Sarah Perreault

The use of basiliximab–infliximab combination for the treatment of severe gastrointestinal acute GvHD

After allogeneic stem cell transplant, severe grade III–IV gastrointestinal (GI) acute GvHD is associated with significant morbidity and mortality, and generally results in poor outcomes. Salvage therapy for patients who fail steroid therapy is not well defined in the literature. In the current retrospective study, we reviewed our experience with the combination of basiliximab and infliximab in 21 patients with severe, grade III–IV GI acute GvHD of whom 16 met the definition for steroid-refractory disease. The overall response rate was 76%, with 43% CR at a median time of 21 days after beginning treatment. The survival at 1 year was 24%, with most deaths due to complications from GvHD and recurrence of primary disease. All five of the long-term survivors have chronic GvHD. On the basis of a review of the literature, this regimen does not seem to be significantly more effective than other strategies for severe GI GvHD and seems to be worse than the results reported for basiliximab alone. Future studies of single-agent basiliximab and newer agents are required.

Hypomethylating agents in relapsed and refractory AML: outcomes and their predictors in a large international patient cohort

Although hypomethylating agents (HMAs) are frequently used in the frontline treatment of older acute myeloid leukemia (AML) patients, little is known about their effectiveness in relapsed or primary treatment-refractory (RR)-AML. Using an international multicenter retrospective database, we studied the effectiveness of HMAs in RR-AML and evaluated for predictors of response and overall survival (OS). A total of 655 patients from 12 centers received azacitidine (57%) or decitabine (43%), including 290 refractory (44%) and 365 relapsed (56%) patients. Median age at diagnosis was 65 years. Best response to HMAs was complete remission (CR; 11%) or CR with incomplete count recovery (CRi; 5.3%). Additionally, 8.5% experienced hematologic improvement. Median OS was 6.7 months (95% confidence interval, 6.1-7.3). As expected, OS differed significantly by best response, with patients achieving CR and CRi having a median OS of 25.3 and 14.6 months, respectively. In multivariate analysis, the presence of ≤5% circulating blasts and a 10-day schedule of decitabine were associated with improved response rates, whereas the presence of >5% circulating blasts and >20% bone marrow blasts were associated with decreased OS. A significant subset of RR-AML patients (16%) achieved CR/CRi with HMAs and experienced a median OS of 21 months. Outside of a clinical trial, HMAs represent a reasonable therapeutic option for some patients with RR-AML.

Combination liposomal amphotericin B, posaconazole and oral amphotericin B for treatment of gastrointestinal Mucorales in an immunocompromised patient

Mucormycosis is a life threatening infection caused by fungi in the order Mucorales. Mucormycosis can affect any organ system with rhino-orbital-cerebral and pulmonary infections being the most predominant infection types. Gastrointestinal mucormycosis is rare and accounts for only 4–7% of all cases. Here, we present a case of invasive gastrointestinal mucormycosis in an immunocompromised host treated with systemic and topical anti-mold therapy.

Use of arsenic trioxide in a hemodialysis-dependent patient with relapsed acute promyelocytic leukemia

Arsenic trioxide has been established for use in both relapsed and front-line treatment of acute promyelocytic leukemia. Dose adjustments are recommended to be considered in severe renal impairment although dosage reduction guidelines are not provided. In addition, toxicities of arsenic are significant. The use of arsenic trioxide has not been well studied in dialysis patients and there is a paucity of data in the literature to support the use in such a situation. We describe an 81-year-old relapsed acute promyelocytic leukemia hemodialysis-dependent patient with a pre-existing cardiac condition who was treated with 10 mg arsenic trioxide three times weekly after dialysis. These findings provide support along with the marginal amount of currently published data for an arsenic trioxide dosing regimen in hemodialysis patients.

Utility of fosfomycin as antibacterial prophylaxis in patients with hematologic malignancies

