Phase II pilot study of oral dasatinib in patients with higher-risk myelodysplastic syndrome (MDS) who failed conventional therapy

Leukemia Research 37 (2013) 300–304

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Phase II pilot study of oral dasatinib in patients with higher-risk myelodysplastic syndrome (MDS) who failed conventional therapy夽 Vu H. Duong a , Michael V. Jaglal b , Ling Zhang b , Vishakha Kale c , Jeffrey E. Lancet b , Rami S. Komrokji b,∗ , Alan F. List b a

University of Maryland Greenebaum Cancer Center, Baltimore, MD, United States H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States c South Texas Veterans Health Care System, San Antonio, TX, United States b

a r t i c l e

i n f o

Article history: Received 28 August 2012 Received in revised form 31 October 2012 Accepted 1 November 2012 Available online 27 December 2012 Keywords: Myelodysplastic syndromes Myelodysplastic-myeloproliferative diseases Dasatinib Azacitidine Decitabine

a b s t r a c t Given evidence for the role of Src family kinases, especially Lyn kinase, in myeloblast proliferation and the in vitro inhibitory activity of dasatinib on Src and Lyn, we conducted a phase II study to assess overall response to 100 mg/day dasatinib in patients with higher-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, or acute myeloid leukemia arising from MDS and who had failed prior treatment with azanucleoside analogs. Among 18 patients treated, 3 responded, 4 had stable disease, and 10 experienced disease progression. Toxicities were limited and consistent with previous reports. Dasatinib appears to be safe but with limited efficacy. © 2012 Elsevier Ltd. All rights reserved.

1. Introduction Higher-risk myelodysplastic syndrome (MDS) has a poor prognosis with a high rate of progression to acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplant (ASCT) is the only potentially curative option for this disease; however, it is associated with considerable treatment-related morbidity and mortality. The azanucleosides have potent disease-altering effects in patients; however, survival is poor upon treatment failure with no effective salvage alternatives [1–3]. Therefore, novel therapeutics that impact cellular events inherent to the pathobiology of MDS may offer benefit. Src family kinases (SFKs) consist of 9 members (c-Src, Lyn, Hck, Fyn, Yes, Blk, Lck, Yrk, and Fgr) that regulate multiple cellular functions ranging from proliferation and differentiation to cell migration [4,5]. They are actively involved in signaling pathways important in the initiation and progression of various human malignancies. In AML, SFKs are highly phosphorylated compared

夽 Preliminary data were presented at The American Society of Hematology Annual Meeting, December 2011 (Abstract #1727). ∗ Corresponding author at: H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, FOB-3, Room 3117, Tampa, FL 33612, United States. Tel.: +1 813 745 4291; fax: +1 813 745 5617. E-mail address: rami.komrokji@moffitt.org (R.S. Komrokji). 0145-2126/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2012.11.001

to normal hematopoietic progenitors, including the leukemia stem cell-rich compartment (CD34+, CD38−, CD123+) [6]. Lyn kinase in particular plays a critical role in the proliferative response of myeloid leukemia cells to cytokine signals and is constitutively active in AML myeloblasts and MDS megakaryocyte progenitors [7,8]. Inhibition of Lyn kinase activity using different strategies, such as antisense oligonucleotides, small interfering RNA, and Src kinase inhibitors suppresses leukemia cell growth [6,7,9]. We previously reported that Lyn kinase inhibition in leukemic cells suppresses STAT5 activation accompanied by induction of apoptosis in sensitive cells. Furthermore, treatment of primary bone marrow specimens from 13 AML patients and 1 chronic myelomonocytic leukemia (CMML) patient with the dual Src/Abl inhibitor SKI-606 inhibited proliferation of leukemic blasts in a concentration-dependent manner in 5 out of 14 samples with a 50% inhibitory concentration of less than 500 nM [9]. Dasatinib is an orally available multi-kinase inhibitor that is FDA approved for the treatment of chronic myelogenous leukemia [10,11]. It has activity against a broad spectrum of tyrosine kinases, including SFKs, breakpoint cluster region-Abelson (BCR-ABL), cKIT, platelet-derived growth factor receptor-␤, and EphA. It is less potent against 16 other unrelated protein tyrosine kinases and serine/threonine kinases [12,13]. Given evidence for the role of SFKs, especially Lyn kinase, in myeloblast proliferation and the in vitro inhibitory activity of dasatinib on Src and Lyn, we conducted

