Colombe Saillard

Critically ill allogeneic hematopoietic stem cell transplantation patients in the intensive care unit: reappraisal of actual prognosis

The outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients has significantly improved over the past decade. Still, a significant number of patients require intensive care unit (ICU) management because of life-threatening complications. Literature from the 1990s reported extremely poor prognosis for critically ill allo-HSCT patients requiring ICU management. Recent data justify the use of ICU resources in hematologic patients. Yet, allo-HSCT remains an independent variable associated with mortality. However, outcomes in allo-HSCT patients have improved over time and many classic determinants of mortality have become irrelevant. The main actual prognostic factors are the need for mechanical ventilation, the presence of GvHD and the number of organ failures at ICU admission. Recently, the development of reduced-intensity conditioning regimens, early ICU admission and the increased use of noninvasive ventilation, combined with time effect and general advances in hematology, in allo-HSCT procedures and in ICU management have contributed to improve general outcome. A rational policy of ICU admission triage in these patients is very hard to define, as each decision for ICU admission is a case-by-case decision at patient bedside. The collaboration between hematologists and intensivists is crucial in this context.

National Institutes of Health classification for chronic graft-versus-host disease predicts outcome of allo-hematopoietic stem cell transplant after fludarabine–busulfan–antithymocyte globulin conditioning regimen

Abstract In 2005, the National Institutes of Health (NIH) proposed standard criteria for diagnosis, organ scoring and global assessment of chronic graft-versus-host disease (cGvHD) severity. We retrospectively reclassified cGvHD with NIH criteria in a monocentric cohort of 130 consecutive adult patients with hematological malignancies presenting cGvHD after receiving allo-hematopoietic stem cell transplant (HSCT) with a fludarabine–busulfan–antithymocyte globulin (ATG) conditioning regimen, among 313 consecutive HSCT recipients. We compared NIH and Seattle classifications to correlate severity and outcome. The follow up range was effectively 2–120 months. Forty-four percent developed Seattle-defined cGvHD (22% limited, 78% extensive forms). Using NIH criteria, there were 23%, 40% and 37% mild, moderate and severe forms, respectively, and 58%, 32% and 8% classic cGvHD, late acute GvHD and overlap syndrome. Five-year overall survival was 55% (49–61), and cumulative incidences of non-relapse mortality (NRM) and relapse/progression at 2 years were 19% (14–23) and 19% (14–24). NIH mild and moderate forms were associated with better survival compared to severe cGvHD (hazard ratio [HR] = 3.28, 95% confidence interval [CI]: 1.38–7.82, p = 0.007), due to higher NRM among patients with severe cGvHD (HR = 3.04, 95% CI: 1.05–8.78, p = 0.04) but comparable relapse risk (p = NS). In conclusion, the NIH classification appears to be more accurate in predicting outcome mostly by the reclassification of old-defined extensive forms into NIH-defined moderate or severe.

Neutropenic cancer patients with severe sepsis: need for antibiotics in the first hour

