Hypophosphatemia, with associated changes in bone and mineral metabolism, develops in a proportion of patients taking imatinib for either chronic myelogenous leukemia or gastrointestinal stromal tumors. The drug may inhibit bone remodeling (formation and resorption), even in patients with normal serum phosphate levels.

Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle-emitting radionuclide bismuth-213 ( 213 Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213 Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy. Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatmentrelated deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by Although standard induction therapy with cytarabine and an anthracycline produces complete remissions (CR) in 50% to 70% of patients with acute myeloid leukemia (AML), long-term survival is seen in only 20% to 40% of patients (1). Following relapse, additional chemotherapy produces remissions in only 20% to 25% of patients. Although allogeneic hematopoietic stem cell transplantation (HSCT) can produce long-term remissions in ∼30% of patients with relapsed AML, most patients are not appropriate candidates due to age, comorbidities, or lack of a suitable donor (2). The prognosis for older patients is even worse, with a 5-year survival rate of 5% for patients ≥65 years of age (3). Therefore, new therapies are needed to improve overall survival and reduce therapyrelated toxicity.Early studies showed that β-particle-emitting anti-CD33 constructs containing iodine-131 or yttrium-90 could eliminate large leukemic burdens but produced prolonged myelosuppression requiring HSCT (4, 5). The unique physical and radiobiological properties of α-particles, however, may provide more efficient tumor cell killing and reduce the nonspecific cytotoxic effects seen with β-emitters. Compared with β-particles, α-particles have a shorter range (50-80 versus 800-10,000 μm) and a higher linear energy transfer (100 versus 0.2 keV/μm; ref. 6). As few as one or two α-particles can kill a target cell. Therefore, the potential for specific antitumor effects makes α-particle immunotherapy an attractive approach for the treatment of cytoreduced or minimal disease.Lintuzumab (HuM195) is a humanized monoclonal antibody that targets CD33, a 67-kDa cell surface glycoprotein expressed on most myeloid leukemia cells. It is also found on committed myelomonocytic and erythroid progenitors but not on pluripotent stem cells, granulocytes, or nonhematopoietic tissues (7,8). Lintuzumab induces Authors' Affiliations:

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Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.