Cerebrospinal fluid distribution and pharmacokinetics of ponatinib in Ph1⁺ acute lymphoblastic leukemia Free

TO THE EDITOR:

The central nervous system (CNS) frequently serves as a migration site for acute lymphoblastic leukemia (ALL). Approximately 5% to 10% of patients manifest overt CNS involvement at diagnosis, with a reported incidence of 3% to 40% at relapse, depending on the intensity of CNS-directed prophylactic treatment.^1-3 Philadelphia chromosome–positive B-cell ALL (Ph⁺ ALL) is particularly at risk for CNS localization.² Modern CNS prophylaxis include intrathecal and/or systemic methotrexate, cytarabine, and corticosteroids, whereas encephalic radiotherapy remains controversial.^4,5 Over the past 2 decades, the treatment landscape of Ph⁺ ALL has undergone significant transformations, primarily owing to the integration of tyrosine kinase inhibitors (TKIs) into chemotherapy regimens.^6,7 The advent of more potent TKIs has led to the design of lower-intensity chemotherapy regimens⁸ and more recently, chemotherapy-free approaches combining a TKI, corticosteroids,⁹ and immunotherapy.¹⁰ However, the evidence for the efficacy of blinatumomab in the context of CNS disease is limited to a small retrospective cohort,¹¹ and there are no data regarding inotuzumab.

Despite encouraging results with TKI-based regimens, CNS involvement is still associated with inferior outcomes in Ph⁺ ALL, emphasizing the critical role of effective CNS prophylaxis.^12,13 Although imatinib, due to its inability to cross the blood-brain barrier,¹⁴ may contribute to the relapse rates, dasatinib has shown promise in preventing intracranial tumor growth in a mouse model.¹⁵ In the same study, dasatinib showed CNS blast cells clearance in 7 of 11 patients with CNS Ph⁺ leukemia, although the duration of response was short, and examination of cerebrospinal fluid (CSF) pharmacokinetic samples showed detectable levels of dasatinib in only 2 of 15 adult patients. In a pediatric trial comparing TKIs in association with chemotherapy, dasatinib reduced the risk of CNS relapse compared with imatinib.¹⁶ Despite limited data in adult patients, dasatinib is generally considered to be the TKI of choice in the setting of Ph⁺ ALL with CNS involvement, although it is not clear whether there is a relationship between clinical antitumor efficacy in CNS disease and the TKI CSF concentrations. Ponatinib, a third-generation BCR::ABL1 TKI, has been investigated in the frontline setting, including in chemotherapy-free regimens,¹⁰ but little is known about its CNS activity. Indeed, the largest trials investigating ponatinib in ALL do not report CNS relapse rates.^17,18 Moreover, its ability to reach the CNS has never been evaluated in humans, although a mouse model suggests it might be able to cross the blood-brain barrier and achieve higher concentration in brain tissue than dasatinib.¹⁹ We aimed to explore ponatinib concentrations in the CSF of adult patients with Ph⁺ ALL.

All patients aged >18 years with a confirmed diagnosis of Ph⁺ ALL receiving ponatinib treatment in 2 French tertiary care centers and at least 1 CSF ponatinib quantification between March 2018 and December 2023 were included. CSF ponatinib quantification was collected via lumbar puncture only after a minimum of 7 days of exposure to ponatinib and at least a month after any dose modification.

Ponatinib was administered orally at 15, 30, or 45 mg daily. Electronic medical files were extracted for the following parameters: age, sex, height, weight, disease characteristics, treatment regimens, overall survival, and relapse-free survival.

Ponatinib quantification in plasma and CSF collected at steady state was centrally performed in Saint-Louis Hospital Pharmacology Department, according to a previously published method.²⁰ Numerical variables were expressed as median and interquartile range (IQR). Correlation between continuous variables was studied using Pearson correlation coefficient; Wilcoxon rank-sum test or Kruskal-Wallis test was used to compare numerical variables between groups when applicable. The level of significance in all analyses was set at P value <.05. Statistical analysis was performed using RStudio 2023.09.0. According to French law, all patients provided a nonopposition statement to have their anonymous medical data collected. This study was conducted in accordance with the Declaration of Helsinki.

