Driss Chaoui

Breast cancer resistance protein and P-glycoprotein in 149 adult acute myeloid leukemias.

Purpose: Recently, a new ABC protein, breast cancer resistance protein (BCRP), was described. But its prognosis is not known in acute myeloid leukemia (AML). In addition, the prognosis of P-glycoprotein (Pgp) and BCRP in patients treated homogeneously by the same anthracycline (daunorubicin, idarubicin, or mitoxantrone) during all of the treatment with aracytine is not known. Therefore, we have evaluated the relationship between drug resistance phenotype, in vitro anthracene sensitivity, and the relation to treatment outcome. Experimental Design: We have analyzed 149 AML treated according to protocol of the European Organization for Research and Treatment of Cancer group. The prognostic value of BCRP and Pgp were analyzed in the whole population and according to intercalating agent. Results: BCRP was a prognostic factor, for achievement of complete remission (43% in positive patients and 69% in negative patients, P = 0.005), the 4-year disease-free survival (12% versus 33%, P = 0.03), and the 4-year overall survival (19% versus 38%, P = 0.003). When BCRP expression and Pgp function were categorized in three groups, +/+, +/− or −/+, and −/−, the achievement of complete remission was 45%, 66%, and 90% (P = 0.0003), the 4-year disease-free survival was 8%, 26%, and 40% (P = 0.01), and the 4-year overall survival was 16%, 37%, and 48% (P = 0.001), respectively. Pgp function was a prognostic factor in patients treated by daunorubicin and idarubicin but not by mitoxantrone. In contrast, BCRP expression was a prognostic factor in patients treated by daunorubicin and mitoxantrone but not by idarubicin. Conclusions: BCRP would be implicated in the resistance to chemotherapies in AML. But these are the patients expressing both BCRP and Pgp who have the poorest prognosis.

Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis

Myeloproliferative disorders (MPD) are reported in 25–65% of patients with splanchnic vein thrombosis (SVT). Diagnostic criteria for MPD have not been fully established in this context. Using clusters of abnormal megakaryocytes in bone marrow (BM) biopsy as a reference standard for Philadelphia negative MPD, we assessed the relevance of other criteria currently recommended for the diagnosis of MPD in SVT (128 consecutive SVT patients). First, usual criteria were compared with BM results: endogenous erythroid colony formation (EEC) was strongly correlated with BM results; splenomegaly, blood cell count, total red cell volume, erythropoietin level and cytogenetic were much less accurate. Then, patients were assigned to three groups according to the combination of BM and EEC findings (group I: both present; group II: both absent; group III: other patients); clinical presentation and outcome were compared in each group. At a mean follow‐up of 6·09 ± 6·6 years, progression to a severe form of MPD occurred in 7 of 31 group I patients (23%), in 1 of 34 group III patients (3%) and 0 of 63 group II patients. The combination of marked splenomegaly and platelet count >200 × 109/l was restricted to groups I and III. In conclusion, in patients with SVT, BM findings and EEC allowed the diagnosis of MPD at risk of aggravation. Marked splenomegaly in association with platelet counts >200 × 109/l constitute a simple index with high specificity but low sensitivity.

MRP3, BCRP, and P-Glycoprotein Activities are Prognostic Factors in Adult Acute Myeloid Leukemia

Purpose: P-Glycoprotein (Pgp) is associated with poor outcome in acute myeloid leukemia (AML). We have investigated other ATP-binding cassette proteins such as BCRP, MRP1, MRP2, MRP3, and MRP5 for their potential implication in chemoresistance. Experimental Design and Results: Eighty five AML patient samples were analyzed in this study. First, MRP3 function was higher in patients which had a high level of leukocytes (P = 0.01), a M5 FAB subtype (P = 0.04), and an intermediate or poor cytogenesis (P = 0.05). BCRP activity was not correlated with clinical or biological variables, but high Pgp activity was correlated with the following variables: CD34 expression (P = 0.002), FAB subtype (P = 0.002), intermediate or poor cytogenesis (P = 0.02), and elderly patients (P = 0.03). Second, Pgp, MRP3, and BCRP activities were correlated with complete remission (P = 0.02, P = 0.04, and P = 0.04, respectively), disease-free survival (P = 0.02, P = 0.03, and P = 0.25, respectively), and overall survival (P = 0.04, P = 0.04, and P = 0.05, respectively) in multivariate analysis. The patient samples expressing one or none of these Pgp, MRP3, or BCRP functional proteins have a better prognosis than the patients expressing two or three of these functional proteins (complete remission, P = 0.02; disease-free survival, P = 0.01; overall survival, P < 0.001). Conclusions: BCRP and MRP3 may also be involved in chemoresistance in AML, especially MRP3 in patients with M5 FAB. Additional modulation of BCRP or MRP3 to Pgp modulation may be necessary in some patients in order to improve the treatment outcome.

Incidence and prognostic value of respiratory events in acute leukemia

Acute respiratory failure and infectious pneumonia are the major causes of death during induction chemotherapy of acute leukemia. However, the causes, incidence and prognostic value of all respiratory events (REs) occurring in this context have never been assessed prospectively. We recruited 65 consecutive patients with newly diagnosed acute leukemia into a 1-year prospective study (December 2000–November 2001) to evaluate the incidence and prognostic value of these events. REs were frequent: 38 were recorded in 30 patients. There was a significant relationship between REs and pre-existing respiratory disease and/or smoking. REs were caused by infection in 34% of cases, by an established cause other than infection in 42% and had an undetermined cause in 24%. Poor early outcome (death within 45 days of starting induction chemotherapy) in patients experiencing an RE was independently associated with a >25/min respiratory rate (P=0.003) and the nonachievement of complete remission (CR) (P<0.0001). Predictors of overall survival in the entire patient population were the absence of CR (P<0.0001), REs (P=0.02) and a ⩾2 performance status (P=0.03). In conclusion, REs are frequent during induction chemotherapy of acute leukemia and represent an independent prognostic factor of poor outcome, regardless of their cause.

