Search

Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase–CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase–CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits.

BACKGROUND: Ponatinib is a third generation tyrosine kinase inhibitor (TKI) used to treat resistant chronic myeloid leukemia (CML). It has been associated with cardiovascular adverse events (CAEs); most specifically hypertension and arterial thrombotic events. Most CAEs are dose-dependent. The frequency of CAEs in the real-world setting has not been previously described. In this study, we describe the survival outcomes and associated toxicities in ponatinib-treated patients at Moffitt Cancer Center (MCC). METHODS: A retrospective review of CML patients treated with ponatinib at MCC between years 2011 and 2017 was performed to identify patients treated with ponatinib. Demographics, disease-specific variables and clinical outcomes were collected in accordance with the Institutional Board Review approved protocol. Frequency of adverse events on ponatinib were categorized. Pearson's chi-square test for independence was used to determine significance for categorical variables. Kaplan-Meier analysis with log-rank test was performed to estimate overall survival (OS). RESULTS: A total of 78 patients (38 females/40 males) treated with ponatinib with median age of 42.5 (range 14-70) years were included in the analysis. At the time of ponatinib initiation, 51 patients were in chronic phase (CP), 9 in accelerated phase (AP), and 18 in blast phase (BP). Ponatinib was 3rd or 4th line therapy in 65% of CP patients, with a mean starting dose of 39.65 mg per day. Dose reduction occurred in 64.7% of patients with CP and the mean duration of ponatinib was 14.6 months. The most common non-cardiovascular adverse events (NCAEs) were thrombocytopenia (39.7%), abdominal pain (33.3%), anemia (28.2%), elevated lipase (28.3%), and rash (26.9%) in a dose-dependent fashion. Most common new onset CAEs included arrhythmia (9%) and hypertension (7.7%). Three patients (3.8%) experienced a myocardial infarction, and two of these had significant cardiovascular risk factors at baseline. No other arterial thrombotic events were reported. A total of 18 patients (23.1%) experienced some form of CAE. Prior to 2014, more patients were placed on 45 mg ponatinib and more CAEs occurred during that time. After 2014, there is an increased awareness of potential cardiotoxicity associated with ponatinib and referral to cardio-oncology (CO) became a routine practice in our institution. Figure 1 summarizes the cardiac safety profile of ponatinib and frequency of CO referral. Ponatinib 45 mg and CAEs are not independent (X2 (1, N = 82) = 7.68, p < 0.05), but this correlation was lost when testing CAEs against patients who were on ponatinib 45 mg and either referred to CO or on cardiac protective medications (X2 (1, N = 82) = 3.55, p > 0.05) suggesting CAEs become independent of ponatinib dosing when cardioprotective measures are put in place. In patients with CP-CML, 69.6% achieved a complete cytogenetic response (CCyR) and 58.7% had a major molecular response (MMR). Patients with AP and BP achieved CCyR in 37.5% and 68.8%, respectively. Among the BP patients who achieved at least CCyR (n = 11), 81.1% of the patients had received TKI with chemotherapy at the time of BP. Five-year median OS of the entire cohort was 63%. With a median follow up of 32.5 months, the median OS from ponatinib initiation was not reached (NR) in CP with allogeneic stem cell transplantation (allo-SCT) (n = 17) or without allo-SCT (n = 34); was 32.9 months in AP with allo-SCT (n = 4), NR in AP without allo-SCT (n = 5); and NR in BP with allo-SCT (n = 6), and 5.45 months in BP without allo-SCT (n = 12) (p < 0.0001). CONCLUSIONS: In our series, the incidence of new arterial thrombotic events and hypertension appears lower than reported in the PACE trial. The incidence of CAEs declined after 2014 when early dose reductions became standard practice and early referrals to cardio-oncology increased. Non-CAEs and outcomes were similar to previous reports. Limitations of this analysis include its retrospective nature and small sample size. Future studies analyzing the impact of specific interventions on mitigating cardiovascular events are needed. Disclosures Sweet: BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Agios: Consultancy; BMS: Honoraria; Agios: Consultancy; Astellas: Consultancy; Phizer: Consultancy; Jazz: Speakers Bureau; Phizer: Consultancy; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau.

