Luger, Selina M

CD25 is a subunit of the interleukin-2 (IL-2) receptor on T cells and natural killer (NK) cells. Acute leukemias with oncogenic tyrosine kinases often include CD25 + leukemia subpopulations, which portend poor clinical outcomes for patients; however, acute leukemia cells do not respond to IL-2. Here, we identified CD25 and its phosphorylation by protein kinase Cδ (PKCδ) as central elements of a feedback loop that stabilized fluctuations in oncogenic tyrosine kinase signaling in acute lymphoblastic and myeloid leukemia. Genetic ablation of CD25 in murine and patient-derived xenograft (PDX) models of acute leukemias reduced clonal fitness, colony formation, and leukemia-initiation capacity in serial transplant recipients. Oncogenic tyrosine kinase signaling in leukemia cells stimulated NF-κB–mediated CD25 expression, whereas PKCδ-mediated phosphorylation of CD25 suppressed oncogenic tyrosine kinase signaling through inhibitory phosphatases, such as PTPN6. Interactome analyses and mass spectrometry–based global phosphoproteomic analyses showed that CD25 deletion abolished the phosphatase activity of PTPN6, resulting in enhanced activation of tyrosine kinases and NF-κB. Four injections of a CD25 antibody-drug conjugate induced complete remission in mice transplanted with PDX refractory leukemia. These findings highlight the dependency of tyrosine kinase–driven leukemias on robust feedback control and the role of PKCδ and CD25 in assembling its components.

AbstractIntroductionRelapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B‐ and T‐ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L‐VCR and VEN for patients with r/r B‐or T‐cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644).MethodsIn a 3+3 dose escalation design, r/r ALL subjects were given single‐agent VEN doses reaching 400, 600, or 800 mg for the three respective dose levels. Weekly L‐VCR at 2.25 mg/m2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination.ResultsAmong the 18 patients in phase I, grade ≥ 3 treatment‐related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose‐limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600 mg). Twenty‐two percent of evaluable patients (N = 4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD).ConclusionThe combination of VEN and L‐VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L‐VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate.

BackgroundAcute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low‐intensity therapy, to elderly patients with newly diagnosed AML.MethodsThis randomized, open‐label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1‐hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1‐hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109/L and ≥10 × 109/L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1‐year survival. The trial is registered at ClinicalTrials.gov (NCT01303796).ResultsBetween October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P = .8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P = .1468). In patients with white blood cell counts <10 × 109/L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P = .145), as was the CR rate (21.5% vs 8.6%; P = .0017).ConclusionsThe regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109/L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed.

PURPOSE Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin. METHODS In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment. RESULTS A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) ( P = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively ( P = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone. CONCLUSION LEN restores sensitivity to recombinant erythropoietin in growth factor–insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813 ).