Real-world outcomes in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia treated with ponatinib – final 6-year results from a Belgian registry

Efficacy and Safety of Ponatinib in CML and Ph+ ALL Patients in Real-World Clinical Practice: Data from a Belgian Registry

Real-Life Outcomes of Ponatinib Treatment in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): Data from a Nationwide Belgian Registry

Data on clinical use of ponatinib are limited. This prospective registry aimed to evaluate outcomes of ponatinib treatment in routine practice over 3 years (2016–2019) in Belgium (NCT03678454). Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) were treated with ponatinib per current label. Fifty patients (33 CML and 17 Ph+ ALL) were enrolled. Fifty-five percent of CML and 29% of Ph+ ALL patients had received ≥3 prior tyrosine kinase inhibitors (TKIs). Reasons for starting ponatinib were intolerance (40%), relapse or refractoriness (28%) to previous TKIs, progression (16%), or T315I mutation (16%). Median follow-up was 15 months for CML and 4.5 months for Ph+ ALL patients. Best response was a major molecular response in 58% of CML and 41% of Ph+ ALL patients. Of 20 patients who started ponatinib due to intolerance to previous TKIs, 9 (64%) CML and 4 (67%) Ph+ ALL achieved a major molecular response. Three-year estimates of overall survival were 85.3% and 85.6%, respectively, in CML and Ph+ ALL patients; estimated progression-free survival was 81.6% and 48.9%. Adverse reactions were reported in 34 patients (68%); rash (26%) and dry skin (10%) were most common. Reported cardiovascular adverse reactions included vascular stenosis (3), arterial hypertension (2), chest pain (1), palpitations (1), and vascular occlusion (1). This Belgian registry confirms results from the PACE clinical trial and supports routine ponatinib use in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or with the T315I mutation.

Minimal Residual Disease following Allogeneic Hematopoietic Stem Cell Transplantation

A Novel Approach to Identify a Putative Leukemia Stem Cell Population in Acute Lymphocytic Leukemia (ALL) and Distinguish Philadelphia Chromosome-Positive ALL from Lymphoid Blast Crisis Chronic Myeloid Leukemia

Ponatinib, a third-generation tyrosine kinase inhibitor that inhibits BCR/ABL independent of the mutation status, is currently approved for the treatment of patients with chronic myeloid leukemia or acute lymphoblastic leukemia that are either resistant or unable to tolerate another tyrosine kinase inhibitor. Its US Food and Drug Administration approval was based on results from long-term follow-up of the pivotal Phase II PACE trial, which demonstrated deep and durable molecular responses in the treated patients. Despite the remarkable responses, ponatinib has been associated with high frequency of severe vascular events, which led to its withdrawal from the market in 2013. Following analysis of the risk factors of patients who developed vascular side effects, ponatinib was reintroduced in the market 1 year later with specific dose-reduction recommendations and carrying a black box warning. Thus, careful patient selection with identification of patients whose potential benefit from ponatinib exceeds the potential risks associated with its use is crucial. Ongoing and future studies are focusing on earlier detection of mutations, strategies to minimize side effects, and potential expansion of the treatment indications. Clinical trials testing the safety and efficacy of ponatinib as frontline therapy are ongoing.

Low-dose ponatinib is a good option in chronic myeloid leukemia patients intolerant to previous TKIs.

Clinical features and outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia: A 15-year retrospective study

Olverembatinib (HQP1351) Combined with Chemotherapy Is an Effective and Safe Treatment in Patients with Philadelphia Chromosome-Positive (Ph +) Acute Lymphoblastic Leukemia (ALL) and Chronic Myeloid Leukemia in Lymphoid Blast Phase (CML-LBP) That Failed TKI-Based Regimens

Dasatinib is effective for the treatment of chronic myeloid leukemia (CML) patients resistant or intolerant to imatinib. However, to date, most of the available data come from studies in which censorization was applied. One-hundred and fourteen CML patients resistant or intolerant to imatinib received dasatinib as second-line therapy outside from clinical trials. Response (hematologic, cytogenetic, and molecular), toxicities, event-free survival (EFS) and overall survival (OS) were evaluated. At 12 months, cumulative incidences of complete hematologic response, complete cytogenetic response (CCyR), and major molecular response were 94%, 51%, and 32%. Cumulative EFS and OS were 91 and 93%. Neither the dose, nor the duration, nor the response to prior imatinib affected the probability of achieving CCyR at 1 year with dasatinib (P = 0.7, 0.9, and 0.8). Moreover, we observed statistically significant better EFS and OS for patients receiving low-dose continuous therapy with dasatinib after dose reduction due to toxicity (50/70 mg/day) with respect to patients who received higher doses (100/140 mg/day) but discontinued temporarily the treatment (P = 0.04, P = 0.04). These findings show, for the first time, a possible effect for dasatinib at low doses in inducing or maintaining response (hematologic, cytogenetic, and molecular) in CML patients resistant or intolerant to Imatinib.

