Curt A. Ries

Fungal infections in patients with acute leukemia

We reviewed the records of 32 patients with acute leukemia and proved invasive fungal infections to determine the clinical and pathologic characteristics of systemic mycosis in patients undergoing intensive induction chemotherapy. The incidence of invasive fungal infections among our patients was at least 27 percent, and Candida and Aspergillus accounted for the majority of these infections. Patients with systemic candidiasis generally had prolonged severe neutropenia, fever refractory to antibiotics, and evidence of mucosal colonization by fungi. At autopsy, Candida was always widely disseminated. Patients with aspergillosis generally had neutropenia, fever, and pulmonary infiltrates at the time of admission to the hospital and, at autopsy, their infections were primarily confined to the lungs. Patients infected with both Candida and Aspergillus had clinical and pathologic findings that were a combination of the features of each type of infection. A diagnosis of invasive fungal infection was established before death in only nine of the patients, all of whom had systemic candidiasis. Four of these patients were successfully treated and survived their hospitalization. The reasons for frequently misdiagnosing and unsuccessfully treating systemic mycosis in patients with acute leukemia are examined, and suggestions are made for improved management of patients at high risk for these infections. These suggestions are based upon recognition of the clinical settings in which fungal infections occur, the aggressive use of invasive diagnostic procedures, and the early empiric use of amphotericin B.

Intensified and Shortened Cyclical Chemotherapy for Adult Acute Lymphoblastic Leukemia

PURPOSE To assess the efficacy and toxicity of a new treatment program of intensified and shortened cyclical chemotherapy (protocol 8707) in adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Previously untreated adults < or = 60 years old with ALL were treated with a four-agent induction chemotherapy regimen. This was followed by cyclical postremission therapy with high-dose cytarabine/etoposide; high-dose methotrexate/6-mercaptopurine; and daunorubicin, vincristine, prednisone, and asparaginase. Maintenance chemotherapy with oral methotrexate and 6-mercaptopurine was continued for 30 months. CNS prophylaxis was given with intrathecal methotrexate in addition to the systemic chemotherapy indicated above. RESULTS Seventy-eight of 84 patients (93%) achieved complete remission. With a median follow-up of 5.6 years, 5-year event-free survival (EFS) of all remission patients is 52%. Patients with high-risk features including adverse cytogenetics, failure to achieve remission with the first cycle of chemotherapy, and B-precursor disease with WBC counts more than 100,000/microL all relapsed unless taken off study for transplantation. For patients without these high-risk features, 5-year EFS was 60%. Compared with our previous treatment regimen, results appear to be improved for patients with standard-risk B-precursor disease (5-year EFS, 66% v 34%; P =.01). CONCLUSION Intensified and shortened chemotherapy may improve the outcome for patients with ALL with B-precursor disease lacking high-risk features. Further trials of this regimen are warranted.

Candida infections in patients with acute leukemia: Ineffectiveness of nystatin prophylaxis and relationship between oropharyngeal and systemic candidiasis

Ninety‐three hospitalizations of 70 patients, who underwent induction chemotherapy for acute leukemia to determine the effectiveness of oral nystatin in preventing oropharyngeal and systemic candidiasis were reviewed. Sixty‐two percent of patients who received prophylactic nystatin and 58% of patients who did not receive nystatin developed oropharyngeal candidiasis; 11% of patients who received prophylaxis and 21% of those who did not receive prophylaxis developed systemic candidiasis. The use of oral nystatin did not significantly diminish the risk of developing either type of Candida infection. Oropharyngeal candidiasis occurred more commonly in patients who had severe and prolonged leukopenia, had received more parenteral antibiotics, and had developed chemotherapy‐induced mucositis. Systemic candidiasis developed almost exclusively in patients who had prior oropharyngeal candidiasis. Guidelines for the empiric use of amphotericin B in these patients are provided.

High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with renal insufficiency.