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a phase II pilot study to assess response to dasatinib treatment in patients with International Prognostic Scoring System (IPSS)defined higher-risk MDS [14]. 2. Materials and methods 2.1. Study design This was a single-center, open-label, 2-stage phase II study of dasatinib in patients with intermediate-2 or high-risk MDS by IPSS, CMML, and MDS/AML with ≤30% blasts (ClinicalTrials.gov Identifier NCT00624585). The primary objective was to estimate the overall response rate after 16 weeks of study treatment according to International MDS Working Group (IWG) 2006 Criteria for Response Assessment [15]. Secondary objectives were to assess the rate of hematologic improvement, time to AML progression, median duration of response, and overall survival, as well as to assess the relationship between response to study treatment and inhibition of Src-Tyr416 phosphorylation in bone marrow myeloblasts. The study was approved by the Moffitt Cancer Center Scientific Review Committee and University of South Florida Institutional Review Board. Informed written consent was obtained from all patients. 2.2. Patient eligibility and selection Patients ≥18 years of age with a documented bone marrow diagnosis of MDS or MDS/myeloproliferative neoplasm (MPN) with intermediate-2 or high-risk IPSS scores were eligible for study treatment. Patients with AML with multilineage dysplasia with <30% blasts who declined induction chemotherapy or were deemed unfit for induction chemotherapy were also eligible. Patients previously treated with azanucleosides were eligible, provided that their last dose was administered no less than 2 months before the first dose of dasatinib. Prior investigational therapy was permitted if discontinued at least 4 weeks before dasatinib treatment. Patients were also required to have an ECOG performance status of 0–2, adequate liver function (total bilirubin <2 times the upper limit of normal (ULN) and AST/ALT ≤ 2.5 times the institutional ULN) and renal function (serum creatinine <1.5 times the ULN), and a prothrombin time and partial thromboplastin time of less than 1.5 times the ULN. Patients with a leukocyte count >50,000 off hydroxyurea for greater than 72 h, with another malignancy that required radiotherapy or systemic treatment within the past 3 years, or who were receiving concurrent therapy for MDS or AML were excluded. Patients with medical conditions that were judged potentially to increase the risk of toxicity on dasatinib were excluded, including those with pleural or pericardial effusions, active coronary arterial disease or congestive heart failure, prolonged QT syndrome, significant arrhythmias, and significant bleeding disorders. Bisphosphonate use was prohibited. Pregnant or breastfeeding women were excluded, and females of child-bearing age were required to use adequate contraception.

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documented. After hematologic response was achieved, CBCs were monitored every 4 weeks. 2.5. Assessment of toxicity and response All patients who received study drug were assessed for response and toxicity. Adverse events were assessed at every visit according to NCI Common Terminology Criteria for Adverse Events version 3.0 and deemed to be likely related, possibly related, not likely related, or not related to the study drug. All responses were assessed according to the 2006 IWG Response Criteria. 2.6. Immunohistochemical staining for phospho-Src-Tyr416 Immunohistochemical staining for phospho-Src-Tyr416 was performed using a Ventana Discovery XT automated system (Ventana Medical Systems, Tucson, AZ) according to the manufacturer’s recommended protocol with proprietary reagents. Slides were deparaffinized on the automated system with EZ Prep solution (Ventana). Enzymatic retrieval method was used in Protease 1 (Ventana). The rabbit primary antibody that recognizes the human activation loop phospho-Src-Tyr416 (number 05–677, Millipore, Darmstadt, Germany) was used at a 1:200 concentration in PSS diluent (Ventana) and incubated for 60 min. The Ventana OmniMap antimouse secondary antibody was applied for 16 min. The detection system used was the Ventana ChromoMap kit, and slides were then counterstained with hematoxylin. Slides were then dehydrated and coverslipped as per normal laboratory protocol. 2.7. Statistics Sample size was calculated using Simon’s minimax 2-stage design. Eighteen patients were to be accrued in the first stage of the study. If 2 or fewer responses were observed, then the trial would be terminated for futility. Otherwise, if at least 3 responses were observed in the first stage, then an additional 8 evaluable patients would be enrolled during stage 2. If 6 or fewer responses were observed by the end of stage 2, then the protocol treatment would be deemed ineffective. However, if 7 or more responses were observed, the response rate to the protocol treatment would be at least 30%. The overall significance level of the design was 0.14 with a power of 0.70. Overall survival was defined as the time from enrollment to the date of death, and patients who were lost to follow-up were censored at the time they were last known to be alive. Time to AML progression was defined as the time from enrollment to the date of initial diagnosis of AML with ≥20% blasts. Those who died without disease progression as defined by IWG 2006 criteria were censored at the time of death. Both outcomes were assessed by the Kaplan–Meier method.

