Arnaud Pigneux

Acute myeloid leukemia ontogeny is defined by distinct somatic mutations

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637.

Is Cytarabine Useful in the Treatment of Acute Promyelocytic Leukemia? Results of a Randomized Trial From the European Acute Promyelocytic Leukemia Group

PURPOSE Several phase II studies have suggested that cytarabine (AraC) was not required in the treatment of newly diagnosed acute promyelocytic leukemia (APL) patients receiving all-trans-retinoic acid (ATRA), an anthracycline, and maintenance therapy, and we aimed at confirming this finding in a randomized trial. PATIENTS AND METHODS Newly diagnosed APL patients younger than age 60 years with a WBC count of less than 10,000/microL were randomly assigned to receive either ATRA combined with and followed by three daunorubicin (DNR) plus AraC courses and a 2-year maintenance regimen (AraC group) or the same treatment but without AraC (no AraC group). Patients older than age 60 years and patients with initial WBC count of more than 10,000/microL were not randomly assigned but received risk-adapted treatment, with higher dose of AraC and CNS prophylaxis in patients with WBC counts more than 10,000/microL. RESULTS Overall, 328 (96.5%) of 340 patients achieved complete remission (CR). In the AraC and the no AraC groups, the CR rates were 99% and 94% (P = .12), the 2-year cumulative incidence of relapse (CIR) rates were 4.7% and 15.9% (P = .011), the event-free survival (EFS) rates were 93.3% and 77.2% (P = .0021), and survival rates were 97.9% and 89.6% (P = .0066), respectively. In patients younger than age 60 years with WBC counts more than 10,000/microL, the CR, 2-year CIR, EFS, and survival rates were 97.3%, 2.9%, 89%, and 91.9%, respectively. CONCLUSION These results support a role for AraC in addition to ATRA and anthracyclines in the treatment of newly diagnosed APL, at least using DNR at the cumulative dose we used and with the consolidation and maintenance regimens we used.

Liposomal Amphotericin B in Combination With Caspofungin for Invasive Aspergillosis in Patients With Hematologic Malignancies : A Randomized Pilot Study (Combistrat Trial)

Invasive aspergillosis (IA) has a poor prognosis in immunocompromised patients. Combinations of drugs that act on different targets are expected to improve the clinical efficacy of separate compounds.

Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia

Not all patients with core binding factor acute myeloid leukemia (CBF-AML) display a good outcome. Modern risk factors include KIT and/or FLT3 gene mutations and minimal residual disease (MRD) levels, but their respective values have never been prospectively assessed. A total of 198 CBF-AML patients were randomized between a reinforced and a standard induction course, followed by 3 high-dose cytarabine consolidation courses. MRD levels were monitored prospectively. Gene mutations were screened at diagnosis. Despite a more rapid MRD decrease after reinforced induction, induction arm did not influence relapse-free survival (RFS) (64% in both arms; P = .91). Higher WBC, KIT, and/or FLT3-ITD/TKD gene mutations, and a less than 3-log MRD reduction after first consolidation, were associated with a higher specific hazard of relapse, but MRD remained the sole prognostic factor in multivariate analysis. At 36 months, cumulative incidence of relapse and RFS were 22% vs 54% (P < .001) and 73% vs 44% (P < .001) in patients who achieved 3-log MRD reduction vs the others. These results suggest that MRD, rather than gene mutations, should be used for future treatment stratifications in CBF-AML patients. This trial was registered at EudraCT as #2006-005163-26 and at www.clinicaltrials.gov as #NCT 00428558.

Noninvasive continuous positive airway pressure in neutropenic patients with acute respiratory failure requiring intensive care unit admission.

ObjectiveTo evaluate the tolerance and the efficacy of noninvasive continuous positive airway pressure (CPAP) in severe acute respiratory failure occurring in intensive care unit (ICU) neutropenic patients with hematologic malignancies, and to establish predictive variables of efficacy of this method. DesignProspective study over a 5-yr period. SettingHematologic and medical intensive care unit of a teaching hospital. MethodsAmong 129 neutropenic patients admitted to the ICU, 64 patients presented with febrile acute hypoxemic normocapnic respiratory failure (Pao2/Fio2 ratio <200) and were enrolled. In addition to standard therapy, patients received CPAP with a facial mask. The initial settings of the CPAP were 6 cm H2O positive end-expiratory pressure and Fio2 0.8 (80%). Physiologic measurements were performed at the end of 45 mins of ventilation with first adjustments. CPAP was used with a sequential mode (45 mins/3 hrs). CPAP was efficient if intubation was avoided. ResultsThe setting of CPAP, after adjustments, was as follows: positive end-expiratory pressure 7 ± 1 cm H2O and Fio2 0.7 ± 0.1 (70% ± 10%). For the 64 patients, CPAP was administered for a total of 6 ± 2 hrs during the first 24 hrs. The mean duration of CPAP was 7 ± 3 days. A reduction in respiratory rate to less than 25 breaths/min was achieved in 53% of patients. Pao2/Fio2 ratio increased from 128 ± 32 to 218 ± 28. CPAP was successful in avoiding endotracheal intubation in 16/64 patients. A total of 16 responders and four nonresponders survived. Hepatic failure was a criterion indicating the failure of CPAP1/16 vs. 26/48 (p = .001). In multivariate analysis, two variables were predictive of failure of CPAPSimplified Acute Physiology Score II (58 ± 14 vs. 41 ± 11) and a hepatic failure at the entry into the study. ConclusionCPAP was efficient in 25% of cases. All the responders survived. This noninvasive method was used as a way to avoid mechanical ventilation, which is well correlated with a poor prognosis in neutropenic ICU patients. Further controlled studies are needed to confirm the efficacy of noninvasive CPAP and to evaluate the most appropriate selection of immunocompromised patients.

