The role of vitamin D on redox regulation and cellular senescence.

We thank Dr Campiotti and colleagues for their interest in our point of view, which highlighted achievements and unsettled issues emerging from the ESC position paper on cardiovascular toxicities of targeted therapies [1]. We concur with the authors on the need for a pragmatic view in daily practice, which relies on prognosis and overall survival to select a tailored approach for managing and preventing cardiotoxicity [2]. Our overview was intended to cover the variegate cardiovascular toxicities of consolidated anticancer drugs, providing a broad indication of relevant frequencies (incidence rates) to support decision making by cardiooncology healthcare professionals in clinical practice. Campiotti et al. add an important perspective by focusing on an emerging safety issue, i.e., the cardiovascular safety of patients with chronic myeloid leukemia (CML), who should be treated indefinitely (apart from selected cases) with tyrosine kinase inhibitors (TKIs). We fully agree with the authors’ view: an increased risk of dose-dependent vascular occlusive events is found for all new-generation TKIs as compared to imatinib, without a substantial improvement in overall survival at 1 year [3]. The case of ponatinib is noteworthy: the risk of serious cardiovascular toxicities emerged from the phase 3 EPIC trial, which was terminated early for adverse vascular events, and actually caused its clinical use as a third-line TKI agent in CML to be downgraded. This drug is a paradigmatic example of the importance of considering pharmacological properties to anticipate predictable clinically relevant cardiovascular toxicities: ponatinib inhibits multiple kinases, including different vascular endothelium growth factor receptors, which also explains the high incidence of hypertension. Recent data suggest that ponatinib carries the highest vascular risk among TKIs, and that arterial thrombosis is the main contributor to the observed occlusive events [4]. The precise underlying mechanism is still uncertain, and the drug can also provoke bleeding by reducing platelet aggregation through blocking of platelet immune-receptor tyrosinebased activation motif signaling. However, because of an obvious channeling bias (the high number of patients had preexisting cardiovascular risk factors, particularly in those with advanced leukemia who did not respond or could not tolerate previous TKIs), the actual contribution of the drug is hard to interpret. There is no recognized evidence-based approach to manage thrombosis in patients with cancer, as recognized by the ESC guideline, which states that “the use of antithrombotic therapies, thrombolysis or endovascular intervention should be discussed on a case-by-case basis with multidisciplinary consultation involving the cardio-oncology team, when available.” Pharmacological therapies with low-dose acetyl-salicylic acid and statins, as suggested by Campiotti et al., may represent a clinical option as secondary preventive measures, provided that peripheral arterial disease and hypercholesterolemia are documented. The treatment of cancer-associated thrombosis is an evolving field, and data have started to accrue on the role of direct oral anticoagulants in comparison with low-molecular weight heparins, with edoxaban showing a lower rate of recurrent venous thromboembolism, but a higher rate of major bleeding as compared to subcutaneous dalteparin. We would like to spend a final note on the often neglected aspect of drug–drug interactions, considering the likelihood of poly-pharmacotherapy and comorbidities affecting elderly * Emanuel Raschi emanuel.raschi@unibo.it

ESC position paper on cardiovascular toxicity of cancer treatments: challenges and expectations-authors' reply.

The use of tyrosine kinase inhibitors (TKIs) as a treatment for CML has improved the natural history of the disease and increased the duration of survival. Tyrosine kinase inhibitors represent the success of target therapies that work on molecular targets, although some patients still have therapy failure. Vitamin D has anti-proliferative, pro-apoptotic, and anti-angiogenic effects on cells, therefore it can be considered as a potential cancer preventative and treatment agent. Inecalcitol (TX-522) is the14-epi-analogue of Calcitriol (1,25(OH)2-vitamin D3), and inhibits cancer cell proliferation more effectively than Calcitriol. This study was conducted to evaluate the antiproliferative and synergistic effects of the anticancer drugs Imatinib and Dasatinib in combinations with Inecalcitol on human chronic myeloid leukemia K-562 cells. The growth inhibitory activities of Inecalcitol, Imatinib, Dasatinib, and different combinations of one of the two drugs (Imatinib and Dasatinib) with Inecalcitol, were determined in vitro using MTT assay against K-562 cell line. Inecalcitol, Imatinib, and Dasatinib showed potent antiproliferative activities against K-562 cells with GI50 values of 5.6 µM, 0.327 µM, and 0.446 nM, respectively. Combinations of Imatinib or Dasatinib with different concentrations of Inecalcitol increased significantly the antiproliferative activities and potencies of both drugs (****p < 0.0001), with optimal GI50 values of 580 pM (Imatinib) and 0.51 pM (Dasatinib). The study demonstrated that the human chronic myeloid leukemia K-562 cells were subjected to a synergistic growth inhibitory impact when antileukemic drugs (Imatinib or Dasatinib) were combined with Inecalcitol, therefore, it is recommended that these combinations be viewed as promising novel antileukemic medications and used in place of individual medications with lower dosages and negligible side effects in the treatment of CML. 

