Leukemia (2012) 26, 959 --962 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu

ORIGINAL ARTICLE Nilotinib is effective in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blastic phase

FJ Giles1, HM Kantarjian2, PD le Coutre3, M Baccarani4, F-X Mahon5, RE Blakesley6, NJ Gallagher7, K Gillis6, SL Goldberg8, RA Larson9, A Hochhaus10 and OG Ottmann11

Nilotinib is a selective inhibitor of BCR-ABL approved for use in newly diagnosed and imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) in chronic phase. In this study, 400 mg of nilotinib was administered twice daily to the patients with myeloid (MBP, n ¼ 105) or lymphoid blastic phase (LBP, n ¼ 31) CML. After a minimum follow-up of 24 months, major hematologic responses were observed in 60% (MBP) and 59% (LBP) of patients. Major cytogenetic responses (MCyR) were attained in 38% (MBP) and 52% (LBP) of patients; and complete cytogenetic responses in 30% and 32%, respectively. Median duration of MCyR was 10.8 (MBP) and 3.2 months (LBP). Median overall survival was 10.1 (MBP) and 7.9 (LBP) months with 12- and 24-month survival of 42% (MBP 44%, LBP 35%) and 27% (MBP 32%, LBP 10%), respectively. Twelve MBP patients and two LBP patients received subsequent stem cell transplantation. Myelosuppression was frequent, with grade 3/4 neutropenia, thrombocytopenia, and anemia in 68%, 63% and 47% of patients, respectively. Grade 3/4 hypophosphatemia, hyperbilirubinemia and lipase elevation were observed in 15%, 11% and 11% of patients, respectively. Nilotinib has significant efficacy in patients with BP CML, but given the limited long-term survival of these patients, novel agents are needed.

Leukemia (2012) 26, 959--962; doi:10.1038/leu.2011.355; published online 13 December 2011 Keywords: nilotinib; chronic myeloid leukemia; blastic phase; BCR-ABL; imatinib resistance; mutations

INTRODUCTION open-label, multicenter, phase II study of nilotinib in patients with Current therapies for patients with advanced phase chronic imatinib failure in BP was conducted. myeloid leukemia (CML) are inadequate, with median duration of overall survival (OS) from diagnosis of blastic phase (BP) disease MATERIALS AND METHODS of B6--9 months; the great majority of patients alive 41 year Adults with CML in BP who had imatinib resistance or intolerance from diagnosis with BP have received stem cell transplantation received oral nilotinib at a starting dose of 400 mg twice daily on (SCT).1,2 Most of the patients with BP CML can be immunophe- an empty stomach. Patients were allowed a dose increase of notypically defined as having myeloid blastic phase (MBP) or nilotinib to 600 mg twice daily if therapy was well tolerated and lymphoid blastic phase (LBP) disease.1,3 Imatinib mesylate (Glivec, patient showed a suboptimal response. Definitions for BP CML, Gleevec; Novartis Pharmaceuticals Corporation, East Hanover, NJ, imatinib resistance or intolerance, and for disease progression USA), the prototypic BCR-ABL kinase inhibitor, has modest activity were as previously reported.7 Response assessments included in patients with BP, with sustained complete hematologic CHR, marrow response (MaR; no blasts in peripheral blood, responses (CHR) and complete cytogenetic responses (CCyR) neutrophil count X1.0 Â 109/l, platelet count X20 Â 109/l and in B7--13% of patients and an estimated median duration of OS basophils o5%) and major hematologic response (MHR), which of B7 months.2 Nilotinib hydrochloride monohydrate (Tasigna; was defined as achievement of MaR or CHR where (i) MaR is Novartis Pharmaceutical Corporation, East Hanover, NJ, USA), a precisely as defined here, and (ii) CHR is no blasts in peripheral high-affinity aminopyrimidine-based ATP competitive inhibitor of blood, neutrophil count X1.5 Â 109/l, platelet count X100 Â 109/l BCR-ABL, has significant activity in patients with chronic phase and basophils o5%. McyR was defined as CCyR, (0% Philadelphia (CP) CML who have failed or are intolerant of imatinib therapy.4 chromosome-positive (Ph þ ) metaphase cells) or partial cytoge- Nilotinib has also recently been shown to be more effective than netic response (PCyR, 40top35% Ph þ cells). Other study end imatinib as frontline therapy for CP CML in terms of achievement points were duration of MHR and MCyR, and OS. Analyses of time of CCyRs, major cytogenetic responses (MCyRs), major molecular to MHR and duration of MHR were restricted to patients who were remissions and lower rates of disease progression to accelerated not in MHR at the time of study entry. Baseline assessment of BCR- phase (AP) or BP.5,6 Because of nilotinib’s activity in patients with ABL mutation phenotype was performed where possible.8 Adverse CP or AP CML who have failed imatinib therapy and in patients events were assessed continuously and were graded according to with BP, noted in the nilotinib phase I study,7 an international, the National Cancer Institute Common Terminology Criteria for

