Leukemia

Our Clinical Trials Continually updated listing of our clinical trials for leukemias more

Our leukemia research team is working to develop better treatments for all types of leukemia in adult patients. Clinical research in leukemia is conducted by a multidisciplinary team that includes hematologists, medical oncologists, radiologists, pathologists, surgeons, and specialists in bone marrow transplantation and infectious diseases.

Our investigators are at the leading edge of developing new treatments for leukemia, including the development of new targeted therapies and immunologic drugs. We also collaborate very closely with basic scientists working in the laboratory, thereby taking important discoveries from bench to bedside.

Among our recent research accomplishments:

• We have generated tumor-reactive T cells genetically targeted to the CD19 protein, and we plan to initiate clinical trials of this treatment in patients with lymphoid leukemias.

• In an interprogrammatic effort on the pathogenesis of therapy-related myelodysplastic syndrome (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 identified 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.

• Since a complete response is achievable in most patients with acute leukemia, relapse remains the most significant cause of treatment failure. A major focus of our investigators, therefore, is the targeting of minimal residual disease (MRD). We have an active program investigating antibodies, both conjugated and naked, for effective targeting. In acute promyelocytic leukemia (APL), we previously found that the unconjugated humanized anti-CD33 MAb HuM195 eliminated MRD in 50 percent of patients and that retinoic acid, HuM195, and chemotherapy produced long-term remissions in more than 90 percent of patients. Based on these results, we developed a risk-adapted approach to postremission therapy using sequential HuM195, arsenic trioxide, and idarubicin. Molecular monitoring allowed a reduction in the number of idarubicin courses, while maintaining a 93 percent three-year disease-free survival rate. We now plan to exploit the synergistic activity of retinoic acid and arsenic trioxide to eliminate post-remission anthracycline therapy in APL.

• In studies assessing radioimmunotherapy, we previously reported that á-emitting isotopes, such as 131I and 90Y, could potentially be used to intensify conditioning prior to hematopoietic stem cell transplantation, and we are now studying 90Y-HuM195 as part of a reduced-intensity transplant regimen. We have also investigated the use of high-energy, short-range á-emitters for the eradication of residual disease. Our investigators conducted the first study to demonstrate the safety, feasibility, and antitumor activity of this approach in patients using 213Bi-HuM195. In ongoing follow-up studies, we observed complete remissions in patients with poor-risk acute myelogenous leukemia (AML) with 213Bi-HuM195 after partial cytoreduction with cytarabine. Antitumor effects may be further enhanced by the use of 225Ac immunoconjugates, which serve as in vivo alpha particle generators and are up to 1,000 times more potent than their 213Bi analogs. We have begun phase I testing of 225Ac-HuM195 in myeloid leukemias.

• In the development of small molecules, we have participated in several studies of FLT-3 inhibitors (PKC-412 and MLN-518); collaborations with investigators in Boston; Mainz, Germany; and elsewhere identified a FLT3 mutation present prior to therapy and also a novel FLT3 mutation occurring during therapy, leading to partial resistance. We have also shown that patients with CBF AML have high levels of TRKA. A planned trial of CEP-701, a FLT3 inhibitor that also inhibits TRKA, will help us determine whether signaling through TRKA is clinically relevant. Blood 2006;107:293-300. [PubMed Abstract]; Blood 2006;108:3674-81. [PubMed Abstract]; Proc Natl Acad Sci 2005;102:4016-4021. [PubMed Abstract]

• Our researchers are utilizing gene-transfer techniques to enhance T cell-mediated tumor recognition and rejection. Autologous T cells may be genetically modified to express artificial T cell receptors designed to target specific tumor cell antigens. Human T cells engineered to express a CD19-targeted artificial receptor, termed 19z1, specifically lyse CD19+ tumor cell lines in vitro and cure a majority of immune-compromised SCID-Beige mice bearing established human CD19+ B-cell tumors. We have enhanced the signaling potential of the 19z1 receptor by adding the CD28 cytoplasmic signaling domain to the receptor construct (19-28z). T cells bearing 19-28z have superior antitumor activity both in vitro and in vivo when compared to the 19z1. We are planning an initial two-step phase I clinical trial to study autologous 19-28z+ T cell infusion in patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL). In the first step, we will assess the safety and antitumor efficacy of autologous 19-28z+ T cells using a dose-escalation scheme. In the second step, patients will be pretreated with lymphodepletion to assess enhancement of in vivo survival and antitumor efficacy of 19-28z+ T cells. Extension of this approach to patients with relapsed acute lymphocytic leukemia (ALL) is expected in late 2008.

• In prior studies, we showed that peptides spanning the Philadelphia chromosome breakpoints can elicit T cell responses in chronic myelogenous leukemia (CML) patients. More recently, we found that a vaccine composed of a mixture of native and synthetic heteroclitic bcr-abl breakpoint-derived peptides consistently produces CD4 and CD8 responses in patients. Half of the patients had at least a one-log reduction in the number of bcr-abl transcripts by qPCR. A multicenter trial based on this work is now planned. Additional studies using second-generation tyrosine kinase inhibitors in combination with imatinib are planned to address MRD in CML. A similar strategy targeting WT1 will be investigated in patients with AML.

• In clinical trials assessing new chemotherapeutic approaches of CLL and ALL, pentostatin and cyclophosphamide produced responses in 75 percent of previously treated patients with acceptable toxicity; the addition of rituximab to this combination significantly prolonged response. This combination is now under study in patients with previously untreated CLL. For ALL, a multicenter phase III study under our direction showed improved three-year disease-free survival rates for patients receiving intensive induction therapy with high-dose cytarabine and mitoxantrone compared with a standard vincristine/prednisone-based regimen. Based on these results, a risk-stratified program integrating this intensive induction is under development. We also plan to investigate dose-intense induction in combination with second-generation tyrosine kinase inhibitors for patients with Philadelphia chromosome-positive ALL. J Clin Oncol 2006;24:1575-1581. [PubMed Abstract]; Proc ASCO, 2005.