New Targeted Drugs for Acute Myeloid Leukemia and Antifungals: Pharmacokinetic Challenges and Opportunities.

BACKGROUND: Acute myeloid leukemia (AML) is a life-threatening disease whose treatment is made difficult by a number of mutations or receptor overexpression in the proliferating cellular clones. Life expectancy of patients diagnosed with new, relapsed-refractory, or secondary AML has been improved by drugs targeted at such moieties. Regrettably, however, clinical use of new AML drugs is complicated by pharmacokinetic interactions with other drugs the patient is exposed to. SUMMARY: The most relevant drug-drug interactions (DDI) with clinical implications build on competition for or induction/inhibition of CYP3A4, which is a versatile metabolizer of a plethora of pharmacological agents. Here, we review DDI between AML drugs and the agents used to prevent or treat invasive fungal infections (IFI). The pathophysiology of AML, characterized by functionally defective white blood cells and neutropenic/immunosuppressive effects of concomitant induction chemotherapy, can in fact increase the risk of infectious complications, with IFI causing high rates of morbidity and mortality. Triazole antifungals, such as posaconazole, are strong inhibitors of CYP3A4 and may thus cause patient's overexposure to AML drugs that are metabolized by CYP3A4. We describe potential strategies to minimize the consequences of DDI between triazole antifungals and targeted therapies for AML and the role that collaboration between clinical pharmacologists, hematologists, and clinical or laboratory microbiologists may have in these settings. KEY MESSAGES: Therapeutic drug monitoring and clinical pharmacology stewardship could represent two strategies that best express multidisciplinary collaboration for improving patient management.

Cardiac Anthracycline Accumulation and B-Type Natriuretic Peptide to Define Risk and Predictors of Cancer Treatment-Related Early Diastolic Dysfunction.

Diastolic dysfunction (DD) was reported to precede heart failure (HF) in patients with cancer who were treated with chemotherapy. We aimed at defining risk versus dose relationships and risk predictors in patients with cancer treated mainly with anthracyclines. Data from 67 patients without comorbidities (60 treated with anthracyclines, 7 with nonanthracycline chemotherapy) were retrospectively incorporated in a mathematical function that correlated DD risk with experimental indices of anthracycline accumulation in human myocardium. Risk was calculated for all patients and for subgroups stratified by intertreatment levels of the endogenous cardiac relaxant agent, B-type natriuretic peptide (BNP). Grade I DD (impaired relaxation) occurred in 14 of 67 patients, and 5% risk doses were much lower for DD than HF (mg of anthracycline/m2: 210 vs. 470 or 190 vs. 450 for all patients or anthracycline-treated patients in isolation, respectively; P ≤ 0.01 for DD vs. HF). Patients with transient BNP elevations showed the lowest 5% risk dose (150 mg/m2), whereas patients with persistent elevations showed the highest risk dose (280 mg/m2; P < 0.05). Patients with or without DD were similar for systemic and cardiac exposure to anthracyclines; however, high-risk patients with transient BNP elevations and DD were older and presented at baseline with lower indices of transmitral flow. In conclusion, DD risk develops after lower anthracycline doses than HF and intertreatment levels of BNP help to identify patients with high or low DD risk. These findings are of potential value to monitor or treat the patient with cancer at risk of DD. SIGNIFICANCE STATEMENT: DD is an early manifestation of cardiotoxicity from anthracyclines and nonanthracycline chemotherapeutics. We show that merging preclinical characterization of cardiac anthracycline accumulation with clinical data from patients treated primarily with anthracyclines identifies DD risk from very low anthracycline doses. DD risk is associated with older age, baseline diastolic indices toward the lower limit of normal, and transient intertreatment elevations of the endogenous cardiac relaxant agent, BNP. These findings have numerous pharmacological implications.

Predictors of Early or Delayed Diastolic Dysfunction After Anthracycline-Based or Nonanthracycline Chemotherapy: A Pharmacological Appraisal.

