Phase I trial and pharmacokinetic study of high-dose clofarabine and busulfan and allogeneic stem cell transplantation in adults with high-risk and refractory acute leukemia.

We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine with high-dose busulfan followed by allogeneic stem cell transplantation (SCT) in patients with high-risk and refractory acute leukemia. Patients received intravenous busulfan 0.8 mg/kg every 6 h on days -6 to -3 and clofarabine 30-60 mg/m(2) per day on days -6 to -2. Graft-versus-host disease prophylaxis included sirolimus plus tacrolimus (days -2 to +180). A total of 15 patients, median age 48 (30-58) years, with acute leukemia that was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1), were treated at four clofarabine dose levels: 30 (n=3), 40 (n=3), 50 (n=3) and 60 mg/m(2) per day (n=6) with busulfan. All engrafted, and the MTD was not reached. Grades 3-4 non-hematological toxicities included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), acute renal failure (n=1) and reversible elevation of aspartate aminotransferase/alanine aminotransferase (n=10). The 1-year event-free survival was 53% (95% confidence interval: 33-86%), and the 1-year overall survival was 60% (95% confidence interval: 40-91%). Given the good tolerability and promising results, we recommend clofarabine 60 mg/m(2) per day × 5 days as a phase II dose in combination with busulfan (12.8 mg per kg total dose) for further study as a myeloablative regimen for allogeneic SCT for high-risk acute leukemia.

Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia.

A total of 50 consecutive patients (median age, 57.5 years) with AML (n=30) or myelodysplasia (MDS, n=20) underwent HLA matched related donor (MRD, n=27) or unrelated donor (MUD, n=23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n=19)+/-mycophenolate mofetil (n=31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan-Meier analysis, year 1-4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P=0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.

Phase II clinical trial of arsenic trioxide with liposomal doxorubicin, vincristine, and dexamethasone in newly diagnosed multiple myeloma.

In patients with multiple myeloma, there is preclinical justification to combine arsenic trioxide (ATO and As(2)O(3)) with DVd (Doxiltrade mark, vincristine, and dexamethasone) for newly diagnosed patients. Eleven patients on this phase II trial received 0.15 mg/kg of ATO for five consecutive days followed by four cycles of DVd plus ATO with the ATO at 0.25mg/kg IV twice per week. The most common grade 3 toxicities were hyperglycemia, hyponatremia, and hypocalcemia. There were four partial and no complete responses. We could not demonstrate that the addition of ATO with this schedule improved the response rate of MM to DVd.

High-dose busulfan, cyclophosphamide, and etoposide does not improve outcome of allogeneic stem cell transplantation compared to BuCy2 in patients with acute myeloid leukemia.

SUMMARY: To reduce relapse following allogeneic transplantation for AML, intensification of high-dose busulfan/cyclophosphamide using additional agents has been investigated but with few reported comparisons. We compared an intensified regimen of etoposide (60 mg/kg), busulphan (14 mg/kg), and cyclophosphamide (120 mg/kg) (BuCyVP) with BuCy2 in 237 AML patients. No significant difference in overall outcome was observed following BuCyVP (n=127) or BuCy2 (n=110). The 5-year survival was 27.3 and 30.1% following BuCyVP and BuCy2, respectively (P=0.48). Similarly, the 5-year cumulative incidence of relapse (CIR) was 28.3 and 34.8% with BuCyVP and BuCy2 (P=0.45), respectively. On multivariable analysis, patients transplanted in CR1 (P=0.002) and from related donors (P=0.013) had longer survival, while disease status at transplant was the only factor predicting CIR (P=0.002). In a separate analysis of CR1 patients (n=56), there was no significant difference in survival (P=0.37) or CIR (P=0.87) between the two regimens. However, for more advanced disease, there was a trend towards less relapse with BuCyVP (P=0.08), which was balanced by a higher cumulative incidence of transplant-related deaths (P=0.03) compared to BuCy2, resulting in similar survival. Overall, our results do not support the use of the more intensive BuCyVP regimen over BuCy2 in either early or more advanced disease AML patients.

Chronic graft-versus-host disease: where do we go from here?

Chronic graft-versus-host disease (GvHD) remains a significant cause of late morbidity and mortality following allogeneic stem cell transplantation. However, patients with chronic GvHD are very heterogeneous, making evaluation and treatment difficult. Corticosteroids remain the most effective primary treatment of this condition. Randomized trials have not confirmed the beneficial effect of additional cyclosporine, even in patients with higher risk features. For patients failing initial therapy, no standard therapy is available. A plethora of drugs have been reported to have activity and promise in this disease. However, the majority of reports are small retrospective studies, with few prospective trials. The marked variability in the reported response rates for many of these novel agents highlights a number of problems in the evaluation and management of chronic GvHD. In addition to the heterogeneity of patients, there are no uniform definitions for treatment failure, prognostic criteria to stratify patients according to risk, or to evaluate response to treatment, which in many cases is largely subjective. The challenge ahead is to develop more uniform criteria for defining many of these important variables, which is likely to lead to the design of better prospective clinical trials to improve the outcome of patients with this condition.

