Publication

Article

Supplements and Featured Publications
Understanding the Current Unmet Needs in Acute Myeloid Leukemia Management and Evolving Treatment Approaches
Volume 24
Issue 16

Current and Emerging Therapies for Patients With Acute Myeloid Leukemia: A Focus on MCL-1 and the CDK9 Pathways

Am J Manag Care. 2018;24:-S0

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that largely impacts the elderly population. Not all AML patients are candidates for the mainstay induction and consolidation treatment options. In addition, despite available therapies, most patients will eventually relapse on, or be refractory to, standard induction therapy, with limited subsequent choices and poor prognosis. Recently, several new and emerging therapies, with a variety of mechanisms of action, have broadened the treatment landscape in newly diagnosed and relapsed/refractory (R/R) AML, providing patients and healthcare providers with more options and several targeted treatment approaches. Preclinical data indicate that the anti-apoptotic protein myeloid cell leukemia-1 (MCL-1) is important to AML cell survival. Cyclin-dependent kinase 9 (CDK9), a transcriptional activator necessary for the expression of MCL-1, represents a promising target for future AML therapies. A number of CDK9 inhibitors, as well as several direct MCL-1 inhibitors, are currently in clinical or preclinical development. The CDK9 inhibitors alvocidib, atuveciclib, and TG02 have completed phase 1/2 clinical trials, with results available for the alvocidib trial showing improved complete remission rates (70% vs 46%; P = .003) for alvocidib in combination with cytarabine and mitoxantrone, versus cytarabine/daunorubicin, in patients with newly diagnosed AML. In addition, several phase 1 clinical trials with CDK9 inhibitors are currently recruiting for treatment of advanced AML. A phase 1b study is also ongoing to investigate alvocidib in combination with B-cell lymphoma-2 inhibitor venetoclax for R/R AML. Although further research is needed, CDK9 inhibitors represent a promising new approach for the treatment of AML.Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that can affect individuals of any age but is most frequently diagnosed in those aged 65 to 74 years, with a median age at diagnosis of 68 years.1,2 AML is the most common acute leukemia in adults but represents approximately 1.1% of all new cancer cases in the United States.1,2 AML can arise de novo or from other factors, including previous cytotoxic or radiation therapy or from antecedent hematologic disorders.2 Prognosis is generally poor and worsens with advanced age.1,3 Poor prognosis is associated with certain chromosomal and genetic aberrations (ie, complex karyotype, MLL rearrangements, FLT3 mutations).4 Novel, targeted treatment options are urgently needed for AML to prolong survival and improve patient outcomes.2

Standard-of-Care Therapy for AML

Current first-line treatment options for AML include induction chemotherapy. The goals of induction therapy in AML are to reduce leukemic burden by inducing complete remission (CR) and to restore normal hematopoiesis.2 The primary option for induction therapy in the first-line AML setting has been for many years the “7 + 3” regimen, composed of 7 days of cytarabine, an analog of cytosine that incorporates into DNA during replication and inhibits DNA synthesis, and 3 days of an anthracycline, one in a cytotoxic class of drugs with multiple mechanisms of action, including DNA intercalation, inhibition of topoisomerase II, and generation of free radicals.5-8

Recently, several new drugs with varied mechanisms of action have been approved by the FDA for the treatment of AML in the first-line setting, adding to the treatment options for patients and healthcare providers. These include midostaurin, a small-molecule multiple tyrosine kinase inhibitor with FMS-like tyrosine kinase 3 (FLT3) inhibitory activity; CPX-351, a fixed-combination of daunorubicin and cytarabine; and gemtuzumab ozogamicin, a CD33-directed antibody-drug conjugate (Table 1).9-16 Emerging therapeutic options include venetoclax, a small-molecule inhibitor of anti-apoptotic B-cell lymphoma-2 (BCL-2) protein.17-19

Venetoclax in combination with low-dose cytarabine has received a breakthrough therapy designation from the FDA for use in frontline therapy in elderly patients with AML who are not eligible for intensive chemotherapy.20 Venetoclax has also been granted FDA breakthrough therapy designation for use with hypomethylating agents as frontline therapy in elderly patients with AML who are not eligible for intensive induction therapy.21 Venetoclax is also being studied in combination with dose-modified intensive chemotherapy.22 Furthermore, the histone deacetylase inhibitor pracinostat, plus azacitidine, received a breakthrough therapy designation from the FDA in August 2016 for use in elderly patients with AML who are not eligible for induction therapy.23