3. Results

2.3. Treatment

3.1. Patients

All patients received a continuous daily oral dose of dasatinib 100 mg. In the absence of at least a partial remission after 8 weeks of treatment or drug intolerance, the dose was increased to 150 mg/day. Final response to study treatment was assessed after 16 weeks of dasatinib treatment. Responding patients continued dasatinib for up to 48 weeks in the absence of disease progression, limiting toxicity, or secondary treatment failure. Treatment was held for any ≥ grade 3 nonhematological adverse event with suspected drug association until resolution to < grade 2. Upon resolution of the toxicity, dasatinib was dose-reduced to 70 mg if the toxicity occurred at the 100-mg dose and to 50 mg if the toxicity occurred at the 70mg dose. Patients who did not experience resolution of non-hematological adverse effects to < grade 2 within 4 weeks were removed from the study. Similarly, dasatinib treatment was interrupted and dose-reduction permitted for a decline of 50% in the absolute neutrophil count (ANC) if the baseline ANC was ≤500/␮L and for a decrease in ANC to <500/␮L for patients with a baseline ANC >500/␮L. Dose modification for thrombocytopenia was only done at the completion of a 28-day cycle, and dasatinib was held when the platelet count fell below 30,000/␮L and resumed at the next lower dose upon recovery to ≥30,000/␮L. Patients who were intolerant of 50 mg of daily dasatinib were removed from the study. Study treatment was discontinued for progressive disease, withdrawal of consent, pregnancy, or any clinical adverse event, laboratory abnormality, or intercurrent illness, which, in the opinion of the investigators, indicated that continued treatment with dasatinib was not in the best interest of the patient.

Eighteen patients were enrolled in the study at the Moffitt Cancer Center. Baseline patient characteristics are summarized in Table 1. Patients were generally older (median age 73.5) with a male predominance (55%). Most patients had refractory anemia with excess blasts (RAEB)-2 MDS (55%), and all patients failed treatment with at least one azanucleoside analog. Three patients who had lower-risk disease were enrolled but were still evaluated for response and toxicity. Upon central review, 3 patients were found to have AML with bone marrow blast percentage >30%.

2.4. Evaluation and follow-up Patients were evaluated by history and physical examination every 4 weeks, and complete blood counts (CBC) were obtained every 2 weeks. Bone marrow aspiration and biopsy (including cytogenetics by karyotyping and phospho-Src-Tyr416 by immunohistochemical staining) were performed at screening, at 8 and 16 weeks of treatment, at discontinuation of study therapy, and every 16 weeks in responding patients. If a patient continued on study drug beyond 16 weeks but did not experience a hematologic response, CBC was obtained every 2 weeks until response was

3.2. IWG response and disposition Three of the 18 patients (17%) had a response to study treatment, two of whom achieved marrow complete remission (mCR) without hematologic improvement. One responder was a 73-year-old male with RAEB-2 (13% blasts) at baseline and an IPSS score of 2.5. He achieved mCR and subsequently received an ASCT 4 months after starting study therapy, but died 9 months after his transplant without evidence of relapse or disease progression. The second patient achieving mCR was a 68-year-old female with RAEB-2 (13% blasts) and an IPSS score of 1.5. She discontinued therapy after 23 weeks due to lack of improvement in peripheral blood counts and died 6 months later without disease progression. The third patient with clinical benefit was a 75-year-old female with acute myelomonocytic leukemia with 14% blasts and 18% promonocytes at baseline, who experienced a >50% reduction in bone marrow blasts to 1.5%

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Table 1 Baseline patient characteristics. Characteristic

N = 18

Median age, year (range) Sex, n (%) Male Female Race, n (%) Caucasian Non-Caucasian WHO classification, n (%) RAEB-1 RAEB-2 AML CMML IPSS score, n (%) <1.5 1.5 2 2.5 Median % blasts at enrollment (range) ANC <1000, n (%) Hemoglobin <10 g/dL, n (%) Platelets <100,000, n (%) Cytogenetics, n (%) Favorable Intermediate Unfavorable Prior therapies, n (%) Growth factors Lenalidomide Hypomethylating agents