1HRB Clinical Research Facility, National University of Ireland Galway & Trinity College Dublin,, University Road, Galway, Ireland; 2Department of Leukemia; M.D Anderson Cancer Center, Houston, TX, USA; 3Charite´-Universita¨tsmedizin Berlin, Berlin, Germany; 4Institute of Hematology and Medical Oncology ‘L. e A. Sera`gnoli,’ University of Bologna, Bologna, Italy; 5Department of Leukemia, Universite Victor Segalen Bordeaux 2, Bordeaux Cedex, France; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Novartis Pharma AG, Basel, Switzerland; 8Division of Leukemia, Hackensack University Medical Center, Hackensack, NJ, USA; 9University of Chicago, Chicago, IL, USA; 10Universita¨tsklinikum Jena, Jena, Germany and 11Johann Wolfgang Goethe Universita¨t, Frankfurt, Germany. Correspondence: Dr FJ Giles, HRB Clinical Research Facility, National University of Ireland, University Road, Galway, Ireland. E-mail: [email protected] Data contained within this article were presented at the June 2010 European Hematology Association 14th Annual Congress in Berlin, Germany. Received 4 October 2011; accepted 19 October 2011; published online 13 December 2011 Nilotinib is effective in blastic-phase CML FJ Giles et al 960 Adverse Events version 3.0. Efficacy analyses were performed for Patients were intensively pretreated, with 37% having received all the patients who received at least one dose of nilotinib. Two- prior cytarabine therapy and 13% having received a prior SCT. sided 95% exact confidence intervals were calculated for response More than half of the patients had cytogenetic abnormalities in rates. Duration of response was measured from the first day so addition to the Philadelphia chromosome. Baseline distribution of that relevant criteria were met until either discontinuation due to BCR-ABL mutation genotypes is summarized in Table 2. Mutation disease progression or death; response duration was censored for analysis was performed in 114 patients at baseline, 43 (38%) of patients who discontinued for reasons other than disease whom had detectable mutations. T315I mutations were detected progression or death at the time of their last assessment. in 1% of patients in MBP and 7% of patients in LBP. OS was estimated by Kaplan--Meier method. All patients had a Of 119 patients who did not have a hematologic response at minimum observation time of 24 months or discontinued early. baseline, 71 (60%) achieved this milestone on nilotinib therapy---54 The data cutoff was June 6, 2008. of 90 (60%) in MBP and 17 of 29 (59%) in LBP; a CHR was obtained in 24% and 21% patients, respectively. Median time to MHR was 1.4 months overall, 1.9 months for patients in MBP and 1.2 months RESULTS for patients in LBP. The median duration of MHR was 24.7 months One hundred and thirty-six patients were entered on study. (range 10.6--27.7) for patients in MBP and 12.9 months (range 4.5-- Baseline patient demographics are summarized in Table 1. The 17.8) for patients in LBP. At 12 and 24 months, 63% and 51% of best previous response to imatinib was either stable or patients in MBP, and 57% and 21% of patients in LBP, respectively, progressive disease in 46% of patients, with only 10% and 11% maintained MHR (Figure 1). achieving previous CHR or MCyR, respectively. The other 33% of Sixteen of 136 (12%) patients had a baseline cytogenetic patients had best prior response of: return to CP (4%), MR (4%), response. An MCyR was observed in 56 of 136 (41%) patients, 40 minimal CyR (o1%), minor CyR (o1%) or unknown (22%). of 105 (38%) patients in MBP and 16 of 31 (52%) patients in LBP, with a CCyR obtained in 30% and 32% patients, respectively. Median time to MCyR among responders was 1.2 months overall, 1.8 and 1.0 Table 1. Patients demographics (N ¼ 136) months in responders in MBP and LBP, respectively. Median Median age, years (range) 54 (18--79) duration of MCyR was 10.8 months for patients in MBP, with an Male, n (%) 83 (61) estimated 44% maintaining response at 24 months, and 3.2 months Female, n (%) 53 (39) for patients in LBP, among whom none were known to have maintained cytogenetic response at 24 months (Figure 2). The Blastic phase, n (%) median OS was 10.1 months for patients in MBP and 7.9 months for Lymphoid (LBP) 31 (23) patients in LBP, with 12- and 24-month survival rates of 42% (44% Myeloid (MBP) 105 (77) MBP, 36% LBP) and 27% (32% MBP, 10% LBP), respectively (Figure 3). Median duration of previous imatinib, days (range) 490 (1--3267) Imatinib resistant, n (%) 111 (82) Imatinib intolerant, n (%) 25 (18)

