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Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) that can effectively treat patients with acute lymphoblastic leukaemia (ALL), particularly those with Philadelphia chromosome-positive (Ph+ALL) subtype, who are resistant or have previously received other TKIs. We report a case of a 42-year-old female with Ph+ALL who was admitted to the intensive care unit with respiratory failure and severe acute respiratory distress syndrome (ARDS), while on treatment with ponatinib. Despite being treated with multiple antibiotics and antivirals, the patient\'s condition continued to worsen, and pulmonary complications secondary to TKI were suspected. After starting a steroid regimen, the patient\'s condition improved drastically with resolution of the pulmonary complications. While many adverse events (AEs) happen in the beginning stages of TKI treatment, certain toxicities may not arise until months after therapy initiation. Cardiovascular complications are the most common AE of ponatinib, including heart failure and arterial hypertension. Pulmonary complications may occur, and management includes drug cessation and individualised steroid therapy. In case of respiratory failure without signs of infection and no improvement with antimicrobial treatment, clinicians should consider the possibility of pulmonary toxicity associated with ponatinib.
CONCLUSIONS: Although rarely reported, ponatinib may have pulmonary toxicity presenting as new onset of respiratory insufficiency.Management of pulmonary complications includes adjusting or discontinuation of ponatinib and simultaneous treatment with steroids.

BACKGROUND: Tyrosine kinase inhibitors combined with conventional chemotherapy (CC) in treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) has achieved promising efficacy and safety outcomes. The study was conducted to compare the cost-effectiveness between imatinib (HANSOH Pharma, Jiangsu, China) and dasatinib (CHIATAI TIANQING Pharma, Jiangsu, China) in treating pediatric Ph-positive ALL when combined with CC from the perspective of the health system in China.
METHODS: A Markov model was established to simulate a hypothetical cohort of pediatric Ph-positive ALL patients receiving imatinib or dasatinib, combined with CC. The model was designed using a 10-year horizon, a 3- month cycle, and a 5% discount rate. Three health states were included: alive with progression-free survival, progressed disease, and death. Patient characteristics and transition probabilities were estimated based on clinical trials. Other relevant data, such as direct treatment costs and health utility data were extracted from published literature and Sichuan Province\'s centralized procurement and supervision platform. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the results. The willingness-to-pay (WTP) was set as three times China\'s GDP per capita in 2021.
RESULTS: In the base-case analysis, the total medical costs were $89,701 and $101,182, and the quality-adjusted life years (QALYs) gained were 1.99 and 2.70, for imatinib and dasatinib regimens, respectively. The incremental cost-effectiveness ratio for dasatinib versus imatinib was $16,170/QALY. The probabilistic sensitivity analysis indicated that treatment with dasatinib combined with CC achieved a 96.4% probability of cost-effectiveness at a WTP threshold of $37,765/QALY.
CONCLUSIONS: Dasatinib combined with CC is likely to be a cost-effective strategy compared to imatinib combination therapy for pediatric Ph-positive ALL in China at a WTP threshold of $37,765/QALY.

Central nervous system leukemia (CNSL) is the most common extramedullary relapse site in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL), with a poor prognosis and high relapse rate.
We characterized the clinical data of 21 Ph-positive B-ALL patients to analyze the efficacy and safety of ponatinib for patients with central nervous system relapsed Ph-positive ALL retrospectively.
There were 11 males and 10 females in the cohort, and their median age was 45 (9-58) years old. The total CR (complete remission) rate was 90.5%. All 9 patients achieved CR in the ponatinib group, and 10 patients achieved CR in the dasatinib group (100% vs 83.3%, respectively; P = .486) and minimal residual disease-positive CR in the ponatinib group and dasatinib group (88.9% vs 58.3%, P = .178). The medium time after achieving CR was 5 and 8 weeks (P = .047). The total median overall survival (OS) was 31.1 months, and the 3-year OS was 49.0%. The median relapse-free survival (RFS) was 31.0 months, and the 3-year RFS was 45.2%. Patients in the ponatinib group showed a significantly longer OS than those patients in the dasatinib group with (medium OS not reached vs 27.6 months, P = .045) or without (medium OS not reached vs 27.6 months, P = .039) T315I mutations. The median RFS between the ponatinib group and the dasatinib group with T315I was not reached and 16.2 months, P = .065. The median RFS between the ponatinib group and the dasatinib group without T315I was not reached and 16.2 months, P = .036. No treatment-related deaths were observed during the therapy.
(1) Ph-positive CNSL patients seemed to have a high rate of response and postinduction MRD negativity with ponatinib and dasatinib, but ponatinib seemed to show a shorter time to achieve remission than dasatinib. (2) Ponatinib maintenance treatment might show superior survival for Ph-positive CNSL patients with or without the T315I mutation. (3) Ponatinib and dasatinib seemed to be both safe for the clinical application of Ph-positive CNSL.

Incidence rates of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are lower but more aggressive in children than in adults due to different biological and host factors. After the clinical application of tyrosine kinase inhibitor (TKI) blocking BCR/ABL kinase activity, the prognosis of children with CML and Ph+ ALL has improved dramatically. Yet, off-target effects and drug tolerance will occur during the TKI treatments, contributing to treatment failure. In addition, compared to adults, children may need a longer course of TKIs therapy, causing detrimental effects on growth and development. In recent years, accumulating evidence indicates that drug resistance and side effects during TKI treatment may result from the cellular metabolism alterations. In this review, we provide a detailed summary of the current knowledge on alterations in metabolic pathways including glucose metabolism, lipid metabolism, amino acid metabolism, and other metabolic processes. In order to obtain better TKI treatment outcomes and avoid side effects, it is essential to understand how the TKIs affect cellular metabolism. Hence, we also discuss the relevance of cellular metabolism in TKIs therapy to provide ideas for better use of TKIs in clinical practice.