Follow-Up of Complete Cytogenetic Remission in Patients With Chronic Myeloid Leukemia After Cessation of Interferon Alfa

PURPOSE A small proportion of patients with chronic myeloid leukemia (CML) achieve a complete cytogenetic response (CCR), defined as the disappearance of Philadelphia (Ph) chromosome-positive metaphases, after treatment with interferon alfa (IFN). In this population of patients, the question of whether treatment should then be withdrawn is not yet resolved. PATIENTS AND METHODS In the present study, we followed 15 patients who stopped IFN after achieving CCR. In nine patients IFN was stopped in view of adverse reactions (n = 8) or patients choice (n = 1). For the remaining six patients, the treatment was stopped because no BCR/ABL rearrangement could be detected by reverse transcriptase polymerase chain reaction (RT-PCR) in four successive analyses using peripheral-blood samples. RESULTS Loss of CCR and survival were not statistically different (P =.48; P =.7) for the 15 patients who stopped IFN compared with 41 other CCR patients who continued IFN therapy in our institution. The median follow-up after discontinuation of IFN treatment was 36 months (range, 6 to 108 months). Seven patients (47%) (females, or CCR > 24 months and RT-PCR negative before IFN cessation; P <.0001) did not relapse. Eight other patients (53%) relapsed (lost CCR) within 3 to 33 months of treatment discontinuation. One of them relapsed in major cytogenetic remission (MCR) and was still in MCR 87 months after stopping therapy without any treatment. CONCLUSION It is possible to stop IFN treatment at least in some patients with CML who achieve a prolonged period of CCR. This study also illustrates the hypothesis that persistence of low numbers of Ph-positive cells does not necessarily imply hematologic relapse.

Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group

Internal tandem duplications (ITDs) of the FLT3 gene have been observed in about 35% of APL cases. If FLT3-ITD is associated with a worse outcome in patients with acute myeloid leukemia (AML) in general, its prognostic value in acute promyelocytic leukemia (APL) is still a matter of debate. We investigated incidence, associated clinical features, and prognostic implication of FLT3-ITD, but also FLT3-D835 point mutation and N-Ras or K-Ras mutations in 119 APL patients, all prospectively enrolled in the two consecutive APL-93 and APL-2000 trials. Mutation incidences were 38, 20, and 4%, for FLT3-ITD, FLT3-D835, and Ras, respectively. The presence of FLT3-ITD was associated with high white blood cell count, high Sanz index, M3-variant subtype, and V/S PML-RARα isoforms. Complete remission (CR), induction death, and death in CR rates were not affected by FLT3 or Ras mutations, as well as cumulative incidence of relapse. However, a trend for a shorter overall survival (P=0.09) was observed in FLT3-ITD patients, because of a very poor postrelapse survival (P=0.02). This feature, which has been also reported in patients with AML in general, is suggestive of an underlying genetic instability in FLT3-ITD patients, leading to the acquisition of additional unknown bad-prognosis gene mutations at relapse.

Utility of fiberoptic bronchoscopy in neutropenic patients admitted to the intensive care unit with pulmonary infiltrates.

