Leukemia & Lymphoma

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Clinical features of life-threatening complications following autologous stem cell transplantation in patients with lymphoma Lionel Kerhuel, Sandy Amorim, Elie Azoulay, Catherine Thiéblemont & Emmanuel Canet To cite this article: Lionel Kerhuel, Sandy Amorim, Elie Azoulay, Catherine Thiéblemont & Emmanuel Canet (2015): Clinical features of life-threatening complications following autologous stem cell transplantation in patients with lymphoma, Leukemia & Lymphoma To link to this article: http://dx.doi.org/10.3109/10428194.2015.1034700

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Accepted online: 27 Mar 2015.Published online: 12 May 2015.

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Date: 17 September 2015, At: 05:03

Leukemia & Lymphoma, 2015; Early Online: 1–6 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2015.1034700

ORIGINAL ARTICLE: CLINICAL

Clinical features of life-threatening complications following autologous stem cell transplantation in patients with lymphoma Lionel Kerhuel1, Sandy Amorim2, Elie Azoulay1,3, Catherine Thiéblemont2 & Emmanuel Canet1 1Medical Intensive Care Unit, and 2Hematology-Oncology Department, Saint Louis University Hospital, Paris, France

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and 3Paris Diderot University, Sorbonne Paris Cité, Paris, France Abstract Toxic effects of high dose therapy (HDT) combined with autologous stem cell transplantation (ASCT) can lead to lifethreatening conditions that may require intensive care unit (ICU) admission. We conducted a retrospective observational study over a 10-year period of all patients admitted to the ICU within 3 months after HDT/ASCT for lymphoma. Among the 532 patients treated by HDT/ASCT at our hospital, 27 (5%) were admitted to the ICU. Infections accounted for 88% (n  24) of diagnoses, in whom 50% were microbiologically documented. Primary sources of infections were neutropenic enterocolitis (n  9, 33%) and pneumonia (n  9, 33%). Bacteria were identified in 83% of documented infections. ICU mortality was 18.5% (n  5), representing 0.9% of the 532 patients. Among the 22 ICU survivors, 72.7% (n  16) were alive and in complete remission 6 months after ICU discharge. In our experience, maximal intensive care support is justified for HDT/ASCT recipients with severe complications.

likelihood of ICU admission and the mortality rate varied widely among studies from 9–18% and 33–69%, respectively. Several factors have been identified that may explain this disparity: changes in transplantation practice, differences in ICU admission policies, and improvements in supportive care. Furthermore, the heterogeneity of inclusion criteria regarding age, comorbidities, underlying disease (hematological malignancies, solid tumors, autoimmune disorders), ECOG Performance status at the time of transplantation, and pooled analysis of both autologous and allogeneic SCT may have contributed to this variability of outcome data between studies [15]. Although a substantial number of studies have documented the outcome of allogeneic SCT recipients admitted to the ICU [16–19], there is little information about the clinical features and outcome of patients presenting a life-threatening complication after ASCT according to the underlying disease. We retrospectively studied a homogeneous population of adult patients admitted to the ICU within 3 months of ASCT for the treatment of a relapse or refractory lymphoma. The objectives of the study were to describe the clinical features and outcome, and to assess the relevance of ICU care in this population.

Keywords: Autologous stem cell transplantation, intensive care unit, lymphoma, mortality

Introduction High dose therapy (HDT) combined with autologous stem cell transplantation (ASCT) has been shown to improve survival in patients either in front-line for mantle cell lymphoma or in relapsed setting for the other lymphoma subtypes [1–3]. Nevertheless, this procedure may be associated with serious complications such as chemotherapy-induced organ damage and infections that may require intensive care unit (ICU) admission. The risk of infection induced by prolonged neutropenia can be reduced by the infusion of autologous stem cells and the use of hematopoietic growth factors [4]. European data report an increasing number of hematopoietic SCT, either autologous or allogenic transplant, in the past decades [5,6]. In France, in 2012, ASCT accounted for 62% of hematopoietic stem-cell transplantation, and lymphoma was the most common indication (48.8%) of ASCT [7]. Studies assessing the prognosis of hematopoietic SCT recipients admitted to the ICU are numerous [8–14]. The

Methods As required by our institutional review board (CECIC Clermont Ferrand – IRB no.5891; Ref: 2007-16), informed consent was obtained from each patient prior to participation in this non-interventional study with anonymous data collection.