The achievement of a 3-month complete molecular response (CMR) is a major prognostic factor for survival in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). However, 25% of patients relapse during therapy with tyrosine kinase inhibitors (TKIs).
The authors reviewed 204 patients with Ph-positive ALL who were treated between January 2001 and December 2018 using the combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus a TKI (imatinib, 44 patients [22%]; dasatinib, 88 patients [43%]; or ponatinib, 72 patients [35%]). Progression-free survival (PFS) was defined as the time from the start date of therapy to the date of relapse, death, or last follow-up. Overall survival (OS) was defined as the time from the start date of therapy to the date of death or last follow-up.
Overall, a 3-month CMR was observed in 57% of patients, including 32% of those who received imatinib, 52% of those who received dasatinib, and 74% of those who received ponatinib. The median follow-up was 74 months (imatinib, 180 months; dasatinib, 106 months; ponatinib, 43 months). Among 84 patients in 3-month CMR, 17 (20%) proceeded to undergo allogeneic stem cell transplantation (ASCT). The 5-year PFS and OS rates were 68% and 72%, respectively. By multivariate analysis, ponatinib therapy was the only significant favorable independent factor predicting for progression (P = .028; hazard ratio, 0.388; 95% CI, 0.166-0.904) and death (P = .042; hazard ratio, 0.379; 95% CI, 0.149-0.966). ASCT was not a prognostic factor for PFS and OS by univariate analysis.
In patients with Ph-positive ALL, ponatinib is superior to other types of TKIs in inducing and maintaining a CMR, thus preventing disease progression. ASCT does not improve outcome once a 3-month CMR is achieved.

Lymphoblastic lymphomas (LBLs) are neoplasms of precursor B and T cells; they are considered in the same spectrum as precursor B and T cell acute lymphoblastic leukemia (ALL). The World Health Organization classification classifies both LBL and ALL as one disease entity. While chromosome abnormalities are well defined with all of their therapeutic and prognostic implications in ALL, these are not well studied in LBL. Here, we describe a case of Philadelphia chromosome-positive LBL and review the available literature regarding this entity.

In Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL), additional chromosomal abnormalities (ACAs) are frequently observed. We investigated the cytogenetic characteristics and prognostic significance of ACAs in Ph-positive ALL. We reviewed the clinical data and bone marrow cytogenetic findings of 122 adult Ph-positive ALL patients. The ACAs were examined for partial or whole chromosomal gains or losses, and structural aberrations. The overall survival (OS) and disease-free survival (DFS) of patients who received hematopoietic cell transplantation were compared between the isolated Ph group and ACA group. ACAs were present in 73.0% of all patients. The recurrent ACAs were extra Ph (24.7%), 9/9p loss (20.2%), and 7/7p loss (19.1%). Complex karyotype was found in 28.1% of patients in the ACA group. Younger patients (19-30 years) in the ACA group showed the highest frequency of extra Ph (54%) compared to other age groups. The OS in the ACA group was significantly shorter than in the isolated Ph group. The presence of an extra Ph chromosome or 9/9p loss was significantly associated with shorter OS and DFS, whereas 7/7p loss and complex karyotype were not associated with poorer prognosis. We suggest that subclassification of ACAs could be applied to prognostic investigation of Ph-positive ALL.

OBJECTIVE: To evaluate the cost-effectiveness of second-line nilotinib vs dasatinib among patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) who are resistant or intolerant to imatinib, from a US third-party perspective.
METHODS: A lifetime partitioned survival model was developed to compare the costs and effectiveness of nilotinib vs dasatinib, which included four health states: CP on treatment, CP post-discontinuation, progressive disease (accelerated phase [AP] or blast crisis [BC]), and death. Time on treatment, progression-free survival, and overall survival of nilotinib and dasatinib were estimated using real-world comparative effectiveness data. Parametric survival models were used to extrapolate outcomes beyond the study period. Drug treatment costs, medical costs, and adverse event costs were obtained from the literature and publicly available databases. Utilities of health states were derived from the literature. Incremental cost-effectiveness ratios, including incremental cost per life-year (LY) gained and incremental cost per quality-adjusted life-year (QALY) gained, were estimated comparing nilotinib and dasatinib. Deterministic sensitivity analyses were performed by varying patient characteristics, cost, and utility inputs.
RESULTS: Over a lifetime horizon, nilotinib-treated patients were associated with 11.7 LYs, 9.1 QALYs, and a total cost of $1,409,466, while dasatinib-treated patients were associated with 9.5 LYs, 7.3 QALYs, and a total cost of $1,422,122. In comparison with dasatinib, nilotinib was associated with better health outcomes (by 2.2 LYs and 1.9 QALYs) and lower total costs (by $12,655). Deterministic sensitivity analysis results showed consistent findings in most scenarios.
CONCLUSIONS: In the absence of long-term real-world data, the lifetime projection could not be validated.
CONCLUSIONS: Compared with dasatinib, second-line nilotinib was associated with better life expectancy, better quality-of-life, and lower costs among patients with Ph+ CML-CP who were resistant or intolerant to imatinib.