A phase II study of omacetaxine mepesuccinate for patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia after failure of hypomethylating agents

Abstract

The outcome of patients with myelodysplastic syndromes (MDS) after failure of hypomethylating agents (HMAs) failure is poor with a median overall survival (OS) of only 4–6 months. Omacetaxine mepesuccinate (OM) is safe and effective in myeloid malignancies but has not been studied in MDS with HMA failure. We conducted a phase II study of OM in patients with MDS or chronic myelomonocytic leukemia (CMML) who had previously failed or been intolerant to HMAs. Patients received OM at a dose of 1.25 mg/m² subcutaneously every 12 hours for 3 consecutive days on a 4–7 week schedule. The primary endpoints were the overall response rate (ORR) and OS. Forty-two patients were enrolled with a median age of 76 years. The ORR was 33%. Patients with diploid cytogenetics were more likely to respond to OM than were those with cytogenetic abnormalities (58% versus 23%, respectively; P=0.03). Overall, the median OS was 7.5 months and 1-year OS rate was 25%. Patients with diploid cytogenetics had superior OS to those with cytogenetic abnormalities (median OS 14.8 versus 6.8 months, respectively; P=0.01). Two patients had ongoing response to OM of 2 years or longer (both MDS with diploid cytogenetics and RUNX1 mutation). The most common grade ≥3 adverse events were infections in 11 patients (26%), febrile neutropenia in 4 (10%), and hemorrhage in 3 (7%). Overall, OM was safe and active in patients with MDS or CMML who experienced HMA failure. These results support the further development of OM in this setting.

Introduction

For patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), the use of hypomethylating agents (HMAs) such as azacitidine and decitabine is standard of care.^1,2 Responses are achieved in up to 40% of patients; however, HMA therapy is not curative and patients nearly universally lose response. For patients who do not respond to HMAs or who subsequently relapse, the outcomes are dismal with a median overall survival (OS) of only 4–6 months for patients with higher-risk MDS.^3,4 In the setting of MDS with HMA failure, there is no clear standard of care.

Omacetaxine mepesuccinate (OM), or semisynthetic homoharringtonine (HHT), is a protein synthesis inhibitor that inhibits protein translation via interaction with the ribosomal A-site.⁵ This leads to downregulation of proteins that regulate cell proliferation and survival, eventually leading to apoptosis of leukemic cells. HHT and OM are active in a variety of myeloid malignancies, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and MDS. Several older studies have evaluated HHT in patients with AML and MDS using continuous intravenous (IV) infusions of higher doses of HHT. Using doses of 5–7 mg/m² IV continuously for 7–9 days, complete response (CR) rates of 16–25% were achieved in patients with relapsed or refractory AML.^6,7 In a frontline study of HHT in MDS or AML arising from MDS, the CR rate was 25%.⁸ In another small pilot study of HHT in patients with MDS, 1 of 9 patients (11%) achieved CR.⁹ Despite its clinical activity, these high doses of continuous IV HHT resulted in high rates of myelosuppression and cardiovascular toxicity, including severe hypotension and tachycardia, which limited its development for these diseases.

Given the excellent bioavailability of subcutaneous OM and its ability to be administered in the outpatient setting¹⁰, OM was subsequently developed as a treatment for CML. Based on promising clinical activity in several phase II studies, OM was granted U.S. Food and Drug Administration approval in October 2012 for treatment of adults with chronic- or accelerated-phase CML who are resistant and/or intolerant to two or more tyrosine kinase inhibitors.¹¹ Of note, OM is able to overcome the BCR-ABL T315I resistance mutation, which confers resistance to all commercially available tyrosine inhibitors, except ponatinib.^12,13 The approved dose of OM for patients with CML is 1.25 mg/m² subcutaneously twice daily for 14 consecutive days, followed by 7-day schedules of OM after hematologic response is achieved. With these 7- and 14-day schedules, the cardiovascular toxicities of OM are attenuated, although myelosuppression is still a notable issue.

Despite the established clinical activity of HHT/OM in MDS and AML, no study has evaluated OM in MDS after treatment with HMAs. Furthermore, to our knowledge, shorter schedules of OM have not been explored. We therefore designed a phase II study to evaluate the efficacy and safety of a 3-day schedule OM in patients with MDS or CMML who have experienced HMA failure or intolerance.

