We followed 141 patients treated with imatinib mesylate (> 300 mg) for chronicphase chronic myelogenous leukemia (CML) following failure of treatment with interferon. During 12 months from the start of imatinib mesylate treatment, 96.5% achieved a complete hematologic response, 47.0% achieved a major cytogenetic response, and 32.4% achieved a complete cytogenetic response. The proportion of patients with hematologic relapse was 10.9% at 12 months and 14.6% at 18 months. In a univariate Cox regression analysis, the only pretreatment characteristics that correlated with an increased risk of hematologic relapse were hemoglobin level less than 120 g/L (12 g/dL) (P ‫؍‬ .02), increased bands in the peripheral blood (P ‫؍‬ .01), and clonal evolution (P < .0001). In a multivariate analysis, an elevated platelet count (P ‫؍‬ .03) and clonal evolution (P < .0001) were the only significant factors for hematologic relapse. During treatment, the absence of a major cytogenetic response within the first 6 months also significantly correlated with relapse (P ‫؍‬ .03). Notably, patients failing to achieve a major cytogenetic response by 6 months had a significantly higher rate of hematologic relapse (27%) compared with those who achieved a major cytogenetic response by 6 months (3%), and patients with clonal evolution had a significantly higher risk of hematologic relapse (50%) than those without clonal evolution (9%

Growth in children with CML appears to be adversely impacted by imatinib therapy. BMI and IGF-1/IGFBP-3 are maintained during treatment, suggesting a direct effect of imatinib on the growth plate.

was interrupted for hydrocephalus and hearing loss in 1 patient each, although toxicities were not directly attributed to the agent. 2 In their letter, Chamberlain and Glantz comment on the neurologic syndromes we reported and question attribution to liposomal cytarabine. Our attributions were based on 15-year experience in nearly 500 adults with acute lymphoblastic leukemia without central nervous system (CNS) disease, treated with hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) and standard CNS prophylaxis (methotrexate 12 mg day 2; cytarabine 100 mg day 7 for 3-8 cycles). In this setting, seizures are extremely uncommon (3 of 482 patients [0.006%]). The long half-life of liposomal cytarabine made attribution plausible in patient 1, given absence of discernable metabolic or other etiology. We have not observed hydrocephalus with standard CNS prophylaxis. Obesity and corticosteroids contribute to pseudotumor cerebri. Patient 2 was not obese, and dexamethasone dosing was only slightly increased. Investigators in our Department of NeuroOncology have also attributed anecdotal hydrocephalus cases to liposomal cytarabine (Morris D. Groves, M. D. Anderson Cancer Center, written personal communication, March 22, 2007). These data, taken in aggregate with the case in the lymphoma trial, raise the question whether association of hydrocephalus with liposomal cytarabine has been unrecognized or underreported.Findings for patient 3 are better described as partial cauda equina syndrome or sacral radiculopathy. Although Chamberlain and Glantz suggest any chemotherapy given via lumbar puncture (LP) could cause such neurologic sequelae, we have not observed this after standard CNS prophylaxis given almost exclusively via LP. Decreased perineal sensation and lower-extremity paresthesias in patient 4 were also consistent with sacral radiculopathy. Standard intrathecal chemotherapy was delayed until 4 months later. The morbidity of urinary and/or fecal incontinence associated with these syndromes in 2 of 31 patients was considered unacceptable.Encephalopathy is more appropriate terminology for patient 5; encephalitis implies an inflammatory process. Encephalopathy related to high-dose systemic methotrexate-cytarabine usually manifests during administration or immediately thereafter, not on day 15, in this case approximately 36 hours after liposomal cytarabine. An exhaustive evaluation was unable to discern any other etiology for the neurotoxicity, which led to the patient's demise. To what degree each agent contributed is an unanswerable question but does not preclude an association.The character, constellation, and severity of neurotoxicity was concerning in potentially curable patients. We felt it prudent to alert other investigators of the need for monitoring and reporting of neurotoxicity if this agent was used in a similar manner. The absence of similar neurotoxicity in the 56 patients treated with standard CNS prophylaxis since terminating the liposomal cytarabine trial further supports our conclusi...