Consolidation therapy in AML generally consists of chemotherapy to maintain control of the disease or hematopoietic stem cell transplantation as a potentially curative option in certain patients.5,24 However, many patients with AML are not considered to be candidates for current treatment strategies because of significant comorbidities, poor performance status, and older age, among other factors.3,25 In addition, available therapies are not effective for all patients, and resistance to and/or relapse on chemotherapy is common. Depending on a variety of factors, including age and type of induction therapy, only approximately two-thirds of patients achieve CR after induction therapy, and the majority will relapse or die from their disease.24,26,27

Several new and emerging therapies are now available or under investigation in the relapsed/refractory (R/R) setting, which may help to improve the prognosis of certain patients with R/R disease. These therapies include enasidenib, a small-molecule inhibitor approved by the FDA in 2017 for patients with R/R AML with an isocitrate dehydrogenase-2 (IDH2) mutation; ivosidenib, an investigational small-molecule inhibitor for the treatment of patients with R/R AML with an isocitrate dehydrogenase-1 (IDH1) mutation; and quizartinib, gilteritinib, and crenolanib, investigational small-molecule inhibitors for the treatment of patients with R/R AML with an FLT3 mutation (Table 2).17-23, 28-41

Targeting Apoptosis as a Therapeutic Approach in AML

Historically, the primary mechanism of action of treatments for AML, in particular the 7 + 3 regimen, has involved the disruption of cell proliferation.6,7 With progress being made in elucidating the underlying biology behind AML, new potential treatment strategies are being identified. Targeting anti-apoptotic proteins, such as myeloid cell leukemia-1 (MCL-1), could positively impact the balance of pro- versus anti-apoptotic proteins and result in increased death of cancer cells and improved disease control.42,43

MCL-1 in AML

MCL-1 is a member of the BCL-2 family of apoptosis-regulating proteins. MCL-1 blocks pro-apoptotic proteins, such as BAK and BAX, thereby preventing programmed cell death through apoptosis.44 Preclinical studies have suggested a role for MCL-1 in the disease etiology of AML. Clinical samples (leukemic blasts and primary human hematopoietic subsets) from 111 patients with AML demonstrated high levels of MCL-1 protein expression.43

MCL-1 levels have been observed to increase by approximately 2-fold at the time of disease recurrence compared with pretreatment (n = 19).45 Patients with increased MCL-1 levels have showed poor prognosis and/or response to chemotherapy, suggesting that at least some AML malignancies are MCL-1 dependent.45 Downregulation of MCL-1 has been shown to result in the death of murine and human AML cells.42 MCL-1 has also been found to be important for the survival of leukemia stem cells, further underscoring the importance of MCL-1 in the survival of AML cancer cells.46

Preclinical data also suggest possible activity of some agents in targeting multiple pathways. The kinase inhibitor PIK-75 has been found to inhibit both cyclin-dependent kinases (CDK) and BCL-2 family members, inducing apoptosis in a BAK-dependent mechanism.47 Another kinase inhibitor, TG02, has been found to inhibit multiple CDK members as well as other, frequently mutated genes in hematologic malignancies, including janus kinase 2 (JAK2) and FLT3.48

Given the findings of these preclinical studies, targeting MCL-1 seems a reasonable approach for future AML therapies. The short half-life of MCL-1 should be considered as a possible attribute because inhibition of MCL-1 synthesis should rapidly reduce levels of the protein.44 In addition, MCL-1 expression is tightly regulated, suggesting that regulators of expression would be potential targets for new therapies.49 The promising preclinical data and the feasibility of MCL-1 as a possible target of treatment suggest a possible future role for MCL-1 as a biomarker in personalized cancer therapy.45,50

Potential Targets for Reducing Levels of MCL-1

Strategies to reduce MCL-1 expression include direct targeting of MCL-1 and indirect targeting by disruption of transcription/translation. Small-molecule inhibitors are currently in development to directly target MCL-1 and other BCL-2 family members with similar topologies (Table 3).51-55 The second possible avenue—and the overall focus of this report—is targeting the synthesis of

MCL-1, which could involve multiple components, including the promoter sequence, transcription/translation machinery, and transcription/translation regulators.

MCL-1 transcription is controlled by the positive transcription elongation factor b (P-TEFb) complex. P-TEFb, which is made up of CDK9 and cyclin T proteins, activates transcription elongation of multiple genes, including MCL-1.56 CDK9, a transcriptional activator, contains a catalytic domain and phosphorylates the C-terminal domain of RNA polymerase II to activate transcription and elongation, while the cyclin T protein stabilizes CDK9 and plays a regulatory role.57,58 BRD4, a bromodomain protein, anchors the P-TEFb complex to the DNA strand and acts as a positive regulator of transcription.59 CDK9, which is part of a large family of CDKs, represents a possible therapeutic target for reducing MCL-1 synthesis (Figure 1).60-67 Inhibition of CDK9 is known to prevent phosphorylation of the RNA polymerase II C-terminal domain, suggesting that inhibiting CDK9 may prevent the production of anti-apoptotic protein MCL-1, thereby increasing apoptosis.47 Several CDK9 inhibitors are in exploratory and clinical development (Table 4).48,61,63-77

Preclinical and Clinical Evidence of CDK9 Inhibition in AML

As shown in Table 4, a number of CDK9 inhibitors are in development, most in early-stage clinical or preclinical studies.48,61,63-77 TG02, a multi-kinase inhibitor of CDKs, including CDK9, has preliminary results from a dose-escalation phase 1 trial in advanced hematologic malignancies or newly diagnosed AML, which identified a maximally tolerated dose of 50 mg daily.68 Treatment-related adverse events (AEs) included nausea (42%), vomiting (23%), fatigue (18%), decreased appetite (15%), constipation, and diarrhea (13% each).68

Alvocidib

Alvocidib, also known as flavopiridol, was evaluated in a randomized, phase 2 trial in combination with cytarabine and mitoxantrone (ACM), compared with cytarabine plus daunorubicin (7 + 3), in 165 patients with core binding factor-negative newly diagnosed AML.61 For the primary end point, the ACM regimen resulted in higher CR rates versus 7 + 3 (70% vs 46%, P = .003). In an exploratory subgroup analysis of treatment efficacy by aged cohorts, patients younger than 50 years experienced greater benefit from ACM treatment than from 7 + 3.61 No significant survival advantage was documented (median overall survival, 17.5 months with ACM versus 22.2 months with 7 + 3; P = .39), whereas event-free survival, although not significantly different, demonstrated possible clinical improvement with ACM (median event-free survival, 9.7 months with ACM versus 3.4 months with 7 + 3, P = .15).78 Overall, toxicities of grade 3 or higher were comparable in both treatment arms. In the ACM treatment arm, there were 2 early deaths due to tumor lysis syndrome (TLS) and 3 grade 4 TLS toxicities.61

In addition, preclinical data suggest that using a BH3 profiling assay to assess response to NOXA, a selective modulator of MCL-1, may be a viable way to predict response to AML therapy, which supports MCL-1 as a potential biomarker.79 In a recent phase 2, open-label trial that used BH3 profiling, 17 patients with R/R AML (first relapse with CR duration of less than 2 years or primary refractory to 1 to 2 cycles of induction therapy) and a median MCL-1 dependency of 61% (range, 41%-98%, as determined by BH3 profiling) were administered alvocidib as timed sequential therapy prior to cytarabine and mitoxantrone. 80 The overall CR/complete remission with incomplete hematologic recovery (CRi) rate was 59% in 10 patients, and CR rate was 53%.80 Six of 8 (75%) patients with refractory AML (no response to induction therapy or CRi duration less than 90 days) achieved CR, and 5 of these patients were able to proceed to allogeneic stem cell transplant.80 Grade 3 or higher treatment-related nonhematologic AEs seen in more than 1 patient included hypophosphatemia (41%), TLS (35%; 5 grade 3 and 1 grade 4), hypokalemia (29%), elevated aspartate aminotransferase and diarrhea (23% each); hyponatremia, sepsis, and elevated alanine aminotransferase (18% each); and acute kidney injury, hypoalbuminemia, and fainting (12% each).80

Dinaciclib

Initial results were reported from a phase 2 study of the CDK inhibitor dinaciclib in patients with R/R AML (n = 14) or acute lymphoid leukemia (ALL; n = 6).63 The study was terminated early due to a change in the sponsor.63 In the 20 patients who received dinaciclib before study termination, no objective responses were observed.63 Fifteen patients (75%) experienced grade 3 or higher treatment-related AEs, with the most common being hematologic toxicities and fatigue.63 The most common nonhematologic AEs were gastrointestinal effects, fatigue, and disturbances in laboratory values.63 Three patients had grade 3 or higher TLS.63

Atuveciclib (BAY 1143572)

Atuveciclib is a specific, highly selective inhibitor of PTEFb/CDK9. Results from preclinical studies suggest a promising efficacy and tolerability profile of atuveciclib in xenograph models in mice and rats.62 Atuveciclib is currently being investigated in phase 1 clinical studies for its safety and efficacy in patients with AML.71

Combination Therapy With CDK9 Inhibitors and BCL-2 Inhibitors

Several preclinical and clinical studies are also examining CDK9 inhibitors in combination with the BCL-2-selective inhibitor venetoclax, including an ongoing phase 1b study with alvocidib plus venetoclax in patients with R/R AML; however, only preclinical results have been reported to date (Table 4).48,61,63-77

Conclusions

AML remains a serious condition with poor outcomes, particularly in elderly patients. A large proportion of patients relapse on or after standard induction therapy or hypomethylator therapy (the current backbones of AML therapy), with limited future treatment options. New treatment approaches that use novel mechanisms of action are needed and are rapidly being developed to broaden the AML treatment landscape and improve patient outcomes, with a special focus on elderly AML and R/R AML, the areas of greatest unmet need. Preclinical data indicate that AML cells have a high dependency on MCL-1, a protein responsible for suppressing apoptosis. As a transcriptional activator necessary for the expression of MCL-1, CDK9 is a promising target for future AML therapies. Several CDK9 inhibitors are currently in phase 1/2 clinical development as single agents and in combination with chemotherapy, hypomethylating agents, and novel agents, such as venetoclax, in both frontline and R/R AML. Although still in the early stages of clinical research, CDK9 inhibitors represent a promising new avenue for AML therapies. More research is needed to identify optimal dosing strategies, including best combinations, and to increase awareness and improve management of specific AEs to achieve better patient outcomes.Acknowledgement: Medical writing support was provided by Rebecca Miles, PhD.

Author affiliations: Department of Leukemia at The University of Texas, MD Anderson Cancer Center, Houston, TX (ND); Blood Disorders Center, Department of Hematology, University of Colorado Hospital, Aurora, CO (LL).

Funding source: Publication support provided by Boston Biomedical, Inc.

Author disclosures: Dr Daver reports serving as a consultant or on a paid advisory board for AbbVie Inc., Bristol-Myers Squibb, Daiichi-Sankyo, Jazz Pharmaceuticals, Novartis International AG, Otsuka Pharmaceutical, Pfizer Inc. He also reports receipt of honorarium for Bristol-Myers Squibb, Incyte Corporation, Jazz Pharmaceuticals, Novartis International AG; and research funding from Abbvie Inc., Bristol-Myers Squibb, Daiichi-Sankyo, Genentech, GlycoMimetics Inc., Incyte Corporation, Karyopharm Therapeutics, Laboratoires Servier, Pfizer Inc., Sunesis Pharmaceuticals. Dr Lyle reports serving as a consultant or on a paid advisory board for Agios Pharmaceuticals, Celgene, Incyte Corporation, Novartis International AG, and Takeda Oncology.

Authorship information: Acquisition of data (ND); administrative, technical, or logistic support (ND); concept and design (LL); critical revision of the manuscript for important intellectual content (ND, LL); drafting of the manuscript (ND, LL).

Address correspondence to: mruma@panm.com.

1. Noone A, Howlader N, Krapcho M, et al. SEER cancer statistics review (CSR) 1975-2015. National Cancer Institute website. https://seer.cancer.gov/csr/1975_2015/. Published April 16, 2018. Accessed July 21, 2018.

2. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016;6(7):e441. doi: 10.1038/bcj.2016.50.

3. Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179-4187. doi: 10.1182/blood-2008-07-172007.

4. Mrózek K, Marcucci G, Nicolet D, et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012;30(36):4515-4523. doi: 10.1200/JCO.2012.43.4738.

5. Fey MF, Buske C, ESMO Guidelines Working Group. Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi138-vi143. doi: 10.1093/annonc/mdt320.

6. Cohen SS. The mechanisms of lethal action of arabinosyl cytosine (araC) and arabinosyl adenine (araA). Cancer. 1977;40(suppl 1):509-518.

7. Hortobágyi GN. Anthracyclines in the treatment of cancer. an overview. Drugs. 1997;54(suppl 4):1-7.

8. Lichtman MA. A historical perspective on the development of the cytarabine (7days) and daunorubicin (3days) treatment regimen for acute myelogenous leukemia: 2013 the 40th anniversary of 7+3. Blood Cells Mol Dis. 2013;50(2):119-130. doi: 10.1016/j.bcmd.2012.10.005.

9. Vyxeos [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals; 2017.

10. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid Leukemia [published online July 19, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017.77.6112.

11.Idhifa [prescribing information]. Summit, NJ: Celgene Corporation; 2017.

12. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731. doi: 10.1182/blood-2017-04-779405.

13. Mylotarg [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc; 2018.

14. Castaigne S, Pautas C, Terré C, et al; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508-16. doi: 10.1016/S0140-6736(12)60485-1.

15. Rydapt [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017.

16. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5): 454-464. doi: 10.1056/NEJMoa1614359.

17. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov, 2016;6(10):1106-1117. doi: 10.1158/2159-8290.CD-16-0313.

18. Wei A, Strickland SA, Roboz GJ, et al. Phase 1/2 study of venetoclax with low-dose cytarabine in treatment-naive, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes [abstract]. Blood. 2017;130(suppl 1):890.

19. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216-228. doi: 10.1016/S1470-2045(18)30010-X.

20. FDA grants breakthrough therapy designation for Venclexta in acute myeloid leukaemia [press release]. Basel, Switzerland: Roche; July 28, 2017. roche.com/investors/updates/inv-update-2017-07-28.htm. Accessed July 22, 2018.

21. Venetoclax receives 3rd breakthrough therapy designation from the FDA for the combination treatment of patients with untreated acute myeloid leukemia not eligible for standard induction chemotherapy [news release]. North Chicago, IL: AbbVie, Inc; January 28, 2016. news.abbvie.com/news/venetoclax-receives-3rd-breakthrough-therapy-designation-from-fda-for-combination-treatment-patients-with-untreated-acute-myeloid-leukemia-not-eligible-for-standard-induction-chemotherapy.htm. Accessed July 22, 2018.

22. Wei AH, Tiong IS, Roberts AW, et al. Chemotherapy and venetoclax in elderly AML trial (CAVEAT): a phase 1b dose escalation study examining modified intensive chemotherapy in fit elderly patients. Abstract presented at 23rd Annual Congress of the European Hematology Association; June 14-17, 2018; Stockholm, Sweden. learningcenter.ehaweb.org/eha/2018/stockholm/214491/andrew.wei.chemotherapy.and.venetoclax.in.elderly.aml.trial.28caveat29.a.phase.html?f=media=1. Accessed July 22, 2018.

23. MEI Pharma’s Pracinostat receives breakthrough therapy designation from FDA for treatment in combination with azacitidine of patients with newly diagnosed acute myeloid leukemia unfit for intensive chemotherapy [news release]. San Diego, CA: MEI Pharma, Inc; August 1, 2016. investor.meipharma.com/2016-08-01-MEI-Pharmas-Pracinostat-Receives-Breakthrough-Therapy-Designation-from-FDA-for-Treatment-in-Combination-with-Azacitidine-of-Patients-with-Newly-Diagnosed-Acute-Myeloid-Leukemia-Unfit-for-Intensive-Chemotherapy. Accessed July 22, 2018.

24. Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. Blood. 2005;106(4):1154-1163. doi: 10.1182/blood-2005-01-0178.

25. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. doi: 10.1182/blood-2016-08-733196.

26. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361(13):1249-1259. doi: 10.1056/NEJMoa0904544.

