TO THE EDITOR:
In a recent article, Chan et al1 described their experience with ponatinib at a single center in the United States in the real-world setting. They noted a decrease in cardiovascular adverse events (CAEs) after 2014 and correlated it with a reduction in the dose of ponatinib, along with consultations with the cardio-oncology clinic. However, the difference in CAEs between the pre- and post-2014 time periods did not reach statistical significance, and an equal number of patients developed a CAE, even on a lower dose of ponatinib (7, 11, and 7 events on 15 mg, 30 mg, and 45 mg, respectively). We would like to share our experience with using ponatinib in 21 patients across 3 centers in India to highlight the occurrence of CAEs at a lower dose of ponatinib. Ponatinib is not commercially available in India and was obtained with the help of the Max Foundation.2
A total of 21 patients with chronic myeloid leukemia (CML) were treated with ponatinib in our cohort, which included 16 males and 5 females with a median age of 39 years (range, 32-72). Most patients were in the chronic phase of disease (11; 52.7%), and 7 patients (33.3%) and 3 patients (14.3%) were in the accelerated phase and blast crisis phase, respectively. Only 1 patient had a cardiovascular risk factor at baseline (diabetes). Median prior lines of therapy was 2 (range, 1-4); 19 patients (90.4%), 13 patients (61.9%), and 10 patients (47.6%) had received imatinib, dasatinib, and nilotinib, respectively. Fourteen patients (66.7%) had a detectable T315I mutation. One patient defaulted from the therapy after 1 month and was excluded from the analysis.
Nine patients (45%) experienced dose reductions and interruptions, and only 10 patients (50%) received the standard dose of 45 mg once a day (OD) at onset. Median time from diagnosis to starting ponatinib was 68.5 months (range, 10-156), and median time on ponatinib was 10 months (range, 5-34). All patients, with the exception of 1 who was in blast crisis, were able to achieve or maintain a complete hematological response (CHR), whereas 5 patients (25%) achieved a major molecular response (MMR). None of the patients underwent an allogeneic stem cell transplant. The most common side effect was thrombocytopenia (11 patients; 55%), followed by skin rash (6 patients; 30%). Grade 3/4 cytopenias were seen in 9 patients (45%). These adverse effects happened even when patients were taking 15 mg OD of ponatinib. One of the patients experienced a rare ichthyosis-like skin eruption after starting ponatinib.3 Two patients experienced pancreatitis while on ponatinib. Individual patient details are given in Table 1.
Individual patient characteristics
| Patient . | Age, y . | Sex . | Diagnosis . | Time from diagnosis to starting ponatinib, mo . | Ponatinib dose (OD), mg . | Best response . | Adverse event . | Timing of adverse event . | Intervention . |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 35 | Male | CML-AP; T315I mutation | 48 | 30 | CHR | Coronary artery disease (triple-vessel disease) on evaluation for dyspnea; underwent CABG | 5 mo after ponatinib | Ponatinib stopped |
| 2 | 72 | Male | CML-AP; T315I mutation | 16 | 15 | CHR | Thrombocytopenia (grade 4) | 2 mo after ponatinib | Intermittent discontinuation and dose reduction† of ponatinib |
| 3 | 34 | Male | CML-AP; T315I mutation | 73 | 30 | CHR | Thrombocytopenia (grade 4) | 1 mo after ponatinib | Intermittent discontinuation and dose reduction† of ponatinib |
| 4 | 35 | Male | CML-CP; F317L mutation | 121 | 30 | CHR | Thrombocytopenia (grade 3) | 1 mo after ponatinib | Ponatinib continued |
| 5 | 55 | Female | CML-CP; T315I mutation | 90 | 30 | MMR | Skin rash, small vessel vasculitis on skin biopsy | 1 mo after ponatinib | Intermittent discontinuation and dose reduction† of ponatinib |
| 6 | 65 | Female | CML-CP | 43 | 30 | CHR | Skin rash | 2 mo after ponatinib | Ponatinib continued with oral prednisolone |
