Hyperleukocytosis complicating lonafarnib treatment in patients with chronic myelomonocytic leukemia

Buresh, Andrew J.; Perentesis, John P.; Rimsza, Lisa M.; Kurtin, Sandra; Heaton, Ruth; Sugrue, Mary M.; List, Alan F.

doi:10.1038/sj.leu.2403569

Cited by 20 publications

(9 citation statements)

References 8 publications

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“…The significance of this effect is unclear. A similar observation was reported in a study with tipifarnib (R115777) in patients with CML,30 and it has also been reported with lonafarnib therapy in patients with chronic myelomonocytic leukemia 42. This phenomenon may reflect some as‐yet uncharacterized biological effect of lonafarnib on hematopoietic progenitors.…”

Section: Discussionsupporting

confidence: 82%

Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy

Borthakur

Kantarjian

Daley

et al. 2005

Cancer

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BACKGROUNDLonafarnib (SCH66336) is a nonpeptidomimetic farnesyl transferase inhibitor that has demonstrated significant preclinical activity against chronic myelogenous leukemia (CML) cells and in CML animal models.METHODSIn the current study, the efficacy of lonafarnib was investigated in patients with CML in the chronic or accelerated phase that was resistant or intolerant to imatinib. Thirteen patients with CML in the chronic (n = 6 patients) or accelerated (n = 7 patients) phase were treated with lonafarnib at a dose of 200 mg orally twice daily. Ten patients had failed therapy with imatinib and 3 patients were intolerant to imatinib. The median age of the patients was 62 years (range, 38–80 yrs) and the median time from the diagnosis of CML to therapy with lonafarnib was 5 years (range, 0.3–13 yrs). In addition to imatinib mesylate, all patients had received prior therapy with interferon‐α and seven patients had received other treatments. The median duration of therapy with lonafarnib was 8 weeks (range, 2–41 wks).RESULTSTwo patients responded. One patient in the accelerated phase of CML returned to the chronic phase, a response that lasted for 3 months. Another patient with chronic phase disease had lowering of the leukocyte count without the need for hydroxyurea and normalization of the differential count that lasted for 5 months. The most common adverse event was diarrhea, which was noted in 11 patients (84%) (Grade ≥ 3 in 4 patients; 31%; toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Therapy was discontinued in one patient because of diarrhea not responding to dose adjustments.CONCLUSIONSSingle‐agent lonafarnib appears to have clinical activity in a small proportion of patients with CML refractory to imatinib. Cancer 2006. © 2005 American Cancer Society.

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Section: Discussionsupporting

confidence: 82%

Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy

Borthakur

Kantarjian

Daley

et al. 2005

Cancer

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“…In a phase 2 study, 17 patients with CMML-1 or CMML-2 received tipifarnib at a dose of 300-600 mg twice daily, and 3 had CR (18%), with a median survival of 14.5 months [170]. Although myelosuppression was the most commonly observed adverse effect with tipifarnib, it is notable that some CMML patients have had rapid onset of leukocytosis with lonafarnib or tipifarnib treatment, which may be akin to leukemia differentiation syndrome [167, 171]. …”

Section: Treatmentmentioning

confidence: 99%

Chronic myelomonocytic leukemia: Forefront of the field in 2015

Benton

Nazha

Pemmaraju

2015

Critical Reviews in Oncology/Hematology

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Chronic myelomonocytic leukemia (CMML) includes components of both myelodysplastic syndrome and myeloproliferative neoplasms and is associated with a characteristic peripheral monocytosis. CMML is caused by the proliferation of an abnormal hematopoietic stem cell clone and may be influenced by microenvironmental changes. The disease is rare and has undergone revisions in its classification. We review the recent classification strategies as well as diagnostic criteria, focusing on CMML’s genetic alterations and unique pathophysiology. We also discuss the latest molecular characterization of the disease, including how molecular factors affect current prognostic models. Finally, we focus on available treatment strategies, with a special emphasis on experimental and forthcoming therapies.

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“…DLTs occurred with the 300 mg schedule and the maximum tolerated dose (MTD) was 200 mg twice daily. Of note, three patients with proliferative CMML (WBC >12 × 10 9 /L) experienced rapid and sustained leucocytosis, complicated in two cases by pulmonary infiltrates that resolved either after drug discontinuation or treatment with dexamethasone (Buresh et al , 2005).…”

Section: Mds Studiesmentioning

confidence: 99%

Farnesyltransferase inhibitors and their potential role in therapy for myelodysplastic syndromes and acute myeloid leukaemia

Braun

Fenaux

2008

Br J Haematol

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SummaryNovel strategies are required for treatment of acute myeloid leukaemia (AML) and higher risk myelodysplastic syndrome (MDS) patients who are not eligible for intensive chemotherapy and/or allogenic stem cell transplantation. As activating RAS mutations are frequent in these diseases, one novel approach, consisting of interfering with isoprenylation of RAS proteins by farnesyltransferase inhibitors (FTIs), has been proposed. Clinical phase II studies with the oral FTIs tipifarnib and lonafarnib in previously untreated AML, MDS and chronic myelomonocytic leukaemia yielded rather encouraging results while results in relapsed and/or refractory AML were disappointing. Results of a phase III trial in untreated AML in the elderly with tipifarnib were also disappointing. Clinical responses were not related to RAS mutations, suggesting additional actions of FTIs on other molecular targets. The combination of existing FTIs with other treatments, such as chemotherapy (in AML) and hypomethylating agents (in MDS and AML), is under investigation. Ongoing studies will also determine if gene profiling analysis may help to identify patients that will respond to FTIs.

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Hyperleukocytosis complicating lonafarnib treatment in patients with chronic myelomonocytic leukemia

Cited by 20 publications

References 8 publications

Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy

Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy

Chronic myelomonocytic leukemia: Forefront of the field in 2015

Farnesyltransferase inhibitors and their potential role in therapy for myelodysplastic syndromes and acute myeloid leukaemia

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