PurposeProlonged and profound neutropenia is common among hematology and hematopoietic stem cell transplant (HSCT) patients as a result of chemotherapy. The National Comprehensive Cancer Network (NCCN) and Infectious Diseases Society of America (IDSA) currently recommend antibacterial prophylaxis in patients who are deemed at intermediate or high risk for infection. Specifically, fluoroquinolone prophylaxis should be considered for high-risk neutropenic patients. However, with prolonged and frequent exposure to fluoroquinolones, these high-risk patients may develop resistance to these agents. Patients may also have allergies or other contraindications which prohibit the use of fluoroquinolones for antibacterial prophylaxis. Unfortunately, there is no standard recommendation for alternative antimicrobial therapy in this patient population, as well as there is a lack of data to support the use of potential alternative agents.MethodsCurrently, Yale-New Haven Hospital utilizes fosfomycin for antibacterial prophylaxis in patients who are not eligible for fluoroquinolone therapy. The primary objective of this study was to assess the incidence of breakthrough infections in this population receiving fosfomycin. Secondary objectives included organisms identified, types of breakthrough infections, resistance patterns, and time from initiation to onset of fever.ResultsOf the 42 patients who received fosfomycin, 25 patients with 42 admissions met inclusion criteria. A total of 8 (19%) breakthrough infections occurred during the 42 admissions. Organisms included Klebsiella spp. (5), Streptococcus mitis/viridans (2), Pseudomonas aeruginosa (1), and coagulase-negative staphylococcus (1). Infections included the following: bacteremia (7), cellulitis (1), and urine (1).ConclusionGiven the low rate of breakthrough infections, fosfomycin may be a potential alternative option for antibacterial prophylaxis.

Performance of the Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) score in predicting survival benefit with hypomethylating agent use in patients with relapsed or refractory acute myeloid leukemia

Maximilian Stahl, Michelle DeVeaux, Pau Montesinos, Rapha€el Itzykson, Ellen K. Ritchie, Mikkael A. Sekeres, John Barnard, Nikolai A. Podoltsev, Andrew Brunner, Rami S. Komrokji, Vijaya R. Bhatt, Aref Al-Kali , Thomas Cluzeau, Valeria Santini, Gail J. Roboz, Pierre Fenaux, Mark Litzow , Amir T. Fathi, Sarah Perreault, Tae Kon Kim, Thomas Prebet , Norbert Vey, Vivek Verma, Ulrich Germing, Juan Bergua, Josefina Serrano, Steven D. Gore and Amer M. Zeidan Department of Internal Medicine, Section of Hematology, Yale University School of Medicine, New Haven, CT, USA; Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA; Department of Medicine, University of Valencia, Hospital Universitario y Polit ecnico La Fe, Valencia, CIBERONC, Instituto III, Madrid, Spain; Department of Hematology/Oncology, Saint-Louis Hospital, University of Paris 7, France; Division of Hematology and Oncology, Weill Cornell Medicine and The New York Presbyterian Hospital, New York, NY, USA; Leukemia Program Cleveland Clinic, Cleveland, OH, USA; Massachusetts General Hospital Cancer Center Harvard Medical School, Boston, MA, USA; Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE, USA; Mayo Clinic, Rochester, MN, USA; Cote d’Azur University, Nice Sophia Antipolis University, CHU of Nice, Nice, France; Division of Hematology, University of Florence, Florence, Italy; Department of Pharmacy, Yale New Haven Hospital, New Haven, CT, USA; Department of Hematology, Institut Paoli Calmettes, Marseille, France; Department of Hematology, Oncology and Clinical Immunology, HeinrichHeine-University Duesseldorf, Duesseldorf, Germany; Hospital San Pedro Alc antara, C aceres, Spain; Division of Hematology/ Oncology, University Hospital Reina Sofia, Cordoba, Spain

Evaluating a voriconazole dose modification guideline to optimize dosing in patients with hematologic malignancies

Background Voriconazole is an azole antifungal utilized for prophylaxis and treatment of invasive fungal infections in hematologic patients. Previous studies have revealed decreased efficacy and increased toxicity with subtherapeutic <1 mcg/mL and supratherapeutic > 4 mcg/mL levels. A voriconazole dose modification guideline was introduced in July 2014 based on a retrospective analysis. Objective The primary objective was to evaluate the voriconazole dose modification guideline. Secondary objectives were to identify patient-specific characteristics that contribute to inadequate levels, adverse effects, and breakthrough invasive fungal infections. Methods This prospective study included 128 patients with 250 admissions who received voriconazole from July 2014 to February 2016. Eligible adult patients receiving voriconazole for prophylaxis or treatment with at least one trough level, drawn appropriately, were included. Demographics, adverse effects, and breakthrough invasive fungal infections were documented. Results Voriconazole use was categorized as: new start, new start with loading dose, or continuation of home therapy. The median initial levels were 1.5, 3.5, and 1.7 mcg/mL with 62% (73/119), 55% (6/11), and 60% (72/120) within the therapeutic range, respectively. Using the voriconazole dose modification guideline, 80% were within goal by the second dose adjustment. Age ≤ 30 and BMI ≤ 25 kg/m2 had higher rates of subtherapeutic levels in the new start cohorts (p = 0.024 and p = 0.009). Approximately 7.6% of patients experienced an adverse effect with neurologic/psychological being the most common. A total of 8.5% of patients had a possible, probable or proven breakthrough invasive fungal infections while on voriconazole. Conclusion Using the voriconazole dose modification guideline, the number of patients that reached therapeutic range improved from 36% to 80% by the second dose adjustment (p = 0.007). This voriconazole dose modification guideline can be utilized to help dose and adjust voriconazole in order to achieve therapeutic levels.