Previous treatment, % Hydroxyurea 72 Interferon 18 Cytarabine 37 Stem cell transplant 13

Additional chromosomal abnormality, n (%) 73 (54) Abbreviations: LBP, lymphoid blastic phase; MBP, myeloid blastic phase.

Table 2. Baseline BCR-ABL mutations

Imatinib Imatinib Total, Figure 1. Duration of major hematologic response in patients with resistant, intolerant, N ¼ 114, MBP or LBP CML. Pt, patient; Evt, event; Csr, censored observations. n ¼ 94, n ¼ 20, n (%) n (%) n (%)

Any mutation 41 (44) 2 (10) 43 (38) IC50p150 nM 18 (19) 0 18 (16) IC504150 nM 10 (11) 2 (10) 12 (11) Unknown 10 (11) 0 10 (9) No mutation 53 (56) 18 (90) 71 (62) P-loop mutations 11 (12) 1 (5) 12 (11) Non-P-loop 30 (32) 1 (5) 31 (27) mutations Multiple mutations 7 (7) 1 (5) 8 (7) T315I mutation 3 (3) 0 3 (3) P-loop mutations include any mutation falling between amino acids 248 and 256 (inclusive). IC50p150 nM includes M237I, M244V, L248V, G250A, G250E, G250V, Q252H, E255D, E255R, E275K, D276G, E281K, K285N, E292K, F317C, F317L, F317V, D325N, S348L, M351T, E355A, E355G, L387F, M388L and F486S. IC504150 nM includes Y253H, E255K, E255V, F311V, F359C, F359V and A380S. Unknown includes all other mutations except Figure 2. Progression-free survival in patients with MBP or LBP CML. T315I. Pt, patient; Evt, event; Csr, censored observations.

Leukemia (2012) 959 --962 & 2012 Macmillan Publishers Limited Nilotinib is effective in blastic-phase CML FJ Giles et al 961 Table 3. Possibly nilotinib-related non-hematologic adverse events

3 Adverse event All grades, n (%) Grade 4 , n (%)

Rash 25 (18) 1 (o1) Nausea 16 (12) 2 (1) Diarrhea 10 (7) 1 (o1) Vomiting 10 (7) 1 (o1) Fatigue 8 (6) 1 (o1) Pruritus 8 (6) 0 Constipation 8 (6) 0 Headache 7 (5) 1 (o1) Abdominal pain, upper 7 (5) 1 (o1)

Fluid retention and bleeding Figure 3. OS in patients with MBP or LBP CML. Pt, patient; Evt, event; Peripheral edema 13 (10) 1 ( 1) Csr, censored observations. o Pleural effusion 1 (o1) 0 Pericardial effusion 0 0 Pulmonary edema 0 0 GI bleedinga 3 (2) 2 (1) CNS bleedingb 00 Abbreviations: GI, gastrointestinal; CNS, central nervous system. aIncludes the preferred terms: hematemesis, gastrointestinal hemorrhage, melena, hematochezia, rectal hemorrhage, hemorrhoidal hemorrhage, gastric ulcer hemorrhage and duodenal ulcer hemorrhage. bIncludes the preferred terms: subdural hemorrhage and hemorrhage intracranial.