Diastolic dysfunction (DD) is an early manifestation of cancer drug cardiotoxicity. Anthracyclines are considered as more cardiotoxic than other chemotherapeutics, but previous studies have shown that both anthracycline-based and nonanthracycline chemotherapy can cause an early DD, detected 1 week after the end of chemotherapy. Here we characterized if DD also occurred in a delayed form, detected 6 months after chemotherapy. Sixty-seven comorbidity-free patients were examined. DD was diagnosed by echocardiography and cardiac biomarkers. Early or delayed DD occurred in 26 or 13 patients, respectively, sharing a pattern of grade I DD (impaired relaxation at echocardiography) or elevated B-type natriuretic peptide. Binary logistic analysis showed that age, gender, and type of chemotherapy (anthracycline-based vs. nonanthracycline) did not independently increase the probability of early or delayed DD. Early DD was predicted by the patient's cardiovascular profile and in particular by diastolic indices that were in ranges of normality but showed measurable discrepancies from mean control values. Delayed DD was not predicted by the patient's cardiovascular profile but was predicted by postchemotherapy adjuvant treatments (e.g., chest radiation or hormone therapy). Early and delayed DD were accompanied by moderate left ventricular ejection fraction decrements. These findings show that anthracycline-based and nonanthracycline chemotherapy can induce early or delayed DD, which are governed by different patient- or treatment- related factors. Pharmacologic interventions that prevent DD or mitigate its progression toward a more serious cardiac dysfunction should be considered. SIGNIFICANCE STATEMENT: Predictors of early or delayed diastolic dysfunction (DD) were investigated in patients with cancer treated with anthracycline-based or nonanthracycline chemotherapy. The type of chemotherapy did not predict the risk of DD. Early DD was predicted by the patient's cardiovascular profile. Delayed DD was predicted by the adjuvant treatments the patient received after chemotherapy. These findings show that any chemotherapeutic can cause DD; however, the trajectories of DD are differently influenced by patients' characteristics or postchemotherapy exposure to additional cardiotoxic hits.

Choosing Antifungals for the Midostaurin-Treated Patient: Does CYP3A4 Outweigh Recommendations? A Brief Insight from Real Life.

INTRODUCTION: Patients treated with midostaurin and chemotherapy are at risk of invasive fungal disease. Prophylactic posaconazole is recommended for these patients, but posaconazole strongly inhibits the CYP3A4 isozyme that metabolizes midostaurin. Posaconazole therefore introduces a risk of patient's overexposure to midostaurin. METHODS: Blood samples were obtained from 4 patients treated with midostaurin for newly diagnosed FLT3-mutAML. Patients had received a concomitant treatment with posaconazole, isavuconazole, or micafungin, respectively. All blood samples were drawn before daily dose administration of midostaurin. RESULTS: Posaconazole caused a ≥8-fold increase of midostaurin plasma levels at through, which was accompanied by a decreased plasma exposure to O-demethylated or hydroxylated midostaurin metabolites. We also show that hematologists react to risk perception by replacing posaco-nazole with antifungals like micafungin or isavuconazole, which lack a strong inhibition of CYP3A4 and fail to modify midostaurin pharmacokinetics but are not formally recommended in these settings. DISCUSSION: In real-life scenarios, concerns about CYP3A4 inhibition may outweigh compliance with recommendations. Large studies are needed to survey the risk:benefit of hematologist's decision to replace posaconazole with other antifungals.

Further Analytical, Pharmacokinetic, and Clinical Observations on Low-Dose Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

INTRODUCTION: Ponatinib (PNT) is a tyrosine kinase inhibitor approved for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), or chronic myeloid leukemia, resistant or intolerant to other tyrosine kinase inhibitor or showing T315I mutation of BCR-ABL. Unfortunately, the clinical use of PNT is limited by the possible occurrence of vascular occlusive events. The incidence of vascular events seems to correlate with PNT dose intensity and plasma exposure. Dose reductions from 45 mg to 30 or 15 mg/day are increasingly considered to improve PNT safety but a plasma threshold of ∼40 nM must be achieved to ensure that antileukemic activity is preserved. Therapeutic drug monitoring (TDM) would be appropriate for patients treated by PNT. We, therefore, developed and validated a liquid chromatography tandem mass spectrometry (HPLC-MS/MS) assay to measure PNT plasma levels. METHODS: PNT and its deuterated internal standard were extracted from human plasma by one-step protein precipitation. PNT was separated and quantified by HPLC-MS/MS operating in the multiple reaction monitoring acquisition mode. RESULTS: The method was linear from 9.4 to 940 nM PNT. Limits of detection and lower limits of quantification (LLOQ) were, respectively, 1 and 9.4 nM. Selectivity, sensitivity, matrix effect, short-, and long-term stability met criteria of international guidelines for bioanalytical method validation. Intra- and inter-day accuracy and precision were calculated on 4 different concentrations (QCLow, QCMedium, QCHigh, and LLOQ), with all values being <15%. The method was successfully probed in leukemia Ph + ALL patients to show that PNT doses <45 mg/day caused lower plasma exposure but still achieved PNT levels at or above the 40 nM threshold. CONCLUSIONS: We developed a highly sensitive and selective HPLC-MS/MS method to quantify PNT in human plasma. This method might be used for TDM and to guide dose reductions if unnecessary high PNT levels are detected in a patient.

