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Clofarabine Salvage Therapy in Refractory Multifocal Histiocytic

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Clofarabine Salvage Therapy in Refractory Multifocal Histiocytic Pediatr Blood Cancer 2014;61:479–487 Clofarabine Salvage Therapy in Refractory Multifocal Histiocytic Disorders, Including Langerhans Cell Histiocytosis, Juvenile Xanthogranuloma and Rosai–Dorfman Disease 1 2 2 1 3 Stephen J. Simko, MD, * Huy D. Tran, MD, Jeremy Jones, MD, Mrinalini Bilgi, MS, Lynda Kwon Beaupin, MD, 4 5 6 5 Don Coulter, MD, Timothy Garrington, MD, Timothy L. McCavit, MD, Colin Moore, MD, 7 8 9 10 Francisco Rivera-Ortego n, MD, Linda Shaffer, MD, Linda Stork, MD, Lucie Turcotte, MD, 11 12 1 1 Esperanza C. Welsh, MD, M. John Hicks, MD, PhD, DDS, Kenneth L. McClain, MD, PhD, and Carl E. Allen, MD, PhD Background. Existing therapies for recurrent or refractory surviving patients showed demonstrable improvement after two to histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile four cycles of therapy, with 11 (61%) complete responses, 4 (22%) xanthogranuloma (JXG), and Rosai–Dorfman disease (RDD), have partial responses, and 2 patients still receiving therapy. Five patients limited effectiveness. We report our experience with using experienced disease recurrence, but three of these subsequently clofarabine as therapy in children with recurrent or refractory achieved complete remission. All patients with JXG and RDD had histiocytic disorders, including LCH (11 patients), systemic JXG (4 complete or partial response at conclusion of therapy. Side effects patients), and RDD (3 patients). Methods. Patients treated with included neutropenia in all patients. Recurring but sporadic toxicities clofarabine for LCH, JXG, or RDD by Texas Children’s Hospital included prolonged neutropenia, severe vomiting, and bacterial physicians or collaborators between May 2011 and January 2013 infections. Conclusion. Clofarabine has activity against LCH, JXG, were reviewed for response and toxicity. Results. Patients were and RDD in heavily pretreated patients, but prospective multi-center treated with a median of three chemotherapeutic regimens prior to trials are warranted to determine long-term efficacy, optimal dosing, clofarabine. Clofarabine was typically administered at 25 mg/m2/day and late toxicity of clofarabine in this population. Pediatr Blood for 5 days. Cycles were administered every 28 days for a median of six Cancer 2014;61:479–487. # 2013 Wiley Periodicals, Inc. cycles (range: 2–8 cycles). Seventeen of 18 patients are alive. All Key words: clofarabine; histiocytosis; juvenile xanthogranuloma; Langerhans cell histiocytosis; Rosai–Dorfman disease INTRODUCTION conducted for therapy in RDD, but patients have been treated with methotrexate and 6-mercaptopurine, or with cladribine [14–16]. The histiocytic disorders are a heterogeneous group of Clofarabine has been suggested as a potential agent for treating proliferative neoplasms originating from monocyte and macrophage refractory or recurrent LCH [17]. Clofarabine is a second- lineages. The most common of these, Langerhans cell histiocytosis generation purine analog, similar in structure to cladribine and (LCH), is characterized by heterogeneous lesions containing pathologic dendritic cells that express CD207 (Langerin), along with mixed inflammatory infiltrate [1]. LCH lesions primarily 1Texas Children’s Cancer and Hematology Centers, Baylor College of 2 involve bone, skin, lymph nodes, lungs, liver, thymus, spleen, bone Medicine, Houston, Texas; Department of Radiology, Baylor College 3 marrow, and/or the central nervous system (CNS) [2,3]. of Medicine, Houston, Texas; Department of Pediatric Hematology/ Refractory and recurrent multisystem LCH poses a significant Oncology, Roswell Park Cancer Institute, Buffalo, New York; 4Department of Pediatric Hematology/Oncology, University of Ne- therapeutic challenge. Patients with risk-organ (liver, spleen, or braska Medical Center, Omaha, Nebraska; 5Department of Pediatric bone marrow) disease have estimated five year overall survival of Hematology/Oncology, University of Colorado Denver, Denver, approximately 85% but often require intensive therapy, including Colorado; 6Department of Pediatrics, University of Texas Southwestern bone marrow and/or solid organ transplantation [4–6]. Responses to Medical Center, Dallas, Texas; 7Department of Pediatric Hematology/ regimens including cladribine (2-chlorodeoxyadenosine, or 2- Oncology, Hospital San Jose´ Tec de Monterrey, Monterrey, Mexico; CdA), cytarabine, or combinations have been reported, though 8Department of Pediatric Hematology/Oncology, Dell Children’s durable responses are not consistent [7–11]. More intensive Medical Center, Austin, Texas; 9Department of Pediatrics, Oregon 10 therapeutic regimens such as combined cladribine/cytarabine are Health and Science