Prognosis of patients with acute myeloid leukaemia admitted to intensive care

This retrospective study assessed the prognostic factors associated with early and long‐term outcome in consecutive patients with acute myeloid leukaemia (AML) admitted to the intensive care unit (ICU) over a 9‐year period. A total of 83 patients were studied (age 48 ± 16 years), among whom 60% were neutropenic on admission. For 68%, admission occurred within the first month following diagnosis of AML. The main reason for ICU admission was an acute respiratory disease in 82% of cases. Mechanical ventilation (MV) was required in 57% of patients. In‐ICU mortality was 34%. Among patients discharged alive from ICU, 49% died within a year after discharge. Factors significantly associated with in‐ICU death in multivariate analysis were simplified acute physiology score II and need for invasive MV (IMV). Age, performance status, AML3 subtype and complete remission were significantly associated with 1‐year survival. Patients with acute respiratory failure initially supported with non‐invasive MV had significantly better ICU outcome than patients initially supported with IMV. In conclusion, ICU admission is justified for selected patients with AML. The ICU mortality rate is highly predictable by the acute illness severity score. A 1‐year survival is predicted by haematological prognostic factors.

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial

The Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27.

Reticulated platelets: a reliable measure to reduce prophylactic platelet transfusions after intensive chemotherapy

BACKGROUND: Reticulated platelets (RPs) are the youngest circulating platelets (PLTs). The aim of our study was to predict PLT recovery with RP percentage (RP%) and therefore to identify PLT transfusions that could be avoided after autologous peripheral blood progenitor cell (PBPC) transplantation.

Is BAL useful in patients with acute myeloid leukemia admitted in ICU for severe respiratory complications

In patients with hematological malignancy (HM) developing acute respiratory failure (ARF) bronchoalveolar lavage (BAL) is considered as a major diagnostic tool. However, the benefit/risk ratio of this invasive procedure is probably lower in the subset of patients with acute myeloid leukemia (AML). The study was to analyze the yield of BAL performed in HM patients (n=175) with AML or lymphoid malignancies (LM) admitted in intensive care unit (ICU) for ARF and pulmonary infiltrates. BAL was performed in 121 patients (53/73 AML patients (73%) and 68/102 LM patients (67%)) without a definite diagnosis at admission or contraindication for fiberoptic bronchoscopy. Life-threatening complications were noticed in 12/121 patients (10%). The overall diagnostic yield of BAL was 47% (25/53) in AML patients and 50% (34/68) in LM patients. A microorganism was recovered from BAL in 23% (12/53) of AML patients and 41% (28/68) of LM patients (P<0.005). BAL results induced significant therapeutic changes in 17% (9/53) of AML patients vs 35% (24/68) of LM patients (P=0.039). This study underlines the rather low diagnostic yield of BAL for infectious diagnosis and the low rate of therapeutic changes induced by its results in AML patients with ARF admitted in ICU.

Conjunctival low-grade non-Hodgkin's lymphoma: a large single-center study of initial characteristics, natural history and prognostic factors

To define the initial characteristics and prognostic factors of patients with conjunctival low-grade malignant lymphoma, all patients treated for low-grade lymphoma with initial conjunctival involvement were reviewed. Forty-nine cases were selected, including 45 cases with exclusive ophthalmologic conjunctival involvement. Pathologic review showed 55% of mucosa-associated lymphoid tissue type lymphoma, and 23% of lymphoplasmocytic lymphoma. Initial characteristics were median age of 62 years, nodal involvement in 17% of cases, and stage IV in 22% of patients with 10% of bone marrow involvement. With a median follow-up of 75 months, the 5-year disease-free survival (DFS) and overall survival were 65% and 83%, respectively. On multivariate analysis, nodal involvement was the only factor with a pejorative impact on DFS. Our patient cohort represents one of the largest published series defining the characteristics and prognostic factors of primary conjunctival low-grade malignant lymphoma.

Mobilization of peripheral blood progenitor cells after DHAP regimen with or without rituximab: A large multicenter comparative study in patients with malignant lymphoma

DHAP regimen is commonly used in patients with lymphoma. It is routinely used in combination with the monoclonal anti-CD20 antibody rituximab (R-DHAP), particularly for peripheral blood stem cell (PBSC) mobilization. The aim of this study was to assess the impact of rituximab on PBSC mobilization in patients with lymphoma receiving DHAP chemotherapy. We retrospectively reviewed the data of patients treated by DHAP or R-DHAP regimens as PBSC mobilization protocol between July 1998 and June 2005. Sixty-nine patients were included in the study: 21 in the DHAP group and 48 in the R-DHAP group. Both groups were not statistically different in term of clinical and biological presentation of the disease. The first cytapheresis was performed at day 10 in the R-DHAP group versus day 11 in the DHAP group. In contrast, the number of circulating CD34+ cells was higher, but not significant, in the R-DHAP group than the DHAP group, namely 9.7×106 CD34+ cells/kg and 6.1×106 CD34+ cells/kg, respectively. Finally, the complete remission status at time of harvest was the only one factor associated with poor mobilization on multivariate analysis. In conclusion, our results show that rituximab does not impair PBSC collection.