Vincent Levy

Results of Intensive Chemotherapy Followed by Hematopoietic Stem-Cell Rescue in 22 Patients With Refractory or Recurrent Primary CNS Lymphoma or Intraocular Lymphoma

PURPOSE To assess the feasibility and efficacy of intensive chemotherapy with hematopoietic stem-cell rescue (IC + HCR) in patients with refractory or recurrent primary CNS lymphoma (PCNSL) or intraocular lymphoma (IOL). PATIENTS AND METHODS IC consisted of thiotepa 250 mg/m(2)/d days -9 through -7, busulfan 10 mg/kg (total dose) days -6 through -4, and cyclophosphamide 60 mg/kg/d days -3 and -2. Intravenous clonazepam 2 mg/d was given prophylactically from the day before initiation of busulfan therapy to the day after completion of busulfan therapy. Patients with refractory or recurrent PCNSL underwent IC + HCR only if they were chemosensitive to two cycles of salvage treatment with cytarabine (2 g/m(2)/d days 2 through 5 and 50 mg/m(2)/d days 1 through 5 in a 12-hour infusion) and etoposide (VP-16; 200 mg/m(2)/d days 2 through 5) (CYVE). Patients with IOL refractory to high-dose methotrexate (MTX) and cytarabine entered the IC + HCR program directly. RESULTS Twenty-two patients (10 with relapses, 12 with refractory disease) were enrolled. Twenty patients entered the IC + HCR program: twelve entered after CYVE treatment, seven entered directly, and one had previously been retreated with high-dose MTX. Before IC, eight patients were in complete remission (CR), four were in partial remission (PR), one had stable disease, and seven had refractory disease. After IC + HCR, 16 patients entered CR, two remained in PR, one had stable disease, and one had disease progression. Fourteen patients remained alive (median follow-up time, 41.5 months). The overall probability of survival at 3 years was 63.7%. After IC, that probability was 60% and the 3-year probability of event-free survival was 53%. Seven patients had neurologic adverse events during the entire procedure. CONCLUSION IC + HCR proved feasible and effective in patients with refractory or recurrent PCNSL or IOL. The entire procedure seemed to be most toxic in patients > or = 60 years. A prospective multicenter study is ongoing.

Outcome of Cancer Patients Considered for Intensive Care Unit Admission: A Hospital-Wide Prospective Study

PURPOSE To evaluate the outcome of cancer patients considered for admission to the intensive care unit (ICU). PATIENTS AND METHODS Prospective, one-year hospital-wide study of all cancer and hematology patients, including bone marrow transplantation patients, for whom admission to the ICU was requested. RESULTS Of the 206 patients considered for ICU admission, 105 patients (51%) were admitted. Of the 101 patients who were not admitted, 54 patients (26.2%) were considered too sick to benefit, and 47 patients (22.8%) were considered to be too well to benefit from the ICU. Of these 47 patients, 13 patients were admitted later. Survival rates after 30 and 180 days were significantly associated with admission status (P < .0001). Remission of the malignancy (odds ratio [OR], 3.37; 95% CI, 1.25 to 9.07) was independently associated with ICU admission, whereas poor chronic health status (OR, 0.38; 95% CI, 0.16 to 0.74) and solid tumor (OR, 0.43; 95% CI, 0.24 to 0.78) were associated with ICU refusal. In admitted patients, 30-day and 6-month survival rates were 54.3% and 32.4%, respectively. Of the patients considered too sick to benefit from ICU admission, 26% were alive on day 30 and 16.7% on day 180. Among patients considered too well to benefit, the 30-day survival rate was a worrisome 78.7%. Calibration of the Mortality Probability Model (the only score available at triage) was of limited value for predicting 30-day survival (area under the curve, 0.62). CONCLUSION Both the excess mortality in too-well patients later admitted to the ICU and the relatively good survival in too-sick patients suggest the need for a broader admission policy.