Design and setting We retrospectively included consecutive adult patients admitted to the medical ICU of Saint-Louis University Hospital within 3 months following HDT/ASCT for a refractory or relapse lymphoma, between 1 January 2004 and 31 July 2013. The Saint-Louis University Hospital is a 650-bed public hospital, with 330 beds dedicated to patients with various conditions associated with immunodeficiency (hematological malignancies, solid cancers and solid organ transplantation).

Correspondence: Emmanuel Canet, MD, AP-HP, Saint-Louis University Hospital, Medical Intensive Care Unit, 1 avenue Claude Vellefaux, 75010 Paris, France. Tel:  33 142 499 419. Fax:  33 142 499 426. E-mail: [email protected] Received 15 November 2014; revised 15 February 2015; accepted 17 March 2015

1

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2  L. Kerhuel et al. The Hematology-Oncology Department of Saint Louis Hospital is a referral cancer unit treating over 380 lymphoma patients at diagnosis a year, dedicated to the management and follow-up of lymphoid malignancies [20]. ASCT procedures are performed in this unit. The medical ICU of Saint Louis Hospital is a 12-bed unit that admits 750–850 patients per year of whom about one-third have hematological malignancies. Information on the organization of the ICU and criteria for ICU admission have been published elsewhere [21]. Mandatory ICU admission reasons are defined by at least one organ failure and the need for at least one of the following therapies: supplemental nasal oxygen  3 L/min, use of vasoactive drugs, sustained volemic expansion, invasive or non-invasive mechanical ventilation, or renal replacement therapy. ICU admission policies remained unchanged throughout the study period. At our institution, intensivists and hematologists are available 24 hours a day 7 days a week and work together to manage all high-risk hematology patients.

Eligibility criteria The following lymphoid malignancies were considered in this study: Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, T-cell lymphoma, primary cerebral lymphoma and Burkitt’s lymphoma. All patients admitted to the ICU within the 3 months following HDT/ASCT during the study period were eligible. Exclusion criteria were: a combined autologous/allogeneic stem cell transplant, and a time to ICU admission exceeding 3 months. In accordance with the hematologic team, the threshold of 3 months has been defined as the cut-off value for patient inclusion because immune recovery is mostly achieved at this point, and organ failures requiring ICU management should not be attributed to HDT beyond this period.

Patient management HDT/ASCT procedure was performed in the HematologyOncology Department. High dose chemotherapy was prescribed by the hematologist in charge of the patient, according to the best standard of care. Conditioning regimen varied according to the underlying disease. Mobilized peripheral blood progenitor cells were used as the sole source of stem cells. Anti-infectious prophylaxis included oral trimethoprim-sulfamethoxazole (400 mg once daily) and oral valaciclovir (500 mg once daily) from day 1 to day 100. Before 2009, subcutaneous Granulocyte ColonyStimulating Factor (G-CSF) administration was performed from day 1 after ASCT, and from day 8 after that year. When organ failure occurred, the decision for intensive care admission was based on a multidisciplinary approach, as previously published by our group [21,22]. All patients had full resuscitative directives. The diagnostic strategy for sepsis at ICU admission consisted of non-invasive tests (echocardiography, computed tomography, blood cultures, sputum and urine examination, urine and serum antigen assays). Decision to perform fiber-optic bronchoscopy and bronchoalveolar lavage was based on criteria that have been published elsewhere [23]. Life-sustaining therapies were implemented according to the best standard of care.

Broad-spectrum antibiotics and empirical antifungal therapy were implemented when infectious conditions occurred, especially during neutropenia. After ICU discharge, all patients were managed in our hospital.

Data collection Patients were identified through the ASCT database of the Hematology-Oncology Department. All data were obtained from medical records and patient charts. Baseline patient characteristics were collected, including demographics, comorbidities, underlying disease, International Prognostic Index (IPI) score, Performance Status (PS), hematologic status at transplantation, conditioning regimen and duration of neutropenia. Variables recorded regarding ICU admission and treatments were: data relative to clinical presentation, reason for ICU admission, time of admission and discharge from ICU, diagnosis, therapies implemented, microbiological documentation whenever possible, and ICU outcome data. Disease severity at ICU admission was assessed using the Sequential Organ Failure Assessment (SOFA) score [24]. Hematological status (alive with complete remission, alive with relapsed or refractory malignancy, or dead), 6 months after ICU discharge was available for all patients.

Statistical analysis Standard descriptive data analyses were performed using Excel software. Categorical variables were reported as proportions and continuous variables were reported as medians and interquartile ranges (IQR).