Dear Editor, Neutropenic cancer patients are at high risk of sepsis [1]. The delay and adequacy of antimicrobial treatment are likely to influence the outcomes of such patients. From 2008 to 2010, all neutropenic cancer patients admitted to our intensive care unit (ICU) for severe sepsis (n = 48) and septic shock (n = 70) were prospectively included in the present study. Our goal was to identify at ICU admission predictive factors associated with ICU mortality. Briefly, our methodological design was similar to that reported in a previous study [2]. Patient features were collected at ICU admission. In the ICU, antibiotics were initiated, continued, or adapted according to microbial documentation. The first antimicrobial treatment initiated in the ICU was a beta-lactam directed against Gram-negative bacilli in all patients. A combined regimen was administered to 69 (58 %) patients, consisting of addition of aminoglycosides (n = 34) or fluoroquinolones (n = 35). Moreover, 54 (46 %) patients received vancomycin (n = 42) or linezolid (n = 12). Our strategy was in compliance with the published guidelines [2]. The ICU and 1-year mortality rates were 34 and 63 %, respectively. In the univariate analysis, we confirmed predictive factors such as severity scores at admission, organ failure at the sepsis onset, and need for invasive mechanical ventilation (p \ 0.05). In the multivariate analysis (Table 1), during the ICU stay, the major predictive factor for ICU mortality was the interval ([1 h) between the first sign of sepsis and the initiation of antimicrobial treatment. In addition, we identified three independent predictors: inappropriate antimicrobials in the ICU, severity score at admission, and non-fermenting Gram-negative bacilli infection. Age, comorbidity, status of malignancy, and hematopoietic stem cell transplantation did not affect ICU mortality. Hence, those criteria are irrelevant for the decision of ICU admission. Our data underline the need for a prompt initiation of an appropriate antimicrobial treatment in neutropenic cancer patients admitted to ICU for severe sepsis. This finding was clearly shown in non-neutropenic patients. An early appropriate antimicrobial therapy in non-neutropenic patients is associated with better survival, although pathogen species are not associated with mortality [3]. In a large cohort of 28,150 non-neutropenic patients with severe sepsis, delay in the first antibiotic administration was associated with increased hospital mortality. A linear relationship was found between the mortality and each hour delay in antibiotic administration [4]. Previously, a retrospective study analyzed the impact of time before antibiotic administration in a cohort of cancer patients, including 53 % of neutropenic patients. A 2-h delay between ICU admission and the first antibiotic treatment administration was associated with increased mortality [5]. Within the limitations of our study due to the study design and sample size, our findings suggest that, in the ICU, a 1-h delay between the antimicrobial treatment initiation and the first sign of sepsis was the strongest predictor of ICU mortality in neutropenic cancer patients. Thereafter,

SynthèsePrise en charge de la neutropénie fébrile chez le patient d’onco-hématologie admis en réanimationFebrile neutropenia in onco-hematology patients hospitalized in Intensive Care Unit

Febrile neutropenia in cancer patients is associated with a high mortality. Patients are frequently admitted to Intensive Care Unit (ICU) for severe sepsis or septic shock. Empirical antibiotic treatment, including monotherapy β-lactam covering Pseudomonas aeruginosa, must be prompt. The ICU management is slightly different, due to a particular microbial ecology. A standardized approach to obtain a microbiological documentation is the cornerstone in these patients, leading to an adapted antimicrobial treatment. Systematic reassessment of initial antibiotic regimen should be realised. Neutropenic patients with severe sepsis or septic shock should receive promptly a β-lactam-aminoglycoside combination, as well as glycopeptides in case of severity or absence of documented infection. Early catheter removal should be considered widely. In the actual context of growing resistance, antibiotics saving became a major concern. According to context and microbial documentation, an escalade or de-escalade approach is recommended, to take into account multi-resistant pathogens. The addition of antifugal treatment is also a major issue in these patients and has well-defined indications. In neutropenic patients admitted in the ICU for severe sepsis or septic shock, controlling local microbial epidemiology and the emergence of multi-resistant bacteria are the key issues.

Prise en charge de la neutropénie fébrile chez le patient d’onco-hématologie admis en réanimation

Febrile neutropenia in cancer patients is associated with a high mortality. Patients are frequently admitted to Intensive Care Unit (ICU) for severe sepsis or septic shock. Empirical antibiotic treatment, including monotherapy β-lactam covering Pseudomonas aeruginosa, must be prompt. The ICU management is slightly different, due to a particular microbial ecology. A standardized approach to obtain a microbiological documentation is the cornerstone in these patients, leading to an adapted antimicrobial treatment. Systematic reassessment of initial antibiotic regimen should be realised. Neutropenic patients with severe sepsis or septic shock should receive promptly a β-lactam-aminoglycoside combination, as well as glycopeptides in case of severity or absence of documented infection. Early catheter removal should be considered widely. In the actual context of growing resistance, antibiotics saving became a major concern. According to context and microbial documentation, an escalade or de-escalade approach is recommended, to take into account multi-resistant pathogens. The addition of antifugal treatment is also a major issue in these patients and has well-defined indications. In neutropenic patients admitted in the ICU for severe sepsis or septic shock, controlling local microbial epidemiology and the emergence of multi-resistant bacteria are the key issues.

