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Phase I/II Study of Subcutaneous Homoharringtonine in Patients With Chronic Myeloid Leukemia Who Have Failed Prior Therapy Alfonso Quinta´s-Cardama, MD1 Hagop Kantarjian, MD1 Guillermo Garcia-Manero, MD1 Susan O’Brien, MD1 Stefan Faderl, MD1 Zeev Estrov, MD1 Francis Giles, MD1 Anthony Murgo, MD2 Nakia Ladie, RN1 Srdan Verstovsek, MD1 Jorge Cortes, MD1 1
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas. 2
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
BACKGROUND. Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon. METHODS. A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m2 s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m2 over 24 hours, followed by 1.25 mg/m2 s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT.
RESULTS. Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable.
CONCLUSIONS. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure. Cancer 2007;109:248–55. 2006 American Cancer Society.
KEYWORDS: homoharringtonine, imatinib, chronic myelogenous leukemia, ABL mutations.
I
Address for reprints: Jorge Cortes, MD, Professor of Medicine, Department of Leukemia, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 428, Houston, TX 77030; Fax: (713) 794-4297; E-mail:
[email protected] Received August 18, 2006; revision received October 10, 2006; accepted October 17, 2006.
ª 2006 American Cancer Society
matinib (Gleevec; Novartis, Basel, Switzerland) has caused a paradigm shift in the treatment of chronic myelogenous leukemia (CML). By selectively inhibiting the Bcr-Abl tyrosine kinase in CML leukemic cells, imatinib induces complete cytogenetic (CG) responses in 40% to 60% of patients in chronic phase (CP) postfailure of therapy with interferon (IFN)-a1,2 and in 80% to 90% of previously untreated patients.3–5 Response rates in more advanced stages of CML are significantly lower and responses are of shorter duration.6–9 In addition, some patients who respond well to imatinib may eventually develop resistance through 1 of several mechanisms of resistance that have been reported, including mutations of the Bcr-Abl kinase domain, amplification and overexpression of Bcr-Abl, and overexpression of other kinases.10–12 Therefore, despite the outstanding results obtained with imatinib therapy, there is a subset of patients with CML for whom new therapeutic strategies are needed.
DOI 10.1002/cncr.22398 Published online 7 December 2006 in Wiley InterScience (www.interscience.wiley.com).
Subcutaneous HHT for CML/Quinta´s-Cardama et al.
Homoharringtonine (cephalotaxine, 4-methy-2hydroxy-4-methylpentyl butanedioate) (HHT) is a cephalotaxus alkaloid obtained by alcoholic extraction from the evergreen tree Cephalotaxus harringtonia k. koch var harringtonia. HHT has shown activity against myeloid leukemias by inhibiting protein synthesis, promoting cell differentiation, and inducing apoptosis via a caspase-3-dependent mechanism.13–15 A racemic mixture of harringtonine (HHT minus a methylene group) and HHT was first used in China for the treatment of acute myelogenous leukemia (AML) and CML in the 1970s.16,17 Until the advent of imatinib, HHT was the most effective agent for treatment of patients with CML after IFN-a failure.18,19 Treatment with HHT in late-phase CML after IFN-a failure was associated with a complete hematologic response (CHR) rate of 72% and a CG response rate of 31% (complete CG response [Ph 0%] in 15% of patients).18 In vitro studies showing synergy of HHT with ara-C and IFNa20 led to clinical trials of combinations of HHT and low-dose Ara-C,21 IFN-a,19,22 or both.23 With the introduction of imatinib the focus for HHT development has shifted to investigate its potential to overcome resistance to imatinib. Recently, HHT has been shown to have a synergistic or additive effect with imatinib in vitro against imatinib-resistant cell lines24–26 and against cells from patients with CML in blastic phase.24 Clinical studies with HHT have typically used a formulation administered by intravenous (i.v.) infusion in a continuous fashion over 14 days, which greatly reduced the cardiovascular toxicity seen with bolus infusion. Subcutaneous (s.c.) administration would make the administration of HHT more convenient for patients, provided it had a similar safety and clinical profile when administered by this route. Therefore, we designed a Phase I/II trial to investigate the safety and efficacy of s.c. HHT in the treatment of CML patients after failure to imatinib therapy.