Methods

Patients

Patients were required to have one of the following: 1.) MDS with 5–29% blasts, 2.) CMML with 5–19% blasts and/or 3.) MDS or CMML classified as either intermediate-1, intermediate-2, or high-risk by the International Prognostic Scoring System (IPSS).¹⁴ Eligible patients must also have previously failed or been intolerant to HMA therapy with azacitidine or decitabine. HMA failure and intolerance were defined as lack of response, progression, or relapse following ≥4 cycles of HMAs and/or drug-related grade 3 or 4 hepatic or renal toxicity leading to HMA discontinuation during the preceding 2 years. Patients were required to have a European Cooperative Oncology Group performance status of 0–2 and adequate renal and hepatic function, including a total bilirubin <1.5 mg/dL, ALT/AST <2.5 times the upper limit of normal, and serum creatinine ≤1.5 mg/dl. Patients eligible for hematopoietic stem cell transplantation were excluded from the study. This study was approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center and was registered at ClinicalTrials.gov ( NCT02159872). All patients provided informed consent according to institutional guidelines and the Declaration of Helsinki.

Treatment

OM was given at a dose of 1.25 mg/m² subcutaneously every 12 hours for 3 days (i.e. 6 doses per cycle). A cycle was 4–7 weeks in duration, as permitted by peripheral blood count recovery and resolution of any intercurrent illnesses. Responding patients could receive up to 24 cycles of OM. Dose reductions or delays for toxicities were allowed. Bone marrow aspiration and/or biopsy were performed at the end of cycle 2 and then every 2–3 cycles thereafter.

Gene sequencing

Mutation analysis was performed using a 28-gene panel as previously described within 2 months prior to enrollment.^15–17 Genomic DNA was extracted from bone marrow aspirates or peripheral blood. Amplicon-based next-generation sequencing targeting the entire coding regions of a panel of 28 genes associated with myeloid neoplasms was performed using a MiSeq platform (Illumina, San Diego, CA). The genes analyzed included ABL1, ASXL1, BRAF, DNMT3A, EGFR, EZH2, FLT3, GATA1, GATA2, HRAS, IDH1, IDH2, IKZF2, JAK2, KIT, KRAS, MDM2, MLL, MPL, MYD88, NOTCH1, NPM1, NRAS, PTPN11, RUNX1, TET2, TP53, and WT1. For clinical reporting, a minimum sequencing coverage of 250X (bi-directional true paired-end sequencing) was required. The analytical sensitivity was established at 5% mutant reads in a background of wild-type reads. Previously described somatic mutations registered at the Catalogue of Somatic Mutations in Cancer (COSMIC: http://cancer.sanger.ac.uk/cosmic) were considered as potential driver mutations.

Statistical Methods

The primary objectives of this phase II study were the overall response rate (ORR) and OS of the regimen. Secondary objectives include the RFS and safety profile of OM. Responses were coded according to the modified 2006 International Working Group (IWG) criteria.¹⁸ Differences among variables were evaluated by the Chi-square test and Mann–Whitney U test for categorical and continuous variables, respectively. RFS and OS were calculated with Kaplan-Meier estimates, and survival estimates were compared with the log-rank test. Relapse-free survival (RFS) was calculated from the time of CR, marrow CR, or hematologic improvement (HI) until relapse or death. OS was calculated from the time of treatment initiation until death. The data cutoff for this analysis was January 1, 2018. The data analyses were done using GraphPad Prism 6.

Results

Patient Characteristics

Between February 2015 and November 2017, 42 patients were enrolled. Baseline patient characteristics are shown in Table 1. The median age was 76 years (range, 61–87 years) and median bone marrow blasts was 10% (range, 2–20%). Most patients (81%) had a diagnosis of MDS. Nineteen patients (45%) had received at least 2 prior therapies. The median number of prior cycles of HMA was 9 (range, 3–62 cycles). Twenty-seven patients (64%) had relapsed after prior HMA, 14 patients (33%) were refractory to HMA, and 1 patient (2%) was intolerant to HMA. Cytogenetics were poor-risk in 17 patients (40%), and 32 patients (76%) had intermediate-2 or high-risk disease by IPSS. A TP53 mutation was identified in 12 patients (29%). A detailed list of mutations by patient is shown in Supplemental Table 1.

Table 1.

Baseline characteristics (N=42)

Baseline Characteristics	n (%) / median [range]
Age, years	76 [61–87]
Diagnosis  MDS  CMML	34 (81) 8 (19)
WBC, 109/L	2.2 [0.5–58.4]
Hemoglobin, g/dL	9.1 [6.1–12.8]
Platelets, 109/L	35 [3–151]
BM blasts, %	10 [2–20]
Cytogenetics  −5, −7 and/or complex  Diploid  Others	17 (40) 12 (29) 13 (31)
IPSS risk group  Intermediate-1  Intermediate-2  High	10 (24) 24 (57) 8 (19)
IPSS-R risk group  Low  Intermediate  High  Very high	1 (2) 7 (17) 15 (36) 19 (45)
Therapy-related MDS/CMML	4 (10)
≥2 prior therapies	19 (45)
Number of prior cycles of HMA	9 [3–62]
Prior response to HMA  Relapsed  Refractory  Intolerant	27 (64) 14 (33) 1 (2)
Performance status≥2	5 (12)
Mutational analysis*  TP53  RUNX1  ASXL1  TET2  KRAS/NRAS  IDH1/2  DNMT3A  WT1  EZH2  No mutations identified	12 (29) 11 (26) 8 (19) 4 (10) 3 (7) 2 (5) 2 (5) 2 (5) 2 (5) 9 (21)

^*Mutations identified in at least 2 patients are included in the table.