We identified 22 CSF ponatinib quantification samples from 16 patients with Ph⁺ ALL during their first line of treatment (n = 9) or at relapse (n = 7). Table 1 reports baseline patient characteristics at the time of the first CSF ponatinib quantification. Median age was 57.2 years (IQR, 38-61), and ponatinib dose was 15 mg/day in 2 cases, 30 mg/day in 14 cases, and 45 mg/day in 6 cases. CSF quantifications were performed while patients received systemic (vincristine, n = 11; vindesine, n = 2; blinatumomab, n = 2; methotrexate, n = 1) or intrathecal chemotherapy in 16 and 11 cases, respectively.

Median CSF ponatinib concentration was 1.20 ng/mL (IQR, 0.15-4.03). Of the 22 CSF ponatinib quantifications in 16 patients, only 1 (receiving 30 mg daily) was above the 21.30 ng/mL (40 nM) threshold that was defined in preclinical cell–based mutagenesis assays as preventing the development of resistant clones.²¹ In 31% of cases (7/22), ponatinib CSF concentration was inferior to the IC50 for native ABL1 (0.50 nM = 0.26 ng/mL). Concomitant ponatinib trough plasma concentration was evaluated in 15 cases and was consistent with previously published studies²² (median concentration, 35.7 ng/mL [IQR, 23.3-40.1]). The CSF-to-plasma ratio varied among patients, with a median of 5.5% (IQR, 0.6%-12.8%). There was no statistical association between ponatinib plasma concentration and CSF concentration (correlation coefficient, 0.39 IQR [–0.2196; 0.7203]; P = .23). There was no correlation between ponatinib CSF concentration and age ≥50 years, sex, ponatinib dose, previous irradiation, concomitant administration of systemic or intrathecal chemotherapy, or active CNS involvement (Table 2). This lack of correlation may be related to intercurrent or unidentified parameters or to the small size of this cohort. Relapse occurred in 4 patients undergoing ponatinib therapy (2 isolated CNS and 2 systemic relapses), with no difference in median CSF ponatinib concentration between those who relapsed or remained in remission at 2 years (2.10 vs 1.65 ng/mL; P = .93).

One isolated CNS relapse case (patient 6) was observed after 18 months on ponatinib, with a CSF concentration of 2.30 ng/mL at relapse and a plasma concentration of 39.9 ng/mL, within the expected range. Patient 10 was switched to ponatinib due to poor dasatinib tolerance 8 months after allogeneic stem cell transplant. Three months later, isolated CNS relapse occurred with a CSF blast count of 2000/mm³. BCR::ABL1 tyrosine kinase domain sequencing performed on CSF blasts showed 2 point mutations, E255K and E255V, whereas the ponatinib CSF concentration was 0.12 ng/mL. Meanwhile, concomitant bone marrow evaluation did not reveal any morphological evidence of blast cells, with a BCR::ABL1 quantitative polymerase chain reaction molecular residual disease of 1.5%. Bone marrow BCR::ABL1 sequencing retrieved only the E255K mutation, suggesting that poor ponatinib CSF distribution might have permitted the emergence of these clones with probable reduced sensitivity to ponatinib. Several reports describe a significant increase in IC50 to ponatinib in these mutants compared with wild-type BCR::ABL1.

Poor ponatinib exposure in the CSF may be the consequence of limited blood-brain barrier penetration due to efflux transporters (P-glycoprotein and Bcrp)²³ and wider distribution in tissue and cells than in extracellular fluids due to high protein-binding properties and a high volume of distribution.²⁴ Underexposed clones may drive CNS and/or systemic relapse and should be considered when designing Ph⁺ ALL trials, including ponatinib with chemotherapy-free/low regimens. Regimens combining ponatinib and blinatumomab are promising, but exclusion of patients with active CNS disease from blinatumomab trials and limited understanding of its CSF penetration pose concerns, as seen in a phase 2 trial in which 3 of 6 relapses were CNS only despite prophylactic intrathecal chemotherapy.²⁵ 

Our study is limited by the small number of patients and the fact that most of them had only 1 measurement, which precludes a precise assessment of interindividual and intraindividual variation. It is also unknown whether CSF concentration of ponatinib reflects its antileukemic properties in the CNS.

In conclusion, our results indicate that ponatinib has limited distribution in the CSF of patients with Ph⁺ ALL, highlighting the need for further investigation into optimal CNS-directed therapies.