Allogeneic Hematopoietic Stem Cell Transplantation Following the Use of Hypomethylating Agents among Patients with Relapsed or Refractory AML: Findings from an International Retrospective Study

Patients with primary refractory or relapsed acute myeloid leukemia (RR-AML) have very poor prognosis. Due to limited treatment options, some patients are treated with hypomethylating agents (HMAs) due to their tolerability. Little is known about the role of allogeneic hematopoietic stem cell transplantation (HSCT) following HMA therapy in this setting. We retrospectively analyzed an international cohort of 655 RR-AML patients who received HMA therapy to study patterns and outcomes with HSCT. Only 37 patients (5.6%) patients underwent HSCT after HMA therapy. The conditioning regimen was myeloablative in 57% and nonmyeloablative in 43%. Patients received matched unrelated donor, matched sibling, haploidentical and mismatched unrelated HSCT in 56%, 24%, 16% and 4% of cases, respectively. Acute GvHD and chronic GvHD were observed in 40% and 17% of patients. While the median OS for the entire cohort of patients was 15.3 months (95% CI 9.5 - 21.7 months), OS reached 29.7 months (95% CI 7.01 - not-reached) for patients who achieved a complete remission (CR) to HMA and no intervening therapies between HMA therapy and HSCT. Our study suggests that HMA therapy can effectively bridge some patients with RR-AML to HSCT.

Long-term follow-up of a single institution pilot study of sirolimus, tacrolimus, and short course methotrexate for graft versus host disease prophylaxis in mismatched unrelated donor allogeneic stem cell transplantation

Dear Editor, Allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment for patients with hematologic malignancies [1]. However, overall survival (OS) is often compromised by treatment-related complications such as graftversus-host disease (GVHD). Recipients of fully HLAmatched sibling donors (MSD) have an acute GVHD rates between 30 and 40% and severe life-threatening acute GVHD may occur in 15% of patients [2, 3]. Many patients who could potentially benefit from allo-SCT do not have a MSD or a matched unrelated donor (MUD) based on highresolution molecular matching techniques [4]. Partially, HLAmismatched unrelated donor (MMUD) transplantation is a viable option for patients lacking a fully matched donor; however, HLA mismatches significantly increase the risk of GVHD and confer an inferior OS [5]. Treatment for acute GVHD is not successful in all patients and may impact long-term survival. Patients with grade III–IV acute GVHD who do not respond to frontline therapy with corticosteroids have only a 30% 2-year overall survival [6]. Pharmacologic immunosuppression is the most commonly applied method for prevention of GVHD and has been traditionally performed using a calcineurin inhibitor in combination with a short course of methotrexate [7, 8]. These regimens effectively prevent severe GVHD in the majority of MSD andMUD transplantation. However, there is no uniformly accepted guideline for GVHD prophylaxis for MMUD transplants. Sirolimus is an immunosuppressant derived from Streptomyces hygroscopicus [9], which is structurally similar to tacrolimus [10]. Sirolimus binds mammalian target of rapamycin (mTOR), that inhibits co-stimulatory pathway (e.g., CD28-AKT) and IL-2 driven pathway [11]. Sirolimus has potent anti-rejection activity in solid organ transplantation [12] and demonstrated activity as therapy of steroid-resistant GVHD [13]. Since tacrolimus and sirolimus have distinct mechanisms of action, combination therapy confers a synergistic effect [14, 15] to inhibit rejection in human organ allografting. Sirolimus does not cause nephrotoxicity and neurotoxicity, and is therefore less likely to cause synergistic adverse effects with a calcineurin inhibitor. The combination of sirolimus, tacrolimus, and low-dose methotrexate was initially tested as GVHD prophylaxis in both matched related and limited numbers of mismatched related transplants, with reported rates of overall acute GVHD of 26% and severe acute GVHD (grades III–IV) of 13% [16]. Here, we aimed to study the activity of sirolimus/ tacrolimus/low-dose methotrexate solely in MMUD transplantation and performed extended follow-up of patients registered in our pilot study. This pilot study enrolled 25 recipients of MMUD allografts recruited at Yale University between 2008 and 2011.Wemonitored the efficacy of a regimen of sirolimus, tacrolimus, and methotrexate as GVHD prophylaxis for MMUD allo-grafting with extended follow-up until 2015. This study was approved by the Institutional Review Board of Yale University and * Stuart Seropian stuart.seropian@yale.edu