Response Rates

Fourteen patients (33%) had a response to OM: 13 (31%) achieved marrow CR and 1 achieved HI (2%). One of the 13 patients who achieved marrow CR also met criteria for HI of neutrophils. The median number of cycles to best response was 2 (range, 1–9 cycles). Six patients (14%) had stable disease and received 4 cycles (n=4), 6 cycles (n=1) or 8 cycles (n=1) of OM. Four patients (10%) died prior to response assessment, and 18 (43%) did not respond to OM nor achieve stable disease (i.e. treatment failure). Of the 7 patients with abnormal cytogenetics at baseline who responded to OM, only 1 (14%) achieved complete cytogenetic response (i.e. diploid karyotype) at the time of best response. Responses by disease, cytogenetics and mutation status are shown in Figure 1. In a post hoc analysis of predictors for response, no difference in response to OM was observed among patients with respect to age, white blood cell count, hemoglobin, platelets, bone marrow blast percentage, diagnosis of MDS versus CMML, IPSS or IPSS-R risk group, or prior response to HMA (i.e. relapsed versus refractory). Only cytogenetics predicted for response. Patients with diploid cytogenetics had a significantly higher response rate to OM than did patients with cytogenetic abnormalities (58% versus 23%, respectively; P=0.03). Among the 17 patients with poor-risk cytogenetics, 4 patients responded to OM (24%). No differences in response were observed according to presence of either TP53 mutation (25% versus 37% for wild type; P=0.47) or RUNX1 mutation (45% versus 30% for wild type; P=0.36).

Figure 1. Response rates by disease, cytogenetics and mutation status.

Responses (black [marrow CR] or gray [hematologic improvement]) are shown according to disease (blue), cytogenetics (green) and mutations (red).

Survival Outcomes

With a median duration of follow-up of 25 months, the median RFS was 5.3 months, and the 1-year RFS rate was 34% (Figure 2A). Of the 14 responders, 4 remain on study, 7 subsequently lost response, 2 died while in response (both from infection-related complications), and 1 was lost to follow-up. No patients underwent subsequent hematopoietic stem cell transplantation. Among the 7 patients who lost response, the median time to relapse was 5.0 months (range, 2.9–8.5 months).

Figure 2. Survival outcomes.

(A) Relapse-free survival and (B) overall survival.

The median OS was 7.5 months and 1-year OS rate was 25% (Figure 2B). In a post hoc analysis of predictors for survival, OS was significantly longer in patients who responded to OM compared to those who did not (median OS 8.2 versus 6.3 months, and 1-year OS rate 41% versus 16%, respectively; P=0.02). Similarly, patients with diploid cytogenetics had superior OS to those with cytogenetic abnormalities (median OS 14.8 versus 6.8 months, and 1-year OS rate 53% versus 14%, respectively; P=0.01). No other baseline factors predicted for OS in patients treated with OM. At last follow-up, two patients were alive with ongoing response to OM after 24 and 30 months. Both of these patients had MDS with diploid cytogenetics and RUNX1 mutation.

Treatment Intensity, Safety, and Early Mortality

The median number of cycles of OM received was 3 (range, 1–23 cycles). Four patients (10%) received treatment with OM for at least 1 year. Table 2 shows the adverse events observed in patients treated on this study. Treatment was overall well-tolerated with most adverse events being grade 1–2. Grade ≥3 adverse events were observed in 15 patients (36%). The most common grade ≥3 adverse events were infections in 11 patients (26%), febrile neutropenia in 4 (10%), and hemorrhage in 3 (7%). The infections included pneumonia (n=6), sepsis (n=2), bacteremia (n=1), urinary tract infection (n=1), and upper respiratory tract infection (n=1). Of the hemorrhagic episodes, two were upper gastrointestinal bleeding and one was subarachnoid hemorrhage after a fall. Of 39 patients who received ≥2 cycles of OM, 8 (21%) required dose reduction. The 30-day and 60-day mortality rates were 10% and 14%, respectively.

Table 2. Adverse events.

Adverse events of any grade observed in ≥10% of patients and all grade ≥3 adverse events are shown. Events are reported regardless of attribution to the study drug.

