Researchers from Italy, the United States and Japan report details of new studies and findings in the area of leukemia

06-08-2006

Leukemia data are the focus of recent research from Italy, the United States and Japan.

Study 1: Chronic myeloid leukemia (CML) response to imatinib could be predicted by prospective quantitation of BCR-ABL transcript.

"Imatinib mesylate (STI571), a specific Bcr-Abl inhibitor, has shown a potent antileukemic activity in clinical studies of CML patients. Early prediction of response to imatinib cannot be anticipated," investigators in Italy reported.

"We used a standardized quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR) for BCR-ABL transcripts on 191 out of 200 late-chronic phase CML patients enrolled in a phase II clinical trial with imatinib 400 mg/day," explained G. Martinelli and colleagues, University of Bologna. "Bone marrow samples were collected before treatment, after 12, 20 and at the end of study treatment (52 weeks) while peripheral blood samples were obtained after 2, 3, 6, 10, 14, 20 and 52 weeks of therapy.

"The amount of BCR-ABL transcript was expressed as the ratio of BCR-ABL to beta 2-microglobulin (beta 2M). We show that, following initiation of imatinib, the early BCR-ABL level trends in both bone marrow and peripheral blood samples made it possible to predict the subsequent cytogenetic outcome and response."

The researchers concluded, "We propose this method as the method of choice for monitoring patients on imatinib therapy. QRT-PCR studies may be able to identify degrees of molecular response that predict both complete cytogenetic response and long term stability, as well as patterns of response that provide an early indication of relapse and imatinib resistance."

Martinelli and colleagues published their study in Annals of Oncology (Prediction of response to imatinib by prospective quantitation of BCR-ABL transcript in late chronic phase chronic myeloid leukemia patients. Ann Oncol, 2006;17(3):495-502).

For additional information, contact G. Martinelli, University of Bologna, Institute Hematology & Med Oncology Seragnoli, Molecular Biology Unit, Via Massarenti 9, I-40138 Bologna, Italy.

Study 2: Lonafarnib could be used to treat select patients with chronic myelogenous leukemia (CML) refractory to imatinib.

According to recent research published in the journal Cancer, "Lonafarnib (SCH66336) is a nonpeptidomimetic farnesyl transferase inhibitor that has demonstrated significant preclinical activity against CML cells and in CIVIL animal models. In 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-alpha and 7 patients had received other treatments. The median duration of therapy with lonafarnib was 8 weeks (range, 2-41 wks)," explained G. Borthakur and colleagues, M.D. Anderson Cancer Center.

"Two 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 1 patient because of diarrhea not responding to dose adjustments."

The researchers concluded, "Single-agent lonafarnib appears to have clinical activity, in a small proportion of patients with CML refractory to imatinib."

Borthakur and colleagues published their study in Cancer (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. Cancer, 2006;106(2):346-352).

For additional information, contact J. Cortes, University of Texas, M.D. Anderson Cancer Center, Dept. Leukemia, 1515 Holcombe Blvd., Box 428, Houston, TX 77030, USA.

Study 3: NS-187 was proposed as a novel agent for imatinib-resistant leukemia.

"Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region-Abl (Bcr-Abl)-positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib," scientists writing in the journal Blood reported.

"We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl-bearing tumors and markedly extends the survival of mice bearing such tumors. The inhibitory effect of NS-187 extends to 12 of 13 Bcr-Abl proteins with mutations in their kinase domain but not to T315l. NS-187 also inhibits Lyn without affecting the phosphorylation of Src, Blk, or Yes," explained S. Kimura and colleagues, Kyoto University Hospital.

The researchers concluded, "These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia."

Kimura and colleagues published their study in Blood (NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood, 2005;106(12):3948-3954).

Additional information can be obtained by contacting S. Kimura, Kyoto University Hospital, Dept. Transfusion Med & Cell Therapy, Sakyo Ku, 54 Kawahara Cho, Kyoto 6068507, Japan.

Keywords: Kyoto, Japan, Hematology, Leukemia, Proteins, Proteomics, Tyrosine Kinase, NS-187, CNS-9, Imatinib-Resistant Leukemia, Kinase Inhibition, Drug Resistance.

This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2006, Clinical Oncology Week via NewsRx.com.