Identification of Prognostic Factors in 61 Patients With Posttransplantation Lymphoproliferative Disorders

PURPOSE Prognostic studies of posttransplantation lymphoproliferative disorders (PTLDs) are hindered by the small number of cases at each transplant center. We analyzed prognostic factors and long-term outcome according to clinical manifestations, pathologic features, and treatment and investigated the prognostic value of the non-Hodgkins lymphoma International Prognostic Index (IPI) in 61 patients with PTLD. PATIENTS AND METHODS We studied 61 patients in two institutions who developed PTLD and analyzed factors influencing the complete remission and survival rates. RESULTS In univariate analysis, factors predictive of failure to achieve complete remission were performance status (PS) > or = (P =.0001) and nondetection of Epstein-Barr virus (EBV) in the tumor (P =.01). Only a negative link with PS > or = 2 was observed in multivariate analysis. In univariate analysis, factors predictive of lower survival were PS > or = 2, the number of sites (one v > one), primary CNS localization, T-cell origin, monoclonality, nondetection of EBV, and treatment with chemotherapy. The IPI failed to identify a patient subgroup with better survival and was less predictive of the response rate than was a specific index using two risk factors (PS and number of involved sites), which defined three groups of patients: low-risk patients whose median survival time has not yet been reached, intermediate-risk patients with a median survival time of 34 months, and high-risk patients with a median survival time of 1 month. CONCLUSION PS and the number of involved sites defined three risk groups in our population. The value of these prognostic factors needs to be confirmed in larger cohorts of patients treated in prospective multicenter studies.

Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R).

In patients with chronic‐phase chronic myeloid leukemia (CP‐CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325‐fold more potent inhibition than imatinib against unmutated Bcr‐Abl in vitro. Data with a minimum of 2 years of follow‐up were available for the current study of dasatinib and high‐dose imatinib in CP‐CML resistant to imatinib at daily doses from 400 mg to 600 mg.

Predictors of short-term mortality in critically ill patients with solid malignancies

Abstract Admission of cancer patients with serious medical complications to the ICU remains controversial primarily because of the high short-term mortality rates in these patients. However, the cancer patient population is heterogeneous regarding age, underlying conditions, and curability of their disease, suggesting that large variations may occur in the effectiveness of intensive care within this subgroup of critically ill patients.¶Objectives: To identify factors predicting 30-day mortality in patients with solid tumors admitted to a medical ICU.¶Patients and methods: We conducted a retrospective study in 120 consecutive cancer patients (excluding patients with hematological malignancies) admitted to the medical ICU of a 650-bed university hospital between January 1990 and July 1997. Medical history, physical and laboratory test findings at admission, and therapeutic interventions within the first 24 h in the ICU were recorded. The study endpoint was vital status 30 days after ICU admission. Stepwise logistic regression was used to identify independent prognostic factors.¶Results: The observed 30-day mortality rate was 58.7 % (n = 68), with most deaths (92 %) occurring in the ICU. Univariate predictors of 30-day mortality were either protective [prior surgery for the cancer (p = 0.01) and complete remission (p = 0.01)] or associated with higher mortality [Knaus scale C or D (p = 0.02), shock (p = 0.04), need for vasopressors (p = 0.0006) or for mechanical ventilation (p = 0.0001), SAPS II score greater than 36 (p = 0.0001), LOD score greater than 6 (p = 0.0001), and ODIN score > 2 (p = 0.0001)]. Three variables were independent predictors: previous surgery for the cancer (OR 0.20, 95 % CI 0.07–0.58), LOD score > 6 (OR 1.26, 95 % CI 1.09–1.44), and need for mechanical ventilation (OR 3.55, 95 % CI; 1.26–6.7). Variables previously thought to be indicative of a poor prognosis (i. e., advanced age, metastatic or progressive disease, neutropenia or bone marrow transplantation) were not predictive of outcome.¶Conclusion: When transfer to an ICU is considered an option by patients and physicians, 30-day mortality is better estimated by an evaluation of acute organ dysfunction than by the characteristics of the underlying malignancy.

Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: a prospective study.

Mantle cell lymphoma (MCL) is a distinct clinico-pathological entity with a poor prognosis. We have conducted a prospective study in patients with MCL to evaluate a therapeutic strategy in which CHOP polychemotherapy was followed by DHAP if CHOP failed to induce complete remission. Responding patients then proceeded to an intensification therapy with autologous peripheral blood stem cell transplantation (APBSCT). Twenty-eight consecutive patients with newly diagnosed aggressive MCL were included. After four cycles of CHOP regimen, two complete responses (CR) were obtained (7%) and 14 (50%), five (18%) and seven (25%) patients achieved partial (PR), minor (MR) and no response, respectively (one patient died from septic complications during CHOP induction). The two patients in CR after CHOP underwent intensification with TBI, high-dose cyclophosphamide–etoposide and APBSCT. The other twenty-five patients received DHAP and in this group a response rate of 92% (21 CR (84%), two PR (8%)) was observed. Two patients had progressive disease. The twenty-three responding patients received high-dose therapy (TAM8 regimen: TBI–cytarabine–melphalan) followed by APBSCT. One of the two partial responding patients achieved CR after TAM8. After a median follow-up of 47.6 months (range, 14–70), seven patients have relapsed. Our data confirm that: (1) CHOP regimen induces a low CR rate in MCL; (2) CHOP plus DHAP appears to be much more efficient and allows a large proportion of patients to proceed to high-dose therapy in CR; (3) consolidation therapy including TBI and high-dose Arac-C followed by APBSCT may improve event-free survival.

Efficacy of Prevention by High-Efficiency Particulate Air Filtration or Laminar Airflow Against Aspergillus Airborne Contamination During Hospital Renovation

OBJECTIVE To evaluate efficacy of laminar airflow facilities plus high-efficiency particulate air (HEPA) filtration and HEPA filtration alone in preventing environmental Aspergillus contamination during hospital renovation. To show the usefulness of environmental surveillance to facilitate protection of patients at risk for invasive pulmonary aspergillosis. DESIGN Prospective sampling of air and surfaces for Aspergillus conidia during 2-year period. SETTING A hematological department adjacent to building renovation at a university hospital. RESULTS 1,047 air samples and 1,178 surface samples were collected from January 1996 to December 1997. Significantly more air samples were positive for Aspergillus species during the period of building renovation than during the periods before and after renovation in a unit without a protected air supply adjacent to the building work area (51.5% vs 31.7%; odds ratio [OR], 2.3; 95% confidence interval [CI95], 1.4-3.7; P<.001). A major increase in the frequency of positive air samples was also found in another adjacent unit that was protected with HEPA filtration alone (from 1.8% to 47.5%; OR, 48.9; CI95, 12-229; P<10(-7)). In addition, in this unit, the mean count of Aspergillus conidia in positive air samples increased significantly during construction (4 colony-forming units [CFU]/m3 to 24.7 CFU/m3; P=.04) and the proportion of positive surface samples showed a significant increase during renovation (from 0.4% to 9.7%; OR, 28.3; CI95, 3.4-623; P=10(-4)). However, none of 142 air samples collected during renovation in the area protected with laminar airflow plus HEPA filtration showed Aspergillus conidia. In a unit distant from the building renovation site, the results of air and surface samples were not affected by renovation. CONCLUSION This study showed a strong association between building renovation and an increase in environmental Aspergillus contamination. Results confirmed the high efficacy of laminar airflow plus HEPA filtration and a high air-change rate. Although filtration with HEPA was effective during normal conditions, it alone was unable to prevent the rise of Aspergillus contamination related to building renovation. This study emphasized the necessity of an environmental survey of airborne contamination related to construction, to facilitate prevention of nosocomial aspergillosis outbreaks. A standardized protocol for aerobiological surveillance is needed.

