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Hyperleukocytosis complicating lonafarnib treatment in patients with chronic myelomonocytic leukemia A Buresh1, J Perentesis2, L Rimsza1, S Kurtin1, R Heaton1,3, M Sugrue4 and A List1,31Departments of Medicine and Pathology, The Arizona Cancer Center, University of Arizona College of Medicine, Tucson, AZ, USA2University of Cincinnati and Children s Hospital, Cincinnati, OH, USA3Hematologic Malignancy Program, Department of Interdisciplinary Oncology, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA4Schering Plough Research Institute, Schering Plough Corporation, Kenilworth, NJ, USACorrespondence: Dr A List, Hematologic Malignancy Program, Department of Interdisciplinary Oncology, H Lee Moffitt Cancer Center and Research Institute at the University of South Florida, 12902 Magnolia Drive, Rm 24038, SRB 4, Tampa, FL 33612, USA.TO THE EDITORCase 1: Patient UPN 005 is a 64 year old male who presented in June 1998 with complaints of skin rash and increased bruisability. Physical examination revealed obesity, isolated ecchymoses, and lower extremity petechiae, without appreciable splenic enlargement. Laboratory studies revealed leukocytosis and monocytosis (28 800/l with 38% monocytes), associated with thrombocytopenia (27 000/l). The bone marrow (BM) was hypercellular accompanied by intense myeloid hyperplasia with less than 5% blasts and a maturation arrest at the myelocyte stage; megaloblastoid erythropoiesis and megakaryocytic dysplasia were apparent consistent with a diagnosis of CMML. Cytogenetic analysis revealed a normal male karyotype. Mutations of N , H , or K RAS were not detected by single strand conformational polymorphism (SSCP) and heteroduplex analysis. The patient received treatments with oral etoposide, and subsequently thalidomide without hematologic improvement. in a phase I/II clinical trial (Schering Plough Eligible patients had CMML, refractory anemia with excess blasts (RAEB), or RAEB in transformation with symptomatic cytopenias. Pretreatment white blood count was 24 200/l with 44% monocytes, hemoglobin 13.4 g/dl, and platelet count 10 000/l (Figure 1); BM examination was unchanged compared to the diagnostic study. The arrow indicates onset of respiratory distress and development of pulmonary infiltrates.Full figure and legend (51K)The patient experienced a progressive rise in leukocyte count, reaching 61 000/l by day 12. Diarrhea ensued associated with profound hypokalemia (potassium 1.5 meq/l), necessitating temporary withdrawal of study drug treatment by day 16. Gastrointestinal symptoms promptly resolved with a corresponding decline in the leukocyte count to baseline values. By day 3 of Real Moncler treatment at the attenuated dose, the patient experienced rapid onset of dyspnea and orthopnea, accompanied by a 10 pound weight gain. On physical examination, the patient was in respiratory distress with physical findings of tachypnea, generalized inspiratory rales, peripheral edema, and an oxygen saturation of 84% on 6 l of supplemental oxygen administered by nasal cannulae. An arterial blood gas obtained without supplemental oxygen revealed a pH of 7.48, pO2 42 mmHg (79% saturation), and pCO2 26 mmHg. Chest radiograph (Figure 2a) revealed bilateral alveolar infiltrates, whereas high resolution spiral computerized tomography (CT) of the chest confirmed diffuse interstitial infiltrates manifested as bilateral ground glass consolidation. Laboratory studies revealed a leukocyte count of 80 000/l, with 38% monocytes and 50% segmented neutrophils, without significant change in cytologic appearance on the peripheral smear. An echocardiogram revealed tachycardia with normal wall motion and left ventricular ejection fraction of 63%. The patient was aggressively diuresed and was hospitalized in the intensive care unit where he required 50% supplemental oxygen administered by venti mask. Bronchoscopy demonstrated normal appearing airway mucosa; however, lavage fluid cytospins yielded a monocytic infiltrate (Figure 2c). Stains and cultures for bacterial, fungal, and viral pathogens were unremarkable. Intravenous dexamethasone was administered and lonafarnib was discontinued. The patient experienced rapid resolution of hypoxemia and pulmonary infiltrates (Figure 2b) permitting discharge on oral corticosteroids by hospital day 3. The chest X ray reveals bilateral nodular, alveolar filling infiltrates confirmed by chest CT scan. (b) Near complete resolution of the diffuse interstitial infiltrates 48 h after initiation of treatment with dexamethasone. (c) Cytospin preparation from bronchoalveolar levage fluid demonstrating increased number of mature appearing monocytes (arrows). Papanicolaou stain, 1000.Full figure and legend (160K)Cases 2 and 3. Two additional CMML patients treated on the same trial at the