n=6) received escalating doses of DLI on days +35, +63, +92. In addition, dogs in group 4 received pentostatin (4 mg/m2) 2 days prior to each infusion of DLI.Results: All dogs achieved initial engraftment between 1 to 2 weeks after transplant and survived 5 weeks or longer with mononuclear cell chimerism ranging from 2% to 98% (median 37%) on day +35. Higher cell subset levels in the PBSC graft were associated with stable donor engraftment: total nucleated cells (p=0.03), CD4+ (p=0.01), CD8+ (p=0.03) and CD14+ (p=0.009) cells. Also, there was a trend in the number of CD34+ (p=0.10) and CD3+(p=0.07) cells. Graft rejection was seen in 7 of 13 dogs without DLI (groups 1 and 2) and in 7 of 16 dogs that received DLI (groups 3 and 4). There was no statistically significant association between DLI and rejection (p=0.44). Six of 16 dogs who received DLI and 1 of 13 dogs with no DLI achieved full donor chimerism (p=0.18), yet there was no statistically significant association between the four groups (p=0.52). There was a trend for higher counts of CD4+ and CD8+ cells (p=0.08) and achievement of full donor chimerism. However, the use of pentostatin before each DLI (group 4) did not impact achievement of full donor chimerism (p>0.95). Duration of mixed chimerism was associated with higher cell subset levels of infused PBSC; CD34+ (p=0.06), CD4+ (p=0.02), CD14+ (p=0.05), CD3+ (p=0.09), CD8+ (p=0.08).Conclusions: The use of DLI with or without prior infusion of pentostatin after initial engraftment of DLA-haploidentical donor graft did not facilitate conversion to full donor chimerism, sustain mixed chimerism, or prevent graft rejection. However, the infusion of haploidentical donor PBSC graft with higher numbers of TNC, CD34+, CD3+, CD4+, CD8+ and CD14+ cells could prolong donor chimerism and prevent graft rejection.

The Impact of Rituximab in the Development of Acute Graft Versus Host Disease (GVHD) Following Allogeneic Stem Cell Transplantation (SCT) for Acute Lymphoblastic Leukemia (ALL).

We investigated the safety and efficacy of administering rituximab in combination with a standard myeloablative conditioning regimen of cyclophosphamide (Cy, 60 mg/kg daily x 2 doses) and total body irradiation (TBI, 12 Gy in four daily fractions) with allogeneic SCT in adult patients (pts) with ALL. Pts were eligible if their disease expressed CD20 in >20% blasts by flow cytometry. Rituximab was administered at 375 mg/m2 on days 6, −1, +7 and +14 following stem cell infusion. 24 pts were entered on study. The results were retrospectively compared with those of a historical control group of 31 pts receiving the same preparative regimen without rituximab. The two treatment groups had similar numbers of matched sibling and unrelated donor grafts. Pt and donor characteristics are detailed in Table 1. GVHD prophylaxis consisted of tacrolimus and methotrexate for nearly all pts in both study and control groups; 4 pts in the control group and 1 pt in the study group received pentostatin in addition to tacrolimus and methotrexate. Preliminary data suggests that pentostatin reduces the incidence of acute GVHD (de Lima et al. Blood 2004; 104:727a). The cumulative incidence of non-relapse mortality (NRM) at 2 years was 18% for the study group and 33% for the controls. There was no delay in engraftment or increased incidence of infection in pts treated with rituximab. Despite the greater use of pentostatin in the control group, the incidence of grade II–IV acute GVHD tended to be lower in pts treated with rituximab as compared to controls: 17% vs. 39%, p=0.07. The incidence of chronic extensive GVHD was not significantly different between the two groups: 37% vs. 34%, p=0.7. OS at 2 years was 45% for the study group and 38% for the controls, p=0.5. PFS at 2 years was 31% for the study group and 38% for the control group, p=0.8. Treatment outcomes are summarized in Table 1. In conclusion, our results demonstrate that the addition of rituximab to standard Cy/TBI conditioning for allogeneic SCT in ALL is associated with a relatively low rate of acute GVHD and NRM. Differences in pt characteristics preclude direct comparison. However, there is no apparent benefit for the addition of rituximab on disease relapse.Table 1Patient, Donor Characteristics, and OutcomesCy/TBI/rituximab No. ptsCy/TBI No. ptsP-valueTotal Pts2431Median Recipient Age, yrs (range30 (18–54)35 (18–53)Median Pt Age, yrs (range)138 (15–53)36 (14–54)Donor Type (%)Matched related15 (62)21 (68)Matched unrelated9 (38)10 (32)0.7Stem Cell Source (%)BM9 (38)17 (55)PB15 (62)14 (45)0.2Sex donor/pt mismatch (%)8 (33)12 (40)0.7CMV donor/pt mismatch (%)10 (43)12 (40)0.8ABO donor/pt mismatch (%)14 (58)10 (33)0.05Graft Composition, median (range)Total nucleated cells (x108/kg)4 (1–14)4 (1–9)0.6CD34+(x106/kg)5 (1–9)5 (2–8)0.9CD3+ (x106/kg)110 (8–370)37 (5–286)0.2Disease Status at SCT (%)CR16 (25)17 (54)Remission, beyond CR113 (54)7 (23)Not in Remission5 (21)7 (23)0.03Acute GVHD II–IV17%39%0.07Chronic Extensive GVHD37%34%0.7OS, 2 yrs45%37%0.5PFS, 2 yrs31%38%0.81. Donor age missing for 1 pt in each treatment group.

Therapeutic potential for transient inhibition of adenosine deaminase in systemic inflammatory response syndrome.

We sought to determine the potential usefulness of 2'-deoxycoformycin (pentostatin), an inhibitor of adenosine deaminase, as a postinsult, or prophylactic treatment for systemic inflammatory response syndrome resulting from fecal peritonitis. Prospective, randomized, controlled experiment. Small animal basic science laboratory. Male Spague-Dawley rats, weighing 300 to 350 g. Rats with fecal peritonitis (intraperitoneal cecal slurry) were treated with 1 mg/kg pentostatin intraperitoneally 24 hrs before, or intravenously when signs of illness presented (2 hrs after induction of peritonitis). Signs of illness included tachycardia, tachypnea, and leukopenia. All rats received 50 mL/kg 0.9% saline resuscitative fluid at 2 hrs. Survival to day 6 was 100% in nonseptic sham rats, but 33% in untreated septic rats. In rats given pentostatin either 2 hrs after the insult, or 24 hrs before the insult, 6-day survival improved to 81% and 78%, respectively. Histology revealed diffuse peritonitis, and evidence of systemic inflammatory response syndrome, including local and distant site vascular damage and leukocyte activation. These responses to the septic challenge were abrogated by pentostatin treatment. Return of significant amount of tissue adenosine deaminase activity by 24 hrs and later recovery of white blood cell counts argue against any potential for inappropriate immunosuppression by pentostatin. These data indicate that the novel use of pentostatin to prevent systemic inflammatory response syndrome secondary to fecal peritonitis shows uncommon promise as a therapeutic tool. All indices of systemic inflammatory response syndrome were abrogated and survival improved when pentostatin was not given until after signs of the illness became manifest. Because protection was afforded with treatment 24 hrs in advance of the inciting insult, pentostatin also has the unique potential for use as a true prophylactic agent.