Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.

BACKGROUND: The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. METHODS: We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m2 on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS: Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m2 and 28 to 90 mg/m2) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m2 on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m2 on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). INTERPRETATION: More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m2 in a 5-day schedule versus standard of care. FUNDING: Astex Pharmaceuticals and Stand Up To Cancer.

Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid.

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.

Translocation t(11;17) in de novo myelodysplastic syndrome not associated with acute myeloid or acute promyelocytic leukemia.

Translocation t(11;17) is a well-recognized variant of acute promyelocytic leukemia (APL) and has also been identified in patients with mixed-lineage leukemia (MLL) non-APL acute myeloid leukemia. Here, we describe two patients bearing translocation t(11;17) presenting with a clinical diagnosis of de novo myelodysplastic syndrome (MDS): the first with sole karyotypic abnormality 46,XY,t(11;17)(p11.2; p13) and the second where it represented one of the two karyotypic abnormalities 46,XX,del(5)(q13q33)46,XX,del(5)(q13q33),t(11;17)(q24;q23). Molecular characterization of both cases failed to identify fusion transcripts involving MLL or PLZF-RARA and no collaborating somatic mutations commonly found among MDS patients were seen in either case, suggesting the presence of an as yet unidentified oncogenic fusion protein.

Treatment of Patients with Acute Myeloid Leukemia with the Targeted Alpha-Particle Nanogenerator Actinium-225-Lintuzumab.

PURPOSE: The anti-CD33 antibody lintuzumab has modest activity against acute myeloid leukemia (AML). To increase its potency, lintuzumab was conjugated to actinium-225 (225Ac), a radionuclide yielding 4 α-particles. This first-in-human, phase I trial was conducted to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab. PATIENTS AND METHODS: Eighteen patients (median age, 64 years; range, 45-80) with relapsed or refractory AML received a single infusion of 225Ac-lintuzumab at activities of 18.5 to 148 kBq/kg. RESULTS: The maximum tolerated dose was 111 kBq/kg. Dose-limiting toxicities included myelosuppression lasting > 35 days in one patient receiving 148 kBq/kg and death from sepsis in two patients treated with 111 and 148 kBq/kg. Myelosuppression was the most common toxicity. Significant extramedullary toxicities were limited to transient grade 3 liver function abnormalities. Pharmacokinetics were determined by gamma counting serial whole blood, plasma, and urine samples at energy windows for the 225Ac daughters, francium-221 and bismuth-213. Two-phase elimination kinetics were seen with mean plasma t1/2 - α and t1/2 - ß of 1.9 and 38 hours, respectively. Peripheral blood blasts were eliminated in 10 of 16 evaluable patients (63%) but only at doses of ≥ 37 kBq/kg. Bone marrow blasts were reduced in 10 of 15 evaluable patients (67%), including 3 patients with marrow blasts ≤ 5% and one patient with a morphologic leukemia-free state. CONCLUSIONS: Therapy for AML with the targeted α-particle generator 225Ac-lintuzumab was feasible with an acceptable safety profile. Elimination of circulating blasts or reductions in marrow blasts were observed across all dose levels.

Long-Term Benefits of Tagraxofusp for Patients With Blastic Plasmacytoid Dendritic Cell Neoplasm.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy. We report long-term results, including data from the continued access phase, of the largest prospective BPDCN trial evaluating the CD123-targeted therapy tagraxofusp (TAG) in adults with treatment-naive and relapsed/refractory BPDCN. The primary outcome was complete response (CR) + clinical CR (CRc: CR with residual skin abnormality not indicative of active disease). Eighty-four (65 treatment-naive and 19 relapsed/refractory) of 89 patients received TAG 12 µg/kg once daily; the median follow-up was 34.0 months. For treatment-naive patients, the overall response rate was 75%; 57% achieved CR + CRc. The median time to remission was 39 (range, 14-131) days, and the median CR + CRc duration was 24.9 (95% CI, 3.8 to not reached) months. Nineteen patients (51%) with CR + CRc were bridged to stem-cell transplant, with a median CR + CRc duration of 22.2 (range, 1.5-57.4) months. Most common adverse events were increased alanine (64%) or aspartate (60%) aminotransferase and hypoalbuminemia (51%); most occurred in cycle 1 and were transient. Capillary leak syndrome occurred in 21% of patients (grade ≥ 3: 7%). In first-line patients with BPDCN, TAG monotherapy resulted in high and durable responses, allowing many to bridge to stem-cell transplant. TAG was generally well-tolerated with a predictable and manageable safety profile.

Targeted alpha-particle immunotherapy for acute myeloid leukemia.

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.

Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death.

We hypothesized that the high early death rate (EDR) due to bleeding in acute promyelocytic leukemia (APL) is in part attributable to delays in all- trans retinoic acid (ATRA). We conducted a retrospective analysis of the timing of ATRA administration. 204 consecutive patients with newly diagnosed APL between 1992 and 2009 were identified. The EDR was 11%. 44% of early deaths occurred in the first week. Hemorrhage accounted for 61% of early deaths. ATRA was ordered the day APL was suspected in 31% of patients. Delays in ATRA administration led to increases in the percentage of early deaths from hemorrhage.

Induction and postremission strategies in acute myeloid leukemia: state of the art and future directions.

Although the past decade has brought improvements in the treatment of AML, particularly for younger individuals, most patients succumb to the disease. With current induction therapy, most patients achieve remission, but the optimal strategy for post-remission therapy is unclear. Refinements to risk classification systems that incorporate additional molecular markers may better guide physicians in recommendations for postremission therapy. The prognosis for older patients with AML remains uniformly poor, because only a minority can benefit from intensive chemotherapy and novel HCT strategies. Despite active investigation, no standard of care has emerged for patients who are not suitable candidates for standard induction therapy. The development of less toxic, more effective therapies for this population is sorely needed. Advances in molecular genetics, immunology, and the biology of normal and malignant hematopoiesis pathogenesis have led to an improved understanding of the pathogenesis of AML and to the discovery of potential therapeutic targets. Until a greater proportion of individuals with AML attain long-term survival, patients should routinely be referred to cancer centers and enrolled in investigational studies.

Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia.

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 ß-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. EXPERIMENTAL DESIGN: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m(2)/d) for 5 days followed by (213)Bi-lintuzumab (18.5-46.25 MBq/kg). RESULTS: The MTD of (213)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%). Treatment-related 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 (213)Bi-lintuzumab was achieved after partial cytoreduction with cytarabine. CONCLUSIONS: Sequential administration of cytarabine and (213)Bi-lintuzumab is tolerable and can produce remissions in patients with AML.