Pharmacology of Ranolazine versus Common Cardiovascular Drugs in Patients with Early Diastolic Dysfunction Induced by Anthracyclines or Nonanthracycline Chemotherapeutics: A Phase 2b Minitrial.

We have reported that anthracyclines and nonanthracycline chemotherapeutics caused diastolic dysfunction in cancer patients without cardiovascular risk factors. Diastolic dysfunction occurred as early as 1 week after the last chemotherapy cycle and manifested as impaired myocardial relaxation at echocardiography or persistent elevations of B-type natriuretic peptide (BNP) or troponin. The antianginal drug ranolazine shows cardiac relaxant effects that we considered of value to treat early diastolic dysfunction induced by cancer drugs; therefore, 24 low-risk patients with post-chemotherapy diastolic dysfunction were randomized (1:1) to ranolazine or the investigator's choice of common cardiovascular drugs, such as ß-blockers and/or angiotensin-converting enzyme inhibitors or loop diuretics (best standard therapy, BST). After 5 weeks, 12 of 12 patients on ranolazine recovered from diastolic dysfunction, whereas 3 of 12 patients on BST did not improve; however, adverse events (not serious) were apparently more frequent for ranolazine than for BST (4/12 vs. 1/12). Ranolazine did not lower blood pressure, whereas BST reduced systolic pressure and caused a trend toward a reduced diastolic pressure. Most patients at randomization showed tachycardia resulting from chemotherapy-related anemia. Hemoglobin recovery contributed to normalizing heart rate in these patients; however, some patients in the ranolazine arm developed tachycardia through chronotropic effects of high BNP levels and returned to a normal heart rate through the effects of ranolazine on decreasing BNP levels. This minitrial describes the potential effects of ranolazine on relieving chemotherapy-related diastolic dysfunction; however, clinical implications of these findings need to be characterized by studies with an adequate sample size. SIGNIFICANCE STATEMENT: The antianginal drug ranolazine causes cardiac relaxant effects that might relieve diastolic dysfunction. In a clinical pharmacology study, 24 patients were randomized (1:1) to receive ranolazine or common cardiovascular drugs to treat early diastolic dysfunction induced by anthracycline-based or nonanthracycline chemotherapy. Ranolazine relieved diastolic dysfunction in these patients. The safety profile of ranolazine in cancer patients is similar to that of the general population. Compared with common cardiovascular drugs, ranolazine relieved diastolic dysfunction without lowering blood pressure. The sample size of this study was nonetheless too small to permit considerations about the potential clinical value of ranolazine for oncologic patients with early diastolic dysfunction induced by anthracyclines or nonanthracycline chemotherapeutics. This information should be obtained by studies with an adequate sample size.

Cardiotoxicity of Targeted Cancer Drugs: Concerns, "The Cart Before the Horse," and Lessons from Trastuzumab.

PURPOSE OF REVIEW: Modern oncology is witnessing a renaissance of its pharmacologic armamentarium. Old generation drugs, such as anthracyclines and other cytotoxic or cytostatic drugs, were plagued with a lack of specificity and with the possible occurrence of untoward effects in the cardiovascular system and other healthy tissues. The old drugs are now combined with, or replaced by, new agents that are more specific in attacking some unique moieties and vital functions of cancer cells, causing less noxious effects in healthy tissues. Regrettably, however, the new "targeted" drugs still cause varying levels of cardiac or vascular toxicity. Here, we describe the case of trastuzumab, a monoclonal antibody that dramatically improved the life expectancy of women with Erbb2-overexpressing breast tumor, while also raising concerns about a possible incidence of cardiac dysfunction. RECENT FINDINGS: The scientific community counts experts that label trastuzumab as a "cardiotoxic agent" and other experts that maintain a more benign assessment. We describe the biologic foundations and clinical evidence for such controversy. We show that trastuzumab cardiotoxicity is probably overrated, leading some experts to raise unjustified overconcerns about the cardiotoxicity of trastuzumab as a single agent or in combination with anthracyclines or other old and new drugs. We analyze the biases that caused trastuzumab cardiotoxicity to be overrated. Trastuzumab is a life-saving agent showing a moderate and clinically manageable cardiac dysfunction, and yet, it is portrayed as cardiotoxic. We take the trastuzumab lesson to reaffirm that cardio-oncologists should provide cancer patients with the best therapeutic opportunity, as is the case for trastuzumab, while also devising the necessary strategies of risk assessment and mitigation.

Correction to: Cardiotoxicity of Targeted Cancer Drugs: Concerns, "The Cart Before the Horse," and Lessons from Trastuzumab.