PURPOSE To determine the impact of high-dose cytarabine (ARA-C) (HDAC) dose modification, based on renal function, on the incidence of neurotoxicity (NT). PATIENTS AND METHODS We retrospectively analyzed the records of 256 patients treated with HDAC (> or = 2.0 g/m2 per dose) for acute myelogenous leukemia (AML) at the University of California, San Francisco (UCSF). From 1985 to 1994, a total of 358 cycles of HDAC were administered, using either a twice-daily schedule (n = 208) or a once-daily regimen (n = 48). In 1989, a dose-modification algorithm was initiated at our institution, which reduced ARA-C doses in the setting of renal insufficiency (RI). For patients with a serum creatinine (Cr) level of 1.5 to 1.9 mg/dL during treatment, or an increase in Cr during treatment (deltaCr) of 0.5 to 1.2 mg/dL, ARA-C was decreased to 1 g/m2 per dose. For patients with a Cr > or = 2.0 mg/dL or a deltaCr greater 1.2 mg/dL, the dose was reduced to 0.1 g/m2/d. RESULTS Overall, the incidence of NT was 16% (34 of 208) for patients treated with twice-daily HDAC and 0% (none of 48) for patients treated with daily HDAC (P = .003). NT occurred more often in patients treated on a twice-daily schedule with 3 g/m2 per dose compared with 2 g/m2 per dose (25% v 8%; P = .009). NT occurred in 55% of the twice-daily-treated patients with RI, compared with 7% of those with normal renal function (P = .00001). In patients with RI, NT occurred in none of 11 dose-modified cycles versus five of 11 (45%) total unmodified cycles (P = .01). None of 14 patients treated with once-daily HDAC given during RI developed NT, compared to 55% of patients (23 of 42) receiving twice-daily HDAC during RI (P = .009). By univariate analysis, NT was not associated with patient age or serum alkaline phosphatase, but NT was significantly increased in patients treated with twice-daily HDAC when the serum bilirubin was > or = 2.0 mg/dL compared with twice-daily HDAC given when the total bilirubin was less than 2.0 mg/dL (33% v 14%; P = .017). Multivariate analysis confirmed that RI was the most significant risk factor associated with the development of NT. CONCLUSION HDAC NT is strongly associated with RI. The risk of HDAC NT can be reduced by the following: (1) routinely reducing the ARA-C dose from 3 to 2 g/m2 per dose; (2) modifying the ARA-C dose based on daily Cr values; and (3) administering HDAC on a once-daily rather than twice-daily schedule.

Autologous stem cell transplantation for acute myeloid leukemia in first remission

We studied the feasibility, toxicity, and efficacy of a 2-step approach to autologous stem cell transplantation for patients with acute myeloid leukemia in first remission. Step 1 consisted of consolidation chemotherapy including cytarabine 2000 mg/m2 twice daily for 4 days concurrent with etoposide 40 mg/kg by continuous infusion over 4 days. During the recovery from this chemotherapy, peripheral blood stem cells were collected under granulocyte colony-stimulating factor stimulation. Step 2, autologous stem cell transplantation, involved the preparative regimen of busulfan 16 mg/kg followed by etoposide 60 mg/kg and reinfusion of unpurged peripheral blood stem cells. A total of 128 patients were treated. During step 1, there was 1 treatment-related death. A median CD34+ cell dose of 14 (x10(6)/kg) was collected in 3 aphereses. Ten patients suffered relapse before transplantation, and 117 patients (91%) proceeded to transplantation. During step 2, there were 2 treatment-related deaths, and 35 patients subsequently suffered relapse. With median follow-up of 30 months, 5-year disease-free survival for all patients entered in the study is projected to be 55%. By cytogenetic risk group, 5-year disease-free survival is 73% for favorable-risk patients, 51% for intermediate-risk patients, and 0% for poor-risk patients. We conclude that this 2-step approach to autologous transplantation produces excellent stem cell yields and allows a high percentage of patients to receive the intended therapy. Preliminary efficacy analysis is very encouraging, with outcomes that appear superior to those of conventional chemotherapy.

A randomized trial of high- vs standard-dose mitoxantrone with cytarabine in elderly patients with acute myeloid leukemia.

To evaluate the efficacy and tolerability of a high-dose mitoxantrone-based induction regimen without consolidation therapy in patients over age 60 with newly diagnosed acute myeloid leukemia (AML), 54 patients aged 60–83 were randomized to receive mitoxantrone, either 80 mg/m2 on day 2, or 12 mg/m2 on days 1–3 in addition to cytarabine, 3 g/m2 on days 1–5. Significant toxicity included mucositis, diarrhea, transient hyperbilirubinemia and cardiac events. No difference in toxicity was observed between the two dosage regimens. Overall, 27 patients achieved a complete remission (CR), 16/28 CR in the high-dose and 11/26 in the lower-dose group. Induction death occurred in 11 patients, three in the high-dose and eight in the low-dose arm. Actuarial median survival was 6 months for the low-dose and 9 months for the high-dose group, and the respective relapse-free survival is 3 and 5 months. The observed differences in outcome were not statistically significant. Patients in both arms of this trial, who received no consolidation, appear to have response and survival rates equivalent to those of standard-dose induction with repetitive consolidation. This approach might offer elderly patients equivalent outcome with fewer days of treatment, presumably enhancing quality of life.