Arizona Cancer Center experienced a prompt and sustained leukocytosis response (>5000/l/week) to lonafarnib (Table 1). Each of the patients described had stable leukocyte counts prior to study treatment, and none received cytotoxic therapy within 3 months of study entry. Patient UPN 1109 experienced an immediate rise in white blood cell (WBC) count averaging 7128/l per week after initiation of the study drug. By day 21, the WBC count exceeded 41 000/l and the patient reported low grade fever, dyspnea, and lower extremity edema. Clinical evaluation revealed hypoxemia with diffuse interstitial infiltrates on chest radiographs that resolved following drug withdrawal. Patient UPN 1112 experienced a rapid elevation in WBC count from 57 100/l at baseline to 150 000/l by day 8 of Winter Coats Moncler study treatment without accompanying pulmonary symptoms. Lonafarnib was continued and hydroxyurea was added and the WBC count returned to the baseline level within 2 weeks of combined treatment. Among these, 15 (43%) experienced a rise in total leukocyte count that exceeded 5000/l/week (Figure 3). Using these parameters, 14 of 26 patients (54%) with proliferative CMML (WBC>12 000/l) at study entry experienced a leukemoid response to lonafarnib, compared to one of nine patients (11%) with the nonproliferative variant (P=0.025; two tailed Students t test). Prestudy WBC counts in patients with proliferative CMML ranged from 12 220 to 79 370/l (median, 26 920/l). Complete blood counts were monitored on days 1, 15, and 22 of each 28 day cycle. Represented patients experienced a rise in WNC count that exceeded 5000/l/week.Full figure and legend (17K)The patients described herein developed rapid and progressive elevations in WBC count with lonafarnib treatment, associated in two cases with respiratory distress that resolved promptly following treatment with dexamethasone or study drug withdrawal. An infectious etiology was excluded in both patients presenting with pulmonary infiltrates, whereas cytological examination of the bronchioalveolar lavage fluid in patient UPN 005 confirmed alveolar infiltration by mature monocytes. Despite associated neutrophilia, expansion of a comparatively mature monocytic clone distinguishes these cases from the leukemia differentiation syndrome described with ATRA treatment of APL. These cases represent the first description of leukemia differentiation like syndrome occurring in patients treated with an FTI. Patients with proliferative CMML (WBC>12 000/l) in particular appear to be at significant risk for this complication. An excessive leukemoid response (>5000/l/week) was observed in 54% of patients with proliferative CMML compared to 11% of patients with the nonproliferative subtype (P=0.025).Constitutive Ras/mitogen activated protein kinase (MAPK) activation is demonstrable in 40 of CMML cases, resulting either from mutations within RAS alleles or from reciprocal translocations deregulating receptor tyrosine kinases.6 Leukemic cells from two of the patients evaluated lacked activating point mutations of RAS proto oncogenes and none harbored chromosome translocations, indicating that screening for RAS mutations per se is insufficient to identify those patients at risk. Like the retinoic acid syndrome in APL, leukocytosis response to lonafarnib may occur in the absence of pulmonary signs or symptoms. Nevertheless, investigators participating in current FTI trials should be aware of the potential for this complication and consider close monitoring of patients experiencing a rapid rise in leukocyte count and/or pulmonary symptoms.Lonafarnib and tipifarnib (R115777 or ZarnestraTM; Janssen Pharmaceuticals, Beerse, Belgium and Spring House, PA, USA) are the leading nonpeptidic, orally bioavailable FTIs that are currently completing phase II clinical investigations in hematologic malignancies.6 No similar cases have been reported to date in preliminary testing of tipifarnib in patients with either myelodysplastic or myeloproliferative syndromes, raising consideration that pharmacologic features unique to lonafarnib may be responsible for this potential biologic effect.7 Nonetheless, in selected cell line models, suppression of Ras signaling or the farnesylated Rho B proteins promotes heterotypic adhesion through activation of beta 1 and/or beta 2 integrin binding avidity or increased sensitivity to the inhibitory effects of TGF, suggesting that promotion of heterotypic adhesion may arise as a class effect of Ras protein signal inhibition.8 Fashion Moncler Down Jackets Women Pink Additional investigations are necessary to discern the relevant cellular target(s) of lonafarnib and possibly other FTIs that may promote transient expansion of leukemia mass and possibly predispose to endovascular complications.

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