Neutropenic Enterocolitis in Critically Ill Patients: Spectrum of the Disease and Risk of Invasive Fungal Disease.

OBJECTIVES: Neutropenic enterocolitis occurs in about 5.3% of patients hospitalized for hematologic malignancies receiving chemotherapy. Data from critically ill patients with neutropenic enterocolitis are scarce. Our objectives were to describe the population of patients with neutropenic enterocolitis admitted to an ICU and to investigate the risk factors of invasive fungal disease. DESIGN: A multicentric retrospective cohort study between January 2010 and August 2017. SETTING: Six French ICUs members of the Groupe de Recherche Respiratoire en Onco-Hématologie research network. PATIENTS: Adult neutropenic patients hospitalized in the ICU with a diagnosis of enteritis and/or colitis. Patients with differential diagnosis (Clostridium difficile colitis, viral colitis, inflammatory enterocolitis, mesenteric ischemia, radiation-induced gastrointestinal toxicity, and Graft vs Host Disease) were excluded. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: We included 134 patients (median Sequential Organ Failure Assessment 10 [8-12]), with 38.8% hospital mortality and 32.1% ICU mortality rates. The main underlying malignancies were acute leukemia (n = 65, 48.5%), lymphoma (n = 49, 36.6%), solid tumor (n = 14, 10.4%), and myeloma (n = 4, 3.0%). Patients were neutropenic during a median of 14 days (9-22 d). Infection was documented in 81 patients (60.4%), including an isolated bacterial infection in 64 patients (47.8%), an isolated fungal infection in nine patients (6.7%), and a coinfection with both pathogens in eight patients (5.0%). Radiologically assessed enteritis (odds ratio, 2.60; 95% CI, 1.32-7.56; p = 0.015) and HIV infection (odds ratio, 2.03; 95% CI, 1.21-3.31; p = 0.016) were independently associated with invasive fungal disease. CONCLUSIONS: The rate of invasive fungal disease reaches 20% in patients with neutropenic enterocolitis when enteritis is considered. To avoid treatment delay, antifungal therapy might be systematically discussed in ICU patients admitted for neutropenic enterocolitis with radiologically assessed enteritis.

Killer Cell Immunoglobulin-Like Receptor-Ligand Mismatch in Donor versus Recipient Direction Provides Better Graft-versus-Tumor Effect in Patients with Hematologic Malignancies Undergoing Allogeneic T Cell-Replete Haploidentical Transplantation Followed by Post-Transplant Cyclophosphamide.

We evaluated the impact of unidirectional donor versus recipient killer cell immunoglobulin-like receptor (KIR)-ligand mismatch (KIR-Lmm) on the outcomes of T cell-replete haploidentical stem cell transplantation (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) in a cohort of 144 patients treated for various hematologi diseases. We separately analyzed 81 patients in complete remission (CR group) and 63 with active disease (no CR group) at the time of Haplo-SCT. One-third of patients in each group had KIR-Lmm. In the no CR group, KIR-Lmm was associated with a significantly lower incidence of relapse (hazard ratio, .21; P = .013) and better progression-free survival (hazard ratio, .42; P = .028), with no significant increase in graft-versus-host disease incidence or nonrelapse mortality. In contrast, in the CR group no benefit of KIR-Lmm was observed. Our results encourage considering KIR-Lmm as an additional tool to improve donor selection for T cell-replete Haplo-SCT with PT-Cy, especially in patients with high-risk diseases.

Prolymphocytic Leukemia: New Insights in Diagnosis and in Treatment.

PURPOSE OF REVIEW: We aimed to produce a comprehensive update on clinical and biological data regarding two rare lymphoid neoplasms, B and T prolymphocytic leukemias, and assess therapeutic management in the light of new molecular insights and the advent of targeted therapies. RECENT FINDINGS: B cell prolymphocytic leukemia (B-PLL) diagnosis remains challenging in the absence of clear immunophenotypic or cytogenetic signature and overlap with mantle cell lymphoma. New molecular defects have been identified in T cell prolymphocytic leukemia (T-PLL), especially in the JAK STAT pathway. Like in chronic lymphocytic leukemia (CLL), B-PLL treatment depends on the presence of TP53 dysfunction. In T-PLL, alemtuzumab still remains the standard of care. Allogeneic transplantation is the only curable option. Thanks to reduced intensity conditioning regimens, it has become accessible to a larger number of patients. PLL prognosis remains poor with conventional therapies. However, great advances in the understanding of both T- and B-PLL pathogenesis lead to promising new therapeutic agents.

Management of central nervous system involvement in chronic lymphocytic leukaemia: a retrospective cohort of 30 patients.

Central nervous system involvement (CNSi) is a rare and poorly reported complication of chronic lymphocytic leukaemia (CLL). Establishing cause and effect between the CLL and the neurological symptoms remains challenging. We have analysed a retrospective cohort of 30 CLL patients with CNSi, documented by lymphocytic infiltration either by flow cytometry of the cerebrospinal fluid (CSF; n = 29) or CNS biopsy (n = 1). Neurological symptoms were heterogeneous. At the time of CNSi, less than half of the patients had a progressive CLL and 20 had never been treated for CLL. Initial treatment with fludarabine-based immuno-chemotherapy, with or without intra-CSF therapy, led to durable response in eight out of nine untreated patients. In contrast, 50% patients receiving various prior treatments needed additional therapy within a median of 4 months (1-16). Ibrutinib led to complete response in 4/4 heavily pre-treated patients. From CNSi, 5-year overall survival was 72% and 48% for treatment-naïve and previously treated patients respectively (P = 0·06); 5-year progression-free survival (PFS) was 43% and 0% (P = 0·125). 17p deletion was significantly associated with poor PFS (P = 0·006). CNSi may be the only sign of progression of CLL and should be considered an initiation criterion of systemic treatment. Prognosis seemed to be related to CLL characteristics rather than to CNSi itself.

The efficacy and safety of a new reduced-toxicity conditioning with 4 days of once-daily 100 mg/m(2) intravenous busulfan associated with fludarabine and antithymocyte globulins prior to allogeneic stem cell transplantation in patients with high-risk myelodysplastic syndrome or acute leukemia.

The optimal intensity of myeloablation associated with a reduced-toxicity conditioning (RTC) regimen in order to decrease the relapse rate without increasing non-relapse mortality (NRM), is not well established yet. This retrospective analysis was done on 30 patients with hematological malignancies. The aim was to assess the safety of a RTC regimen based on the busulfan at a dose of 100 mg/m(2)/d intravenously for 4 d, fludarabine at a dose of 30 mg/m(2)/d for 5 d, and anti-thymoglobulins at a dose of 2.5 mg/kg/d for 2 d. The cumulative incidences of grade 2-4 acute graft-versus-host disease (GVHD) and all grades chronic GVHD were 37% and 42%, respectively. Median 1-year overall survival and disease-free survival were 66% and 50%, respectively. At 1 year, the cumulative incidence of relapse/disease progression was 33%. NRM was 3% and 17% at day 100 and 1 year, respectively. This RTC conditioning regimen can lead to a long-term disease control. Moreover, it appears to be safe with a low NRM rate among high-risk patients.

Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities.

Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo-transplanted and achieved a 21-month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI-1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation.