Efficacy and safety of nilotinib 300mg twice daily in patients with chronic myeloid leukemia in chronic phase who are intolerant to prior tyrosine kinase inhibitors: Results from the Phase IIIb ENESTswift study

Background Some patients receiving a tyrosine kinase inhibitor (TKI) for the first-line treatment of chronic phase chronic myeloid leukemia (CML-CP) experience intolerable adverse events. Management strategies include dose adjustments, interrupting or discontinuing therapy, or switching to an alternative TKI. Methods This multicenter, single-arm, Phase IIIb study included CML-CP patients intolerant of, but responsive to, first-line treatment with imatinib or dasatinib. All patients were switched to nilotinib 300 mg bid for up to 24 months. The primary endpoint was achievement of MR4.5 (BCR-ABL transcript level of ≤0.0032% on the International Scale) by 24 months. Results Twenty patients were enrolled in the study (16 imatinib-intolerant, 4 dasatinib-intolerant); which was halted early because of low recruitment. After the switch to nilotinib 300mg bid, MR4.5 at any time point up to month 24 was achieved in 10 of 20 patients (50%) in the full analysis set. Of the non-hematological adverse events associated with intolerance to prior imatinib or dasatinib, 74% resolved within 12 weeks of switching to nilotinib 300mg bid. Conclusion Nilotinib 300mg bid shows minimal cross intolerance in patients with CML-CP who have prior toxicities to other TKIs and can lead to deep molecular responses

Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial

Background Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P < 0.001) and relapse-free survival by 5.3 months (P < 0.001) compared with placebo in patients with AML in first remission after IC who were not candidates for transplant. Currently, the QUAZAR AML-001 trial provides the most comprehensive safety information associated with oral azacitidine maintenance therapy. Reviewed here are common adverse events (AEs) during oral azacitidine treatment in QUAZAR AML-001, and practical recommendations for AE management based on guidance from international cancer consortiums, regulatory authorities, and the authors’ clinical experience treating patients in the trial. Methods QUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug. Results A total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1–80) oral azacitidine treatment cycles or 6 (1–73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3–4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications. Conclusion Oral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy. Trial registration. This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in <i>RUNX1</i>, <i>GATA2</i>, and <i>DDX41</i>

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted

Evaluation of anti-proliferative and pro-apoptotic effects of tyrosine kinase inhibitors on CML-CD34+ cells.

Although imatinib (IM) has revolutionalised CML management, 30 to 40% patients fail IM therapy. Many of these patients can be rescued with second generation tyrosine kinase inhibitors (TKI), dasatinib, nilotinib and bosutinib. This research elucidates the dasatinib cellular transport pathways and its role in mediating dasatinib resistance. It also assesses dynamics of Bcr-Abl kinase inhibition and apoptosis in CML lines and CML-CD34+ progenitors. Lastly it addresses the role of cytokines in mediating TKI resistance and possible combination therapy to circumvent cytokine mediated TKI resistance. The organic cation transporter (OCT-1) mediates IM influx and low OCT-1 activity is a major contributor to suboptimal response in CML patients treated with IM. In the current study the relevance of OCT-1 activity and efflux pumps in determining intracellular concentration (IUR) of dasatinib were assessed. In contrast to IM, dasatinib cellular uptake is not significantly affected by OCT-1 activity, so that expression and function of OCT-1 is unlikely to affect response to dasatinib. Dasatinib is a substrate of efflux proteins, ABCB1 and ABCG2. Overexpression of these proteins can mediate dasatinib resistance. There is increasing evidence that nilotinib is an ABCB1 inhibitor. These different interactions of dasatinib and nilotinib with ABCB1 were exploited for combination therapy. Nilotinib increased 14CDasatinib IUR and had synergistic effect in inducing cell death in ABCB1 overexpressing cells. These data suggest that combinations of these two TKI can overcome ABCB1 mediated dasatinib resistance and may allow the use of lower concentrations of each drug. In contrast to IM, dasatinib cellular influx is predominantly passive and maximum intracellular concentration is achieved within a few minutes. This was further confirmed by the observation of maximum Bcr-Abl kinase inhibition within 30 minutes of culture with dasatinib. Despite reactivation of Bcr-Abl kinase within 30 minutes of drug washout, short-term (30 minutes) intense (>90%) Bcr-Abl kinase inhibition with dasatinib triggers apoptosis in CML cell lines. This is in contrast to the previously established paradigm that continuous kinase inhibition is required for optimal response to IM. These results were further supported by a recently published dasatinib dose optimisation study. Further work in this thesis demonstrated that although Bcr-Abl kinase reactivates within 30 minutes of drug washout, the prosurvival proteins Erk, AKT and STAT5 dephosphorylated rapidly while the apoptotic proteins remained phosphorylated. This differential degradation of prosurvival and apoptotic proteins might be responsible for a state of “oncogenic-shock”, as described by Sharma et al. Subsequent studies demonstrated that in the absence of cytokines, short-term intense Bcr-Abl kinase inhibition with therapeutically achievable concentration of dasatinib (100 nM dasatinib) eliminated 70 to 80% of CML-CD34+ progenitors. However, in the presence of cytokines despite >90% Bcr-Abl kinase inhibition it did not trigger cell death in CML progenitors. These results suggest that intense Bcr-Abl kinase inhibition alone may not be adequate to trigger cell death in CML progenitors. Further studies demonstrated that cytokines mediate TKI resistance by activating JAK2-STAT5 pathway and that the combination of JAK2 inhibitor and TKI can circumvent cytokine mediated TKI resistance.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201

Special Issue “Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms”

Myeloid neoplasms (MNs) constitute a diverse group of haematological malignancies that includes myelodysplastic neoplasms (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndrome, and acute myeloid leukaemia (AML) [...