In the original publication, there were two errors in Fig. 2. "Anhracyline" should be "Anthracycline" and "targetd" should be "targeted." The original article has been corrected.

Low-Dose Anthracycline and Risk of Heart Failure in a Pharmacokinetic Model of Human Myocardium Exposure: Analog Specificity and Role of Secondary Alcohol Metabolites.

Cumulative doses of doxorubicin and other antitumor anthracyclines may cause heart failure (HF). Cardiotoxicity is determined by cardiac exposure to anthracyclines and to more toxic secondary alcohol metabolites that are formed inside cardiomyocytes or diffuse from the bloodstream. Concerns exist that HF might be caused by cumulative anthracycline doses that were thought to be safe. Patients with gain-of-function polymorphism of carbonyl reductase 3 (CBR3), which converts anthracyclines to secondary alcohol metabolites, would be at a higher risk of HF. Recently, a pharmacokinetic model was developed that simulated clinical exposure of human myocardium to anthracyclines and incorporated simulations of CBR3 polymorphism. It was shown that HF risk could occur after lower doxorubicin doses than previously reported, particularly for patients with CBR3 polymorphism. In this study, we show that also daunorubicin and idarubicin, but not epirubicin, might cause HF after reportedly safe cumulative doses. CBR3 polymorphism increased HF risk from daunorubicin and idarubicin to a greater extent as compared with doxorubicin. This was caused by daunorubicin and idarubicin forming higher levels of toxic metabolites in human myocardium; moreover, daunorubicin and idarubicin metabolites diffused from plasma and accumulated in cardiac tissue, whereas doxorubicin metabolite did not. CBR3 polymorphism did not aggravate HF risk from epirubicin, which was caused by the very low levels of formation of its toxic metabolite. These results support concerns about HF risk from low-dose anthracycline, characterize the analog specificity of HF risk, and illuminate the role of secondary alcohol metabolites.

The Endogenous Lusitropic and Chronotropic Agent, B-Type Natriuretic Peptide, Limits Cardiac Troponin Release in Cancer Patients with an Early Impairment of Myocardial Relaxation Induced by Anthracyclines.

We have reported that cancer patients treated with anthracycline-based or nonanthracycline chemotherapy developed an early impairment of myocardial relaxation at echocardiography or persistent elevations of the cardiac hormone B-type natriuretic peptide (BNP). Post-hoc pharmacologic analyses showed that BNP elevations were induced by impaired relaxation and caused positive lusitropic effects that maintained normal relaxation. High BNP levels and impaired relaxation were therefore characterized as mutually exclusive manifestations of diastolic dysfunction, but high BNP levels resulted in positive chronotropism and inappropriate tachycardia. Some patients developed increased circulating levels of cardiac troponin I isoform (cTnI), a marker of cardiomyocyte necrosis. Here we have characterized whether cTnI elevations correlated with diastolic dysfunction that manifested as impaired relaxation or a high level of BNP. The effects of high BNP levels on cTnI elevations were also characterized. We show that impaired relaxation or high BNP levels were significantly more frequent in patients with cTnI elevations. High BNP levels diminished the plasma peak and area under the curve of cTnI, but this result was accompanied by inappropriate tachycardia. cTnI elevations occurred only in patients treated with anthracyclines; moreover, the association of impaired relaxation or high BNP levels with cTnI elevations was significantly more frequent in doxorubicin-treated patients compared with patients treated with its analog, epirubicin. These findings describe cause-and-effect relations between impaired relaxation and cardiomyocyte necrosis, illuminate the role of anthracycline analogs, denote that the beneficial effects of BNP in relieving impaired relaxation and cardiomyocyte necrosis are counterbalanced by inappropriate tachycardia. Patients showing troponin elevations and impaired relaxation or high BNP levels should be treated with lusitropic drugs that lack a positive chronotropism.

Pharmacology of Cardio-Oncology: Chronotropic and Lusitropic Effects of B-Type Natriuretic Peptide in Cancer Patients with Early Diastolic Dysfunction Induced by Anthracycline or Nonanthracycline Chemotherapy.

