Peter A. Cassileth

Rituximab-CHOP Versus CHOP Alone or With Maintenance Rituximab in Older Patients With Diffuse Large B-Cell Lymphoma

PURPOSE To address early and late treatment failures in older patients with diffuse large B-cell lymphoma (DLBCL), we designed a two-stage randomized trial of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus rituximab plus CHOP (R-CHOP), with a second random assignment to maintenance rituximab (MR) or observation in responding patients. PATIENTS AND METHODS Untreated DLBCL patients who were 60 years or older were randomly assigned to R-CHOP (n = 318) or CHOP (n = 314); 415 responders were randomly assigned to MR (n = 207) or observation (n = 208). The primary end point was failure-free survival (FFS). All P values were two sided. RESULTS Three-year FFS rate was 53% for R-CHOP patients and 46% for CHOP patients (P = .04) at a median follow-up time of 3.5 years. Two-year FFS rate from second random assignment was 76% for MR compared with 61% for observation (P = .009). No significant differences in survival were seen according to induction or maintenance therapy. FFS was prolonged with MR after CHOP (P = .0004) but not after R-CHOP (P = .81) with 2-year FFS rates from second random assignment of 77%, 79%, 74%, and 45% for R-CHOP, R-CHOP + MR, CHOP + MR, and CHOP, respectively. In a secondary analysis excluding MR patients, R-CHOP alone reduced the risks of treatment failure (P = .003) and death (P = .05) compared with CHOP alone. CONCLUSION Rituximab administered as induction or maintenance with CHOP chemotherapy significantly prolonged FFS in older DLBCL patients. After R-CHOP, no benefit was provided by MR. These results, which are consistent with an additive effect of rituximab, suggest that future studies could focus on maintenance strategies with novel agents as well as new induction therapies.

Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.

The National Cancer Institute (NCI) sponsored a workshop to develop a set of standardized diagnostic and response criteria for acute myeloid leukemia (AML) clinical trials. The French-American-British (FAB) classification was retained for diagnosing AML, with the addition of patients with bone marrow morphologic features of a myelodysplastic syndrome and less than 30% bone marrow blasts, but with greater than or equal to 30% blasts in the peripheral blood. In this report, there are four important subgroups of AML not defined in the FAB classification that are discussed: undifferentiated acute leukemia, MO (AML lacking definitive myeloid differentiation by morphology or conventional cytochemistry but with ultrastructural or immunophenotypic evidence for AML), mixed lineage leukemia, and hypocellular AML. Definitions of response for clinical trials are presented to facilitate comparisons among different studies. Complete remission is considered the only response worth reporting in phase III trials, since lesser responses do not improve survival. Partial remissions may be of interest to identify active new agents in phase I and II studies. Monoclonal antibodies and cytogenetic studies are not part of the routine assessment of remission or reassessment at relapse, and their role in the evaluation of patients with AML is currently being evaluated in clinical trials. Although we recognize that some of the definitions in this report are arbitrary, generalized use of these guidelines will make results of clinical trials more comparable and interpretable.

Prolonged Granulocytopenia: The Major Risk Factor for Invasive Pulmonary Aspergillosis in Patients with Acute Leukemia

A case-control study of patients with acute leukemia was done to identify significant risk factors for invasive pulmonary aspergillosis by reviewing the medical histories of 15 cases of pathologically proven invasive pulmonary aspergillosis and 45 controls. A history of lung or sinus disease, smoking, and multiple recurrences of leukemia did not increase the risk of invasive pulmonary aspergillosis. Cases and controls received similar chemotherapeutic regimens, and exposure to aminoglycosides, carbenicillin, trimethoprim-sulfamethoxazole, or corticosteroids was not significantly associated with development of invasive pulmonary aspergillosis. Among the factors tested, only granulocytopenia was associated with development of invasive pulmonary aspergillosis. Early in the course of granulocytopenia, patients developed signs of invasive pulmonary aspergillosis at a rate of approximately 1% per day. As the duration of granulocytopenia increased, the rate increased, approximating 4.3% per day between the 24th and 36th days. Of the 13 patients remaining granulocytopenic at 28 days, 7 had developed signs of invasive pulmonary aspergillosis. For patients with acute leukemia, granulocytopenia persisting longer than three weeks is the major risk factor for developing invasive pulmonary aspergillosis.

