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.
A multicentric retrospective cohort study between January 2010 and August 2017.
Six French ICUs members of the Groupe de Recherche Respiratoire en Onco-Hématologie research network.
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.
None.
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.
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.
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.
Summary
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.
Summary
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.
Allogeneic Hematopoietic stem cell transplantation (Allo-HSCT) is a curative option for advanced Non Hodgkin Lymphoma (NHL). Reduced intensity conditioning or reduced toxicity conditioning (RIC/RTC) ...allows improving survival and decreasing non-relapse mortality. Nevertheless it is well known that status disease before transplant is highly related to survival. Indeed, patients in non-responsive disease (ie stable disease or progressive disease (SD/PD)) have very poor outcomes compared to patients achieving a response. We addressed the question whether in responsive patients the level of response (partial response (PD) vs. complete response (CR)) had a profound impact on outcome in the context of RIC/RTC transplantation.
Inclusion criteria for this bi-centric retrospective study were 1) first Allo-HSCT 2) aggressive NHL including Diffuse Large B-cell Lymphoma (DLBCL), Mantle-cell Lymphoma (MCL) and nodal T-cell NHL 3) Matched related donor (MRD), 8/8 or 10/10 matched unrelated donor (MUD) and Haploidentical related donor (HRD) 4) conditioning including RIC or RTC. All patients in this cohort are considered as intermediate risk group in the DRI classification (Armand et al, Blood, 2012). Extranodal T-cell NHL, NK-cell NHL, Cord Blood Unit transplant, partially matched (HLA 7/8 or 9/10) unrelated donor, myeloablative conditioning and patients in SD/PD before transplantation were not included in this study. We used Cheson criteria (Cheson et al, JCO, 2007) to evaluate the disease status before Allo-HSCT and we focused on patients with PET positivity using Deauville criteria before transplantation.
115 patients included between 06.1999 and 09.2013. Diagnoses were DLBCL, MCL and nodal T-cell NHL in 40%, 30% and 30% respectively. Median age was 54 years old. Median line of treatments before transplantation was 3 (1-5), 81% of patients received an autologous SCT (31% in a tandem auto/allo and 50% relapsed after auto SCT). Donor types were MRD, MUD and HRD in 57,4%, 25,1%, and 57,4% of patients respectively. Conditioning was for 86% of patients a RIC and for 14% a RTC generally including Thiothepa.
Patients were in CR in 80 cases (69.6%) and in PR in 35 cases (31.4%) according to Cheson criteria. 5-years PFS and OS for patients in CR were 61.1% (49,1-76) and 64,3% (52,6-78,6) respectively, whereas 5-years PFS and OS for patients in PR were 38,7% (21,9-68,4) and 38,1% (21,5-67,6) respectively with a significant difference (p=0,04 and p=0,05 respectively). Among this cohort, 80 patients (33 DLBCL, 19 MCL and 28 nodal T-cell NHL) had a PET TDM before Allo-HSCT and 11 patients had a positive PET using Deauville criteria. PFS and OS for patients with PET negative were 65.5% and 65,8% respectively and PFS and OS for PET positive patients were 46,8% and 45,5% (p=0,32 and 0,33 respectively). In multivariate analysis including histology, type of donor, type of conditioning, age and status disease at transplantation, the only factor having a negative impact both on PFS and OS were disease status according to Cheson criteria: PR at transplantation is associated with a lower PFS an OS with a Hazard Ratio of 2 (p= 0,04).
In conclusion: for aggressive NHL, PR before Allo-HSCT evaluated with Cheson Criteria increases by 2 fold the risk of death or relapse in comparison with CR, indicating that either better response should be searched or transplant procedure should be adjusted to this risk.
Blaise:Sanofi: Honoraria, Research Funding.
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.
Introduction: Chronic lymphocytic leukaemia (CLL) with central nervous system involvement (CNSi) i.e. cerebrospinal fluid (CSF) infiltration and/or invasion of brain parenchyma is rare and poorly ...documented. There is currently no consensus either for diagnosis criteria or therapeutic management of CNSi in CLL. In order to characterize the clinical and biological features and determine the outcome after treatment, we present a retrospective cohort of 30 CLL patients with CNS involvement.
Patients and methods: We collected CLL patients fulfilling criteria for CNSi and treated within thirteen centres of the French Innovative Leukaemia Organization (FILO group) between 1995 and 2015.
CNSi was defined as lymphocytic documentation either leptomeningeal by positive CSF cytology and flow cytometry, or histopathological by CNS biopsy. Patients were excluded if CNS involvement was made of large cells in the context of Richter transformation.
