Viki Anders

Pentostatin in Steroid-Refractory Acute Graft-Versus-Host Disease

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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). CONCLUSION 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.

Phase II Study of Pentostatin in Patients With Corticosteroid-Refractory Chronic Graft-Versus-Host Disease

PURPOSE 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 AND METHODS 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. RESULTS 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. CONCLUSION Pentostatin has immunosuppressive effects that are currently being explored further for treatment of cGVHD.

Weight loss and malnutrition in patients with chronic graft-versus-host disease.

It is well known that weight loss occurs in patients with chronic graft-versus-host disease. However, the severity and frequency of weight loss in this population have not been adequately described. Recent data suggest that a body-mass index (BMI) below 21.9 is an independent risk factor for mortality. In our analysis we have shown that out of 93 patients with cGVHD, 43% are malnourished as evidenced by a BMI less than 21.9 and 14% are severely malnourished (BMI less than 18.5). In addition, there is a clear trend showing that patients with active, ongoing cGVHD have lower BMIs (P = 0.02). Furthermore, we show that many symptoms thought to contribute to weight loss in patients with cGVHD, such as odynophagia and oral sensitivity, are not related to weight loss in our population. We conclude that, in all likelihood, unknown causes still exist that are responsible for weight loss in this group of patients. Elevated resting energy expenditure and elevated serum tumor necrosis factor-α are potential contributors to weight loss that will be tested in future studies. We also conclude that treating cGVHD aggressively may help reverse weight loss and malnutrition, which may be independent risk factors for mortality in this population.Bone Marrow Transplantation (2002) 29, 231–236. doi:10.1038/sj.bmt.1703352

Clinical importance of confirming or excluding the diagnosis of chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation. The presentation of this disease is varied, and it requires histological confirmation for diagnosis. In addition, cGVHD can often mimic other diseases, and vice versa. We have conducted a retrospective analysis of 123 patients referred to the GVHD clinic at the Johns Hopkins Oncology Center from 1994 to 1998 with a diagnosis of active cGVHD. Of these, nine patients (7%) had no evidence of cGVHD, and 25 patients (20%) had inactive cGVHD. Many of these patients were found to have other processes accounting for their ongoing symptoms. We conclude that since the therapy for this disease has significant toxicities and since what appears to represent cGVHD may actually be another disease, correct diagnosis of cGVHD or exclusion of this diagnosis is essential.Bone Marrow Transplantation (2001) 28, 1047–1051.

Pentostatin for the treatment of chronic graft-versus-host disease in children

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.

Predonor lymphocyte infusion treatment with 5-azacytidine as salvage treatment in relapsed acute myeloid leukaemia secondary to myelodysplastic syndrome.

A 46-year-old Caucasian woman presented with acute myeloid leukaemia (AML) evolving from a myelodysplastic syndrome (MDS) with a complex karyotype [51,XX,þ X,þ 13,þ 14,þ 21,þ 22(17)/ 46,XX(5) November 1996 and 51,XX,þX, 7,þ 13,þ 14,þ 21,þ 21,þ 22(17)/ 46, XX(3) January 1997] and received induction treatment without response; thus, she received an unrelated allogeneic bone marrow transplant in 1997 for her primary refractory AML. She achieved a complete remission. Eleven years later, in July 2008, her complete blood count showed leukopenia (2200 cells/mm; absolute neutrophils 440), normocytic normochromic anaemia (haemoglobin 9.3 g/dl) and slight thrombocytopenia (139 000/mm). Bone marrow biopsy/aspirate was hypocellular with 20–30% blasts, and chromosomal analysis showed 50,XX,þX,add(2)(q37), 7, del(7)(q?22),del(9)(q13q32),þ 13,þ 14,þ 21, þ 22(11)/ 46,XX (9). She was a mixed chimera. It was decided to proceed with donor lymphocyte infusion (DLI) from the same unrelated donor after therapy with 5-azacytidine, given her history of insensitivity to chemotherapy. The patient received 75 mg/m/day for 7 days by subcutaneous injection for five cycles and achieved complete remission. A bone marrow biopsy and aspirate obtained 5 days before DLI showed normal trilineage haematopoiesis without evidence of leukaemia. DLI was given afterwards without complications. One month after the DLI, the patient had normal blood counts [white blood cells 5300 (absolute neutrophil count 2364); haemoglobin 10 g/dl; platelet count 243 000] without acute graft-versus-host disease. She developed chronic graft-versus-host disease later characterized by dry eyes and mouth as well as lichenoid skin changes requiring steroid therapy. Four months after the DLI, she had a normal bone marrow examination with a normal male karyotype (donor) and fluorescence in-situ hybridization, and her chimerism studies showed 100% donor DNA.