Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome

Jorge E Cortes, Florian H Heidel, Andrzej Hellmann, Walter Fiedler, B Douglas Smith, Tadeusz Robak, Pau Montesinos, Daniel A Pollyea, Pierre DesJardins, Oliver Ottmann, Weidong Wendy Ma, M Naveed Shaik, A Douglas Laird, Mirjana Zeremski, Ashleigh O'Connell, Geoffrey Chan, Michael Heuser, Jorge E Cortes, Florian H Heidel, Andrzej Hellmann, Walter Fiedler, B Douglas Smith, Tadeusz Robak, Pau Montesinos, Daniel A Pollyea, Pierre DesJardins, Oliver Ottmann, Weidong Wendy Ma, M Naveed Shaik, A Douglas Laird, Mirjana Zeremski, Ashleigh O'Connell, Geoffrey Chan, Michael Heuser

Abstract

Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9-9.9) months with glasdegib/LDAC and 4.9 (3.5-6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39-0.67, P = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit-risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.

Conflict of interest statement

JEC received research funding and consulting honoraria from Pfizer, Novartis, Astellas, Daiichi, and Celgene. FHH received honoraria from Pfizer. WF participated in advisory boards for Amgen, Pfizer, Novartis, Jazz, and ARIAD/Incyte; has patents and royalties from Amgen; and received support for meeting attendance from Amgen, Gilead, GSO, Teva, and Jazz and research funding from Amgen and Pfizer. BDS served on an advisory board and was a consultant for Celgene, Jazz Pharmaceuticals, Novartis, and Pfizer. TR received research funding from Pfizer. PM served on an advisory board for Celgene, Jazz, Janssen, and Novartis and has received research funding from Pfizer and Celgene. DAP served on an advisory board for Agios, Celgene, Curis, Takeda, Servier, Jazz, and Gilead and has received research funding from Pfizer and Agios. AH, PD, and OO were investigators for this Pfizer-funded study and received study drugs provided by Pfizer. MH received research funding and honoraria from Pfizer. WWM, MNS, ADL, MZ, AO, and GC are employees of and own stock in Pfizer Inc.

Figures

Fig. 1
Fig. 1
Patient disposition. This study is ongoing; the first patient randomization visit took place on 3 January 2014, and the primary analysis data cutoff was 3 January 2017. The randomization errors in 7/132 patients (5%) were due to patients withdrawing consent or failing to maintain eligibility requirements. Discontinuations were attributed to the last study treatment received. Treated was defined as patients who received at least one non-zero dose of glasdegib or LDAC. AE adverse event, IVRS interactive voice response system, LDAC low-dose cytarabine, PK pharmacokinetic(s)
Fig. 2
Fig. 2
Kaplan–Meier estimate of overall survival, full analysis set. CI confidence interval, HR hazard ratio, LDAC low-dose cytarabine, OS overall survival
Fig. 3
Fig. 3
Kaplan-Meier estimate of overall survival, full analysis set, in patients at A good/intermediate cytogenetic risk and B poor cytogenetic risk. CI confidence interval, HR hazard ratio, LDAC low-dose cytarabine, OS overall survival