MATERIALS AND METHODS Eligibility Requirements Patients age 12 years or older with Philadelphia chromosome (Ph)-positive CML in CP, accelerated (AP), or blast phase (BP) were eligible. Patients in early CP CML (time from diagnosis to therapy less than 12 months) were not eligible and those in late CP were eligible only after the maximal tolerated dose (MTD) or level 3 (whichever came first) was reached. In addition, patients in late CP were eligible only if they had failed imatinib therapy, whereas these prior treatment restrictions did not apply to patients in AP or BP. Other eligibility criteria included: 1) life expectancy
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sufficiently long to fully evaluate the effects of at least 2 courses of chemotherapy; 2) performance status 2 or less by the Zubrod scale; 3) adequate hepatic and renal function (ie, bilirubin and creatinine < 2.0 mg/ dL); and 4) adequate cardiac status (New York Heart Association class 50 109/L with each course. Should extramedullary toxicity due to HHT occur (specifically headache, diarrhea, mucositis, or cardiovascular) the daily dose was reduced by 25% for grade II toxicity and by 50% for grade III or IV toxicity. Courses were given at monthly intervals provided the neutrophil count had recovered to >1.5 109/L and the platelet count to >80 109/L. Subse-
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quent courses could be started earlier than 28 days if counts had recovered above these levels provided there had been no grade 3 or 4 nonhematologic toxicity in the prior course. Treatment with s.c. HHT was discontinued 1) if unacceptable (grade 3–4) toxicity occurred in the absence of significant antileukemic effect; 2) if a patient in CP developed AP or BP while on study; 3) if patients showed a steady increase in white blood cell count (WBC) in peripheral blood (>40 109/L or a 25% increase in WBC for patients beginning with WBC >40 109/L) while receiving HHT at the highest tolerated dose; or 4) on patient request.
Response and Toxicity Criteria Response criteria were as previously described.2,27 Briefly, CHR was defined as normalization for at least 4 weeks of the bone marrow (less than 5% blasts) and peripheral blood with WBC 450 109/L) but at least 50% less than pretreatment. All other responses were considered failures. Toxicities were graded according to the NCI Common Toxicity Criteria (v. 2.0). Duration of remission was measured from the date remission was obtained to the date recurrence was documented. Survival was calculated from the time the treatment began until death from any cause or last follow-up. Evaluation Complete peripheral blood counts (CBC) and differential were performed every 4 to 7 days during remission induction chemotherapy and at least once every week during maintenance therapy. Bone marrow aspirate and CG studies were performed every 3 to 4 months to evaluate CG response. Biochemistries were done every 2 weeks during induction, then every 2 to 6 weeks. During the Phase I part of the study and in the first 6
patients treated at the MTD, patients were hospitalized or monitored in an outpatient 24-hour facility for cardiovascular side effects for the first cycle of therapy. After that, patients were evaluated for local reactions 1 day after the start of injections (2 injections given). They were instructed to call and return earlier (to the emergency room) if pain, redness, swelling, or tenderness was judged moderate or worse by the patient.
Statistical Considerations Phase I of the study used a classic ‘3þ3 design.’ For the first 3 patients the initial dose was 0.5 mg/m2. The dose was then escalated according to side effects. MTD was defined as one where 1 of 3 patients experienced dose-limiting toxicity (DLT). DLT was defined as any grade 3 or 4 nonhematologic toxicity, except for nausea, vomiting, and diarrhea, which were considered DLT only if uncontrolled by adequate symptomatic therapy. One objective of the trial was to evaluate the efficacy of s.c. HHT for the treatment of CP CML. The outcome of major interest was achievement of CHR. The CHR rate achieved in a trial of about 100 patients treated with intravenous HHT is 60%. A Bayesian approach was used to provide a basis for early termination in the event there was convincing evidence that the CHR rate was unlikely to be equivalent to the previous regimen. Patient accrual was to be stopped if there was 5000 nmol/L).31 Both mutations disappeared 1 month after s.c. HHT was started and shortly thereafter this patient achieved a minor CG response. This patient eventually lost response associated with recurrence of the Y253F mutation. Patient 15 had mutation F359I at study entry, and it became undetectable after 4 months on s.c. HHT. This was associated with clinical response. Unfortunately, he then developed multifocal extramedullary skeletal blast disease requiring radiotherapy while maintaining a complete CG response in both PB and bone marrow. Because the mechanism of action of HHT is independent of configuration of the Abl kinase, probably including inhibition of transcription of Bcr-Abl,32 it is conceivable that it might have activity against Abl kinase domain mutants. Indeed, there is preliminary evidence to suggest activity against the T315I mutation that is highly resistant to imatinib, nilotinib, and dasatinib.33 In this study, HHT decreased the total protein level of Bcr-Abl Ba/F3 cells transfected with either wildtype Bcr-Abl or Bcr-Abl with the Abl kinase domain mutations E255K or T315I, and hence its kinase activity. In addition, cells transfected with the mutated Bcr-Abl were equally sensitive to HHT as those with wildtype Bcr-Abl in clonogenic assays, with an IC50 of 127 to 232 nM for all cell lines. Further confirmation of the clinical activity observed in this trial, including in patients with the T315I mutation, is warranted. In summary, the data from this trial demonstrate that therapy with HHT administered s.c. has an acceptable toxicity profile and clinical activity in patients with CML after imatinib failure. Importantly, its clinical benefit seems to be independent of the presence of mutations in the BCR-ABL tyrosine kinase domain, thus offering a potential therapeutic alternative for this patient population.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16. 17.
