Our hematology research encompasses a variety of cancers and nonmalignant hematologic conditions, including multiple myeloma, amyloidosis, myelodysplastic syndromes, and aplastic anemia. We also develop stem cell transplantation techniques for the treatment of hematologic cancers. (For information on leukemia and lymphoma research, please refer to those respective separate sections.)
Our autologous stem cell transplant team has been a world leader in developing new approaches that improve survival while reducing treatment-related mortality. We have also participated in numerous clinical trials evaluating new chemotherapy agents and other investigational approaches. These include drugs that treat disease as well as those that abrogate the side effects of transplantation.
Among our recent research accomplishments:
- We are currently investigating the safety and efficacy of escalating doses of tretinoin, a form of vitamin A, in combination with the DMT inhibitor decitabine in patients with myelodysplastic syndromes (MDS). We will explore the treatment’s mechanism of action by analyzing cell differentiation, apoptosis, gene-expression profiles, and DNA methylation status in cells derived from responding patients’ blood samples
- We are searching for markers that could be used for predicting an MDS patient’s response to DMT inhibitors. By analyzing patient samples collected in our clinical trials, we hope to identify new genetic alterations in MDS and correlate those with patients’ sensitivity or resistance to DMT inhibitors and other therapies that act by modulating gene transcription.
- We are examining the HDAC inhibitor depsipeptide in patients with myelodysplastic syndrome and acute myelogenous leukemia. A pilot trial revealed cumulative nonhematologic toxicities including fatigue and gastrointestinal symptoms in some patients, with one patient having a complete response. We also found that depsipeptide induced apoptosis in peripheral blood and bone marrow mononuclear cells of most evaluable patients. Clin Cancer Res. 2008 Feb 1;14(3):826-32. [PubMed Abstract]
Detection, Diagnosis, and Prognosis
- In an interdisciplinary effort to study the pathogenesis of therapy-related MDS and acute myelogenous leukemia (AML), BAC/CGH screening of 20 patients with de novo AML and 20 patients with therapy-related AML or MDS was used to locate several previously unidentified regions of chromosome loss. Translational extensions of this work include therapeutic transcriptional modulation in myeloid malignancies, during which our investigators will seek changes in DNA methylation in patients receiving decitabine or 5-azacytidine, changes in gene expression by qPCR, and changes in histone modifications.
- By comparing transcriptional profiles of bone marrow myeloma cells with those in extramedullary plasmacytomas, we have identified several genes that may be involved in promoting angiogenesis. Follow-up studies will assess circulating endothelial progenitors (FACS analysis of CD34+ VEGFR2 subsets) in patients with high-risk myeloma. The majority of these patients will have both soft tissue plasmacytomas and marrow myeloma cells cryopreserved for later analysis.
- We have also been evaluating the presence and significance of the inhibitory Fc receptor on myeloma and light-chain amyloidosis plasma cells. We have confirmed the presence of the receptor on all light-chain amyloid plasma cells and are examining a link between the level of receptor expression and disease behavior. For amyloidosis, we are continuing to identify prognostic factors to refine the current risk-adaptive therapeutic program. Our large patient series examining the diagnostic process of typing amyloid as light-chain or hereditary shows that a small fraction of patients (2 to 10 percent) with a tissue diagnosis of amyloidosis may have two amyloid-related proteins: an Ig light chain and a hereditary protein. The amyloid is likely caused by only one of them. Therefore, in some cases AL-amyloidosis can be misdiagnosed and hereditary amyloidosis not diagnosed. We now routinely screen patients in certain categories for both sources. Blood. 2006 May 1;107:3489-91. [PubMed Abstract]
- The results of several completed myeloma therapeutic trials have shown that melphalan can mobilize hematopoietic stem cells with little contamination by myeloma cells. We have also reported a conditioning regimen combining BCNU with melphalan that produced little pulmonary toxicity and excellent disease control. Sequential initial therapy involving doxorubicin and dexamethasone followed by thalidomide and dexamethasone will serve as the basis for future studies including bortezomib, which has been extensively studied in our institution in patients with non-Hodgkin lymphoma. We will study the endothelial progenitor cell compartment in the marrow and blood of newly diagnosed high-risk myeloma patients. Br J Haematol. 2006 Jan;132(2):155-61.[PubMed Abstract]; Leukemia. 2006 Feb;20(2):345-49. [PubMed Abstract]
- Our high-dose therapy program for amyloidosis has proven safe and effective, with long-term survival of approximately 50 to 60 percent. A completed clinical trial of high-dose melphalan with transplant followed by thalidomide and dexamethasone adjuvant therapy in patients with persistent clonal plasma-cell disease showed significant improvement in response with adjuvant therapy.