| 7* | 58 | Male | CML-CP; T315I mutation | 99 | 45 | CHR | Peripheral vascular disease, coronary artery disease. Died from heart failure | 4 mo after ponatinib | Ponatinib stopped |
| 8 | 43 | Male | CML-AP; T315I mutation | 156 | 30 | CHR | Thrombocytopenia (grade 4), skin rash | 2 mo after ponatinib | Intermittent discontinuation and dose reduction† of ponatinib |
| 9* | 47 | Female | CML-AP; T315I mutation | 80 | 30 | MMR | Desquamating skin rash. Died from acute coronary event. | Skin rash after 2 mo of ponatinib, cardiac event after 6 mo of ponatinib | Intermittent discontinuation and dose reduction† of ponatinib after skin rash |
| 10 | 35 | Male | CML-CP | 48 | 45 | MMR | Thrombocytopenia (grade 3), skin rash | 7 mo after ponatinib | Ponatinib continued |
| 11 | 38 | Male | CML-CP; T315I mutation | 64 | 45 | MMR | — | — | — |
| 12 | 38 | Male | CML-BC | 15 | 45 | CHR | Thrombocytopenia (grade 4) | 4 mo after ponatinib | Ponatinib continued |
| 13 | 35 | Male | CML-CP; T315I mutation | 10 | 45 | MMR | — | — | — |
| 14 | 35 | Female | CML-CP; T315I mutation | 110 | 15 | CHR | Thrombocytopenia (grade 4) | 1 mo after ponatinib | Ponatinib continued |
| 15 | 37 | Male | CML-CP; F311L mutation | 126 | 45 | CHR | Thrombocytopenia (grade 1) | 2 mo after ponatinib | Ponatinib continued |
| 16 | 32 | Male | CML-BC | 43 | 45 | CHR | Thrombocytopenia (grade 1) | 1 mo after ponatinib | Ponatinib continued |
| 17 | 39 | Female | CML-AP; T315I mutation | 99 | 45 | CHR | Thrombocytopenia (grade 4) | 2 mo after ponatinib | Ponatinib continued |
| 18* | 47 | Male | CML-AP; T315I mutation | 126 | 45 | CHR | Thrombocytopenia (grade 4), skin rash, venous thromboembolism. Died from progressive disease. | 4 mo after ponatinib | Intermittent discontinuation of ponatinib |
| 19 | 60 | Male | CML-CP; T315I mutation | 39 | 45 | CHR | — | — | — |
| 20 | 39 | Male | CML-BC; T315I mutation | 23 | 30 | CHR not achieved | Pancreatitis | 1 mo after ponatinib | Intermittent discontinuation of ponatinib |
| Patient . | Age, y . | Sex . | Diagnosis . | Time from diagnosis to starting ponatinib, mo . | Ponatinib dose (OD), mg . | Best response . | Adverse event . | Timing of adverse event . | Intervention . |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 35 | Male | CML-AP; T315I mutation | 48 | 30 | CHR | Coronary artery disease (triple-vessel disease) on evaluation for dyspnea; underwent CABG | 5 mo after ponatinib | Ponatinib stopped |
| 2 | 72 | Male | CML-AP; T315I mutation | 16 | 15 | CHR | Thrombocytopenia (grade 4) | 2 mo after ponatinib | Intermittent discontinuation and dose reduction† of ponatinib |
| 3 | 34 | Male | CML-AP; T315I mutation | 73 | 30 | CHR | Thrombocytopenia (grade 4) | 1 mo after ponatinib | Intermittent discontinuation and dose reduction† of ponatinib |
| 4 | 35 | Male | CML-CP; F317L mutation | 121 | 30 | CHR | Thrombocytopenia (grade 3) | 1 mo after ponatinib | Ponatinib continued |
| 5 | 55 | Female | CML-CP; T315I mutation | 90 | 30 | MMR | Skin rash, small vessel vasculitis on skin biopsy | 1 mo after ponatinib | Intermittent discontinuation and dose reduction† of ponatinib |
| 6 | 65 | Female | CML-CP | 43 | 30 | CHR | Skin rash | 2 mo after ponatinib | Ponatinib continued with oral prednisolone |
| 7* | 58 | Male | CML-CP; T315I mutation | 99 | 45 | CHR | Peripheral vascular disease, coronary artery disease. Died from heart failure | 4 mo after ponatinib | Ponatinib stopped |
| 8 | 43 | Male | CML-AP; T315I mutation | 156 | 30 | CHR | Thrombocytopenia (grade 4), skin rash | 2 mo after ponatinib | Intermittent discontinuation and dose reduction† of ponatinib |
| 9* | 47 | Female | CML-AP; T315I mutation | 80 | 30 | MMR | Desquamating skin rash. Died from acute coronary event. | Skin rash after 2 mo of ponatinib, cardiac event after 6 mo of ponatinib | Intermittent discontinuation and dose reduction† of ponatinib after skin rash |
| 10 | 35 | Male | CML-CP | 48 | 45 | MMR | Thrombocytopenia (grade 3), skin rash | 7 mo after ponatinib | Ponatinib continued |
| 11 | 38 | Male | CML-CP; T315I mutation | 64 | 45 | MMR | — | — | — |
| 12 | 38 | Male | CML-BC | 15 | 45 | CHR | Thrombocytopenia (grade 4) | 4 mo after ponatinib | Ponatinib continued |
| 13 | 35 | Male | CML-CP; T315I mutation | 10 | 45 | MMR | — | — | — |
| 14 | 35 | Female | CML-CP; T315I mutation | 110 | 15 | CHR | Thrombocytopenia (grade 4) | 1 mo after ponatinib | Ponatinib continued |
| 15 | 37 | Male | CML-CP; F311L mutation | 126 | 45 | CHR | Thrombocytopenia (grade 1) | 2 mo after ponatinib | Ponatinib continued |
| 16 | 32 | Male | CML-BC | 43 | 45 | CHR | Thrombocytopenia (grade 1) | 1 mo after ponatinib | Ponatinib continued |
| 17 | 39 | Female | CML-AP; T315I mutation | 99 | 45 | CHR | Thrombocytopenia (grade 4) | 2 mo after ponatinib | Ponatinib continued |
| 18* | 47 | Male | CML-AP; T315I mutation | 126 | 45 | CHR | Thrombocytopenia (grade 4), skin rash, venous thromboembolism. Died from progressive disease. | 4 mo after ponatinib | Intermittent discontinuation of ponatinib |
| 19 | 60 | Male | CML-CP; T315I mutation | 39 | 45 | CHR | — | — | — |
| 20 | 39 | Male | CML-BC; T315I mutation | 23 | 30 | CHR not achieved | Pancreatitis | 1 mo after ponatinib | Intermittent discontinuation of ponatinib |
AP, accelerated phase; BC, blast crisis; CABG, coronary artery bypass graft surgery; CP, chronic phase.
Died during follow-up.
If on 15 mg, ponatinib was reduced to alternate days.
CAEs were seen in 4 patients (20%). The first patient had underlying diabetes and was started on ponatinib, 45 mg once daily. He experienced exacerbation of preexisting peripheral vascular disease and underwent amputation of his left lower limb. He later developed active ischemic heart disease and underwent a coronary artery bypass but ultimately succumbed to heart failure. The second patient did not have any cardiovascular risk factors at baseline and was on 15 mg of ponatinib. He developed an acute coronary event and died after 6 months of ponatinib therapy. The third patient also did not have any cardiovascular risk factors and was on 30 mg of ponatinib. He developed coronary artery disease and underwent a coronary artery bypass 5 months after starting ponatinib. Three patients in the cohort died: 2 from cardiovascular events and 1 from progressive disease.
Our experience showed the occurrence of CAEs, even with lower doses of ponatinib. In the 5-year analysis of the PACE trial, 50% of the patients experienced their first arterial occlusive event (AOE) while on reduced-dose ponatinib. In fact, 7% of the patients developed their first AOE after stopping ponatinib. Among CML patients in the chronic phase of disease, there was no difference in the occurrence of AOEs between patients who underwent a preemptive dose reduction and those who continued on the same dose of ponatinib after October 2013 (18% vs 19%).4 Robust screening for reversible cardiovascular risk factors, such as dyslipidemia, hypertension, and smoking, may reduce the occurrence of CAEs in patients on ponatinib. In this regard, the creation of a dedicated cardio-oncology team and timely referrals, as suggested by Chan et al,1 may be beneficial. The emerging data regarding the use of asciminib in triple-refractory/intolerant patients are encouraging.5
Data sharing requests should be sent to Pankaj Malhotra (id-hematpgi@gmail.com).
Acknowledgments:
The authors thank The Max Foundation CEO, Pat Garcia-Gonzalez, and South Asia Region Head, Viji Venkatesh, as well as their passionate team, for providing treatment and support to our patients. The authors also thank Takeda for support in ensuring access to ICLUSIG through Max Access Solutions.
Contribution: C.S., A.J., D.L., G.P., A.K., N.V., and P.M. were involved in patient management; D.B., R.A., N.A., and J.E. contributed data from their centers; C.S. wrote the paper; and P.M. edited the paper.
Conflict-of-interest disclosure: The authors declare no competing financial interest.
Correspondence: Pankaj Malhotra, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India; e-mail: hematpgi@gmail.com.