A 68-year-old man with stable chronic myelogenous leukemia received a single dose of clindamycin before having a tooth extracted. He was neutropenic 6 days later, with an absolute neutrophil count of 945 cells/mm3. His neutrophil count returned to normal within 2 weeks. Clindamycin has been implicated in drug-induced neutropenia; however, a review of the literature produced only three reports of this reaction. Only one provided the duration of the neutropenia. To our knowledge, this case report is only the second that provides the duration of the clindamycin-induced neutropenia. Clinicians should be made aware of this potential adverse event.

OBJECTIVES: Imatinib (IM) has demonstrated durable clinical efficacy in the majority of chronic myeloid leukemia (CML) patients. Optimal response may be influenced by multiple innate and external factors, some of which may be controlled by monitoring plasma concentrations of the drug. This abstract reports 6 cases where analyzing plasma IM trough concentrations (Cmin) in patients treated with three commonly used IM doses (400, 600, and 800 mg daily) influenced clinical decision making. METHODS: IM trough blood samples were collected at a time before that day’s IM dosing. Plasma concentrations of IM were determined by a validated LC/MS/MS method. RESULTS: In large population studies of CML patients enrolled in Phase I, II, and III clinical trials, the mean Cmin levels of IM at 400 mg qd, 600 mg qd, and 400 mg bid doses were: 981 (±543, 55%, n=394), 1572 (±1032, 66%, n=14), and 3479 (±1264, 36%, n=14) ng/mL, respectively. Large inter-patient variability was shown at all three doses. Of the 6 cases detailed in the table below, 4 (ID 1, 3, 4, and 5) had dose reduction due to tolerability concerns with subsequent improvement of symptoms following dose adjustment. One patient (ID 2) had a dose increase because of a poor qRT-PCR response. Another (ID 6) had a dose increase due to low plasma IM exposure resulting from drug-drug interaction with phenytoin, a known inducer of CYP3A4 (the major metabolizing isozyme for IM). After dose adjustment, all six patients showed good clinical response to IM treatment. The new mean Cmin value in these patients was 2000 (±471) ng/mL, representing a 24% coefficient of variability. CONCLUSIONS: Although the data is limited, IM drug monitoring proved useful in managing tolerability, lack of efficacy, adherence or potential drug interactions that modulate imatinib drug concentrations. More prospective studies are needed to demonstrate the value of IM drug monitoring in routine clinical practice. Patient ID Age, Sex CML Stage IM Daily Dose 1st Cmin (ng/mL) Reason for Dose Change New Dosing Regimen New Cmin (ng/mL) CP, chronic phase1 1 54, f CP 200 mg bid, Jan 03 3048, Sep 05 transfusion-dependent, anemia, Sep 05 300 mg, Oct 05 2130, Jan 06 2 9, f CP 300 mg, Jan 05 not done qRT-PCR 0.016, Jan 06 400 mg, Jan 06 2341, Jul 06 3 13, f CP 300 mg bid, May 05; 700 mg, Aug 05; 600 mg, Sep 05 1966, Feb 06 nausea, fatigue, arthralgias, myalgia, ongoing 400 mg, Mar 06 1222, May 06 4 67, f CP 400 mg, Feb 05 not done myelosuppression, Mar 05 200 mg, Mar 05 1928, May 06 5 53, f CP 400 mg, Apr 03; 600 mg, May 03; 800 mg, Jul 04 not done inflammatory pulmonary reaction with shortness of breath; dose held, Mar 05 400 mg, Oct 05 2378, May 06 6 73, m CP 350 mg, on phenytoin, Apr 99 35, Jun 99 stopped phenytoin, Jul 99 500 mg, Jul 99 not done; qRT-PCR negative, Jul 06