Radiation-free regimens result in similar outcomes of allogeneic hematopoietic progenitor cell transplantation in patients aged >or=50 years compared to younger adults with low-risk disease.

Age >or=50 years has been reported to be an adverse risk factor for allogeneic BMT, and consequently many of these patients are either not transplanted or treated on nonmyeloablative protocols. To study if older patients perform poorly relative to younger adults following myeloablative allogeneic transplants, we compared the outcomes of consecutive adults aged >or=50 years (n=51) to those <50 years (n=262) who received BU, CY+/-etoposide and allogeneic transplantation for AML, CML, MDS and NHL from 1984 to 2000. Median ages were 53 (range 50-66) and 35 (range 18-49) years for older and younger patients, respectively. Patients were low-risk if they had AML in CR1, CML in first chronic phase, refractory anemia, or NHL in remission or sensitive relapse at the time of transplantation. All others were high-risk. In patients with low-risk disease, there was no significant difference in overall survival (OS) between older and younger adults (P=0.64), while older patients tended to have a shorter OS among high-risk patients (P=0.06). The 3-year OS was 53% (95% CI, 29-77%) compared to 60% (95% CI, 50-69%) for older and younger patients with low-risk disease, respectively. The corresponding 3-year OS were 27% (95% CI, 11-43%) and 37% (95% CI, 25-45%) for high-risk patients. In low-risk patients, the incidence of acute and chronic graft-versus-host disease, and treatment-related mortality were similar in older and younger patients, while older patients experienced more treatment-related deaths by day 100. On multivariable analysis, age >or=50 years was a significant adverse factor only when high-risk patients were considered. We conclude that when radiation-free conditioning is used, age >or=50 years is not a significant adverse risk factor for allogeneic BMT in patients with low-risk disease, and that such patients should not be excluded from conventional myeloablative approaches until the efficacy of nonmyeloablative transplantation is better established.

Clonally rearranged antigen receptor gene DNA studies in evaluation of susceptibility of neoplastic lymphocytic and plasmacytic disorders to selective loss in long-term marrow culture.

Survival of neoplastic cells of disorders involving the lymphocytic lineage in relation to normal hemopoietic cells has been investigated in long-term culture of bone marrow (LTMC) infiltrated by conditions in which a clonally rearranged B- or T-cell antigen receptor gene provided an objective marker of the neoplastic cell population. Relative amounts of clonally rearranged and germline antigen receptor gene DNA were assessed by Southern analysis of bone marrow cell DNA, before and after LTMC in studies on ten cases of non-Hodgkin's lymphoma (NHL), four of myeloma (MM), and two of chronic lymphocytic leukemia (CLL). Clonally rearranged DNA became undetectable during LTMC in 12 studies (seven NHL, four MM, one CLL), and in seven of these studies the extent of the decrease determined by densitometric analysis of rearranged and germline bands on the autoradiograms was sufficient to demonstrate that preferential loss of neoplastic relative to other cell series had taken place. At the same time, there was a net increase in normal myeloid series, to indicate that a selective adverse effect similar to that reported to operate on leukemic cells in LTMC also applied to certain malignancies involving the lymphocytic lineage. In four of the 16 studies (three NHL, one CLL), the neoplastic cells possessing clonally rearranged DNA were maintained in LTMC, demonstrating that susceptibility to this selective adverse effect was not a uniform characteristic of neoplastic lymphocytic disorders.

Fatal disseminated Scedosporium inflatum infection in a neutropenic immunocompromised patient.

Disseminated infection with the fungus Scedosporium inflatum in a neutropenic patient with non-Hodgkins lymphoma presented with the triad of muscle tenderness, papular skin lesions and fever, and progressed rapidly to a fatal outcome. This represents the first reported instance of fatal widely disseminated infection with this organism, and demonstrates that the triad of presenting clinical features, formerly reported to be pathognomic of systemic candidiasis, can no longer be regarded as specific for infection with a particular species of yeast or fungus.

Delay by internists in obtaining diagnostic biopsies in patients with suspected cancer.

OBJECTIVE: To investigate the degree and type of delays in performing diagnostic biopsies in medical patients with suspected malignancy. DESIGN: Retrospective survey of clinical histories of patients referred between January 1985 and March 1989. SETTING: Inner city teaching hospital internal medicine (non-oncologic) services. PATIENTS: Patients with gastrointestinal and lung cancers, adenocarcinoma of unknown primary site, and lymphomas were referred as inpatients by internists. Two hundred fifty-five patients were eligible, and 177 were evaluable. MAIN OUTCOME MEASURES: The number, type, and results of tests done before and after biopsy were analyzed. RESULTS: In 67% of patients the biopsied lesion was detected by the second day of evaluation; however, there was an 8- to 10-day delay before a biopsy was done. This delay was consistent across the four malignancy groups studied. Although logistic and other unavoidable delays occurred in 40% of the cases, in 60% delays could only be attributed to continued, frequently low yield, noninvasive tests. An average of 3.3 tests were made per patient, with only 24% leading to a definitive biopsy. CONCLUSION: Because of the performance of many other tests, a substantial delay exists in proceeding to biopsy during the diagnosis of cancer by internists.