Recent studies suggest that the population of malignant cells found in human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells (LSCs). LSCs have been documented for nearly all AML subtypes and have been phenotypically described as CD34 + /CD38 − or CD34 + /HLA-DR − . Given the potentially critical role of these primitive cells in perpetuating leukemic disease, we sought to further investigate their molecular and cellular characteristics. Flow cytometric studies using primary AML tissue showed that the interleukin-3 receptor alpha chain (IL-3R␣ or CD123) was strongly expressed in CD34 + /CD38 − cells (98 ± 2% positive) from 16 of 18 primary specimens. Conversely, normal bone marrow derived CD34 + /CD38 − cells showed virtually no detectable expression of the CD123 antigen. To assess the functional role of IL-3R␣ positive cells, purified CD34 + /CD123 + leukemia cells were transplanted into immune deficient NOD/SCID mice. These experiments showed that CD123 + cells were competent to establish and maintain leukemic populations in vivo. To begin to elucidate a biological role for CD123 in leukemia, primary AML samples were analyzed with respect to signal transduction activity in the MAPK, Akt, and Stat5 pathways. Phosphorylation was not detected in response to IL-3 stimulation, thereby suggesting CD123 is not active in conventional IL-3-mediated signaling. Collectively, these data indicate that CD123 represents a unique marker for primitive leukemic stem cells. Given the strong expression of this receptor on LSCs, we propose that targeting of CD123 may be a promising strategy for the preferential ablation of AML cells.
Summary:Between April 1997 and March 1998 we evaluated the immune response and outcome in 11 chemosensitive patients who were treated with the anti-idiotype antibody vaccine TriAb after recovery from intensive therapy and autologous stem cell transplant (ASCT). Triab was commenced after recovery from the acute effects of ASCT; a minimum interval of 1 month was required from completion of consolidation radiotherapy, if given. Although intensive therapy and autologous stem cell transplantation (ASCT) produces durable progression-free survival in a small proportion of women with metastatic breast cancer, the majority of patients relapse despite the procedure. 1 A number of different intensive chemotherapeutic agents and dose schedules have been evaluated, but none has clearly produced superior results. 1,2 One approach to try to improve the outcome involves the use of immunotherapy in conjunction with ASCT. The use of immunebased therapy has particular appeal after ASCT, at which time the tumor burden may be small. Several strategies have been proposed in breast cancer patients undergoing ASCT, including the use of cyclosporine to evoke an auto-
7608 Background: Autologous stem cell transplantation (ASCT) using melphalan 200 mg/m2 is a standard part of inital therapy in younger multiple myeloma (MM) patients (pts). We have previously reported an augmented regimen of melphalan 280 mg/m2 with the cytoprotectant agent amifostine (AF) to try to improve the anti-tumor response without increased mucosal toxicity (The Hematol J 2003; 4[suppl]: S207). We now update our experience with this regimen. Methods: Pts without disease progression and adequate organ function (creatinine clearance at least 60 cc/min) were eligible. Pts were treated as part of phase I-II trials approved by each center’s institutional review board. AF 740 mg/m2 was given IV over 5–15 min 24 hr and 15 min prior to melphalan 280 mg/m2 (infused over 15 min). Blood stem cells were reinfused 24 hrs later. The primary endpoint was response rate at day 100. Regimen-related toxicity using the Seattle criteria, progression-free (PFS) and overall survival (OS) were also assessed. Results: 24 pts were transplanted between 5/99–7/02. Median age was 50 (32–65) yrs; 1 pt had primary amyloidosis; median beta2-microglobulin level at diagnosis was 1.98 (0.88–11.80) mg/L. Prior therapy included VAD in 14, dexamethasone alone in 7 plus other regimens in 7. Day 100 responses compared with with pre-ASCT values included CR in 11, near CR (immunofixation positivity only) in 1, VGPR (greater than 90% reduction in serum M protein) in 3, PR in 5 and stable disease in 3. Maximum grade of mucositis was 2 (5 pts); no grade 3 or 4 toxicity was seen. The median day of ANC recovery to 0.5 x 109/L and median day of last platelet transfusion were 11 (6–16) and 10 (7–32), respectively. 4 received thalidomide (1 briefly), while 1 was treated with maintenance alpha interferon after day 100. Median follow-up is 52 (9–72) mos. 7 pts are alive without progression, including 5 in CR and 2 in PR. 16 have progressed at a median of 15 (7–36) mos post-ASCT. 8 have died from MM (7) or lung cancer (1). The 4 yr actuarial PFS is 28% (95% C.I. 34–76%) and OS 58% (95% C.I.11–47%). Conclusions: 1) Melphalan 280 mg/m2 with AF is well-tolerated; 2) the CR + nCR + VGPR rate of 62% warrants further evaluation, perhaps as part of tandem transplants or in conjuction with novel agents. [Table: see text]
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