73.5 (60–84) 10 (55) 8 (44) 17 (94) 1 (6) 2 (11) 10 (55) 3 (17) 3 (17) 3 (17) 3 (17) 6 (33) 5 (28) 13.5% (3–20) 7 (39) 14 (78) 15 (83) 6 (33) 7 (39) 5 (28) 11 (61) 4 (22) 18 (100)

blasts (and 11.5% promonocytes), without improvement in peripheral blood counts. She discontinued therapy after 21 weeks of study therapy due to lack of improvement in peripheral blood counts. At the date of data cut-off, the patient is alive without progression almost 23 months after starting dasatinib. Four patients had stable disease as the best response, and 10 patients had progressive disease. One patient was hospitalized with cholecystitis after 1 week of therapy and eventually elected for hospice care. One of the three responders and 3 of the 4 patients with stable disease had trisomy 8 either as the sole cytogenetic abnormality or in combination with others. Only one other patient enrolled had trisomy 8 as a cytogenetic abnormality and had progressive disease. Five patients continued dasatinib therapy beyond 8 weeks, but none were doseescalated to 150 mg daily. Three of these patients had a confirmed response at 8 weeks, and 2 others had decreases in percentage of blasts (not meeting IWG response criteria) and were continued on the 100-mg daily dose. Four patients had dose reductions to 70 mg daily due to toxicity, of which one had a further dose reduction to 50 mg daily. Fifteen of the 18 patients discontinued therapy due to lack of response or disease progression, 2 due to adverse events and 1 to proceed to ASCT. Although the number of responses exceeded the pre-specified number of 2, the trial was terminated after the first stage due to lack of hematologic improvement even in responders. 3.3. Overall survival and time to AML progression Eight of the 16 patients with MDS or CMML eventually progressed to AML. The median time to progression was 4.4 months [95% confidence interval (CI) of 0.3–8.5 months]. The median overall survival of the entire cohort was 7.6 months (95% CI 2.6–12.5), with an estimated 1-year survival of 38% (see Fig. 1). The 7 patients who either responded or maintained stable disease had prolonged survival (28.5 months, 95% CI 0.0–60.9) compared to the 11 patients with disease progression or failure (4.0 months, 95% CI 1.8–6.3). At the data cut-off date of June 14, 2011, 3 patients were still alive, all of whom had at least stable disease as best response.

Fig. 1. Kaplan–Meier curve of overall survival.

3.4. Toxicity The most commonly reported adverse events included fatigue, dyspnea, and diarrhea. Each occurred in 39% of the patients and was largely grade 1 or 2 in severity. The most common grade 3 or 4 toxicities were fatigue (22%), neutropenic and non-neutropenic infection (28%), anemia (17%), and thrombocytopenia (22%). Twelve (67%) study patients experienced at least one grade 3 or 4 toxicity that was possibly related to treatment. A summary of all toxicities possibly attributable to dasatinib is provided in Table 2.

Table 2 Toxicities possibly related to treatment (experienced in >10% of patients). Toxicity

Grade 1/2

Grade 3/4

Total

Fatigue Dyspnea Diarrhea Nausea/vomiting Fever/infection (non-neutropenic) Hemoglobin Neutropenic fever (with or without documented infection) Platelets Anorexia Constipation Limb edema Cough Dysgeusia Bruising Headache GI hemorrhage Leukocytes Weight loss Pleural effusion (non-malignant) Rash: acne/acneiform Abdominal pain Visual changes Pain – chest wall/breast Diaphoresis Oral mucositis

3 6 7 4 3 1 1

4 1 0 1 2 3 3

7 7 7 5 5 4 4

0 3 3 3 3 3 3 2 2 1 2 2 2 2 2 2 1 2

4 1 0 0 0 0 0 1 1 1 0 0 0 0 0 0 1 0

4 4 3 3 3 3 3 3 3 2 2 2 2 2 2 2 2 2

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Table 3 Immunohistochemical staining for phospho-Src. Patient

1 2 3 4 5

WHO classification

AML RAEB-2 RAEB-2 RAEB-2 RAEB-2

Response

>50% decrease in blasts Marrow CR Marrow CR Disease Progression Disease Progression

