ALBERT

Description: Introduction: Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by the accumulation of mature monoclonal B-lymphocytes. Combination therapies produce high response rates, including complete responses, but all patients will eventually relapse. Novel therapies are needed. Ex-vivo chemosensitivity assays offer two distinct advantages for identifying new CLL therapies. First, agents can be screened without exposing patients to unnecessary risk. Second, no CLL clonogenic cell lines exist, requiring that patient samples be analyzed in an ex-vivo manner. Dasatinib is a potent inhibitor of Src, Abl, and several other tyrosine kinases. B-CLL has been characterized as having anomalous signaling through Lyn kinase, a member of the Src family. We sought to determine the single agent and combination ex-vivo activity of dasatinib in CLL samples. Methods: We used an ATP-luminescent chemosensitivity assay (ViaLight, Lonza, Basel, Switzerland) to assess the activity of single agent dasatinib (0.01 nM to 1 μM), and dasatinib (1, 10, 100 nM) in combination with fludarabine (0.06 to 64 μg/ml), chlorambucil (0.2 to 102.4 μg/ml), or methylprednisolone (0.02 to 2,000 μg/ml) in CLL patient peripheral blood samples. Patients had a diagnosis of B-CLL, WBC count greater than 20 x 109/L, no chemotherapy within 14 days, and no antibody therapy within 28 days. Results: Five patient samples were obtained; 4 from untreated patients and 1 from a patient being treated with fludarabine. Rai stages ranged from 0 to IV. Single agent dasatinib induced apoptosis in 3 of 5 CLL samples tested. The two samples without apoptosis were from untreated patients. IC50 values were 〉1 (no apoptosis), 〉1 (no apoptosis), 0.2, 0.2, and 0.04 (fludarabine treated patient) μM. The IC50 values of single agent fludarabine were 1.3, 0.18, 1, 0.22, and 3 (fludarabine treated patient) μg/ml, respectively. The IC50 values of fludarabine in combination with 100 nM dasatinib were 0.41,

Description: Antibody-mediated cell depletion therapy has proven to provide significant clinical benefit in treatment of lymphomas and leukemias, driving the development of improved therapies with novel mechanisms of cell killing. A current clinical target for B-cell lymphoma is CD22, a B-cell–specific member of the sialic acid binding Ig-like lectin (siglec) family that recognizes α2-6–linked sialylated glycans as ligands. Here, we describe a novel approach for targeting B lymphoma cells with doxorubicin-loaded liposomal nanoparticles displaying high-affinity glycan ligands of CD22. The targeted liposomes are actively bound and endocytosed by CD22 on B cells, and significantly extend life in a xenograft model of human B-cell lymphoma. Moreover, they bind and kill malignant B cells from peripheral blood samples obtained from patients with hairy cell leukemia, marginal zone lymphoma, and chronic lymphocytic leukemia. The results demonstrate the potential for using a carbohydrate recognition–based approach for efficiently targeting B cells in vivo that can offer improved treatment options for patients with B-cell malignancies.

Description: Cladribine induces protracted remissions in patients with hairy cell leukemia (HCL). However, many long-term responders ultimately relapse. We sought to determine whether long-term complete responders subsequent to a single 7-day course of cladribine were without minimal residual disease (MRD) and potentially cured of HCL. From the 358-person Scripps Clinic cladribine database, we identified 19 patients in continuous and complete hematologic response (median age, 75 years; median time from diagnosis, 18 years; and median time from cladribine, 16 years). Nine of 19 (47%) patient samples had no evidence of residual disease; 7 of 19 (37%) samples had MRD; and 3 of 19 (16%) had morphologic evidence of HCL in hematoxylin and eosin–stained bone marrow sections. These results indicate that HCL is potentially curable after cladribine treatment. In addition, patients with MRD and even gross morphologic disease can live many years without manifesting hematologic relapses.

Description: Before the contemporary development of rationally designed antineoplastic therapies, cladribine was identified as a lymphocyte-specific agent. Its profound impact on the natural history of hairy cell leukemia, with responses approaching 100% and a median duration of response of nearly a decade after only a single 7-day course, is well known and revolutionized the treatment of hairy cell leukemia. However, cladribine's impressive activity in other lymphoproliferative disorders has been generally underappreciated. Multiple single-arm phase 2 trials have demonstrated cladribine's potency across the full spectrum of lymphoid malignancies. In a limited number of phase 3 trials and cross-study analyses, cladribine compared favorably with fludarabine, another purine nucleoside analog that is more commonly used in the treatment of indolent lymphoid malignancies. Cladribine has been noted to have particular activity among lymphoid disorders with few effective therapies, specifically, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, and mantle cell lymphoma. Recently approved novel agents may act in synergy with cladribine for these conditions and should be incorporated into future clinical studies.