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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 ncaa shopping 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 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 LSU Tigers 8 Zach Mettenberger White Stitched NCAA Jersey 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 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 2012 New Tigers 2 Newton White Stitched NCAA Jersey 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 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.
Seminoles 5 Jameis Winston Red Stitched NCAA Jersey Hypersensitive Hearing Archive Who else deals with this Buckeyes 2 Cris Carter Red Legends of the Scarlet Gray Throwback Stitched NCAA Jersey crazy symptom from time to time? This has happened to me several times in the past and thankfully lasts a few hours to a couple days. Since getting hit with ON again, it s been happening off and on. And no, it s not going out like I thought it was, he said it s not making any more noise than usual. Hearing a neighbor s squeaking outside door who lives half way down the street is another irritant, china ncaa jerseys along with a neighbor s phone ringing. Since it s the middle of a deep freeze here, I m relatively sure they don t have their windows open. THAT S a new one. Usually I can hear voices but they re muffled. I could hear the person s voice he was talking to on the cell, but their voice was muffled. Hmm, better luck next time! :eek: Anyone else care to share their experiences? :smirk: HEY MSCHEROKEE, can you hear me way down in the SW? j/k lol I actually have the opposite problem. In fact I didn t even know I was having hearing problems until my last round of steroids. After that everything has been normal. But the first couple of weeks with my "new ears" was torture. I ve gotten used to it now. What you are going through must be torture as well. Although, I can t completely relate I can certainly imagine what it is like. I am glad there are others who can relate and share their experiences with you. I will try to type softly for you. LOL Hey tkrik, I think I hear some mumbling. :winky: AMN, yes, certain frequencies drive me nuts. LOL at the part dog. Now I know how my dogs feel. Poor little ones! Do you also hear buzzing noises that everyone else is oblivious to? Not too long ago at work Jayhawks 22 Andrew Wiggins White Basketball Stitched NCAA Jersey I would hear this intermittent buzzing noise and complained about it to co workers who of course heard nothing. Never one to give up, I kept searching for the noise. Ended up it was a bad flourescent light. Called in an electrician and she (yes, SHE :D) immediately found the source it wasn t just a bulb. She found toasted wires. We had an electrical short in the wire that in theory could ve burned the place down! Hey Twinkletoes, good thing you don t work where I do. We have a couple who just love to click those pens and make all kinds of obnoxious noises. I fantasize about coming over the desk at them every once in a while. Thank goodness for self control! But now I feel safer cracking my knuckles here. LOL cracks knuckles before typing A couple of years ago I lay/lie/laid? down in bed and could faintly hear an engine running. Took me awhile, but I finally saw a car down the alley (we live behind Main St.) I called the cops and they told me it was a guy who was too drunk to drive home. It was freezing cold, so he had his car running for the heater! Good for you, MSCherokee. They should pay you extra for your Superman ears! Things like that don t seem to bother DH, which is why I was the one who insisted he check out the constant sound of water running even though everything was turned off. Turns out we had a pinhole leak in an outside water line. There was a big ole muddy mess on the north side of the house. I ve had tinnitus (ringing in the ears) since I can remember. (oldest memory of it goes back to when I was about 3 or 4yrs old) It normally doesnt bother me, but sometimes I can hear an electrical humming in my ears. I wonder if it s coincidental that there are some high tension powerlines that are just on the other side of the street that run the length of my neighborhood. If I stand below the power lines, I can hear almost the same exact humming noise coming from them. Some noises do bother me. My parents seem to both be going deaf. (they constantly say "What?" when we re talking, and they have the tv so loud that I just want to curl up in a fetal ball and cover my ears. They get mad at me when I ask them to constantly turn the freaking tv down. Oh, and some frequencies bother me. My mom, for some reason known only to her, is constantly humming this off tune hum. My mom s sister hums the same tune, but thankfully she can actually sing, but it s the same tune my mom does. I wish she had singing talent like my aunt, because then maybe it wouldnt drive me nuts and make me want to scream. It s like fingernails on a chalkboard. Like getting feedback thru a phone or a microphone. It s not the hum itself that bugs me, because I ve forced myself to sit and try to analyze why the hum bugs me. It s, I guess, the frequency that my mom hums at. What sucks, is that it s apparently an unconcious habit she has, so just asking her to not hum doesnt work for long. She ll be back to humming within a minute or five after asking her to stop. She doesnt realize she s doing it. Spiderman got his abilities from a spider biting him. You ve gotten super hearing from MS. Remember the bionic woman? You re like the bionic woman! I know what you mean tho. I hear high pitched buzzing and I don t know if it s in my ears or somewhere else. I did find the source one time and it was something in the house. Of course DH doesn t hear any of it. For some reason men have a reduced sense of smell and hearing. Or at least my DH does. Sometimes I try and play soothing jazz music to drown out the other stuff. Sia and Norah Jones are much better to listen to than a buzzing noise. |
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