Evaluation of comorbidity indexes in the outcome of elderly patients treated for acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is prevalent mainly in children. Th e use of intensive chemotherapy allows a high curability rate with a reasonable toxicity profi le. Application of these “ pediatric like ” strategies in adults has also improved survival but is associated with a signifi cantly lower tolerability [1,2]. Toxicity is correlated with age, with an increased frequency for patients between 40 and 60 years [3]. Interestingly, only limited data are available in older patients, for whom the benefi t/risk ratio of chemotherapy may be more problematic, and with potential interactions between comorbidities and drugs used in the treatment of ALL, such as high dose steroids or vinca alkaloids. Th e issue of the impact of comorbidities in other hematological malignancies has been largely explored [4 – 6]. Multiple studies have shown that comorbidity

HLA-Matched Sibling versus Unrelated versus Haploidentical Related Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged Over 60 Years with Acute Myeloid Leukemia: A Single-Center Donor Comparison

Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD versus matched sibling donor (MSD) and unrelated donor (UD) allo-HSCT for patients with AML aged ≥60 years. Ninety-four patients (MSD: n = 31; UD: n = 30; HRD: n = 33) were analyzed. The median age was 65 (range, 60 to 73) years. We observed a higher cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) after UD allo-HSCT (MSD versus UD versus HRD: 3% versus 33% versus 6%, respectively; P = .006). Two-year cumulative incidence of moderate or severe chronic GVHD was 17%, 27%, and 16% in the MSD, UD, and HRD groups, respectively (P = .487). No difference was observed in the 2-year cumulative incidence of relapse or nonrelapse mortality (NRM) (relapse: MSD versus UD versus HRD: 32% versus 25% versus 25%, respectively; P = .411; NRM: MSD versus UD versus HRD: 19% versus 27% versus 24%, respectively; P = .709). At 2 years, progression-free survival, overall survival, and GVHD- and relapse-free survival were 48%, 50%, and 39%, respectively, in the MSD group; 48%, 51%, and 23%, respectively, in the UD group; and 50%, 52%, and 32%, respectively, in the HRD group, without statistically significant differences between the groups. We conclude that HRD allo-HSCT is highly feasible and no less efficient than MSD or UD allo-HSCT in patients with AML aged ≥60 years. Thus, the absence of a HLA-identical donor should not limit the consideration of allo-HSCT for the treatment of AML.

The prognostic impact of abdominal surgery in cancer patients with neutropenic enterocolitis: a systematic review and meta-analysis, on behalf the Groupe de Recherche en Réanimation Respiratoire du patient d’Onco-Hématologie (GRRR-OH)

Neutropenic enterocolitis (NE) is a diagnostic and therapeutic challenge associated with high mortality rates, with controversial opinions on its optimal management. Physicians are usually reluctant to select surgery as the first-choice treatment, concerns being raised regarding the potential risks associated with abdominal surgery during neutropenia. Nevertheless, no published studies comforted this idea, literature is scarce and surgery has never been compared to medical treatment. This review and meta-analysis aimed to determine the prognostic impact of abdominal surgery on outcome of neutropenic cancer patients presenting with NE, versus medical conservative treatment. This meta-analysis included studies analyzing cancer patients presenting with NE, treated with surgical or medical treatment, searched by PubMed and Cochrane databases (1983–2016), according to PRISMA recommendations. The endpoint was hospital mortality. Fixed-effects models were used. The meta-analysis included 20 studies (385 patients). Overall estimated mortality was 42.2% (95% CI = 40.2–44.2). Abdominal surgery was associated with a favorable outcome with an OR of 0.41 (95% CI = 0.23–0.74; p = 0.003). Pre-defined subgroups analysis showed that neither period of admission, underlying malignancy nor neutropenia during the surgical procedure, influenced this result. Surgery was not associated with an excess risk of mortality compared to medical treatment. Defining the optimal indications of surgical treatment is needed.Trial registration PROSPERO CRD42016048952

Histone deacetylase inhibitor abexinostat (S78454/PCI-24781) as a successful approach in a case of refractory peripheral angio-immunoblastic T-cell lymphoma, as a bridge to reduced intensity conditioning haplo-identical allogenic stem cell transplant.