Kantarjian H, O’Brien S, Cortes J, et al. Survival advantage with imatinib mesylate therapy in chronic-phase chronic myelogenous leukemia (CML-CP) after IFN-{alpha} failure and in late CML-CP, comparison with historical controls. Clin Cancer Res. 2004;10:68–75. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. New Engl J Med. 2002;346:645–652. Kantarjian HM, Cortes JE, O’Brien S, et al. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood. 2003;101:97–100. Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood. 2004;103:2873–2878. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348:994–1004. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530–3539. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002;99:1928–1937. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood. 2002; 99:3547–3553. Kantarjian HM, O’Brien S, Cortes JE, et al. Treatment of Philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res. 2002;8:2167–2176. Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190–2196. Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102:276–283. Donato NJ, Wu JY, Stapley J, et al. Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Cancer Res. 2004;64:672–677. Fresno M, Jimenez A, Vazquez D. Inhibition of translation in eukaryotic systems by harringtonine. Eur J Biochem. 1977; 72:323–330. Kuliczkowski K. Influence of harringtonine on human leukemia cell differentiation. Arch Immunol Ther Exp (Warsz). 1989;37:69–76. Yinjun L, Jie J, Weilai X, Xiangming T. Homoharringtonine mediates myeloid cell apoptosis via upregulation of proapoptotic bax and inducing caspase-3-mediated cleavage of poly(ADP-ribose) polymerase (PARP). Am J Hematol. 2004; 76:199–204. Hospital CPsLAt. Harringtonine in acute leukemias. Clinical analysis of 31 cases. Chin Med J (Engl). 1977;3:319–324. Group CRC. Cephalotaxine esters in the treatment of acute leukemia. A preliminary clinical assessment. Chin Med J (Engl). 1976;2:263–272.
Subcutaneous HHT for CML/Quinta´s-Cardama et al. 18. O’Brien S, Kantarjian H, Keating M, et al. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood. 1995; 86:3322–3326. 19. O’Brien S, Kantarjian H, Koller C, et al. Sequential homoharringtonine and interferon-alpha in the treatment of early chronic phase chronic myelogenous leukemia. Blood. 1999;93:4149–4153. 20. Visani G, Russo D, Ottaviani E, et al. Effects of homoharringtonine alone and in combination with alpha interferon and cytosine arabinoside on ‘in vitro’ growth and induction of apoptosis in chronic myeloid leukemia and normal hematopoietic progenitors. Leukemia. 1997;11:624–628. 21. Kantarjian HM, Talpaz M, Smith TL, et al. Homoharringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemia. J Clin Oncol. 2000;18:3513–3521. 22. O’Brien S, Talpaz M, Cortes J, et al. Simultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemia. Cancer. 2002;94:2024–2032. 23. O’Brien S, Giles F, Talpaz M, et al. Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase. Cancer. 2003;98:888–893. 24. Tipping AJ, Mahon FX, Zafirides G, Lagarde V, Goldman JM, Melo JV. Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs. Leukemia. 2002;16:2349–2357. 25. Kano Y, Akutsu M, Tsunoda S, et al. In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents. Blood. 2001;97: 1999–2007.
255
26. Scappini B, Onida F, Kantarjian HM, et al. In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells. Cancer. 2002;94:2653–2662. 27. Cortes JE, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review. Am J Med. 1996;100:555–570. 28. Marin D, Kaeda JS, Andreasson C, et al. Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer. 2005;103: 1850–1855. 29. Levy V, Zohar S, Bardin C, et al. A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia. Br J Cancer. 2006;95:253– 259. 30. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and horter survival: a study by the GIMEMA working party on chronic myeloid leukemia. J Clin Oncol. 2005;23:4100– 4109. 31. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65:4500–4505. 32. Chen R, Benaissa S, Plunkett W. A sequential blockade strategy to target the Bcr/Abl oncoprotein in chronic myelogenous leukemia with STI571 and the protein synthesis inhibitor homoharringtonine [Abstract 3788]. Proc Am Assoc Cancer Res. 2003;44:34. 33. Chen R, Plunkett W. Sequential blockade of Bcr-Abl production overcomes resistance to imatinib [Abstract 3010]. Proc Am Assoc Cancer Res. 2006;47.