Results Study population During the study period, 532 HDT/ASCT were performed in the Hematology-Oncology Department for patients with lymphoma. Twenty-seven (5%) patients experienced a lifethreatening complication requiring ICU admission within 3 months following the procedure, equally distributed over the study period (Figure 1).

Figure 1. Flow chart of the study (ICU, intensive care unit; SCT, stem cell transplantation; CR, complete remission).

ICU admission after autologous SCT in lymphoma  3 Patient characteristics are reported in Table I. The most common hematological malignancies were diffuse large B-cell lymphoma (37%) and Hodgkin lymphoma (19%). Two patients had a malignancy with central nervous system involvement (one had Burkitt’s lymphoma and one diffuse large B-cell lymphoma). Hematological status at the time of ASCT was complete remission (CR) for 15 (56%) patients and partial remission (PR) for 12 (44%) patients. The most commonly used conditioning regimens were Z-BEAM (n  11, 41%) and BEAM (n  10, 37%). The average duration of neutropenia was 10 [9;12] days after ASCT.

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Diagnoses and ICU management ICU admission occurred 9 [6;13] days after the transplant procedure. The most common reasons for ICU admission were shock (n  18, 66%) and acute respiratory failure (n  7, 26%). The median SOFA score was 6 [5;8]. Eighteen (66%) patients had neutropenia at ICU admission (Table II). All patients with a suspected infection at ICU admission (n  24, 88%) received antibiotics according to international guidelines [25,26]. Empirical antifungal therapy was used for 12 neutropenic patients with persistent fever after 4 days of antibiotics. Infections accounted for 88% of ICU final diagnoses (24 patients). The main source of infection was gastrointestinal: neutropenic enterocolitis (NEC) in nine patients (33%) and Table I. Characteristics of the 27 study patients. Variables n (%) or median [IQR] Demographics Age (years) Male gender Performance status 0–1  2 Hematological malignancy, n (%) DLBCL Hodgkin lymphoma Follicular lymphoma Mantle cell lymphoma T-cell lymphoma Other Central nervous system involvement, n (%) IPI score Hematological status at transplantation Complete response Partial response Conditioning regimen Z-BEAM BEAM R-BEAM TBE TAM Number of autologous stem cells transfused (.106/kg) Lines of chemotherapy prior to ASCT 1 2  3 Hematopoietic recovery after HDT (days)

All patients (N  27) 54 [38;60] 14 (52) 21 (78) 6 (22) 10 (37) 5 (19) 4 (15) 2 (7) 2 (7) 4 (15) 2 (7) 2 [2;3] 15 (56) 12 (44) 11 (41) 10 (37) 1 (4) 2 (7) 3 (11) 3.28 [3.18;3.59] 10 (37) 14 (52) 3 (11) 10 [9;12]

­ LBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; D BEAM, BiCNU (carmustine) etoposide aracytine melphalan; Z-BEAM, ZevalinBEAM; R-BEAM, Rituximab-BEAM; TBE, thiotepa busulfan endoxan; TAM, total body irradiation aracytine melphalan; ASCT, autologous stem cell transplantation; HDT, high dose therapy.

severe oral mucositis in three patients (11%). Nine patients (33%) had pneumonia, which occurred during neutropenia recovery in 78% (n  7) of cases. Investigations yielded a microbiological identification in 50% (n  12) of cases. Bacterial infections were documented in 10 patients (83%), eight of them (80%) with a positive blood culture. Two patients had severe viral pneumonia (Table III). Three patients (12%) were admitted with a noninfectious complication: one cardiogenic pulmonary edema, one stroke and one gastrointestinal bleed. Life-sustaining therapies were implemented in 15 patients (55.5%) throughout the ICU stay. Vasopressors were used in 14 (52%) patients, intubation and invasive mechanical ventilation in five (19%), non-invasive ventilation in two (7%) and renal replacement therapy was required in four (15%). All patients had full resuscitative directives and no decisions were taken to withdraw life-sustaining therapies. ICU and lengths of hospital stays were 4 [3;7] days and 29 [23;35] days, respectively.