A 66-year-old woman presented in 2012 with an unintentional 10 kg weight loss, intermittent fevers, skin rash, generalized lymphadenopathy and hyper. Evaluation revealed histologically proven peripheral angio-immunoblastic T-cell lymphoma (AITL), (stage IV), with cutaneous and osteomedullary involvement, with two international prognostic index (IPI) risk factors and two risk factors for the prognostic index for peripheral Tcell lymphoma. The patient was treated in a clinical trial up-front and received 2-weekly CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). Evaluation after two cycles showed progressive disease. Salvage chemotherapy consisting of CarboDHAP (carboplatin, cytarabine, and dexamethasone) was started. Clinical progression with lymphadenopathy reappearance and night sweats was observed after one cycle. Treatment was switched to an ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) regimen. After six cycles, the patient achieved a complete response (CR), confirmed by chest tomography. Relapse was observed 1 year after the last ABVD cycle, with recurrence of lymph nodes by fluorodeoxyglucosepositron emission tomography/computed tomography (FDG-PET/CT), confirmed by histology (Fig. 1). The patient was included in an international, multicenter, open-label, phase II dose-escalation study of oral administration of the pan-histone deacetylase (panHDAC) inhibitor abexinostat (S78454/PCI-24781, CL178454-001). She received a dose of 80 mg orally twice daily for 14 days of every 21-day cycle. Treatment was well tolerated, with grade I diarrhea and asthenia. Restaging CT scan after four cycles revealed CR. Ten total cycles were administered. FDG-PET/CT confirmed the persistence of CR after cycle 9. The patient was subsequently evaluated for allogenic hematopoietic stem cell transplant (SCT). We performed reduced-intensity conditioning haplo-identical allogenic SCT with her daughter, using cyclophosphamide (14.5 mg/kg/d 2 days), fludarabine (30 mg/m/d 5 days), total body irradiation (2 Grays) and infusion of 4,9.10 CD34+/kg peripheral blood stem cells. Graftversus-host disease (GVHD) prophylaxis consisted of cyclophosphamide 50 mg/kg/d (day 3 and 4), cyclosporine A and mycophenolate mofetil. No acute or chronic GVHD were observed. Chimerism was total donor at day 60. The only complications were cytomegalovirus reactivation, successfully treated with ganciclovir, and an Aspergillus fumigatus documented sinusitis successfully treated with voriconazole. The patient has now reached a follow-up of 10 months post-transplant, she is in excellent general health, and without evidence of recurrent disease. The peripheral T-cell lymphomas (PTCLs), including AITL, represent 20% of mature T-cell and NK-cell neoplasms, and encompass a heterogeneous group of diseases associated with a poor prognosis. The International T-Cell Project (ITCP) and the British Columbia Cancer Agency (BCCA) series are the largest retrospective studies of PTCLs and include outcomes on 1314 and 199 cases, including 213 and 10 AITL patients

Response to immunosuppressive treatment predicts outcome in patients with chronic graft-versus-host disease: a single-center analysis of longitudinal data.

It has been reported that chronic graft-versus-host disease (cGVHD) is associated with significant morbidity and mortality after allogeneic stem cell transplantation (allo-SCT). The risk of relapse is generally reduced when cGVHD is present, but prognosis may be affected by increased toxicity and/or risk of infection associated with immunosuppressive treatment (IST). We performed a longitudinal data analysis of cGVHD, including the evolution of cGVHD itself over time in response to IST, in a single-center cohort of 313 consecutive patients undergoing allo-SCT. We found that lack of sustained response without withdrawal of IST within 6 months of cGVHD development was associated with higher transplantation-related mortality (hazard ratio, 2.32; 95% confidence interval, 1.24-4.33) compared with cGVHD-free patients. Conversely, response conferred better overall survival (hazard ratio, 0.42; 95% confidence interval, 0.18-0.95). Our analytical approach allowed us to integrate the evolution of cGVHD in a predictive model of transplantation outcome; notably, remission associated with permanent discontinuation of IST within the first 6 months from the occurrence of cGVHD seemed to correlate most closely with final outcome. Further confirmation from larger studies is needed.