References

    1. Klepin HD, Rao AV, Pardee TS. Acute myeloid leukemia and myelodysplastic syndromes in older adults. J Clin Oncol. 2014;32:2541–52. doi: 10.1200/JCO.2014.55.1564.
    1. Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109:1114–24. doi: 10.1002/cncr.22496.
    1. Burnett AK, Hills RK, Hunter A, Milligan D, Kell J, Wheatley K, et al. The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome. Leukemia. 2011;25:1122–7. doi: 10.1038/leu.2011.59.
    1. Burnett AK, Russell NH, Culligan D, Cavanagh J, Kell J, Wheatley K, et al. The addition of the farnesyl transferase inhibitor, tipifarnib, to low dose cytarabine does not improve outcome for older patients with AML. Br J Haematol. 2012;158:519–22. doi: 10.1111/j.1365-2141.2012.09165.x.
    1. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30:2670–7. doi: 10.1200/JCO.2011.38.9429.
    1. Döhner H, Lübbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, et al. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood. 2014;124:1426–33. doi: 10.1182/blood-2014-03-560557.
    1. Heiblig M, Elhamri M, Tigaud I, Plesa A, Barraco F, Labussiere H, et al. Treatment with low-dose cytarabine in elderly patients (age 70 years or older) with acute myeloid leukemia: a single institution experience. Mediterr J Hematol Infect Dis. 2016;8:e2016009. doi: 10.4084/mjhid.2016.009.
    1. Ok CY, Singh RR, Vega F. Aberrant activation of the hedgehog signaling pathway in malignant hematological neoplasms. Am J Pathol. 2012;180:2–11. doi: 10.1016/j.ajpath.2011.09.009.
    1. Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood. 2012;119:2196–204. doi: 10.1182/blood-2011-10-383752.
    1. Heidel FH, Arreba-Tutusaus P, Armstrong SA, Fischer T. Evolutionarily conserved signaling pathways: acting in the shadows of acute myelogenous leukemia’s genetic diversity. Clin Cancer Res. 2015;21:240–8. doi: 10.1158/1078-0432.CCR-14-1436.
    1. Wellbrock J, Latuske E, Kohler J, Wagner K, Stamm H, Vettorazzi E, et al. Expression of Hedgehog pathway mediator GLI represents a negative prognostic marker in human acute myeloid leukemia and its inhibition exerts antileukemic effects. Clin Cancer Res. 2015;21:2388–98. doi: 10.1158/1078-0432.CCR-14-1059.
    1. Queiroz KC, Ruela-de-Sousa RR, Fuhler GM, Aberson HL, Ferreira CV, Peppelenbosch MP, et al. Hedgehog signaling maintains chemoresistance in myeloid leukemic cells. Oncogene. 2010;29:6314–22. doi: 10.1038/onc.2010.375.
    1. Sadarangani A, Pineda G, Lennon KM, Chun HJ, Shih A, Schairer AE, et al. GLI2 inhibition abrogates human leukemia stem cell dormancy. J Transl Med. 2015;13:98. doi: 10.1186/s12967-015-0453-9.
    1. Fukushima N, Minami Y, Kakiuchi S, Kuwatsuka Y, Hayakawa F, Jamieson C, et al. Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci. 2016;107:1422–9. doi: 10.1111/cas.13019.
    1. Martinelli G, Oehler VG, Papayannidis C, Courtney R, Shaik MN, Zhang X, et al. Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study. Lancet Haematol. 2015;2:e339–46. doi: 10.1016/S2352-3026(15)00096-4.
    1. Minami Y, Minami H, Miyamoto T, Yoshimoto G, Kobayashi Y, Munakata W, et al. Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. Cancer Sci. 2017;108:1628–33. doi: 10.1111/cas.13285.
    1. Savona M, Pollyea D, Stock W, Oehler V, Schroeder M, Lancet J, et al. Phase Ib study of Glasdegib, a Hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. Clin Cancer Res. 2018;24:2294–303. doi: 10.1158/1078-0432.CCR-17-2824.
    1. Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, et al. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol. 2018;93:1301–10. doi: 10.1002/ajh.25238.
    1. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51. doi: 10.1182/blood-2009-03-209262.
    1. Kantarjian H, O’Brien S, Cortes J, Giles F, Faderl S, Jabbour E, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106:1090–8. doi: 10.1002/cncr.21723.
    1. Döhner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an International Expert Panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74. doi: 10.1182/blood-2009-07-235358.
    1. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–88.
    1. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–9. doi: 10.1200/JCO.2003.04.036.
    1. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–25. doi: 10.1182/blood-2005-10-4149.
    1. Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15:241–3. doi: 10.1002/pds.1211.
    1. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with>30% blasts. Blood. 2015;126:291–9. doi: 10.1182/blood-2015-01-621664.
    1. Dennis M, Hills R, Thomas I, Kallenbach M, Hemmaway C, Greaves P, et al. A randomised evaluation of low-dose Ara-C plus tosedostat versus low dose Ara-C in older patients with acute myeloid leukaemia: results of the LI-1 trial. EHA2018 Abstract S117. . Accessed on 25 Oct 2018.
    1. Burnett AK, Hills RK, Hunter AE, Milligan D, Kell WJ, Wheatley K, et al. The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia. 2013;27:75–81. doi: 10.1038/leu.2012.229.
    1. Burnett AK, Russell N, Hills RK, Panoskaltsis N, Khwaja A, Hemmaway C, et al. A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia. Leukemia. 2015;29:1312–9. doi: 10.1038/leu.2015.38.
    1. Lindsley RC, Mar BG, Mazzola E, Grauman PV, Shareef S, Allen SL, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367–76. doi: 10.1182/blood-2014-11-610543.
    1. Sekeres MA, Lancet JE, Wood BL, Grove LE, Sandalic L, Sievers EL, et al. Randomized phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults with untreated acute myeloid leukemia. Haematologica. 2013;98:119–28. doi: 10.3324/haematol.2012.066613.
    1. Döhner H, Symeonidis A, Sanz MA, Deeren D, Demeter D, Anagnostopoulos JA, et al. Phase III randomized trial of volasertib plus low-dose cytarabine (LDAC) versus placebo plus LDAC in patients aged≥65 years with previously untreated AML, ineligible for intensive therapy. Haematologica. 2016;101(Suppl. 1):185–6.
    1. Heidel F, Cortes J, Rucker FG, Aulitzky W, Letvak L, Kindler T, et al. Results of a multicenter phase II trial for older patients with c-Kit-positive acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) using low-dose Ara-C and Imatinib. Cancer. 2007;109:907–14. doi: 10.1002/cncr.22471.
    1. Kish T, Corry L. Sonidegib (Odomzo) for the systemic treatment of adults with recurrent, locally advanced basal cell skin cancer. P T. 2016;41:322–5.
    1. Migden MR, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16:716–28. doi: 10.1016/S1470-2045(15)70100-2.
    1. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–9. doi: 10.1056/NEJMoa1113713.
    1. Wei A, Strickland SA, Roboz GJ, Hou JZ, Fiedler W, Lin TL, et al. Safety and efficacy of venetoclax plus low-dose cytarabine in treatment-naive patients aged≥65 years with acute myeloid leukemia. Blood. 2016;128:102.
    1. DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, 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;19:216–28. doi: 10.1016/S1470-2045(18)30010-X.
    1. Tibes R, Al-Kali A, Oliver GR, Delman DH, Hansen N, Bhagavatula K, et al. The Hedgehog pathway as targetable vulnerability with 5-azacytidine in myelodysplastic syndrome and acute myeloid leukemia. J Hematol Oncol. 2015;8:114. doi: 10.1186/s13045-015-0211-8.
    1. Borate U, Smith BD, Gore S, Zeidan A, Savona M, Savoie ML, et al. Phase 1B study of glasdegib (PF-04449913) in combination with azacitidine in patients with higher risk myelodysplastic syndrome, oligoblastic acute myeloid leukemia, or chronic myelomonocytic leukemia. Haematologica. 2016;101(uppl 1):73–4.

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