Clinical Leukemia最新文献

Background

Inv(16)(p13q22) or the rare t(16;16)(p13;q22) is characteristic of the M4Eo type of acute myeloid leukemia and results in the fusion of the core binding factor β gene (CBFB) at 16q22 with the smooth muscle myosin heavy chain gene (MYH11) at 16p13. The fusion transcript CBFB/MYH11 plays an important role in leukemogenesis. Many variations of this fusion transcript have been reported, with type A being most common and occurring in > 85% of cases.

Patients and Methods

We studied the fusion transcripts in 4 cases of chronic myelogenous leukemia in myeloid blast phase with inv(16)(p13q22).

Results

Sequencing analysis revealed type B fusion transcript in 3 of the 4 cases. Immunohistochemistry demonstrated both nuclear and cytoplasmic staining for the fusion protein.

Conclusion

Although the biologic significance of this finding is unknown, the high frequency of an unusual type of fusion transcript in the chronic myelogenous leukemia cases in blast phase in which inv(16)(p13q22) first occurred at the time of blast transformation suggests that the type B transcript might play a role in disease progression. The effect of the additional smooth muscle myosin heavy chain sequences in the type B fusion on subcellular localization of the protein product is also suggested.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, primarily affecting patients aged > 60 years. Because of the lack of curative therapies and the increasing prevalence of comorbid conditions in this older population, it is imperative that effective and tolerable agents be developed for patients with CLL. Although the exact mechanism of action has not been fully elucidated, bendamustine is an alkylator that appears to be structurally and mechanistically distinct from agents historically used in CLL treatment. Bendamustine induces extensive and durable double-stranded DNA breaks that result in initiation of the p53-dependent stress response and apoptosis. In addition, although most DNA alkylators target an alkyltransferase DNA-repair mechanism, bendamustine activates a base-excision DNA-repair pathway; this might partially explain bendamustine's activity in relapsed/refractory disease. Preclinical studies indicate that bendamustine and rituximab synergistically inhibit tumor growth and induce apoptosis in non-Hodgkin lymphoma and CLL disease models. Despite bendamustine's availability in Europe for 4 decades, the available clinical data shed little light on its role in the treatment of CLL. Adverse effects include myelosuppression and gastrointestinal complaints. In a recent phase III trial of previously untreated patients with CLL, bendamustine produced superior response rates and progression-free survival compared with chlorambucil, leading to its approval by the US Food and Drug Administration.

Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML), allowing prolonged remissions in patients with chronic-phase disease. However, a substantial number of patients develop resistance and require alternative treatment. Consistent monitoring of bcr-abl transcript levels during treatment is important in the management of CML. The prognostic value of achieving a major molecular response at 12 months is increasingly recognized. Additionally, rising bcr-abl transcript levels provide an early indication of a potential loss of response to treatment. Quantitative reverse-transcriptase polymerase chain reaction is the most sensitive method for detecting changes in the overall disease burden of CML. The recommendations of the National Comprehensive Cancer Network suggest measuring transcript levels every 3 months in patients who respond to treatment with imatinib when a complete cytogenetic response is achieved. Dasatinib and nilotinib are alternative tyrosine kinase inhibitor therapies approved for the treatment of patients with CML who fail initial imatinib therapy. This review discusses the role of molecular monitoring in the management of CML, the methodology used, and molecular responses reported for the available treatments.

Within the past 15 years, the management of chronic lymphocytic leukemia (CLL) has shifted from palliative efforts to modern combination therapies that aim to induce durable remissions and prolong life. A widened spectrum of regimens and novel tools to predict response allows for the tailoring of first- and second-line treatment to a patient's individual risk, age, and medical fitness. Herein, we review current treatment indications and therapeutic options, followed by evidence-based recommendations for the choice of therapy in primary and relapsed CLL. Supported by phase III trial data, combined chemotherapy with fludarabine and cyclophosphamide is considered the standard first-line regimen. In all probability, however, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab will become the standard therapy in the very near future. Patients at poor risk with genetic abnormalities, as well as elderly patients with medical impairments, require special attention because they often do not respond to these novel combination therapies. Salvage therapy (including hematopoietic stem cell transplantation) should be carried out in clinical trials whenever possible because no standard salvage regimen has been defined so far.

The prognosis of patients with chronic myeloid leukemia (CML) has markedly changed since the introduction of tyrosine kinase inhibitors. Currently, imatinib is the only Food and Drug Administration–approved tyrosine kinase inhibitor for the treatment of patients with newly diagnosed CML. With imatinib 400 mg, an estimated 83% of patients are expected to be alive without disease progression, after a median follow-up of 60 months. Although this survival figure is higher than for any other previous therapy in CML, there is still room for improvement. To improve on these results, various approaches in the therapy of newly diagnosed patients with CML were studied. Of these, high-dose imatinib, or one of the new tyrosine kinase inhibitors, ie, nilotinib or dasatinib, shows promise. Our aim is to review the results of various studies using different approaches in the therapy of patients with newly diagnosed CML.