Table 4. Possibly-nilotinib related hematologic and biochemical abnormalities

Laboratory abnormality Grade 3/4 %

Figure 4. OS in patients with MBP or LBP CML with and without Neutropenia 68 BCR-ABL mutations at baseline. Thrombocytopenia 63 Anemia 47 Following a response to nilotinib therapy, 12 (11%) patients in MBP Hypophosphatemia 15 and 2 (6%) patients in LBP received SCT. Baseline BCR-ABL kinase Bilirubin (total) 11 domain mutation data were available for 86 of 105 patients in MBP Lipase elevation 11 Hypokalemia 9 and 28 of 31 patients in LBP; the presence or absence of a Hyperglycemia 9 detectable mutation did not affect OS (Figure 4). Alanine aminotransferase elevation 7 The median duration of nilotinib therapy on study was 84 days Hypocalcemia 5 (range 3--969) at a median dose intensity of 800 mg/day (range Aspartate aminotransferase elevation 4 317--1113). Dose interruptions occurred in 38% of patients, which were usually related to myelosuppression and were of a median total duration of 10 days (range 1--109). Adverse events were ASXL1 or WT1, and 33% had secondary mutations in BCR-ABL. Aside generally mild and were controlled in most cases by transient from patients who undergo successful SCT, long-term survival treatment interruptions and/or dose reductions. The most following diagnosis of BP is rare.1,14 Much effort in frontline therapy common non-hematologic drug-related adverse events were rash, of patients with CP CML is being directed towards reducing the rate nausea, diarrhea and vomiting; these were grade 3/4 in 0.7, 1.5, 0.7 of development of BP over that previously observed in patients and 0.7% of patients (Table 3). Cytopenias were noted in the receiving imatinib therapy. This has proven successful with nilotinib majority of patients in both MBP and LBP, but most patients had therapy in the frontline setting.6 some cytopenia before nilotinib therapy (Table 4). Biochemical In this study, nilotinib therapy was associated with hematologic abnormalities were observed in some patients, with grade 3/4 and cytogenetic responses in the majority of patients. These were hypophosphatemia, increased bilirubin and lipase elevation rapidly attained at a pace equivalent to that observed with observed in 15%, 11% and 11% of patients, respectively; two nilotinib therapy of imatinib-resistant patients in CP or AP.15 --17 (1.5%) patients were removed from study because of a The adverse event profile of nilotinib in the patients in BP appears biochemical observation. equivalent to the profile seen with this agent in other CML settings. There were no extramedullary adverse events or biochemical abnormalities that appeared increased in severity DISCUSSION or incidence in comparison with nilotinib therapy of imatinib- Blastic transformation in patients with CML continues to be a resistant patients in CP or AP or in the third-line setting following difficult therapeutic challenge.9,10 Studies have shown marked failure of both prior imatinib and dasatinib.15,16 Responses broad-spectrum genetic changes in leukemia cells at the time of occurred among the patients with a broad spectrum of BCR-ABL BP transformation.11 It is likely that in BP, mechanisms other than mutations, which is consistent with nilotinib data in other the primary BCR-ABL oncogenic driver become key to the imatinib-resistant CML populations.15,16 Nilotinib has no signifi- pathophysiology of the leukemia.12 Grossman et al.13 have recently cant clinical activity against the T315I mutation, which was reported on a deep-sequencing study in a cohort of 39 patients in observed in 1% and 7% of patients in MBP and LBP, respectively, BP; 77% of patients had mutations, most commonly in RUNX1, in this study. However, some responses were observed in these