Chemotherapy Compared with Autologous or Allogeneic Bone Marrow Transplantation in the Management of Acute Myeloid Leukemia in First Remission

BACKGROUND In young adults with acute myeloid leukemia, intensive chemotherapy during the initial remission improves the long-term outcome, but the role of bone marrow transplantation is uncertain. We compared high-dose cytarabine with autologous or allogeneic marrow transplantation during the first remission of acute myeloid leukemia. METHODS Previously untreated adolescents and adults 16 to 55 years of age who had acute myeloid leukemia received standard induction chemotherapy. After complete remission had been achieved, idarubicin (two days) and cytarabine (five days) were administered. Patients with histocompatible siblings were offered allogeneic marrow transplantation, whereas the remaining patients were randomly assigned to receive a single course of high-dose cytarabine or transplantation of autologous marrow treated with perfosfamide (4-hydroperoxycyclophosphamide). Oral busulfan and intravenous cyclophosphamide were used as preparative regimens for both allogeneic and autologous marrow transplantation. The end points were survival from the time of complete remission and disease-free survival. RESULTS In an intention-to-treat analysis, we found no significant differences in disease-free survival among patients receiving high-dose chemotherapy, those undergoing autologous bone marrow transplantation, and those undergoing allogeneic marrow transplantation. The median follow-up was four years. Survival after complete remission was somewhat better after chemotherapy than after autologous marrow transplantation (P=0.05). There was a marginal advantage in terms of overall survival with chemotherapy as compared with allogeneic marrow transplantation (P=0.04). CONCLUSIONS A postinduction course of high-dose cytarabine can provide equivalent disease-free survival and somewhat better overall survival than autologous marrow transplantation in adults with acute myeloid leukemia.

Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study.

PURPOSE Therapy of hairy cell leukemia has markedly improved. Interferon alfa-2a and pentostatin are active agents. The National Cancer Institute organized an intergroup trial to compare these agents prospectively in untreated patients. METHODS Patients were randomized to receive either interferon alfa-2a (3 x 10(6) U subcutaneously three times per week) or pentostatin (4 mg/m2 intravenously every 2 weeks). Patients who did not respond to initial treatment were crossed over. RESULTS Of 356 patients on study, 313 were eligible. Among interferon patients, 17 of 159 (11%) achieved a confirmed complete remission and 60 of 159 (38%) had a confirmed complete or partial remission. Among pentostatin patients, 117 of 154 (76%) achieved a confirmed complete remission and 121 of 154 (79%) had a confirmed complete or partial remission. Additional patients achieved criteria for complete remission, but lacked confirmatory follow-up evaluation. Response rates were significantly higher (P < .0001) and relapse-free survival was significantly longer with pentostatin than interferon (P < .0001). The median follow-up duration is 57 months (range, 19 to 82). Myelosuppression was more frequent with pentostatin (P = .013). A multivariate logistic regression analysis of the confirmed complete remissions on pentostatin showed the following factors to be important for achieving a complete remission: high hemoglobin level (two-tailed P = .024), young age (P = .0085), and no or little splenomegaly (P = .0029). CONCLUSION Both agents were well tolerated. Pentostatin produced higher response rates, and the responses were durable. Patient age and clinical status had an impact on outcome with pentostatin. Pentostatin is effective therapy for hairy cell leukemia.

Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group.

DESIGN To perform a meta-analysis of all randomized trials that compared chemotherapy (CT) alone versus combined modality treatment (CT + radiotherapy [RT]) for which individual patient data could be made available. PATIENTS AND METHODS Data on 1,740 patients treated on 14 different trials that included 16 relevant comparisons have been analysed. Eight comparisons were designed to evaluate the benefit of additional RT after the same CT (CT1 v CT1 + RT; additional RT design). Eight comparisons were designed to evaluate whether RT in a combined modality setting can be substituted by CT using either more cycles of the same CT or regimens that contain additional drugs (CT1 + CT2 v CT1 + RT or CT1 v CT2 + RT; parallel RT/CT design). RESULTS Additional RT showed an 11% overall improvement in tumor control rate after 10 years (P = .0001; 95% confidence interval [CI], 4% to 18%). No difference could be detected with respect to overall survival (P = .57; 95% CI, -10% to 4%). In contrast, when combined modality treatment was compared with CT alone in the parallel-design trials, no difference could be detected in tumor control rates (P = .43; 95% CI, -6% to 9%), but overall survival was significantly better after 10 years in the group that did not receive RT (P = .045; 8% difference; 95% CI, 1% to 15%). There were significantly fewer fatal events among patients in continuous complete remission (relative risk [RR], 1.73; 95% CI, 1.17 to 2.53; P = .005) if no RT was given. CONCLUSION Combined modality treatment in patients with advanced-stage Hodgkins disease overall has a significantly inferior long-term survival outcome than CT alone if CT is given over an appropriate number of cycles. The role of RT in this setting is limited to specific indications.