Background

Dasatinib is a multi–tyrosine kinase–specific inhibitor with potent inhibitory activity against bcrabl kinase. It has been increasingly used in the treatment of imatinib-resistant chronic myelogenous leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia. However, despite its excellent activity, a proportion of patients present evidence of dasatinib resistance.

Patients and Methods

To assess the potential mechanisms of resistance, we have analyzed the bcr-abl kinase domain from 22 patients with CML who demonstrated clinical evidence of dasatinib failure.

Results

Mutations were present in 16 of 22 patients, and the majority were mapped to the adenosine triphosphate binding pocket. Of these, 7 had panresistant T315I, and 4 had F317L, with 1 F317I mutation. In addition, 3 of 16 patients evaluated had a V299L mutation. All of these mutations were previously reported in association with dasatinib resistance. We also observed that 1 of 7 patients in the chronic phase and 5 of 15 patients in the advanced phase had > 1 mutation in separate clones, as well as compound mutations (1 mRNA had ≥ 2 mutant codons). Interestingly, 4 of 15 patients with documented mutations were found to have a novel V304D mutation, which is located outside of the dasatinib binding site in the β 4-5 loop structure.

Conclusion

It appears that bcr-abl mutations in advanced-phase CML are more common but occur at lower frequencies in patients with chronic-phase disease (93% vs. 62%, respectively). Our results suggest that selection for T315I and F317L mutations occurs frequently in dasatinib-resistant patients, and both mutations were previously shown to affect dasatinib binding. Two additional mutations (V299L and V304D) have been identified with incidences that exceed random occurrence. The significance of these mutations is being evaluated.

Background

Chronic myeloid leukemia (CML) is a malignant disease caused by the protein coded by the Philadelphia chromosome. Imatinib mesylate (IM) is now the treatment of choice for all stages of CML. Clinicoepidemiologic information on CML from developing countries is scattered in the current literature

Patients and Methods

We report on the clincoepidemiologic features and response to therapy with IM in a cohort of patients with all stages of CML at a Mexican institution. Additionally, we describe the failure rate of standard G-banding cytogenetics, and correlate the association of successful standard cytogenetics with fluorescence in situ hybridization (FISH) to validate the results of responses in our patient population. Ninety-nine medical charts were evaluated. Fifty-seven patients were treated with IM, and a historical group consisted of 42 patients.

Results

The median age was 37 years, and the median follow-up of the IM-treated cohort was 26.4 months. The correlation between cytogenetics and FISH was 0.719 (P = .01). The complete cytogenetic response was 88.1% in the IM-treated group, versus 4.8% in the historical group. Patients previously treated with interferon-α (INF-α) had a complete cytogenetic response of 58.8%, versus 77.8% of patients previously treated who were naive to INF-α.

Conclusion

Our report describes a comprehensive picture of a group of patients with CML representative of the Mexican population with socioeconomic and cultural constraints. Except for median age at diagnosis, clinicoepidemiologic features and response rates are in accordance with other series. Fluorescence in situ hybridization was a reliable method for monitoring CML at our institution. However, the role of FISH in monitoring CML, where standard cytogenetic testing and the polymerase chain reaction are less reliable, needs to be clarified more thoroughly.

The classical myeloproliferative disorders (MPDs) of essential thrombocythemia, polycythemia vera, and primary myelofibrosis have an increasing predisposition to transform to overt acute leukemia or MPD-blast phase (MPD-BP). Current therapies for the MPDs are limited, and no therapy other than allogeneic stem cell transplantation (alloSCT) has clearly altered the natural history of these disorders. Pathogenetic mechanisms that lead to an MPD progressing to MPD-BP are incompletely understood but seem to correlate with the accumulation of additional karyotypic abnormalities as opposed to increases in MPD-associated molecular lesion burden (such as JAK2^V617F). The development of MPD-BP is heralded by worsening cytopenias, constitutional symptoms, and a poor survival despite therapeutic intervention. Risk factors for developing MPD-BP include features at diagnosis (such as increased peripheral blood blasts, karyotypic abnormalities, and thrombocytopenia) and exposure to established agents that enhance leukemogenesis (ie, P-32 and alkylators). Multiple avenues of therapeutic investigation are ongoing to treat or prevent MPD-BP, including early alloSCT, hypomethylating agents, and JAK2 inhibition. An improved understanding of the pathogenetic underpinnings of MPD-BP are necessary if more effective targeted therapies are to be developed.