& 2012 Macmillan Publishers Limited Leukemia (2012) 959 --962 Nilotinib is effective in blastic-phase CML FJ Giles et al 962 patients, which suggest that the observed mutated clone was not 9 Giles FJ. New directions in the treatment of imatinib failure and/or resistance. the only driver of imatinib resistance or disease progression in Semin Hematol 2009; 46(Suppl 3): S27 --S33. these patients. This phenomenon has been observed in patients 10 Wadhwa J, Szydlo RM, Apperley JF, Chase A, Bua M, Marin D et al. Factors with BP treated with dasatinib, which also has no significant affecting duration of survival after onset of blastic transformation of chronic activity against the T315I genotype, and in other cohorts of myeloid leukemia. Blood 2002; 99: 2304 --2309. imatinib-resistant patients with CML.18,19 Aside from its activity 11 Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B et al. Gene expression against imatinib-resistant mutated BCR-ABL genotypes, nilotinib’s changes associated with progression and response in chronic myeloid leukemia. activity in patients with BP might be explained in part by Proc Natl Acad Sci USA 2006; 103: 2794 --2799. 12 Perrotti D, Jamieson C, Goldman J, Skorski T. Chronic myeloid leukemia: differences in CML CD34 þ cell accumulation of intracellular mechanisms of blastic transformation. J Clin Invest 2010; 120: 2254 --2264. kinase inhibitor levels. Unlike imatinib, nilotinib has been reported 13 Grossmann V, Kohlmann A, Zenger M, Schindela S, Eder C, Weissmann S et al. A to be neither dependent on active import by hOCT1 nor to be deep-sequencing study of chronic myeloid leukemia patients in blast crisis effluxed through the ATP-binding cassette transporters MDR1 (BC-CML) detects mutations in 76.9% of cases. Leukemia 2011; 25: 557 --560. (ABCB1), MRP1 (ABCC1), or ABCG2 (BCRP).20 --24 14 Gratwohl A, Heim D. Current role of stem cell transplantation in chronic myeloid Dasatinib, a BCR-ABL, SRC-family kinase inhibitor, has also been leukaemia. Best Pract Res Clin Haematol 2009; 22: 431 --443. documented to have activity in patients with BP.18 In patients in 15 le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N et al. MBP (n ¼ 109) or LBP (n ¼ 48), MHR was observed in 34% and 35% Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, patients, respectively, with MCyR in 33% and 52% patients, is active in patients with imatinib-resistant or -intolerant accelerated-phase 25 chronic myelogenous leukemia. Blood 2008; 111: 1834 --1839. respectively. Median OS was 11.8 and 5.3 months, respectively. 16 Giles FJ, Abruzzese E, Rosti G, Kim DW, Bhatia R, Bosly A et al. Nilotinib is active in The overall apparent equivalence in response rates and OS in chronic and accelerated phase chronic myeloid leukemia following failure of patients with BP between nilotinib and dasatinib, two agents that imatinib and dasatinib therapy. Leukemia 2010; 24: 1299 --1301. have significant differences in terms of their spectrum of kinase 17 Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F et al. inhibition,26 suggest that either non-kinase dependent mechan- Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, isms are important in BP or the non-BCR-ABL kinases involved is effective in patients with Philadelphia chromosome-positive chronic myelo- are not inhibited by either agent. genous leukemia in chronic phase following imatinib resistance and intolerance. The currently reported data show that nilotinib can induce Blood 2007; 110: 3540 --3546. durable hematologic and cytogenetic responses in some patients 18 Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with with BP. These responses may be of particular value in allowing imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood patients to receive SCT. However, in the absence of SCT, most 2007; 109: 3207 --3213. responses are not durable, and novel approaches are required for 19 Khorashad JS, Anand M, Marin D, Saunders S, Al-Jabary T, Iqbal A et al. The 2 patients in BP. Nilotinib-based combinations, for example, with presence of a BCR-ABL mutant allele in CML does not always explain clinical stem-cell-modifying agents, such as smoothened inhibitors,27 p53 resistance to imatinib. Leukemia 2006; 20: 658 --663. stabilization with human homolog double minute 2 inhibitions,28 20 Brozik A, Hegedus C, Erdei Z, Hegedus T, Ozvegy-Laczka C, Szakacs G et al. aurora kinase inhibitors,29 --31 or autophagy modifiers,12,32 would Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug seem worthy of urgent study in these patients. transporters: substrates, chemosensitizers or inducers of acquired multidrug resistance? Expert Opin Drug Metab Toxicol 2011; 7: 623 --642. 21 Haouala A, Rumpold H, Untergasser G, Buclin T, Ris HB, Widmer N et al. CONFLICT OF INTEREST siRNA-mediated knock-down of P-glycoprotein expression reveals distinct cellular FJG, MB, F-XM, SLG, RAL, AH and OGO acted as a consultant for and received research disposition of anticancer tyrosine kinases inhibitors. 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