A total of 33 patients with CML and 17 with Ph+ ALL were included in this registry (Table 1). Among the CML patients, 30 were in chronic phase, 1 in accelerated phase, 1 in blastic myeloid phase, and 1 in blastic lymphoid phase. Out of 11 CML and 10 Ph+ ALL patients with mutations in the BCR-ABL1 kinase domain, 6 (55%) CML and 6 (60%) Ph+ ALL patients had the T315I mutation. No mutations were detected in 19 (58%) patients with CML and 7 (41%) patients with Ph+ ALL, and mutation status was not determined for 3 (9%) patients with CML. Median age was 58 (19–83) years for CML and 56 (28–80) years for Ph+ ALL patients (Table 1). In total, 39% of CML and 35% of Ph+ ALL patients had a history of cardiovascular disease, 33% of CML and 35% of Ph+ ALL patients presented with arterial hypertension, 15% of CML and 18% of Ph+ ALL patients had diabetes mellitus, 12% of CML and 6% of Ph+ ALL patients had hyperlipidemia, and 30% of CML and 18% of Ph+ ALL patients were smokers. One patient with Ph+ ALL had a history of heart failure.
Among patients with CML, 3 (9%) received 1 previous line of TKI treatment (all with T315I mutation), 12 (36%) received 2 previous lines, and 18 (55%) received 3 or more previous lines (Table 1). The corresponding numbers among Ph+ ALL patients were 1 (6%), 11 (65%), and 5 (29%), respectively. None of the Ph+ ALL patients had received more than 3 lines of different TKIs. Imatinib was the most commonly used first-line TKI, being used by 22 (67%) CML and 16 (94%) Ph+ ALL patients, while dasatinib was the most common second-line TKI, used in 19 (58%) CML and 14 (82%) Ph+ ALL patients. Nilotinib was used as a third-line therapy in 7 (21%) CML and 4 (24%) Ph+ ALL patients, and bosutinib as a fourth-line therapy in 4 (12%) CML patients. Two (6%) patients with CML and 6 (35%) patients with Ph+ ALL had received an allogeneic stem cell transplantation prior to ponatinib treatment.
Treatment with ponatinib was started in 14 patients with CML due to intolerance to previous TKI (42%), in 6 patients due to progression on previous TKI (18%), in 9 patients due to relapse or refractoriness (absence of response, primary refractoriness, hematological or cytogenetic relapse) to previous TKI (27%), and in 4 patients due to the T315I mutation (12%). Among Ph+ ALL patients, reasons to start treatment with ponatinib were intolerance to previous TKI (6, 35%), disease progression (2, 12%), relapse or refractoriness (absence of response, primary refractoriness, hematological or cytogenetic relapse [5, 30%]), or the T315I mutation (4, 24%) (Fig. 2).
The time from CML or Ph+ ALL diagnosis and the start of ponatinib treatment varied, ranging from 44 to 8139 days for CML patients and from 158 to 3632 days for Ph+ ALL patients. The majority of patients (70% of CML and 76% of Ph+ ALL) received ponatinib at the starting dose of 45 mg/day. The starting dose of 30 mg/day was used in 12% of patients with CML and in 12% of patients with Ph+ ALL, and the starting dose of 15 mg/day was used in 15% of patients with CML and in 12% of patients with Ph+ ALL. One patient with CML started the therapy with 15 mg of ponatinib every other day. There was a difference over time in the proportion of CML patients receiving the registered 45 mg/day starting dose of ponatinib: Among the first 10 patients included in the registry, 86% of CML patients received a starting dose of 45 mg/day, while in the last 10 included patients, only 43% of CML patients started with 45 mg/day.
The median follow-up was 449 days (range, 15–2777) and 135 days (range, 26–2114) for patients with CML and Ph+ ALL, respectively. The median duration of ponatinib treatment was 380 days (range, 15–2777) for CML patients and 123 days (range, 13–2114) for Ph+ ALL patients. A swimmer plot detailing treatment duration and outcomes and of all individual patients in the registry is presented in Fig. 3.