Prospective Evaluation of a Polymerase Chain Reaction–ELISA Targeted to Aspergillus fumigatus and Aspergillus flavus for the Early Diagnosis of Invasive Aspergillosis in Patients with Hematological Malignancies

BACKGROUND Current laboratory and radiological methods for diagnosis of invasive aspergillosis (IA) lack sensitivity and specificity. METHODS We prospectively evaluated the diagnostic value of twice-weekly screening for circulating Aspergillus fumigatus and A. flavus DNA with a polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA). RESULTS Among the 201 adult patients with hematological malignancies who were included in the study, 55 IA cases were diagnosed. On the basis of the analysis of 1205 serum samples from 167 patients, the sensitivity, specificity, and positive and negative predictive values of the PCR-ELISA for proven and probable IA cases were 63.6%, 89.7%, 63.6%, and 89.7%, respectively, when samples with 2 consecutive positive results were used. The use of a combination of the PCR-ELISA and a galactomannan (GM) assay increased the sensitivity to 83.3%, increased the negative predictive value to 97.6%, and decreased the specificity to 69.8%. In most patients with IA, PCR-ELISA positivity anticipated or was simultaneous with the initiation of antifungal therapy, the abnormalities found by computed tomography, the mycological/histological diagnosis, and the GM positivity. Overall, 56.3% of the patients had at least 1 positive sample, and the false single-positive rate was 44.8%. CONCLUSIONS In addition to serial screening for GM antigenemia and radiological surveillance, PCR-ELISA may improve the rates of early diagnosis of IA and the management of patients with hematological malignancies.

Predictive value of serum thymidine kinase level for Ig-V mutational status in B-CLL.

In B-CLL IgVH genes mutational status is a major prognostic factor. Since sequencing of IgVH genes is not available in most laboratories, an easily performed surrogate assay is desirable. To identify the best surrogate assay, and to better discriminate prognostic subgroups we analyzed clinical and biological data from 58 typical CLL cases. A higher serum thymidine kinase level (>15 U/l) proved to be a strong predictor of mutational status, and the only independent one among the studied parameters. To further identify prognostic subgroups, cluster analysis was employed on 38 cases on which all data were available, which segregated two groups including 25 and 13 patients, respectively. These two clusters differed by their proliferative potential and appeared to discriminate patients with very different clinical course and outcome. s-TK was strikingly different among these two clusters, suggesting that s-TK level could be used routinely to identify patients at risk of progression.

Fludarabine plus cyclophosphamide in Waldenström's macroglobulinemia: results in 49 patients.

Fludarabine (FDR) therapy gives a response rate of about 30% in previously treated patients with Waldenströms macroglobulinemia (WM). The combination of FDR and cyclophosphamide (Cy) has been shown to be effective in chronic lymphoproliferative disorders. We administered the combination of FDR (30 mg/m2 i.v. D1–D3) and Cy (300 mg/m2 i.v. D1–D3) to 49 patients. Median age was 64 years. The median hemoglobin, albumin, beta 2 microglobulin and immunoglobulin M (IgM) levels were 9.9 g/100 ml, 39.6 g/l, 3 mg/l and 24.7 g/l, respectively. In all, 14 patients (29%) had not previously been treated. FDR/Cy was administered every 4 weeks for a median of four cycles. In all, 38 patients (77.6%) had partial responses, nine had stable disease and two had progressive disease. After a median of follow-up of 25 months, six patients relapsed and two patients developed large-cell lymphoma. The median time to treatment failure was 27 months. The main toxicity was hematological. In all, 12 patients died, four from progression, one from large-cell lymphoma, three from infection and four from a second malignancy. Two factors negatively influenced overall and event-free survival, age >65 years and IgM <40 g/l. The FDR/Cy combination, therefore, gives a high response rate in WM, even in previously treated patients with factors of poor prognosis.