Clinical Lymphoma and Myeloma最新文献

Allogeneic stem cell transplantation (ASCT) is a potentially curative treatment for patients with chronic myelogenous leukemia (CML) and was previously considered the preferred treatment for newly diagnosed CML. The success of imatinib has changed treatment recommendations, and allogeneic transplants are now reserved for imatinib treatment failures. Previous imatinib treatment does not compromise the results of ASCT, but patients with overt transformed disease have poor results. It is unclear whether patients whose disease is considered to have failed imatinib should be referred immediately for ASCT or receive treatment with a second-generation tyrosine kinase inhibitors (TKI). Patients whose disease fails 2 TKIs should receive ASCT if possible. Nonmyeloablative preparative regimens reduce the toxicity and treatment-related mortality associated with the transplantation procedure and allow transplantations to be performed in older and medically infirm patients. This approach, including posttransplantation treatment with TKIs and donor lymphocyte infusion, produces a high fraction of durable molecular complete remissions.

Myelofibrosis (MF; primary or post–polycythemia vera/essential thrombocythemia) carries the worst prognosis among BCR-ABL–negative myeloproliferative neoplasms (MPNs). Stem cell transplantation is the only curative approach but is hampered by significant nonrelapse mortality. Thus, effective, targeted therapies are needed. A mutated Janus kinase 2 (JAK2) gene (JAK2^V617F), found in a significant portion of patients with MPN, results in increased JAK2 tyrosine kinase activity, leading to clonal proliferation; several small molecules inhibit the growth of hematopoietic colonies harboring JAK2^V617. Several JAK2 inhibitors have reached the clinical trial stage and are reviewed here. The most developed among them is INCB018424, which has demonstrated noteworthy clinical activity, with a rapid and profound reduction in splenomegaly and associated improvement in constitutional symptoms in MF patients receiving 10–25 mg orally twice daily, continuously. Thrombocytopenia (reversible) was the most common adverse event, seen in 30% of patients treated with 25 mg twice daily but not with 10 mg twice daily. Interestingly, INCB018424 was equally active in patients with and without JAK2 mutation. Other JAK2 inhibitors are less developed but show a similar type of clinical benefit. Conclusively, JAK2 inhibitors, particularly INCB018424, are clinically active in MF and are well tolerated. Whether they have an effect on the natural course of MF in treated patients remains to be elucidated.

The development of reduced-intensity regimens has allowed physicians and patients to explore this option even in older patients. Current results underscore that age by itself should no longer be a contraindication for allogeneic transplantation in these patients, and long-term disease control with good quality of life is possible. Future trials combining novel antileukemic therapies and novel transplantation technologies are being explored. These trials should allow more patients with acute myeloid leukemia or myelodysplastic syndromes to achieve long and productive lives.

Although most children with acute lymphoblastic leukemia (ALL) are cured, certain subsets have a high risk of relapse. Relapse risk can be predicted by early response to therapy, clinical and pharmacogenetic features of the host, and genetic characteristics of leukemic cells. Though early treatment response can be assessed by the peripheral blast cell count after 1 week of single-agent glucocorticoid treatment or percent of bone marrow blasts by morphology after 1 or 2 weeks of multiagent induction treatment, determination of minimal residual disease by polymerase chain reaction (PCR) or flow cytometry after 2 to 6 weeks of induction is the most precise and useful measure. Augmented therapy has improved outcome for the poor responders to initial treatment. Infants with mixed-lineage leukemia (MLL)–rearranged ALL comprise a very poor-risk group wherein further intensification of chemotherapy causes significant toxicity. Hybrid protocols incorporating drugs effective for acute myeloid leukemia could improve survival, a strategy being tested in international trials. Studies on the biology of MLL-induced leukemogenesis have prompted the development of novel targeted agents, currently under evaluation in clinical trials. Short-term outcomes of patients with Philadelphia chromosome (Ph)–positive ALL have improved significantly by adding tyrosine kinase inhibitors to standard chemotherapy regimens. New agents and methods to overcome resistance are under investigation, and allogeneic stem cell transplantation is recommended for certain subsets of patients, for example those with Ph⁺ and T-cell ALL with poor early response. Genome-wide interrogation of leukemic cell genetic abnormalities and germline genetic variations promise to identify new molecular targets for therapy.

The large MRC/ECOG Adult Acute Lymphoblastic Leukemia Study establishes the value of sibling donor allogeneic transplantation in patients with standard risk, demonstrating superior outcome to conventional chemotherapy. The small but significant number of patients having matched unrelated donor transplantations on this study protocol appear to do well and might establish the value of such an approach for those without a sibling. Reduced-intensity conditioning might begin to address the transplantation-related mortality problems of the older patients. The youngest adults might not need to undergo transplantation at all. If they are now treated on pediatric chemotherapy protocols, their outcome appears to improve significantly.

Background

The association of acute leukemia and multiple myeloma (MM) has been usually described not only as a complication of chemotherapy but also in the absence of chemotherapy or together at the time of diagnosis. Such leukemias are typically acute myeloid leukemia (AML). The myelomonocytic subtype is particularly found.

Case Report

We report a case of a 68-year-old female who developed AML 2 years after the diagnosis of light chain (κ) myeloma. She had been treated with oral melphalan and prednisone for MM. The patient was treated with an anthracycline-lacking therapy consisting of etoposide 120 mg/m², thioguanine 100 mg/m² orally twice daily on 1-5 days, and cytarabine 40 mg/m² subcutaneously on day 1 (ETC) because of poor cardiac performance.

Conclusion

Following ETC therapy our particular patient has been in complete hematologic remission for 29 months. This therapy might be a safe alternative in secondary leukemia especially for elderly patients.

Although the increased risk of venous thrombotic events with thalidomide in multiple myeloma (MM) has been well described, an association with an increased risk of arterial events is less well appreciated. We describe 5 unusual arterial thromboses in patients with MM shortly after beginning thalidomide-based therapies. The cases are remarkable for a paucity of risk factors and short latency. We also review the literature on arterial thromboembolic events in patients taking thalidomide. Care should be taken in future trials to document arterial events with both thalidomide and lenalidomide.

The management of patients with chronic myeloid leukemia (CML) during pregnancy is a matter of continued debate. We present a 21-year-old woman in whom CML was diagnosed during early pregnancy. Because the patient was asymptomatic and desired to carry the pregnancy to term while minimizing fetal exposure to medication, she was observed with no therapy for the duration of her pregnancy. The white blood cell count showed a slow downward trend throughout her pregnancy. She delivered a healthy baby and breast fed for a time before initiating therapy for CML. We reviewed the published case reports of women who had a pregnancy occur in the setting of treatment with imatinib. Given the adverse effects of fetal exposure to imatinib as treatment for the mother with CML, close observation might be an option for selected patients who are diagnosed with CML while pregnant and who have minimal clinical manifestations of CML.

Multiple myeloma patients with plasmablastic morphology of tumor cells and extramedullary presentation of disease often have an aggressive clinical course and resistance to chemotherapy. We describe a case of an elderly patient who presented with extramedullary, IgA-λ—secreting multiple myeloma with plasmablastic features who demonstrated impressive clinical response to single-agent lenalidomide. This is the first description of a plasmablastic variety of multiple myeloma successfully treated with lenalidomide alone.