MMR (BCR-ABL1 mRNA ≤0.1%) was achieved as best response by 26 patients: 19 (58%) patients with CML and 7 (41%) patients with Ph+ ALL (Fig. 4). Of the CML patients who started with ponatinib at 45 mg/day, 30 mg/day, and 15 mg/day, respectively, 15 out of 23 (65%), none out of 4 and 3 out of 5 (60%) achieved MMR as best response. Also, the only CML patient starting at 15 mg every other day achieved MMR. Of the Ph+ ALL patients who started with 45 mg/day, 30 mg/day, and 15 mg/day, respectively, 6 out of 13 (46%), none out of 2 and 1 out of 2 (50%) achieved MMR as best response. Two (6%) patients with CML and 3 (18%) patients with Ph+ ALL achieved CCyR as best response (including 1 patient with Ph+ ALL who had CCyR before starting ponatinib treatment) and 1 patient from each group (3% and 6% of CML and Ph+ ALL patients, correspondingly) achieved BCR-ABL1 mRNA ≤1% as best response. Nine (27%) patients with CML and 2 (12%) patients with Ph+ ALL did not achieve any response. The median time to best response was 151 days (range, 26–616) for patients with CML and 49 days (range, 14–308) for patients with Ph+ ALL. Among the 20 patients who started ponatinib because of intolerance to previous TKIs, MMR was achieved as best response by 9 (64%) CML and 4 (67%) Ph+ ALL patients and 1 (7%) CML patient achieved BCR-ABL1 mRNA ≤1% (Fig. 4). The median time to best response in patients who started ponatinib due to previous TKI intolerance was 159 days (range, 51–431) in patients with CML and 73 days (range, 14–308) in patients with Ph+ ALL. Among the 30 patients who started ponatinib for reasons other than intolerance to previous TKI(s), 10 (53%) patients with CML and 3 (27%) patients with Ph+ ALL achieved MMR as best response. The median time to best response in these patients was 140 days (range, 26–616) and 36 days (range, 19–97), respectively. A sensitivity analysis, excluding the 3 CML patients in accelerated or blastic phase, did not show any difference in the percentage of CML patients who started ponatinib due to intolerance and who achieved MMR as best response compared to those who did not show intolerance with MMR as best response.
Estimated OS was 85.3% for CML and 85.6% for Ph+ ALL patients over 3 years of the registry duration. Estimated PFS was 81.6% for CML and 48.9% for Ph+ ALL patients (Fig. 5).
Dose reductions occurred in 20 (61%) CML and 7 (41%) Ph+ ALL patients, and dose increases occurred in 14 (42%) and 3 (18%) patients with CML and Ph+ ALL, respectively (Table 2). Dose reductions or interruptions occurred mostly due to AEs, but also to prevent future AEs as part of a risk management strategy in CML and Ph+ ALL patients. Reasons for dose increases in CML patients and Ph+ ALL patients were absent or poor response and good tolerance to a lower dose of ponatinib. Treatment interruptions were registered in 11 (33%) CML and 5 (29%) Ph+ ALL patients, with a median duration of interruption of 24 days (range, 7–126) in CML and 20 days (range, 12–201) in Ph+ ALL patients. In total, 15 CML (45%) and 14 (82%) Ph+ ALL patients terminated the treatment with ponatinib. Eight CML patients and 3 Ph+ ALL patients terminated treatment due to an AE.
In general, results in the subgroup of patients who underwent an allogeneic stem cell transplantation before starting ponatinib were in line with the overall population. Of the 8 patients treated in the NPP who were included in this registry, 6 patients are currently still on treatment and achieved MMR. These patients have been on ponatinib treatment from 4 up to 7 years.
Thirty-four (68%) patients experienced adverse reactions. The most frequently reported adverse reactions (by ≥10% of patients) were rash and dry skin (Fig. 6). Other reported adverse reactions of interest included thrombocytopenia (4), abdominal pain (4), vascular stenosis (3), arterial hypertension (2), chest pain (1), palpitations (1), vascular occlusion (1), pancytopenia (1), increased serum lipase (1), cholecystitis (1), hepatitis (1), cholestasis (1), pneumonia (1), hyponatremia (1), pancreatitis (1), and hepatocellular injury (1).
In total, 5 deaths were registered; none of these was considered by the investigator to be a consequence of the ponatinib treatment. Three patients suffered from general physical health deterioration resulting in death and two patients died from cardiorespiratory arrest induced by euthanasia (one patient with relapse of Ph+ ALL; one patient with both metastatic renal cell carcinoma and relapse of Ph+ ALL).