3.5. Immunohistochemical staining for phospho-Src-Tyr416 Immunohistochemical staining for phospho-Src-Tyr416 was performed on trephine biopsy sections from 5 patients (3 responders and 2 non-responders). The 3 patients who achieved either mCR or >50% blast reduction showed a modest decrease in either the percentage of cells staining for phospho-Src or staining intensity when compared to that shown in the pre-treatment specimens. One patient who had disease progression had no change in the percentage or intensity of staining, whereas a second patient with disease progression showed a slight increase in the percentage of cells staining for phospho-Src from 70% to 90%. A summary of immunohistochemical results is shown in Table 3. 4. Discussion Constitutive activation of Src kinases is common in AML and contributes to myeloblast proliferation. In MDS, dysplastic megakaryocytes display Src activation, inhibition of which promotes maturation and differentiation in vitro. We present results of a phase II pilot study of oral dasatinib in higher-risk MDS patients who had previously failed treatment with azanucleosides. Dasatinib had modest activity, with responses limited to 2 mCRs and a >50% reduction in bone marrow blasts in one patient with AML. Despite preclinical evidence that Src inhibition promotes MDS megakaryocyte maturation, none of the patients experienced hematologic improvement. Half of the MDS and CMML patients progressed to AML. The median overall survival was estimated at 7.6 months, comparable to results previously reported in this patient population [1–3]. Although dasatinib was relatively well-tolerated, immunohistochemical assessment of phospho-Src showed only a modest reduction in target phosphorylation among responding patients. It is important to note that the antibody used in this study recognizes phosphorylation of the activation loop involving all SFKs rather than phospho-Lyn alone. We therefore cannot exclude the possibility that phospho-Lyn was downregulated with dasatinib treatment. Nonetheless, these findings raise the possibility that dosing may have been inadequate to extinguish SFK signaling fully. Among the 5 patients with trisomy 8, either isolated or included in a more complex karyotype, 4 had at least stable disease. A previous phase II study in patients with Philadelphia chromosomenegative myeloid malignancies included 6 patients with MDS or CMML, none of whom had a clinical response at 140 mg or 200 mg daily as a single dose or in 2 divided doses. However, 1 patient among 9 with AML achieved a CR that was maintained for 15 months. Interestingly, this patient also had trisomy 8 in 2/20 metaphases and expressed CD117 (KIT) in 66% of blasts. Trisomy 8 was no longer demonstrable after 2 months of dasatinib treatment, but re-emerged in 16/20 metaphases at 6 months. None of the remaining non-responding AML patients or MDS and CMML patients had a trisomy 8 cytogenetic abnormality. The only other patient in this study with trisomy 8 had chronic eosinophilic leukemia and did not respond to study treatment [16]. Although the sample size was small, these results combined with the results of our study suggest that a subset of patients with this particular

Pre-treatment phospho-Src

Post-treatment phospho-Src

(%)

Intensity

(%)

Intensity

40–50 90 90 90 70

2+ to 3+ 3+ 3+ 2+ 2+ to 3+

30–40 80 90 90 90

2+ 3+ 2+ to 3+ 2+ 2+

cytogenetic abnormality may benefit from dasatinib. Of particular interest, the LYN kinase gene is encoded on the long arm of chromosome 8, suggesting that gene duplication may augment kinase response capacity and proliferative response [17]. Although trisomy 8, either alone or in combination, is one of the most common cytogenetic abnormalities in both MDS [18,19,20] and AML [21,22,23], relatively little is known about the underlying mechanisms of pathogenesis. Trisomy 8 does result in generally increased expression of genes located on chromosome 8 including LYN [24,25,26]; thus, the apparent preferential activity of dasatinib in patients with trisomy 8 in our study and those of Verstovsek et al. [16] could conceivably be due to suppression of Lyn activity in a population in which this tyrosine kinase contributes to proliferative capacity of the disease. However, previous reports have also shown that, despite the increased expression of genes located on chromosome 8, there is no consistent gene expression signature across trisomy 8 samples [24–26]. Although dasatinib is well-known to cause dose-proportional cytopenias, the study drug likely did not exacerbate cytopenias in responding or stable patients given the absence of improvement in peripheral blood counts upon drug withdrawal. The most common adverse events were consistent with those reported in CML, which included fatigue, dyspnea, and diarrhea, most of which were of grade 1 or 2 severity. Fluid retention and pleural effusions, which are well-described associations with this agent, were observed in only 2 patients in our study (both of which were less than grade 3). In conclusion, dasatinib has limited activity in patients with higher-risk MDS who have failed treatment with azanucleosides, but with acceptable toxicity. Although our sample size was small, patients with trisomy 8 may have higher rates of stable disease and response to treatment with this agent, which may merit further investigation. Conflicts of interest None. Acknowledgments We thank Rasa Hamilton (Moffitt Cancer Center) for editorial assistance. This study was funded by Bristol-Myers Squibb. Contributions. All authors contributed to the revisions of the manuscript and approved the final version. In addition: VHD participated in the acquisition and interpretation of the data and drafting of the manuscript. MVJ and LZ participated in the acquisition and interpretation of the data. VK participated in the conception and design of the study. JEL, RSK, and AFL participated in the concept, design, and acquisition and interpretation of the data. References [1] Prebet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol 2011;29:3322–7. [2] Lin K, Reljic T, Kumar A, Lancet JE, List AF, Komrokji RS. Poor outcome of patients with myelodysplastic syndrome (MDS) after azacitidine treatment failure. ASH Annual Meeting Abstracts 2010;116:2913.

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