Targeted treatment of chronic myeloid leukemia: role of imatinib.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by clonal expansion of pleuripotent hematopoetic stem cells. The incidence of CML is 1 to 2 cases per 100,000 people per year; in the Western Hemisphere, CML accounts for 15% of leukemias in adults. Discovery of the specific karyotypic abnormality of the Philadelphia (Ph) chromosome in the pathogenesis of CML has led to a better understanding of the disease and hence to an advancement of targeted therapeutics. Availability of imatinib as an accepted targeted therapy in newly diagnosed patients has changed the treatment paradigm in CML. The majority of CML patients in chronic phase achieve excellent and durable responses with standard-dose imatinib. Mechanisms of primary and secondary resistance to imatinib in CML have been extensively studied and newer tyrosine kinase inhibitors are now being evaluated for clinical use. It is important that at any time the CML treatment and response remain optimal and thus patients on imatinib require continuous monitoring for early detection of resistance. This review will discuss the treatment and guidelines for monitoring CML patients in the imatinib era.

BCNU toxicity presenting with a large pericardial and pleural effusion.

BACKGROUND: Carmustine (BCNU), 1, 3-bis (2-chloroethyl)-1-nitosourea, is an alkylating agent which is commonly used as a part of conditioning regimen for autologous peripheral blood stem cell transplantation. Despite the widespread use of BCNU therapy in adults, cardiopulmonary toxicity presenting with cardiac tamponade has not been reported. CASE REPORT: We present a patient who received BCNU as part of her conditioning regimen followed by autologous peripheral blood stem cell transplantation. This patient subsequently developed bilateral upper lobe pulmonary infiltrates with bilateral pleural effusions and a large pericardial effusion which was a result of BCNU toxicity. CONCLUSIONS: Early institution of glucocorticoids for patients receiving high dose BCNU containing chemotherapeutic regimens has shown to significantly reduce BCNU induced cardio-pulmonary toxicity.

Clonal evolution with +11q 13, t(1;7) and t(1;4) at relapse in a patient with Ph positive acute lymphocytic leukemia (ALL) treated with single agent front line imatinib followed by dasatinib.

Imatinib, a selective ABL kinase inhibitor has improved therapeutic outcome in patients with Philadelphia positive chronic or acute leukemia. In the present study, we describe a 56-year-old male with Philadelphia chromosome positive acute lymphocytic leukemia (ALL) who was treated with up-front single agent imatinib and achieved complete hematologic, cytogenetic and molecular remission. At relapse 11 months later, new chromosomal translocations involving chromosomes 1, 7 and 4 and cryptic addition to chromosome 11 were identified in Ph+ cells and the patient had rapid deterioration with progressive disease. The significance of additional chromosomal abnormalities in imatinib treated patients and secondary chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia and ALL are discussed briefly in this report.

Acute drug induced hepatitis due to erlotinib.

CONTEXT: Acute drug induced hepatitis has not been commonly associated with epidermal growth factor receptor (EGFR) inhibitors. Hepatotoxicity seen with erlotinib, a small molecule tyrosine kinase inhibitor to EGFR, is usually transient with mild elevation of transaminases. CASE REPORT: We report a case of acute severe hepatitis resulting from erlotinib monotherapy in a patient with locally advanced pancreatic cancer. Hepatotoxicity resolved once erlotinib was discontinued and serum transaminases returned to baseline normal values. CONCLUSIONS: Acute severe hepatitis though rare is occasionally observed with EGFR inhibitors gefitinib or erlotinib. As EGFR inhibitors are now incorporated with chemotherapy in advanced pancreatic cancers, clinicians should be aware of this potential complication.

Chronic myeloid leukemia after treatment of lymphoid malignancies: response to imatinib mesylate and favorable outcomes in three patients.

Recent improved treatments for lymphoid malignancies produce more long-term survivors, yet increase the risk for secondary malignancies. Therapy-related myelodysplasia and acute myeloid leukemia are well described, but secondary chronic myeloid leukemia (CML) has only rarely been reported. We report three patients with CML diagnosed 8, 10 and 2.5 years following Hodgkin's disease, non-Hodgkin's lymphoma and chronic lymphocytic leukemia therapy, respectively. BCR-ABL transcripts were not detected after completion of primary therapy in two cases. All three patients received imatinib therapy, with one patient subsequently undergoing allogeneic hematopoietic stem cell transplantation. All three patients have ongoing favorable responses to CML therapy.

Pro-apoptotic therapy with the oligonucleotide Genasense (oblimersen sodium) targeting Bcl-2 protein expression enhances the biological anti-tumour activity of rituximab.

New strategies have evolved in the treatment of patients with non-Hodgkin's lymphoma (NHL). Anti-sense oligonucleotides (ASO) and monoclonal antibody (mAb) therapy, though proven to be safe and effective, have not demonstrated to be curative when used as single agents. We tested an innovative combination strategy involving various mAbs and ASO against Bcl-2 (G3139) in aggressive preclinical models. G3139, under optimal transfection conditions, decreased the proliferation rate of lymphoma cells by 60-75% when compared with controls. In addition, apoptosis was demonstrated in Raji (25%) and DHL-4 cells (30%) treated with Genasense following downregulation of Bcl-2 protein. Downregulation of Bcl-2 by G3139 was associated with a higher degree of rituximab-associated, complement-mediated cytotoxicity and antibody dependent cellular cytotoxicity when compared with rituximab alone-treated controls. In vivo studies in severe combined immunodeficiency (SCID) mice clearly demonstrated synergistic activity between G3139 and rituximab. Treatment of lymphoma-bearing SCID mice with G3139 for two consecutive days prior to each rituximab dose resulted in better disease control and survival than treatment with either agent alone or controls. Our findings suggest that Bcl-2 downregulation by G3139, followed by the administration of rituximab is an efficient anti-tumour strategy associated with improved survival in lymphoma-bearing SCID mice.