27. Bennett JM, Young ML, Andersen JW, et al. Long-term survival in acute myeloid leukemia: the Eastern Cooperative Oncology Group experience. Cancer. 1997;80(11) (suppl):2205-2209.

28. (QuANTUM-R) An open label study of quizartinib monotherapy vs. salvage chemotherapy in acute myeloid leukemia (AML) Subjects Who Are FLT3 ITD Positive. https://clinicaltrials.gov/ct2/show/NCT02039726. Updated July 20, 2018. Accessed July 27, 2018.

29. Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681-3687. doi: 10.1200/JCO.2013.48.8783.

30. Quizartinib with standard of care chemotherapy and as maintenance therapy in patients with newly diagnosed FLT3ITDn (+) acute myeloid leukemia (AML) (QuANTUMFirst). clinicaltrials.gov/ct2/show/NCT02668653. Updated May 21, 2018. July 27, 2018.

31. U.S. FDA grants priority review to Astellas’ new drug application for gilteritinib for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) [news release]. Tokyo, Japan: Astella Pharma Inc; May 29, 2018. newsroom.astellas.us/2018-05-29-U-S-FDA-Grants-Priority-Review-to-Astellas-New-Drug-Application-for-Gilteritinib-for-the-Treatment-of-Adult-Patients-with-Relapsed-or-Refractory-Acute-Myeloid-Leukemia-AML. Accessed July 23, 2018.

32. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1—2 study. Lancet Oncol. 2017;18(8):1061-1075. doi: 10.1016/S1470-2045(17)30416-3.

33. A study of ASP2215 versus salvage chemotherapy in patients with relapsed or refractory acute myeloid leukemia (AML) with FMS-like tyrosine kinase (FLT3) mutation. clinicaltrials.gov/ct2/show/NCT02421939. Updated June 14, 2018. Accessed July 27, 2018.

34. A trial of the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib administered as maintenance therapy following allogeneic transplant for patients with FLT3/Internal tandem duplication (ITD) acute myeloid leukemia (AML). clinicaltrials.gov/ct2/show/NCT02997202. Updated June 28, 2018. Accessed July 27, 2018.

35. A study of ASP2215 (gilteritinib), administered as maintenance therapy following induction/consolidation Therapy for subjects with FMSlike tyrosine kinase 3 (FLT3/ITD) acute myeloid leukemia (AML) in first complete remission. clinicaltrials.gov/ct2/show/NCT02927262. Updated July 26, 2018. Accessed July 27, 2018.

36. A study of ASP2215 (gilteritinib) by itself, ASP2215 combined with azacitidine or azacitidine by itself to treat adult patients who have Recently been diagnosed with acute myeloid leukemia with a FLT3 gene mutation and who cannot receive standard chemotherapy. clinicaltrials.gov/ct2/show/NCT02752035. Updated July 18, 2018. Accessed July 27, 2018.

37. Arog Pharmaceuticals Inc. Arog Pharmaceuticals receives FDA fast track designation for crenolanib

in relapsed or refractory FLT3-positive AML. [news release] globenewswire.com/news-release/2017/

12/01/1216122/0/en/Arog-Pharmaceuticals-Receives-FDA-Fast-Track-Designation-for-Crenolanib-in-Relapsed-or-Refractory-FLT3-Positive-AML.html. Published December 1, 2017. Accessed July 27, 2018.

38. Randhawa JK, Kantarjian HM, Borthakur G, et al. Results of a phase II study of crenolanib in relapsed/refractory acute myeloid leukemia patients (pts) with activating FLT3 mutations [abstract]. Blood. 2014;124(21):389.

39. FDA accepts new drug application and grants priority review for ivosidenib in relapsed or refractory AML with an IDH1 mutation [news release]. Cambridge, MA: Agios Pharmaceuticals, Inc; February 15, 2018. investor.agios.com/news-releases/news-release-details/fda-accepts-new-drug-application-and-grants-priority-review-0. Accessed July 23, 2018.

40. DiNardo CD, Stein EM, deBotton S, et al. Durable remissions with ivosidenib in IDH1-mutated re-lapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. doi: 10.1056/NEJMoa1716984.