Biological Evaluation of Combinations of Tyrosine Kinase Inhibitors with Inecalcitol as novel treatments for Human Chronic Myeloid Leukemia

Vitamin D deficiency is a common side effect of imatinib mesylate (IM) therapy. Transporter polypeptides involved in the disposition of IM may be required for maintenance of adequate vitamin D concentrations.The aim of the present work is to study the association between the plasma concentrations of IM and plasma 25-hydroxyvitamin (25[OH]) D3 with transporter genotypes in patients with chronic myelogenous leukemia.A total of 77 adult patients with chronic myelogenous leukemia treated with IM participated in this study. Peak and trough plasma IM and 25(OH) vitamin D3 concentrations were measured and compared to the results of single nucleotide polymorphisms of the efflux transporting gene ABCB1-1236 C>T and the uptake transporting gene OATP1B3-334 T>G. Multiple linear regressions were used to examine the associations between 25(OH) vitamin D3 concentrations and a number of patient characteristics, including responses to therapy. Binary logistic regression analysis was used to predict odd ratios for the clinical response to IM.Plasma 25(OH) vitamin D3 concentration quartile values were: 25%, 8.2 ng/mL; 50%, 9.8 ng/mL; and 75%, 12 ng/mL. High IM peak concentration, being OATP1B3-334 T>G (TT), and/ or ABCB1-1236 C>T (CT) are associated with lower concentrations of 25(OH) vitamin D3. Moreover, IM peak concentration, IM trough concentration, and plasma concentration of 25(OH) vitamin D3 were associated with the clinical response to IM.vitamin D, IM concentration, as well as the genotype of OATP1B3-334 T>G, had an influence on the response of patients with chronic myelogenous leukemia. 

https://doi.org/10.1016/j.curtheres.2022.100684

Modulation of Plasma 25-Hydroxyvitamin D3 Level by Imatinib Mesylate in Patients with Chronic Myelogenous Leukemia: The Role of Uptake and Efflux Transporters

Objectives The study aimed to compare early molecular response (EMR) rates at 3 months of imatinib therapy with and without vitamin D3 supplementation in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP). The secondary objective was to assess the effects of vitamin D3 on complete haematological response (CHR) and its safety. Design Double-blind, placebo-controlled, exploratory randomised trial. Setting Tertiary care hospital in northern India. Participants Treatment-naive patients with chronic phase chronic myeloid leukaemia (n=62) aged >12 years were recruited from January 2020 to January 2021. Patients with progressive disease, pregnancy and hypercalcaemia were excluded. Intervention Oral vitamin D3 supplementation (60 000 IU) or matched placebo was given once weekly for an initial 8 weeks along with imatinib after randomisation with 1:1 allocation ratio. Primary and secondary outcome measures The primary outcome was to compare EMR (defined as BCR-ABL1 transcript level ≤10%, international scale) at 3 months. The secondary outcomes were to compare effect of the intervention on CHR, correlation of 25(OH)2D3 levels with treatment response and safety according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. Results At baseline, 14.5% of the patients had normal vitamin D3 levels. EMR at 3 months was attained in 24 patients (82.7%) of the vitamin D3 group and 21 (75%) of the placebo group (OR 1.6, 95% CI 0.37 to 7.37, p=0.4). A significant difference in vitamin D3 levels from baseline to the end of study was observed. Patients with vitamin D3 supplementation did not achieve higher CHR in comparison with placebo (OR 1.3, 95% CI 0.25 to 7.23, p=1.0). Vitamin D3 levels were not significantly correlated with BCR-ABL1 levels. No dose-limiting toxicities were observed. Conclusion Vitamin D3 levels were low among patients with CML-CP in this study. Vitamin D3 supplementation with imatinib therapy did not have significant effect on EMR or CHR. Further clinical trials could be undertaken to assess the effective dosage and duration of vitamin D3 supplementation in these patients. Trial registration number CTRI/2019/09/021164.

Safety and efficacy of Vitamin D3 supplementation with Imatinib in Chronic Phase- Chronic Myeloid Leukaemia: an Exploratory Randomized Controlled Trial