Objective To analyze the impact of fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) on guiding the treatment and intensive care unit (ICU) clinical outcome in neutropenic patients with pulmonary infiltrates admitted to the ICU. Design Prospective collection of data. Setting Medical ICU in a teaching hospital. Patients During a 6-yr period, we analyzed the results of 93 fiberoptic bronchoscopies plus BALs performed in 93 consecutive neutropenic ICU patients. We separated the patients into two groups according to the cause of neutropenia (high-dose chemotherapy [n = 41] or stem cell transplantation [SCT; n = 52]). Results Of the 93 BALs, 53 were performed to evaluate diffuse infiltrates and 42 were performed on mechanically ventilated patients. Forty-nine percent of BALs (46 patients) were diagnostic, with a significantly better yield in ICU patients with high-dose chemotherapy-induced neutropenia (26 of 41 BALs). The number of cases of proven infectious pneumonia was significantly higher in this group of ICU neutropenic patients. In patients who underwent SCT, diffuse infiltrates were statistically correlated with a negative result of BAL. Twenty-six patients who underwent diagnostic BALs changed therapy. Sixteen complications (17%) occurred with only two intubations. The overall mortality rate in the ICU and the mortality rate in mechanically ventilated neutropenic patients were 71% and 93%, respectively. In neutropenic patients who underwent SCT, the mortality rate was statistically higher in patients in whom no diagnosis was established. Patients who had a diagnostic BAL that changed therapy did not have an increased probability of survival compared with patients who had a BAL that did not change therapy. Conclusions The use of routine diagnostic BAL in ICU neutropenic patients with pulmonary infiltrates is difficult to establish, even if BAL is helpful in the management of these critically ill patients. BAL in our ICU neutropenic patient population had an acceptable overall diagnostic yield (49%), which was higher in ICU patients with chemotherapy-induced neutropenia. Nevertheless, in the ICU, if BAL had a low complication rate, it had infrequently led to changed treatment and was not associated with improved patient survival.

Allogeneic Hematopoietic Stem-Cell Transplantation After Nonmyeloablative Preparative Regimens: Impact of Pretransplantation and Posttransplantation Factors on Outcome

PURPOSE To analyze the impact of pre- and posttransplantation factors on the outcome of allogeneic transplantation after nonmyeloablative conditioning regimens. PATIENTS AND METHODS Ninety-two allogeneic transplantations after nonmyeloablative preparative regimens were reported to the Société Française de Greffe de Moelle Registry registry. Initial diagnoses were lymphoid diseases (n = 22), myeloma (n = 14), acute leukemia and myelodysplasia (n = 41), chronic myelogenous leukemia (n = 12), and solid tumors (n = 3). Forty-six patients had previously received a transplant, and 49 had progressive disease before transplantation. Three types of conditioning regimens were used with fludarabine or antithymocyte globulins. Eighty-nine patients underwent transplantation, 60 from peripheral-blood progenitor cells. Eighty-six patients received graft-versus-host disease (GHVD) prophylaxis for a median duration of 53 days. RESULTS Seventy-nine patients engrafted, with 40 complete and 21 mixed chimerisms. The acute GHVD rate at 3 months was 50% +/- 11%. Fifty-two patients achieved complete remission and 12, partial remission. At 18 months after transplantation, the overall survival (OS) and the transplant-related mortality (TRM) were 32% +/- 12% and 38% +/- 14%, respectively. Initial diagnosis and disease status before transplantation significantly influenced survival. Age and GHVD prophylaxis type significantly influenced TRM. We also showed an impact of GHVD prophylaxis duration on OS and TRM. In multivariate analysis, three factors remained of prognostic value on OS: initial diagnosis, disease status at transplantation, and GHVD prophylaxis duration. CONCLUSION This series shows encouraging results from nonmyeloablative conditioning regimens before allotransplantation and demonstrates the impact of some pre- and posttransplantation factors on outcome after transplantation.

Voriconazole for secondary prophylaxis of invasive fungal infections in allogeneic stem cell transplant recipients: results of the VOSIFI study

Background Recurrence of prior invasive fungal infection (relapse rate of 30–50%) limits the success of stem cell transplantation. Secondary prophylaxis could reduce disease burden and improve survival. Design and Methods A prospective, open-label, multicenter trial was conducted evaluating voriconazole (4 mg/kg/12 h intravenously or 200 mg/12 h orally) as secondary antifungal prophylaxis in allogeneic stem cell transplant recipients with previous proven or probable invasive fungal infection. Voriconazole was started 48 h or more after completion of conditioning chemotherapy and was planned to be continued for 100–150 days. Patients were followed for 12 months. The primary end-point of the study was the incidence of proven or probable invasive fungal infection. Results Forty-five patients were enrolled, 41 of whom had acute leukemia. Previous invasive fungal infections were proven or probable aspergillosis (n=31), proven candidiasis (n=5) and other proven or probable infections (n=6); prior infection could not be confirmed in three patients. The median duration of voriconazole prophylaxis was 94 days. Eleven patients (24%) died within 12 months of transplantation, but only one due to systemic fungal disease. Three invasive fungal infections occurred post-transplant: two relapses (one candidemia and one fatal scedosporiosis) and one new zygomycosis in a patient with previous aspergillosis. The 1-year cumulative incidence of invasive fungal disease was 6.7±3.6%. Two patients were withdrawn from the study due to treatment-related adverse events (i.e. liver toxicity). Conclusions Voriconazole appears to be safe and effective for secondary prophylaxis of systemic fungal infection after allogeneic stem cell transplantation. The observed incidence of 6.7% (with one attributable death) is considerably lower than the relapse rate reported in historical controls, thus suggesting that voriconazole is a promising prophylactic agent in this population.