Introduction: The treatment of choice for newly diagnosed patients with advanced diffuse large B-cell lymphoma (DLBCL) is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) [Feugier P, Van Hoof A, Sebban C et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2005; 23: 4117-4126]. Anthracycline-based treatment is also superior to other drugs in controlling disease and prolonging survival in elderly patients [Hershman DL, McBride RB, Eisenberger A et al. Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin's lymphoma. J Clin Oncol 2008; 26: 3159-3165], however these individuals frequently have concomitant cardiac comorbidities such as congestive heart failure (CHF) that preclude the use of these agents. Methods: A search of the Moffitt Total Cancer Care™ database between January 1st 2008 and December 31st 2014 identified a cohort of 854 adult patients with a diagnosis of DLBCL. We performed a retrospective chart review of these patients and identified 40 individuals with documented CHF prior to the initiation of chemotherapy, due to either systolic (ejection fraction less than 50%) or diastolic dysfunction. The primary aim was to determine the chemotherapy regimens given to patients with DLBCL and CHF at Moffitt Cancer Center, and their related cardiovascular and oncologic outcomes. The study was approved by the University of South Florida Institutional Review Board. Results: 3 out of the 40 patients did not receive any chemotherapy and were excluded from the analysis. The median age was 71 years (range 21-93) with a median follow-up time of 19 months. Baseline characteristics are represented on table 1. Table 1.NPercentage (%)Sex1129.7FM2670.3Race38.1African AmericanAsian12.7White3389.2ECOG PS924.3011643.22821.6NA410.8Baseline Ejection fraction2156.8=50%1643.2Systolic Heart Failure1540.5NoYes1848.7UNK410.8Diastolic Heart Failure616.2NoYes1643.2UNK1540.5Ann Harbor Stage616.2III513.5III924.3IV1745.9 25 patients (67%) received R-CHOP or R-CHOP like (R-EPOCH) chemotherapy. The remaining patients received non R-CHOP regimens, being R-ICE (n=3), R-Hyper-CVAD (n=1), R-MTX (n=2), R-Bendamustine (n=2), R-CVP (n=2), R-CEOP (n=3). We observed an association between the type of treatment (R-CHOP vs non R-CHOP) and the type of heart failure, with diastolic CHF patients being more likely to receive a R-CHOP chemotherapy. (Table 2) Table 2.R-CHOPnon R-CHOPp-valueOR95% CINPercentage (%)NPercentage (%)Diastolic HFYes1588.2120.00.00530(2.14, 421.12)No211.8480.0Systolic HFYes731.811100 There was a trend toward better response to chemotherapy among patients with diastolic heart failure compared to systolic heart failure. We observed a larger number of cardiac events, defined as hospitalization for CHF, for cerebrovascular insult, for chest pain, for ischemic or non-ischemic cardiac events or cardiac-related deaths, in the group treated with R-CHOP, but this was not statistically significant, given low patients numbers. Although patients treated with a R-CHOP regimen demonstrated higher complete remission rates compared to non R-CHOP regimens (73.7% vs. 55.5% respectively), this result was not statistically significant (p=0.37), and there was no significant difference in overall survival or 2-year relapse free survival. Conclusion: To our knowledge, this is the largest series evaluating DLBCL treatment regimens in elderly patients with baseline cardiac dysfunction. This study demonstrated that elderly patients with DLBCL and baseline systolic CHF were more likely to receive non R-CHOP based regimens compared to patients with diastolic dysfunction. Non R-CHOP treatments seem to be better tolerated with fewer adverse cardiac events. The major limitations of this study are the small sample size from one center and the retrospective design. Future studies examining larger patient populations in a prospective fashion will provide more information about how to best treat DLBCL patients with heart failure. Disclosures No relevant conflicts of interest to declare.