Outcome analysis Of the 27 critically ill ASCT recipients included in the present study, five (18.5%) died in the ICU. The causes of death were: neutropenic enterocolitis (three patients), pneumonia (one patient) and stroke (one patient). The overall hospital mortality of the 532 patients who underwent HDT/ASCT in the Hematology-Oncology Department during the study period was 0.9% (all patients who died from a critical complication were previously admitted to the ICU). Among the 22 ICU survivors, 20 patients were still alive 6 months after ICU discharge. Sixteen (59.2%) of them had persistent CR and four (14.8%) had relapsed from their hematological malignancy. Neither ICU nor month-6 outcomes were influenced by the hematological status at transplantation.

Table II. Characteristics of ICU management and outcome data. Variables n (%) or median [IQR] Time (days) from ASCT to ICU admission Neutropenia ( 1.0G/L), n (%) SOFA Reason for ICU admission Shock Acute respiratory failure Neurologic disorder Bleeding Life-sustaining therapies Vasopressors Invasive mechanical ventilation Non-invasive mechanical ventilation Renal replacement therapy ICU length of stay (days) Hospital length of stay (days) Outcome data ICU mortality Hematological status 6 months after ASCT Alive with persistent complete remission Alive with relapse disease Death

All patients (N  27) 9 [6;13] 18 (66) 6 [5;8] 18 (66) 7 (26) 1 (4) 1 (4) 14 (52) 5 (19) 2 (7) 4 (15) 4 [3;7] 29 [23;35] 5/27 (18,5) 16 (58) 4 (15) 7 (27)

­ SCT, autologous stem cell transplantation; ICU, intensive care A unit; SOFA, sequential organ failure assessment.

4  L. Kerhuel et al. Table III. Characteristics of ICU diagnoses.

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Variables n (%) or median [IQR] Infections Primary source of infection Neutropenic enterocolitis Pneumonia Severe oral mucositis Catheter-related infection Microbiological identification Gram-positive cocci Streptococcus mitis Streptococcus oralis Enterococcus faecium Coagulase-negative Staphylococcus Gram-negative bacilli Escherichia coli Pseudomonas aeruginosa Klebsiella pneumoniae Bloodstream infection Virus Syncytial respiratory virus Parainfluenza virus Invasive fungal infection Non-infectious diagnoses Cardiogenic pulmonary edema Stroke Gastrointestinal bleeding

All patients (N  27) 24 (88) 9 (33) 9 (33) 3 (11) 3 (11) 12/24 (50) 5 (50) 2 1 1 1 5 (50) 2 2 1 8 (33) 2 (16) 1 1 0 (0) 3 (12) 1 (4) 1 (4) 1 (4)

Discussion Among all of the HDT/ASCT for lymphoma performed at our hospital, 5% were admitted to the ICU for a serious complication, most of them (81%) within 2 weeks of transplant, during the period of neutropenia. Shock was the leading cause of ICU admission. Bacterial infections related to the gastrointestinal tract (severe mucositis and NEC) were the most commonly diagnosed. Pneumonia occurring during neutropenia recovery was the second most frequent clinical entity. ICU admission was associated with a substantial mortality rate (18.5%). Nevertheless, among patients discharged alive from the ICU, 91% were still alive at month 6, and 73% reported persistent complete remission of the hematological malignancy. Data on the outcome of critically ill patients following ASCT are scarce. Indeed, most previous studies conducted in the ICU have focused on allogeneic SCT recipients or included both autologous and allogeneic SCT recipients. As a consequence, they reported ICU admission and mortality rates as high as 18% and 77%, respectively [11,27,28]. We decided to focus our study on patients who underwent ASCT for lymphoma. The first reason for this was that ASCT accounted for 62% of SCT activity in France and because lymphoma was the main indication for this procedure [7]. The second was that allogeneic recipients are much more immunosuppressed by the transplant procedure (prolonged neutropenia, administration of steroids to prevent or treat acute or chronic GVHD) and thus cannot be compared to autologous recipients without major confounders. Our results can be compared with two previous studies that focused on ASCT patients admitted to the ICU. Khassawneh et al. [29] reported the outcome of 78 patients receiving mechanical ventilation after ASCT with a hospital mortality of 74%. In a recent cohort study of 34 patients, Trinkaus et al. [30] found a 3.3% ICU admission rate within