Autologous bone marrow transplantation for acute myeloid leukemia using 4-hydroperoxycyclophosphamide-purged bone marrow and the busulfan/etoposide preparative regimen : a follow-up report

We studied the use of autologous bone marrow transplantation (ABMT) as treatment for acute myeloid leukemia (AML) in adults up to age 60. We used a preparative regimen of busulfan 16 mg/kg plus etoposide 60 mg/kg and bone marrow purged with 100 μg/ml of 4-hydroperoxycyclophosphamide (4HC). We treated 50 first remission patients; there were two treatment-related deaths and 13 relapses. With median follow-up of 6.8 years (minimum 4.5) disease-free survival (DFS) is 70%, relapse rate 27% and overall survival 72%. Patients with favorable cytogenetics had DFS 78% and relapse 18% whereas unfavorable patients had DFS 63% and relapse rate 35%. For 25 patients in second or third remission there were five treatment-related deaths and seven relapses. DFS is 52% and relapse rate 35%. None of six patients with primary refractory AML had long-term disease control. These data support the use of ABMT with an intensive preparative regimen and purged bone marrow as a highly effective treatment for adults with AML.

Autologous stem cell transplantation for advanced acute myeloid leukemia

We studied the efficacy of a two-step approach to autologous stem cell transplantation for patients with advanced acute myeloid leukemia. Step 1 consisted of consolidation chemotherapy using cytarabine 2000 mg/m2 twice daily for 4 days plus etoposide 40 mg/kg by continuous infusion over the same 4 days. Peripheral blood stem cells were collected under granulocyte colony-stimulating factor (G-CSF) stimulation during recovery from this chemotherapy. Step 2, autologous stem cell transplantation, utilized the preparative regimen of oral busulfan 16 mg/kg followed by etoposide 60 mg/kg i.v. During step 1, there were no treatment-related deaths among 28 patients, but two patients did not proceed to transplantation because of failure of mobilization. A median CD34+ dose (×106/kg) of 13.6 was collected. Of 26 patients undergoing autologous transplant, there was one treatment-related death and 12 relapses. With a median follow-up of 5.4 years, 5 year event-free survival (EFS) of all patients entered is 54%. The most important prognostic factor was cytogenetic changes. All seven patients with t(15,17) remained in long-term remission whereas EFS for other patients was 38%. We conclude that this two-step approach to autologous transplantation produces excellent stem cell yields, allows a high percentage of patients to receive the intended therapy, and provides effective treatment.Bone Marrow Transplantation (2002) 29, 297–301. doi:10.1038/sj.bmt.1703361

High CD34 Cell Dose Promotes Faster Platelet Recovery after Autologous Stem Cell Transplantation for Acute Myeloid Leukemia

We studied platelet engraftment in 58 patients with acute myeloid leukemia in first remission treated with autologous stem cell transplantation (ASCT) to determine whether CD34+ cell doses >10 x 10(6)/kg were associated with faster platelet engraftment. We compared engraftment rates in patients receiving CD34+ doses between 5 and 10 x 10(6)/kg (standard-dose ASCT) with those receiving doses > or =10 x 10(6)/kg (high-dose [HD] ASCT). We also studied neutrophil engraftment rates and platelet and red blood cell transfusion requirements. In multivariate adjusted models, the rate of platelet recovery to > or =20,000/microL was 4-fold greater among subjects who received HD-ASCT (hazard ratio [HR], 4.1; confidence interval [CI], 1.8-9.2; P =.001), with median recovery times of 14 versus 28 days. The rate of platelet recovery to > or =50,000/microL was 2-fold greater (HR, 2.1; CI, 1.3-5.9; P =.01), with median recovery times of 19 versus 46 days. Faster platelet recovery resulted in the need for fewer platelet transfusions among the subjects who received HD-ASCT (mean transfusions, 3.7 versus 9.8; P =.005). Although not statistically significant, neutrophil recovery data in the adjusted model suggested a similar effect in the HD-ASCT group, with faster engraftment times at absolute neutrophil counts >500/microL (median, 9.2 versus 12 days; HR, 1.6; CI, 0.69-3.5; P =.29) and absolute neutrophil counts >1000/microL (median, 9.5 versus 12 days; HR, 1.3; CI, 0.56-2.8; P =.58). Subjects who received HD-ASCT required fewer red blood cell transfusions (4.0 versus 9.8 units; P =.01). Our findings suggest that CD34+ cell doses >10 x 10(6)/kg CD34+ result in faster engraftment and fewer red blood cell and platelet transfusions.

Vancomycin-induced neutropenia complicating bone marrow recovery in a patient with leukemia. Case report and review of the literature

Neutropenia associated with intravenous vancomycin therapy is reported in a patient with chronic myelogenous leukemia. The patient received 12 days of vancomycin therapy without incidence; however, a second course of vancomycin initiated on hospital day 14 produced severe neutropenia. This delayed onset is typical of vancomycin-induced neutropenia. The neutropenia reversed, without complications, as soon as the vancomycin was discontinued.