41. Garcia-Manero G, Fong CY, Venditti A, Mappa S, Spezia R, Ades L. A phase 3, randomized study of pracinostat (PRAN) in combination with azacitidine (AZA) versus placebo in patients ≥18 years with newly diagnosed acute myeloid leukemia (AML) unfit for standard induction chemotherapy (IC) [abstract]. J Clin Oncol. 2018;36:TPS7078.

42.Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26(2):120-125. doi: 10.1101/gad.182980.111.

43. Xiang Z, Luo H, Payton JE, et al. Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia. J Clin Invest. 2010;120(6):2109-2118. doi: 10.1172/JCI39964.

44. Perciavalle RM, Opferman JT. Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol. 2013;23(1):22-29. doi: 10.1016/j.tcb.2012.08.011.

45. Kaufmann SH, Karp JE, Svingen PA, et al. Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood. 1998;91(3):991-1000.

46. Yoshimoto G, Miyamoto T, Jabbarzadeh-Tabrizi S, et al. FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. Blood. 2009;114(24):5034-5043. doi: 10.1182/blood-2008-12-196055.

47. Thomas D, Powell JA, Vergez F, et al. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-748. doi: 10.1182/blood-2012-08-447441.

48. Goh KC, Novotny-Diermayr V, Hart S, et al. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia. 2012;26(2):236-243. doi: 10.1038/leu.2011.218.

49. Schwickart M, Huang X, Lill JR, et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature. 2010;463(7277):103-107. doi: 10.1038/nature08646.

50. Booher RN, Hatch H, Dolinski BM, et al. MCL1 and BCL-xL levels in solid tumors are predictive of dinaciclib-induced apoptosis. PLoS One. 2014;9(10):e108371. doi: 10.1371/journal.pone.0108371.

51. AMG 176 first in human trial in subjects with relapsed or refractory multiple myeloma and subjects with relapsed or refractory acute myeloid leukemia. clinicaltrials.gov/ct2/show/NCT02675452.Updated April 12, 2018. Accessed July 27, 2018.

52. Caenepeel SR, Belmontes B, Sun J, Coxon A, Moody G, Hughes PE. Preclinical evaluation of AMG 176, a novel, potent and selective Mcl-1 inhibitor with robust anti-tumor activity in Mcl-1 dependent cancer models [abstract]. Cancer Res. 2017;77(suppl 13):2027. doi: 10.1158/1538-7445.AM2017-2027.

53. Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538(7626):477-482. doi: 10.1038/nature19830.

54. Phase I study of S64315 administred intravenously in patients with acute myeloid leukaemia or myelodysplastic syndrome. clinicaltrials.gov/ct2/show/NCT02979366. Updated May 23, 2018. Accessed July 27, 2018.

55. Study of AZD5991 in relapsed or refractory haematologic malignancies. clinicaltrials.gov/ct2/show/NCT03218683. Updated July 26, 2018. Accessed July 27, 2018.

56. Brès V, V, Yoh SM, Jones KA, The multi-tasking P-TEFb complex. Curr Opin Cell Biol. 2008;20(3):334-340. doi: 10.1016/j.ceb.2008.04.008.

57. Garriga J, Graña X. Cellular control of gene expression by T-type cyclin/CDK9 complexes. Gene. 2004;337:15-23. doi: 10.1016/j.gene.2004.05.007.

58. Zaborowska J, Isa NF, Murphy S. P-TEFb goes viral. Inside Cell. 2016;1(2):106-116. doi: 10.1002/icl3.1037.

59. Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell. 2005;19(4):523-534. doi: 10.1016/j.molcel.2005.06.027.

60. Boffo S, Damato A, Alfano L, Giordano A. 4CDK9 inhibitors in acute myeloid leukemia. J Exp Clin Cancer Res. 2018;37(1):36. doi: 10.1186/s13046-018-0704-8.

61. Zeidner, JF, Foster MC, Blackford AL, et al. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015;100(9):1172-1179. doi: 10.3324/haematol.2015.125849.

62. Lücking,U, Scholz A, Lienau P, et al. Identification of atuveciclib (BAY 1143572), the first highly selective, clinical PTEFb/CDK9 inhibitor for the treatment of cancer. ChemMedChem. 2017;12(21):1776-1793. doi: 10.1002/cmdc.201700447.

63. Gojo I, Sadowska M, Walker A, et al. Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias. Cancer Chemother Pharmacol. 2013;72(4):897-908. doi: 10.1007/s00280-013-2249-z.