Dear editor, Vitamin D and calcitriol, participate in critical cell functions such as proliferation, apoptosis, and suppression of inflammation, and play a key role in many cancer hallmarks such as angiogenesis, cell invasion, and metastatic spread [1, 2] (see Fig. 1). Vitamin D levels have a prognostic role in diabetes and cardiovascular disease [3]. As for oncology, a prognostic role of vitamin D deficiency in cancer is established, especially in tumors with strong interaction with the immune system such as melanoma [4], follicular lymphoma [5] and in diffuse large B cell lymphoma [6]. Chronic myeloid leukemia (CML) is a myeloproliferative disorder; characterized by a specific genetic signature, the BCR-ABL gene fusion, a permanently active tyrosine kinase [7]. Tyrosine kinase inhibitors (TKIs) are capable of inhibiting the driver mutation, and rapidly became the standard of care. CML is considered the perfect example of a driver mutation disease, but we often forget that, before the advent of TKIs, CML was considered an immunogenic cancer. The first drug that was able to re-establish normal hematopoiesis in a minority of CML patients was interferon α [8]. Given the possible link between vitamin D and the immune system, we dosed vitamin D levels in patients affected by CML treated with TKIs of first or second generation, and compared vitamin D levels in other inpatients. We included patients affected by CML, in treatment at our institution with Imatinib 400 mg daily or dasatinib 100 mg daily who achieved a stable deep molecular response (SDMR). SDMR includes both complete molecular response (CMR), and major molecular response (MMR), defined as undetectable BCR-ABL and a BCR-ABL/ABL1 IS ratio < 0.1% with a 4.5 log sensibility PCR, respectively. Control was provided by other inpatients. Patients affected by diabetes, renal disease, hepatic disease, cancer, patients who underwent parathyroid or thyroid surgery or patients in therapy with steroids were all excluded, from control as well as from the CML group. Blood samples were collected between December 2016 and February 2017. Vitamin D blood levels were measured by a radio-immunoassay for in vitro quantitative measurement of 25-hydroxy vitamin D3 and D2 in serum (DIA source 25 OH Vitamin D total-RIA-CT kit). Vitamin D levels were defined normal if > 30 ng/mL, low from 15 ng/dL to 29 ng/mL, deficient < 15 ng/mL. Data are reported as median and inter-quartile range (nonnormally distributed data), and comparison between groups were made by independent T test or Mann–Whitney test, as appropriate. All CML and control group patients with vitamin D deficiency received oral supplementation in accordance to international guidelines [9, 10]. We studied 26 CML patients and 52 controls. Median age and male to female ratio were balanced between CML and control group. Patients affected by CML were in treatment with imatinib (18 patients) and dasatinib (8 patients). Median duration of TKIs therapy was 6.3 years (range 5.2–10), see Table 1 for further details. The median vitamin D level in CML patients was 12.45 ng/dL (10.25–15.32 IQR) while controls had a median level of 15.9 ng/dL (12.05–21.38 IQR) (p = 0.018, Fig. 1). We analysed vitamin D levels stratifying CML patients based on their response to TKIs therapy. In our CML cohort, 19 patients achieved MMR and 7 patients achieved CMR; vitamin D levels were lower in patients in MMR compared to CMR patients: 11.3 ng/dL (9.3–13 IQR) and 16 ng/dL (15.1–20.1 IQR), respectively (p = 0.001, Fig. 2 and Table 2). * Leonardo Campiotti leonardo.campiotti@uninsubria.it

Vitamin D and tyrosine kinase inhibitors in chronic myeloid leukemia.

We read with interest the paper published by Raschi et al. about cardiotoxicity of new drugs in cancer treatment [1]. The authors divided new drugs into three groups according to their different therapeutic mechanisms of action. Although this is a sound pharmacological approach, we have to note that, especially for the clinician in everyday practice, an important distinction should be based on the prognosis and the overall survival of patients treated with these drugs, to select a tailored prevention of cardiotoxicity. The large part of new drugs such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, mTOR inhibitors, and immune checkpoint inhibitors are in fact used in patients affected by advanced cancer, with a reduced life expectancy. An exception is the treatment of chronic myeloid leukemia (CML) with TKIs. These patients have, with current therapies, a life expectancy similar to that of the general population, and apart from selected cases, TKIs should be continued indefinitely [2]. As such, cardiotoxicities due to these drugs can become an important concern for the clinician, and should be a key focus in research and preventive measure. In keeping with these observations, we suggest that, in adjunct to those cited in the review, ponatinib should also be included among TKIs with a proven cardiotoxicity. In 2013, the FDA removed ponatinib from the market for cardiotoxicity until safeguards were instituted to manage toxicity [3]. From 2014, ponatinib is employed in the treatment of resistant CML and Philadelphia-positive acute lymphoblastic leukemia, with good clinical results, but it is still hampered by a relevant cardiotoxicity. The PACE trial reports serious cardiovascular toxicities in as much as 5% of patients treated with ponatinib [4] and the EPIC trail report serious arterial thrombotic events in 7% of patients receiving ponatinib [5]. In general, ponatinib is associated with serious cardiovascular toxicity including arterial thrombosis (8%), myocardial infarction (5%), peripheral arterial occlusive disease (2%), and cerebrovascular events (2%). It should be noted that CML patients treated with TKIs more frequently have arterial thrombosis in comparison with venous events. A possible pathophysiologic explanation is TKIs interaction with endothelial cells. In our opinion, preventive measures of these adverse events should include the employment of low-dose aspirin, as just encoded in other chronic myeloid disorder, such as polycythaemia vera and essential thrombocytosis and we advocate for further research into the role of statins in prevention of cardiovascular adverse events in these patients.

ESC position paper on cardiovascular toxicity of cancer treatments: challenges and expectations-comment.

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Vitamin D and tyrosine kinase inhibitors in chronic myeloid leukemia.

ESC position paper on cardiovascular toxicity of cancer treatments: challenges and expectations-comment.