The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myelogenous leukemia in adults: an evidence-based review.

Clinical research examining the role of hematopoietic stem cell transplantation (HSCT) in the therapy of acute myelogenous leukemia (AML) in adults is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations based on the evidence are presented in Table 3, entitled Summary of Treatment Recommendations Made by the Expert Panel for Adult Acute Myelogenous Leukemia, and were reached unanimously by a panel of AML experts. The identified priority areas of needed future research in adult AML include: (1) What is the role of HSCT in treating patients with specific molecular markers (eg, FLT3, NPM1, CEBPA, BAALC, MLL, NRAS, etc.) especially in patients with normal cytogenetics? (2) What is the benefit of using HSCT to treat different cytogenetic subgroups? (3) What is the impact on survival outcomes of reduced intensity or nonmyeloablative versus conventional conditioning in older (>60 years) and intermediate (40-60 years) aged adults? (4) What is the impact on survival outcomes of unrelated donor HSCT vesus chemotherapy in younger (<40 years) adults with high risk disease?

Activity of fludarabine in previously treated non-Hodgkin's low-grade lymphoma: results of an Eastern Cooperative Oncology Group study.

PURPOSE Fludarabine (2-fluoro-arabanoside-monophosphate) is a new antimetabolite chemotherapeutic agent. We performed a multicenter, phase II study of this drug in previously treated patients with refractory or relapsed non-Hodgkins lymphoma (NHL) to determine its response rate by histologic classification. PATIENTS AND METHODS Sixty-two assessable patients were given 18 mg/m2 by intravenous (IV) bolus injection daily for 5 days, every 28 days. Forty-eight percent had previously had one chemotherapy regimen, and the remainder had had two regimens; 42% had had radiation. RESULTS Patients received 273 cycles of fludarabine chemotherapy, with a median of two cycles and ranging up to 25 cycles. Sixty patients were assessable for response, including nine complete responses (CRs; 15%) and nine partial responses (PRs; 15%). The response rate for patients with lower-grade histology was 52% (13 of 25); the greatest response rate was seen in those with follicular small cleaved-cell lymphoma, including seven of 11 treated. Five responders remain in unmaintained remission; the median survival of responders is greater than 30 months. Toxicity included mild neutropenia and a 10% incidence of grade 3 neurologic toxicity with occasional reversible visual and auditory changes. CONCLUSION Fludarabine is active in patients with previously treated NHL (particularly low-grade histologies). Future studies will examine its activity in combination with other chemotherapeutic agents in previously untreated patients.

The oral flora as a source of septicemia in patients with acute leukemia

This study was performed to determine the role of the oral cavity in causing septicemia in patients with acute leukemia. Thirty-three patients with acute nonlymphocytic leukemia were investigated prospectively via clinical, hematologic, and microbiologic techniques. The mouth was the most likely source of septicemia in seven of twelve cases. Necessary dental treatment prior to chemotherapy was accompanied by a significant reduction in the rate of septicemia. The authors conclude that oral sources of bacteremia should be eliminated prior to chemotherapy in patients with acute leukemia.

Role of fiberoptic bronchoscopy in the diagnosis of invasive pulmonary aspergillosis in patients with acute leukemia

The utility and safety of fiberoptic bronchoscopy in the diagnosis of invasive pulmonary aspergillosis in patients with acute leukemia have not been examined. The results of 21 bronchoscopic procedures in 19 patients with invasive pulmonary aspergillosis and acute leukemia were reviewed. Analysis was confined to the 16 patients who had histopathologically documented infection on biopsy or at autopsy. Fiberoptic bronchoscopy established or suggested the diagnosis of invasive pulmonary aspergillosis in eight of 16 (50 percent) patients. Transbronchial or bronchial biopsy added only one diagnosis to those obtained by bronchial washing and brushing. Although fiberoptic bronchoscopy was a safe and well-tolerated procedure in our patients with invasive pulmonary aspergillosis and acute leukemia, its success rate was only 50 percent overall, and it appeared to be even less successful when performed early in the course of the disease. Fiberoptic bronchoscopy is a useful first procedure for the evaluation of patients with acute leukemia and possible invasive pulmonary aspergillosis, but a negative result does not exclude aspergillosis. Further diagnostic procedures, including repeated bronchoscopy, or institution of empiric antifungal therapy may be warranted if the clinical suspicion of invasive pulmonary aspergillosis is high.