Adults with relapsed B-acute lymphoblastic leukemia (ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD−) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated 5 relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD-negative complete remissions as assessed by deep sequencing PCR. Therapy was well tolerated although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Significantly, cytokine elevations directly correlated to tumor burden at the time of CAR modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR modified T cell therapy, ineligible for additional allo-HSCT therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell mediated cytotoxicity suggesting potential clinical benefit of additional CAR modified T cell infusions. These results demonstrate the marked anti-tumor efficacy of 19-28z CAR modified T cells in patients with relapsed/refractory B-ALL and the reliability of this novel therapy to induce profound molecular remissions, an ideal bridge to potentially curative therapy with subsequent allo-HSCT.

The incidence of early death in a large population of unselected patients with acute promyelocytic leukemia (APL) remains unknown because of the paucity of outcome data available for patients treated outside of clinical trials. We undertook an epidemiologic study to estimate the true rate of early death with data from the Surveillance, Epidemiology, and End Results (SEER) program. A total of 1400 patients with a diagnosis of APL between 1992 and 2007 were identified. The overall early death rate was 17.3%, and only a modest change in early death rate was observed over time. The early death rate was significantly higher in patients aged > 55 years (24.2%; P < .0001). The 3-year survival improved from 54.6% to 70.1% over the study period but was significantly lower in patients aged > 55 years (46.4%; P < .0001). This study shows that the early death rate remains high despite the wide availability of all-trans retinoic acid and appears significantly higher than commonly reported in multicenter clinical trials. These data highlight a need to educate health care providers across a wide range of medical fields, who may be the first to evaluate patients with APL, to have a major effect on early death and the cure rate of APL. (Blood. 2011;118(5): 1248-1254)

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:

Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 ((213)Bi)-labeled lintuzumab. In a subsequent study, (213)Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of (213)Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 ((225)Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that (225)Ac-lintuzumab is safe at doses of 3 μCi/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose (225)Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using (213)Bi- and astatine-211 ((211)At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios.

Neither elacytarabine nor any of the seven alternative treatment regimens provided clinically meaningful benefit to these patients. OS in both study arms and for all treatments was extremely poor. Novel agents, novel clinical trial designs, and novel strategies of drug development are all desperately needed for this patient population.

SUMMARY Background Hypomethylating agents azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia (AML), but responses are limited and of short duration, possibly due to short half-lives and suboptimal bone marrow exposure. Guadecitabine (SGI-110), a dinucleotide of decitabine and deoxyguanosine, is resistant to degradation by cytidine deaminase thus achieving longer half-life and exposure of its active metabolite, decitabine. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in treatment-naïve older patients with AML who were not candidates for intensive chemotherapy. Methods In this multicentre, open-label, phase 2 study, treatment-naïve older patients from 14 North American medical centres with AML who were not candidates for intensive chemotherapy were randomly assigned (1:1, using a computer algorithm) to subcutaneous guadecitabine at 60 or 90 mg/m2 on days 1–5 (5-day schedule) of a 28-day treatment cycle. Subsequently, patients were assigned sequentially to subcutaneous guadecitabine at 60 mg/m2 in a 10-day schedule (at least 2 cycles administered on days 1–5 and 8–12, with subsequent cycles given on a 5-day schedule). The objective was to evaluate and compare the activity and safety of two doses and schedules of guadecitabine, with a primary endpoint of composite complete response (including complete response [CR], CR with incomplete platelet recovery [CRp], and CR with incomplete neutrophil recovery regardless of platelets [CRi]). Response was evaluated in all patients (as-treated) as long as a patient received at least one guadecitabine treatment. Secondary endpoints included safety, survival, and pharmacodynamics. We present the final trial analyses, although at time of database lock, 15 patients were still being monitored for survival including six continuing treatment. This study is registered with ClinicalTrials.gov, number NCT01261312 Findings Between Aug 24, 2012, and Sep 15, 2014, 103 patients received treatment: 51 on a 5-day schedule of guadecitabine (24 received 60 mg/m2, 27 received 90 mg/m2) and 52 on the 10-day schedule. Median age was 77 years. Poor prognostic features included ECOG status ≥2 (39 [38%]), poor-risk cytogenetics (43 [42%]), and secondary AML (37 [36%]). Characteristics were generally balanced across doses and schedules. CRc rates were 54% (13 patients), 59% (16 patients), and 50% (26 patients) for the 5-day 60, 5-day 90, and 10-day 60 mg/m2 regimens, respectively. The most common grade 3 or higher adverse events, regardless of relationship to treatment, for the 5- and 10-day schedules, respectively, included febrile neutropenia (31 [61%] and 36 [69%]), thrombocytopenia (25 [49%] and 22 [42%]), neutropenia (20 [39%] and 18 [35%]), pneumonia (15 [29%] and 19 [37%]), anaemia (15 [29%] and 12 [23%]), and sepsis (8 [16%] and 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5- and 10-day schedules, respectively, were febrile neutropenia (2...

Key Points A heteroclitic WT1 peptide vaccine is well tolerated and induces immunologic responses in most acute myeloid leukemia patients post-CR1. Median overall survival for the group of patients vaccinated was not reached but is poised to reach or exceed 67.6 months.

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