Adverse event	Grade 1–2, n (%)	Grade ≥3, n (%)	All grades, n (%)
Fatigue	19 (45)	4 (10)	23 (55)
Nausea/vomiting	20 (48)	0	20 (48)
Infection	1 (2)	11 (26)	12 (29)
Dyspnea	6 (14)	1 (2)	7 (17)
Edema	6 (14)	0	6 (14)
Dizziness	4 (10)	1 (2)	5 (12)
Febrile neutropenia	0	4 (10)	4 (10)
Mouth Sores	4 (10)	0	4 (10)
Forgetfulness	4 (10)	0	4 (10)
Hemorrhage	0	3 (7)	3 (7)
Hyperglycemia	1 (2)	1 (2)	2 (5)
Pain	0	2 (5)	2 (5)
Cardiac ischemia	0	1 (2)	1 (2)
Atrial fibrillation	0	1 (2)	1 (2)

Discussion

The outcomes of patients with high-risk MDS who experience HMA failure is poor, with a median OS of only 4–6 months, and there is no standard of care for these patients. Outside of a clinical trial, therapeutic options for patients with high-risk MDS with HMA failure include switch to an alternative HMA (e.g. azacitidine to decitabine, or vice versa) or combination chemotherapy.¹⁹ However, HMA switch is associated with a modest response rate of only approximately 20% with most responses being generally short-lived.²⁰ Chemotherapy is generally reserved for fit patients without adverse-risk karyotype or mutations. In one study of MDS with HMA failure, low-dose chemotherapy resulted in no responses (out of 18 patients), whereas the response rate with intensive chemotherapy was 14% (3 out of 22 patients).⁴ Allogeneic stem cell transplantation appeared to result in the best responses for these patients (68%), although this is a viable option for only a small minority of patients due to the relatively older age of many patients with MDS. Given the limited options for patients with MDS who experience HMA failure, active and tolerable agents that are capable of prolonging survival are needed.

In the present study, OM was found to be safe and active in patients with MDS or CMML who experienced HMA failure, with an ORR of 33% and median OS of 7.5 months. Of note, this was a particularly poor-risk group of patients, with a median age of 76 years, 40% of patients with poor-risk cytogenetics, 45% having received at least 2 prior therapies. Despite these poor-risk features, the OS in this study was better than that reported in other studies of MDS with HMA failure.^3,4 This favorable survival appears to be largely driven by response to OM, given that responders had a significantly longer 1-year OS rate than did non-responders (41% versus 16%). It is notable that 2 patients had prolonged benefit from OM therapy, with survival of 2 or more years.

Although 13 of the 14 responders achieved marrow CR, no CRs were observed. There are two potential explanations for the incomplete hematologic improvement observed in these responders to OM. One possibility is that this incomplete count recovery may in part be explained by the myelosuppressive effects of OM, as grade ≥3 thrombocytopenia, neutropenia, or anemia were reported in 68%, 46%, and 36% of patients, respectively, who were treated with OM for chronic phase CML.²¹ However, the doses of OM used in this study were significantly lower than those used in CML (i.e. 3-day regimen versus 14-day induction and 7-day consolidation regimen), and therefore the myelosuppressive effects of OM are expected to be less. Alternatively, responses to OM may not have been sufficiently deep to lead to full count recovery. This is suggested by the fact that only 1 out of 7 responders achieved a complete cytogenetic response at the time of best response; this level of cytogenetic response may act as a kind of marker of minimal residual disease and is associated with more durable remissions and prolonged survival in patients with MDS treated with HMAs.^22,23

Although there is no standard of care regimen for patients with MDS and HMA failure, several agents and combination regimens have shown promise in this setting. These include novel HMAs (e.g. guadecitabine), immune check point inhibitors (e.g. nivolumab, pembrolizumab, and ipilimumab), Bcl-2 inhibitors (e.g. venetoclax) and multikinase inhibitors (e.g. rigosertib), among others.¹⁹ Low-dose chemotherapy combinations are also effective in MDS after HMA failure. In one study, the combination of clofarabine and low-dose cytarabine resulted in an ORR of 44% and a median OS of 10 months.²⁴ Similar to the present study in which patients with diploid cytogenetics were more likely to respond to OM than were patients with other cytogenetic abnormalities (58% versus 23%, respectively), the response rate among patients with diploid karyotype treated with clofarabine plus low-dose cytarabine was 64%. It is notable that the ORR with this combination regimen appears superior to that achieved with single-agent oral clofarabine, in which a response rate of 30% was reported in patients with HMA failure.²⁵ Similarly, the addition of other agents (e.g. clofarabine, low-dose cytarabine, rigosertib, etc.) may further improve the responses with OM.

In conclusion, in patients with MDS or CMML who experienced HMA failure, OM resulted in an ORR of 33% and a median OS of 7.5 months. Although responses were observed across cytogenetic risk groups, patients with diploid cytogenetics were most likely to respond, with an ORR of 58% in this subgroup, and some patients experienced durable responses of 2 years or more. Given the lack of effective options for patients after HMA failure, these results support the further development of OM in this setting, including combination therapies.