University, Portland, Oregon; Department of 11 also associated with substantial acute toxicity and delayed immune Pediatrics, University of Minnesota, Minneapolis, Minnesota; De- reconstitution [9,12]. partment of Dermatology, Centro de Especialidades Medicas, Monterrey, Mexico; 12Department of Pathology, Baylor College of Additionally, no standard treatment exists for patients with high- Medicine, Houston, Texas risk manifestations of other more rare histiocytic disorders, including juvenile xanthogranuloma (JXG) and Rosai–Dorfman disease (RDD; Grant sponsor: National Institutes of Health, USA; Grant numbers: K12 also known as sinus histiocytosis with massive lymphadenopathy). CA090433; R01 CA154489; P50 CA126752; Grant sponsor: Histio CURE Foundation; Grant sponsor: Baylor College of Medicine; Patients with systemic and/or central nervous system JXG have been Grant sponsor: Texas Children’s Hospital; Grant sponsor: American successfully treated with vinca alkaloid- and steroid-containing Society of Hematology regimens. However, significant morbidity and death have been reported in patients with disseminated systemic or central nervous Conflict of interest: Nothing to declare. Ã system disease despite therapeutic intervention [13]. RDD is Correspondence to: Stephen Simko, Texas Children’s Hospital, 1102 generally self-limited but may require therapy when significant Bates Street, Suite 750.01, Houston, TX 77030. morbidity or life-threatening complications, such as airway obstruc- E-mail: [email protected] tion or organ compromise, occur. No clinical trials have been Received 1 August 2013; Accepted 21 August 2013 C 2013 Wiley Periodicals, Inc. DOI 10.1002/pbc.24772 Published online 18 September 2013 in Wiley Online Library (wileyonlinelibrary.com). 480 Simko et al. fludarabine, except that its biochemical modifications enhance its Guidelines [23]: better/complete resolution, non-active disease resistance to deamination and degradation. It is converted in vivo to (NAD); better/regression, active disease (AD) better; intermediate/ its active form, clofarabine 50-triphosphate, which subsequently mixed, new lesions in one site, regression in another site; inhibits DNA polymerase and ribonucleotide reductase [18]. intermediate/stable, unchanged disease; or worse, progressive Though only a small percentage of the drug penetrates the disease. Progression free survival was calculated using the log- blood–brain barrier, cytotoxic concentrations of the drug are rank (Mantel–Cox) test; data were censored at time of last follow- achieved in cerebrospinal fluid [19]. It is approved for use in the up. Progression was defined as disease classifiable as intermediate United States for treatment of relapsed acute lymphoblastic or worse response after administration of clofarabine therapy. Data leukemia in children, and it is being tested in multiple clinical analyses and Kaplan–Meier curves were conducted using Prism trials of hematologic malignancies [20,21]. version 5.0d (GraphPad, La Jolla, CA). Clofarabine has been reported to have some effectiveness in treating recurrent risk-organ LCH [17,22]. Here, we conduct a RESULTS retrospective review of the use of clofarabine in recurrent or refractory risk-organ LCH, as well as non-risk-organ LCH, JXG, Patients and RDD. Patients were diagnosed with LCH (n ¼ 11), JXG (n ¼ 4), or RDD (n ¼ 3; Table I). Patients had a median age of 22 months at METHODS diagnosis and were treated with a median of 3 separate treatment regimens prior to initiation of therapy with clofarabine. Clofarabine Patients was started in patients with persistent disease or new lesions. Patient charts were reviewed in accordance with IRB-approved Common therapies given prior to clofarabine included vinblastine/ protocols at Baylor College of Medicine. All patients treated at prednisone, cladribine, and cytarabine (Table I). One patient Texas Children’s Hospital from May 2011 to January 2013 with this received pretreatment with combined high-dose cladribine and regimen were reviewed. Additionally, all patients known to the cytarabine [9]. One infant patient with congenital central nervous Texas Children’s Hospital group from collaborating institutions system JXG started clofarabine as initial therapy. who were treated with clofarabine were offered study enrollment. Clofarabine was started in 15 of 18 (83%) patients at a dose of 2 Patients treated at other institutions were consented by Baylor 25 mg/m /day for 5 days as published previously [17]. Two patients 2 College of Medicine researchers for chart review and for release of started at a dose of 50 mg/m /day, given severe burden of disease information. and poor response to previous chemotherapy. One patient, a 2- month old infant, was administered weight-based dosing of clofarabine (0.8 mg/kg/day). Cycles of therapy were administered Statistics every 28 days, unless
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