64. Yin T, Lallena MJ, Kreklau EL, et al. A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. Mol Cancer Ther. 2014;13(6):1442-1456. doi: 10.1158/1535-7163.MCT-13-0849.

65. Rule S, Kater AP, Brümmendorf TH, et al. A phase 1, open-label, multicenter, non-randomized study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of AZD4573, a potent and selective CDK9 inhibitor, in subjects with relapsed or refractory hematological malignancies. J Clin Oncol. 2018;36(suppl; abstr TPS7588).

66. Walsby, E, Pratt G, Shao H, et al. A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine. Oncotarget. 2014;5(2):375-385. doi: 10.18632/oncotarget.1568.

67. Xie S, Jiang H, Zhai X, et al. Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells. Acta Pharmacol Sin. 2016;37(11):1481-1489. doi: 10.1038/aps.2016.49.

68. Roboz GJ, Khoury HJ, Shammo JM, et al. Phase I dose escalation study of TG02 in patients with advanced hematologic malignancies [abstract]. J Clin Oncol. 2012;30(suppl 15):6577.

69. Alvocidib biomarker-driven phase 2 AML study. clinicaltrials.gov/ct2/show/NCT02520011. Updated January 16, 2018. Accessed July 27, 2018.

70. Ph I study of alvocidib and cytarabine/daunorubicin (7+3) in patients with newly diagnosed acute myeloid leukemia (AML). clinicaltrials.gov/ct2/show/NCT03298984. Updated January 16, 2018. Accessed July 27, 2018.

71. Phase I dose escalation of BAY1143572 in subjects with acute leukemia. clinicaltrials.gov/ct2/show/NCT02345382. Updated June 25, 2018. Accessed July 27, 2018.

72. Phase I trial of BAY1251152 for advanced blood cancers. clinicaltrials.gov/ct2/show/NCT02745743. Updated July 23, 2018. Accessed July 27, 2018.

73. Study to assess safety, tolerability, pharmacokinetics and antitumor activity of AZD4573 in relapsed/refractory haematological malignancies.clinicaltrials.gov/ct2/show/NCT03263637. Updated June 28, 2018. Accessed July 27, 2018.

74. A study of venetoclax and alvocidib in patients with relapsed/refractory acute myeloid leukemia. clinicaltrials.gov/ct2/show/NCT03441555. Updated June 12, 2018. Accessed July 27, 2018.

75. Chen J, Jin S, Tapang P, et al. CDK9 inhibition reverses resistance to ABT-199 (GDC-0199) by down-regulating MCL-1 [abstract]. Blood. 2014;124(21):2161.

76. Bogenberger J, Whatcott C, Hansen,N, et al. Combined venetoclax and alvocidib in acute myeloid leukemia. Oncotarget. 2017;8(63):107206-107222. doi: 10.18632/oncotarget.22284.

77. A Study of venetoclax and dinaciclib (MK7965) in patients with relapsed/refractory acute myeloid leukemia. clinicaltrials.gov/ct2/show/NCT03484520. Updated May 22, 2018. Accessed July 27, 2018.

78. Zeidner JF, Karp JE. Clinical activity of alvocidib (flavopiridol) in acute myeloid leukemia. Leuk Res. 2015;39(12):1312-1318. doi: 10.1016/j.leukres.2015.10.010.

79. Pierceall WE, Lena RJ, Medeiros BC, et al. Mcl-1 dependence predicts response to vorinostat and gemtuzumab ozogamicin in acute myeloid leukemia [abstract]. Blood. 2013;122(21):1305.

80. Zeidner JF, Vigil CE, Lin T, et al. Phase II study incorporating a novel BH3-profiling biomarker approach of alvocidib followed by cytarabine and mitoxantrone in relapsed/refractory acute myeloid leukemia (AML). 23rd Annual Congress of the European Hematology Association; June 14-17, 2018; Stockholm, Sweden. learningcenter.ehaweb.org/eha/2018/stockholm/214729/joshua.f.zeidner.phase.ii.study.incorporating.a.novel.bh3-profiling.biomarker.html?f=topic=1574*media=3. Accessed July 23, 2018.

AJMC Managed Markets Network Logo
CH LogoCenter for Biosimilars Logo