Results: Thirty patients were included. Median age was 69 (range 42-87). Median time from CLL diagnosis to CNSi was 76 months (0-301). At the time of CNSi, Binet stage was A, B and C in 13, 9 and 6 patients respectively. There were 2 Richter syndromes. CLL was not progressive in 16 patients. FISH analysis showed 17p deletion in 5 patients. Clinical manifestations were heterogeneous, with both central (mostly visual disturbance, headache) and peripheral (mainly cranial nerve involvement) symptoms, leading to a diagnosis delay for 14 patients (median delay 6 months; 5 patients diagnosed > 1 year after first neurological symptoms). Diagnosis was based on CSF flow cytometry for 29 patients and 4 had histological diagnosis by biopsy. Lumbar puncture was positive in all cases with large range in cell count as well as in percentage of CLL cells. Median CSF cell count was 36/mm3 (range 1-1980) with predominance of lymphocytes (76 to 99%). Median percentage of CLL cells by flow cytometry was 16 (range 0.5-93). Magnetic resonance imaging was informative in 10 out of 27 patients. MRI abnormalities were FLAIR hyperintensity, pachymeningitis or mass syndrome. From CNSi, 5 years overall survival (OS) and progression free survival (PFS) was 71% and 56% respectively. At the time of CNSi, 20 patients had never been treated for CLL. Eleven patients received rituximab plus fludarabine/cyclophosphamide or bendamustine, with (n=7) or without (n=4) intrathecal chemotherapy (IT) as first line treatment for CNSi. Seven out of 9 patients evaluable for response are in persistent response after a median follow up of 55 months. In contrast, 5 out of 7 evaluable pre-treated patients receiving heterogeneous treatment didn't achieve CR nor PR. Five patients received ibrutinib with or without IT or rituximab. Four were previously treated (median 6 lines, range 2-8). Three out of 4 evaluable patients are in neurological CR. For treatment naïve and previously treated patients, 5 years OS was 80% and 56% (p=0.15), and 5 years PFS was 80% and 0% (p=0.006) respectively.
Conclusion: To our knowledge, this is the largest cohort of CLL patients with specific CNSi. Several important conclusions arise from this study: Symptoms were very heterogeneous and might lead to diagnosis delay. Diagnosis relayed on CSF flow cytometry including very low percentage of CLL cells. CNSi was the only sign of CLL progression in more than half of the cases. CNSi should be recognized as an initiation criterion of systemic treatment. Immunochemotherapy with RFC with or without IT, or R Bendamustine + IT was efficient in treatment naïve patients. Ibrutinib led to neurological response with or without IT in highly pre-treated patients. Prognosis seemed to be directly related to CLL prognosis and CNSi by itself did not appear as a poor prognostic factor.
Choquet:Janssen: Consultancy; Roche: Consultancy. Levy:Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Dupuis:ABBVIE: Membership on an entity's Board of Directors or advisory committees; ROCHE: Speakers Bureau. Johnson Ansah:BMS: Honoraria; Novartis: Honoraria. Troussard:Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Cymbalista:Karyopharm: Honoraria; Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding. Leblond:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Aurran-Schleinitz:CSLBehring: Honoraria; Janssen: Honoraria.
Allogeneic stem cell transplantation (SCT) remains the only curative option in poor risk chronic lymphocytic leukemia (CLL). Reduced intensity conditioning regimens (RIC) have improved outcome and ...enlarged number of patients eligible to SCT. However it is still controversial whether patient characteristics, CLL treatment, conditioning regimen or GVH prophylaxis influence the outcome. Here we present the analysis of our cohort of CLL patients who underwent RIC SCT.
This is a retrospective single center study Primary endpoint was overall survival; secondary endpoints were cumulated incidence of relapse and non-relapse mortality.
From 2000 to 2012, Thirty-nine patients with a sex ratio of 2 were transplanted. At time of transplantation, median age was 59 years (27-68), 82% patients displayed performans status (PS) of 0 and 20% had a comorbidity score ≥3. More than half patients (54%) were Fludarabine refractory and FISH 17p deletion was found in 10 out of 23 tested patients (43%). Median delay between diagnosis and transplant was 92 months (4-182). Patients received a median of 3 (1-9) prior therapies. Last treatment before transplant was fludarabine-based in 12 patients, alemtuzumab in 13, and other (RCHOP, R-Bendamustine, RDHAP) in 14. Median delay between the last treatment and transplantation was 2 months (1-33). At time of transplant, overall response rate was 82% including 33% complete response (CR). Four-color phenotypic MRD was negative (<10-4) in 9 patients (23%). Donor type was HLA matched relative for 22 patients, unrelated for 13 and cord blood for 4. Conditioning regimen varied according to protocols and donor. It consisted of fludarabine, busulfan and antithymocyte globulin in 21 patients, fludarabine, TBI and rituximab in 14 patients and fludarabine, cyclophosphamide and total body irradiation (TBI) in 4 and. Graft versus host disease (GVHD) prophylaxis was provided by cyclosporine alone in 54% patients, and cyclosporine and mycophenolate mofetil in 46%.
After transplant, overall response rate was 90% with 17 patients evolving from partial response or stable disease to complete response and MRD was negative in 28/33 (85%) patients. Donor chimerism was performed for 27 patients, chimerism >90% was obtained in all patients except one, after a median of 90d (19-180) post transplant. Acute and chronic extensive GVHD occurred in 44% and 38% patients respectively.
With a median follow-up of 59 months, median overall survival (OS) was 97 months, 2- and 5-years OS were 72% and 59% respectively. Fifteen patients died, 7 from GVHD, 4 from sepsis, 1 from CLL and 3 from other causes. 2- and 5-years cumulated incidences (CI) of non-relapse mortality (NRM) were 25.6% and 38.3% respectively. Three patients relapsed after transplant, 2 are still alive 82 and 98 months post-transplant. 2- and 5-years cumulated incidences of relapse were 2.8% and 6.8% respectively. In univariate analysis, disease status at transplant and number of prior therapies were significantly associated with better OS (p=0.0009 and p=0.03 respectively), whereas a trend to correlation between PS and OS was observed (p=0.063). In multivariate analysis, PS and achievement of CR or PR before transplant correlated significantly to OS (p=0.015 and p=0.05 respectively). Clearance of MRD before transplant perhaps suggested a better survival (p=0.158).
This retrospective study highlights the ability of allogeneic transplant to improve OS in otherwise very poor prognosis CLL patients and deserve further investigations.
Aurran-Schleinitz:Roche: Honoraria.
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