Cardiovascular system health becomes important with the extended survival of chronic myeloid leukemia (CML) patients. Cardiotoxicities are related to the second- and third-generation tyrosine kinase inhibitors (TKIs). The most frequent and important cardiovascular events are myocardial infarction, stroke and peripheral arterial disease, QT prolongation, pleural effusions, and both systemic and pulmonary hypertension. The aim of this paper is to review the interactions between administrated TKIs and the cardiovascular system during the clinical course of CML. Elucidation of TKI effects on the cardiovascular system is vital since the current goal of CML therapy is a cure that leads to normal age and gender-similar survival with a normal quality of life. Up to August 2022, literature searches were performed via the internet search engines MEDLINE, EMBASE, GOOGLE SCHOLAR: (i) chronic myeloid leukemia; (ii) tyrosine kinase inhibitor; (iii) cardiovascular system. Only articles in English and research including humans were included in the search. Tailored TKI treatment with individual patient characteristics must account for CML disease risk, patient age, patient comorbidities, patient compliance, TKI drug off-target risk profile, accelerated or blastic phase CML disease, pregnancy and allografting in CML. The treatment-free survival, improving quality of life, limiting adverse events of TKIs, and the optimal dose and administration duration of TKIs are still a matter of controversy. Special attention should be paid to the comorbidities of CML patients and clinical TKI effects on CVS since the aim of CML treatment is a cure that leads to normal age and gender-similar survival with a "normal" quality of life. CVS is an important morbidity and mortality cause for adult patients. The discontinuation of TKI treatment in CML and the treatment-free remission of CML patients are very important in order to reduce the risk for cardiovascular adverse effects of TKIs. The frail CML patients and especially the patients who have cardiac comorbidities, should be carefully evaluated for TKI treatment, and hematopoietic stem cell transplantation (HSCT) should be the last choice in these risky CML patients. The current CML treatment target is a cure that leads to normal age and gender-adjusted survival with a "normal" quality of life. Cardiovascular disorders are one of the major obstacles to reaching this target in CML patients. The treatment choices for CML patients must include a cardiovascular perspective.

Oral ponatinib (Iclusig(®)) is a novel kinase inhibitor structurally designed with a carbon-carbon triple bond to accommodate the T315I mutation in the ABL kinase domain. It has demonstrated inhibitory activity against native BCR-ABL tyrosine kinase and a variety of BCR-ABL mutants, including T315I. Ponatinib is approved for the treatment of adults with T315I-positive chronic-, accelerated- or blast-phase chronic myeloid leukaemia (CML), or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) [in the EU and the USA], as well as those with chronic-, accelerated- or blast-phase CML, or Ph+ ALL who are resistant or intolerant to prior tyrosine kinase inhibitor therapy (EU) or for whom no other tyrosine kinase inhibitor therapy is indicated (USA). In a noncomparative, multinational, phase II study, therapy with ponatinib was associated with a major cytogenetic response within the first 12 months in over half of adults with chronic-phase CML and major haematological responses within the first 6 months in at least 50% of adults with accelerated-phase CML and approximately 34% of adults with blast-phase CML or Ph+ ALL after a median follow-up duration of 15, 16 and 6 months, respectively. Such benefits were observed regardless of whether the patients were resistant to dasatinib or nilotinib, or had the T315I mutation. Serious adverse reactions have been reported with ponatinib, with vascular occlusion, heart failure and hepatotoxicity prompting the US FDA to issue boxed warnings. Ponatinib is a valuable treatment option for adults with T315I-positive chronic-, accelerated- or blast-phase CML, or Ph+ ALL, as well as those with chronic-, accelerated- or blast-phase CML, or Ph+ ALL who are resistant or intolerant to prior tyrosine kinase inhibitor therapy, but before starting treatment, clinicians need to consider whether the potential benefits of therapy will outweigh the risks.

Chronic myeloid leukaemia (CML) is a malignant disease of the bone marrow characterised by the presence of the Philadelphia (Ph) chromosome. About 20% of acute lymphoblastic leukaemia (ALL) patients also show this genetic abnormality. A new drug, imatinib (Glivec, Novartis Pharma AG, Basel, Switzerland, and formerly STI571) is having a profound effect on the treatment and management of all stages of CML and Philadelphia chromosome positive (Ph+) ALL. New treatment algorithms are being developed. Should imatinib replace or be combined with existing therapies? To address this question, we review the pros and cons of therapy with interferon-alpha (IFN-alpha), allogeneic transplantation, autologous transplantation, imatinib, and in the case of Ph+ ALL, chemotherapy and experimental approaches. Conservative and aggressive treatments will be discussed and new molecular methods of monitoring cytogenetic response and their significance will also be reviewed.

Dasatinib monotherapy has demonstrated modest clinical activity in chronic myeloid leukemia in lymphoid blastic phase (CML-LBP). The outcome of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) has dramatically improved with hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in combination with tyrosine kinase inhibitors (TKIs). The authors reviewed 85 patients (23 with CML-LBP and 62 with newly diagnosed Ph-positive ALL) who received hyper-CVAD plus dasatinib. In the CML-LBP cohort, 19 had prior chronic myeloid leukemia as chronic phase (n = 17; 74%), accelerated phase (n = 1; 4%), or myeloid blastic phase (n = 1; 4%); 4 (17%) presented with de novo CML-LBP. The BCR-ABL1 transcript was p210 in 22 patients (96%) and p190 in 1 patient (4%). In the Ph-positive ALL cohort, p210 and p190 transcripts were detected in 13 patients (21%) and 48 patients (77%), respectively. Patients with CML-LBP were less likely to achieve deep molecular remission than patients with Ph-positive ALL: the major molecular response (MMR) rates were 70% and 95%, respectively (P = .007), and the complete molecular response (CMR) rates were 55% and 74%, respectively (P = .16). Survival outcomes were similar for CML-LBP and Ph-positive ALL: the 5-year overall survival (OS) rates were 59% and 48%, respectively (P = .97). Allogeneic stem cell transplantation was associated with a better outcome in CML-LBP (5-year OS rate, 88% vs 57%; P = .04). In Ph-positive ALL, the outcome was driven by deeper molecular remission: the 5-year OS rates were 63% and 25% with CMR and MMR, respectively (P = .002). The outcome of CML-LBP has improved with hyper-CVAD plus dasatinib therapy with survival comparable to that of Ph-positive ALL. Further improvement may be achieved with the use of novel TKIs and targeted agents.

High-dose ponatinib in Korean CML and Ph+ ALL: real-world outcomes in early and heavily pretreated settings