A phase II multicenter study of troxacitabine in relapsed or refractory lymphoproliferative neoplasms or multiple myeloma.

Options for patients with relapsed/refractory lymphoproliferative disorders and multiple myeloma are currently limited. Troxacitabine has shown promise in preclinical studies in a variety of malignancies; hence, the current study was conducted to evaluate the activity of troxacitabine in relapsed or refractory lymphoid malignancies. This was a phase II, open-label, multinational, multicenter study of patients with relapsed or refractory lymphoproliferative disorders or multiple myeloma. Thirty-four adults were enrolled in the study and received the study drug at either 5.4 mg/m2 (n = 16) or 4.3 mg/m2 (n = 18). The dose was decided in a phase I study, during which dose escalation was carried to reach a maximum tolerated dose with an acceptable toxicity profile. Two separate phase I studies were performed in Europe and the US. Troxacitabine was administered by intravenous infusion over 30 min daily for days 1 - 5 every 4 weeks. Treatment was continued to disease progression or until the subjects met criteria for withdrawal or unacceptable toxicities were evident as outlined in the protocol. Two patients had a partial response (PR) to treatment with troxacitabine to yield an overall response rate of 13%. There were no complete responses seen with the drug. Stable disease was achieved in 15 patients (44%). All patients had at least one treatment related adverse event, which led to six withdrawals from the study. Hematologic toxicity constituted the most common adverse events. Serious adverse effects were seen in 62% of patients. None of the 13 deaths were attributed directly to troxacitabine. As a single agent, troxacitabine has limited benefit in patients with advanced lymphoproliferative disorders or multiple myeloma. Future studies will be needed to address modified dosing according to emerging pharmacokinetic and pharmacodynamic data and combination therapy which may lead to improved clinical benefit for troxacitabine in hematologic malignancies.

Evidence that donor intrinsic response to G-CSF is the best predictor of acute graft-vs-host disease following allogeneic peripheral blood stem cell transplantation.

OBJECTIVE: Risk factors of acute graft-vs-host disease (GVHD) following allogeneic bone marrow transplantation have been well described before. In this study, we tested the hypothesis that acute GVHD after allogeneic peripheral blood stem cell (PBSC) transplant might be associated with donors' responsiveness to granulocyte colony-stimulating factor (G-CSF), rather than the dose of CD34(+) cells infused. PATIENTS AND METHODS: We retrospectively analyzed mobilization and transplant data (demographic characteristics, donor blood cell subsets after G-CSF, graft composition) in 149 consecutive HLA-identical donor/recipient pairs in order to identify acute GVHD risk factors. RESULTS: In 25% of donors, G-CSF mobilization led to an outstanding response, defined as greater than 117 x 10(6) CD34(+) cells/L. Overall, incidence of grades II-IV acute GVHD was 20.1% (95% CI: 16.6-23.6). Following univariate analysis, the incidence increased significantly in recipients receiving greater than 10 x 10(6) CD34(+) cells/kg (35% vs 15%; p = 0.007), and those transplanted from outstanding mobilizers (41% vs 12%, p < 0.0001). In multivariate analysis, only transplantation from outstanding mobilizers remained significant (p = 0.02). Donor or recipient demographic characteristics and lymphocyte subsets reinfused in the graft had no impact. CONCLUSIONS: We demonstrate for the first time that donor responsiveness to G-CSF is associated with acute GVHD following PBSC transplantation. If confirmed, this correlation will help to identify recipients who could potentially benefit from improved prophylaxis. As further corollary, decreasing the dose of CD34(+) cells infused is unlikely to prevent acute GVHD. Future studies should focus on the molecular bases of interindividual discrepancies in response to G-CSF.

Is severe intestinal chronic graft-versus-host disease an indication for surgery? A report of two cases.

Chronic graft-versus-host disease (cGVHD) frequently complicates allogeneic hematopoietic stem cell transplantation (HSCT), but small bowel involvement with obstruction is rarely observed. We report two patients who underwent allogeneic sibling HSCT and developed severe cGVHD involving the small bowel, causing unremitting obstructive symptoms and malnutrition despite maximal immunosuppression. Both patients underwent ileal resection and stricturoplasties. The first patient promptly improved, and remains asymptomatic 32 months after transplant. Three weeks after the resection of 90 cm of small bowel, the second patient developed leaking stricturoplasty and peritonitis, with a relapse of chronic myelogenous leukemia in accelerated phase. Later, an enterocutaneous fistula required additional small bowel resection and ileostomy. The patient subsequently died from pulmonary infection a few weeks after the last surgical procedure. Similar to inflammatory bowel disease, these two cases highlight that surgery may be a valuable option in patients who present with obstructive severe cGVHD refractory to aggressive immunosuppression.

Acute renal failure in bone marrow transplant patients admitted to the intensive care unit.

BACKGROUND/AIMS: Review of bone marrow transplant (BMT) cases admitted to our intensive care unit (ICU) and to compare co-morbidity and outcome of BMT patients developing or not developing acute renal failure (ARF). METHODS: A case review of BMT patients admitted to the ICU (a 16-bed medico-surgical ICU in a tertiary care teaching institution) over a 4-year period. RESULTS: Between January 1994 and December 1998, 57 among 441 BMT patients (12.9%) were admitted to the ICU, mainly for respiratory distress (58%) and hypotension (32%). Forty-two patients (73.7%) presented ARF as defined as a doubling of serum creatinine. Compared to the 15 other patients, ARF patients had a higher APACHE II score (30 +/- 8 vs. 25 +/- 7, p < 0.05). For ARF vs. non-ARF patients, there was no difference in age (43.8 +/- 10.8 vs. 44.3 +/- 11.1 years), in requirement for mechanical ventilation (76 vs. 73%) and vasopressors (69 vs. 60%), and in prevalence of graft-versus-host disease (19 vs. 13%) or neutropenia (69 vs. 67%), but the prevalence of sepsis (83 vs. 60%) and liver failure (69 vs. 40%) was higher. Maximum serum bilirubin was markedly increased in ARF compared to non-ARF patients (p < 0.005). For both subgroups, no difference in the administration of potential nephrotoxic agents was identified. Usually, ARF was considered multifactorial by clinicians, with ATN being the most frequent diagnosis (55%). Maximum serum creatinine reached a mean of 330 +/- 130 micromol/l. In 74% of cases, ARF occurred concomitantly or after admission to the ICU. Oligoanuria was present in 38%, whereas polyuria was observed in 17%. Fourteen ARF patients (33%) required dialytic support. Mortality rates were significantly different in ARF vs. non-ARF patients (88 vs. 60%, p < 0.05). Predictive factors for the development of ARF were liver failure (odds ratio (OR) 5.9), low serum albumin (OR 1.2) and APACHE II score (OR 1.1), whereas variables predictive of mortality were mechanical ventilation (OR 14.8), ARF (OR 5.8), liver failure (OR 3.7), and APACHE II score (OR 1.2). CONCLUSIONS: This study confirms that ARF in BMT patients admitted to the ICU is frequent, multifactorial, related to liver failure, and that its development has a negative impact on outcome.