100 days of autologous engraftment, and a 38% mortality rate in the ICU. Our outcome of 18.5% hospital mortality compares favorably to these reports but there are a number of factors to explain the difference. The first is that our study population was less sick, as reflected by a lower SOFA score and a lower intubation rate (19% compared to 59% in the Trinkaus study and 100% in the Khassawneh study). The second is that in the two previous studies, myeloma or amyloidosis accounted for more than 80% of the underlying malignancy. We agree with Trinkaus et  al., who highlighted the importance of the underlying malignancy on rates of ICU admission and hospital mortality [30]. Myeloma primarily affects elderly patients, with a potential increased frequency of comorbidities, frailty, and disability. In contrast, our patients were young, with little comorbidity and in good general condition (Performance Status 0–1, 78%) at the time of ICU admission. These characteristics are known to be strongly associated with ICU survival [31]. The third is that we developed an ICU policy that was primarily based on an early admission strategy in case of physiological disturbances [22]. As a consequence, we were able to implement early diagnostic and treatment procedures that might have improved the outcome. In our ICU, we have implemented a diagnostic strategy for infectious complications with iterative non-invasive and invasive procedures [23,32]. This permitted microbiological identification in 50% of the cases, despite the frequent use of broad-spectrum antibiotics for febrile neutropenia prior to ICU admission. Not surprisingly, given the mucosal toxicity of HDT, we documented a high proportion of oropharyngeal (Streptococcus mitis, Streptococcus oralis, Coagulasenegative Staphylococcus) and intestinal (Enterococcus faecium, Klebsiella pneumoniae) pathogens. Nosocomial bacteria (Pseudomonas aeruginosa) isolation was also expected, with regard to the hospital stay experienced by ASCT recipients and the highly probable antibiotic exposure in the previous months. These results are in accordance with previous studies [30,33,34] and support the recent European guidelines for choosing broad-spectrum empirical antibacterial therapy that covers these pathogens [35]. Furthermore, no fungal infection was reported in our study population. These data are in accordance with several studies that assessed infectious complications occurring in hematology departments after HDT/ASCT [36–39]: 29–57% of infections were microbiologically documented, and invasive fungal infections represented 0.9–3.2% of identified pathogens. Trinkaus et  al. [30] reported only two cases of Candidemia (2/34 patients) in their critically ill HDT/ASCT population. Indeed, because of the short duration of neutropenia, patients undergoing HDT/ASCT for lymphoma are not considered to be at high risk for invasive fungal infections and antifungal prophylaxis is not recommended in this population [40]. Nevertheless, these results should be interpreted with caution. One should bear in mind that it reflects a singlecenter epidemiology on a selected lymphoma population. In addition, 50% of the infectious complications remained without documentation. As the primary sources of infection in half of the cases were NEC and severe mucositis, it should be taken into account that fungi are not uncommon in these diseases [41]. In our center, in addition with the general

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ICU admission after autologous SCT in lymphoma  5 supportive measures and broad-spectrum antibiotics, empirical antifungal therapy is implemented in these conditions, at least during neutropenia. The 74% survival rate at 6 months after ICU discharge in our study is quite acceptable compared to the unfavorable prognosis (15–22%) of allogeneic recipients described in previous studies [16–18]. These outcome data strengthen the view that the decision-making process regarding ICU admission for ASCT recipients should be differentiated from allogeneic SCT recipients. In our opinion, there is no doubt that ASCT recipients could greatly benefit from ICU admission for aggressive life support if necessary. The present study has several limitations. First, it was a single-center study. Thus, our admission policy and patient recruitment patterns may have influenced the findings and our results depict our practices. However, the large number of patients treated in the Hematology-Oncology Department and the standardized policy of ICU admission suggest that our results may also apply to other settings. Second, due to the small sample size, our analysis was restricted to descriptive data. A bigger sample may be useful in order to identify independent factors associated with ICU admission and outcome. Third, our inclusion criteria target a specific population. Therefore, our results should not be generalized to ASCT recipients for other diseases (multiple myeloma, solid tumors and auto immune diseases). Nevertheless, our study provides valuable data for hematologists and intensivists on a homogenous population of interest. In summary, although life-threatening complications are infrequent after HDT and ASCT for a relapse or refractory lymphoma, it remains associated with a substantial mortality rate in the case of ICU admission. However, our study reports that most of ICU survivors were still alive and with persistent complete remission of their lymphoma 6 months after ICU discharge. This selected population seems to benefit from life-sustaining therapies with a reasonable likelihood of both short- and long-term survival. Further larger studies are warranted to confirm these results.­­ Potential conflict of interest:  Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

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Clinical features of life-threatening complications following autologous stem cell transplantation in patients with lymphoma.

Toxic effects of high dose therapy (HDT) combined with autologous stem cell transplantation (ASCT) can lead to life-threatening conditions that may re...
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