B-type natriuretic peptide (BNP) is widely used as a diagnostic marker of systolic dysfunction. We previously conducted a clinical study in which anthracycline or nonanthracycline chemotherapy did not cause systolic dysfunction in cancer patients; however, some patients showed asymptomatic alterations in diastolic relaxation, whereas others showed persistent elevations of BNP, measured as prohormone BNP amino-terminal fragment. Here we describe post hoc pharmacologic analyses showing that: 1) impaired relaxation and persistent elevations of BNP were mutually exclusive manifestations of diastolic dysfunction; 2) in some patients, BNP elevations were induced by an early compromise of myocardial relaxation; 3) BNP elevations then halted further deterioration of relaxation in a concentration-dependent manner; and 4) high BNP increased heart rate (HR). BNP elevations therefore caused positive lusitropy and chronotropism, which might be explained by activation of natriuretic receptor-associated guanylyl cyclase and production of cGMP in ventricular myocytes and sinoatrial node, respectively. BNP levels also influenced responses to a lusitropic drug, ranolazine, that was given to treat diastolic dysfunction. For patients with impaired relaxation and normal or only transiently high levels of BNP, ranolazine improved myocardial relaxation without inducing chronotropic effects. For patients in whom relaxation abnormalities were corrected by persistently high BNP levels, ranolazine substituted for BNP and decreased HR by diminishing BNP levels. These findings describe a pharmacologic scenario in which cancer drugs cause an early diastolic dysfunction that in some patients is both heralded and modulated by BNP elevations. Patients showing BNP elevations should therefore receive the adequate pharmacologic treatment of correcting diastolic dysfunction and tachycardia.

Modified Colistin Regimen for Critically Ill Patients with Acute Renal Impairment and Continuous Renal Replacement Therapy.

Colistin is a last resort antibiotic to treat multidrug-resistant Gram-negative bacteria infections. Colistin is administered intravenously in the form of its inactive prodrug colistin methanesulfonate (CMS). For patients with acute kidney impairment and continuous renal replacement therapy high extracorporeal clearance may cause a substantial removal of active colistin from the bloodstream, eventually decreasing its antibacterial efficacy. Currently recommended doses of CMS may therefore be inadequate for these patients. We report on the potential value of a modified regimen that adopts a loading dose of CMS (bolus of 9 MU vs. conventional 3 MU every 8 h), followed by maintenance (3 MU every 8 h). Preliminary pharmacokinetic evidence for the feasibility and efficacy of this regimen is described for 2 patients.

Isavuconazole: Case Report and Pharmacokinetic Considerations.

Invasive fungal disease (IFD) is one of the major causes of morbidity and mortality in immunocompromised patients. Voriconazole (VCZ) and posaconazole (PCZ) remain the most widely used antifungals for the prophylaxis and treatment of IFD. However, VCZ and PCZ are liable for drug-drug interactions and show a pharmacokinetic variability that requires therapeutic drug monitoring (TDM). Isavuconazole (IVZ) is a newest generation triazole antifungal approved for the treatment of invasive aspergillosis (IA) in adult patients and for the treatment of invasive mucormycosis in adult patients for whom treatment with amphotericin B is inappropriate. In clinical trials, IVZ showed linear pharmacokinetics and little or no evidence for interactions with other drugs. There is only modest evidence on IVZ pharmacokinetics and TDM in real-life settings. Here, we report on IVZ pharmacokinetics in a young adult with Ph chromosome-negative acute lymphoblastic leukemia (ALL) who developed a "probable" IA during induction chemotherapy. The patient was initially treated with VCZ, but she developed a severe hepatic toxicity that was associated to the high plasma levels of VCZ. Therefore, VCZ was discontinued and the patient was switched to IVZ. After a loading dose of IVZ, the patient remained on IVZ for 5 months while also receiving standard maintenance chemotherapy for ALL. At day 65 after the start of IVZ, the patient experienced a significant hepatic toxicity; however, no change in IVZ plasma concentrations was observed in the face of a concomitant administration of many other drugs (cancer drugs, antiemetics, other anti-infectives). Hepatic toxicity resolved after discontinuing maintenance chemotherapy but not IVZ. These results show that (i) IVZ plasma concentrations remained stable throughout and were not affected by concomitant ALL therapy, and (ii) there was no relation between IVZ plasma concentration and hepatic toxicity. Thus, in clinical practice IVZ may not require TDM.

Modeling Human Myocardium Exposure to Doxorubicin Defines the Risk of Heart Failure from Low-Dose Doxorubicin.

The antitumor anthracycline, doxorubicin (DOX), can cause heart failure (HF) upon cumulative administration. Lowering the cumulative dose of DOX proved useful to minimize HF risk, and, yet, there is a growing concern that HF might occur after doses that were thought to be safe. Clinical trials that prospectively address such concerns are lacking. Because HF risk correlates with cardiac exposure to DOX, cumulative doses associated with HF risk were re-explored by modeling the accumulation of anthracycline pools in human myocardium. Ex vivo myocardial samples were used in vitro to simulate DOX rapid infusions. The accumulation of anthracycline pools was measured and incorporated into equations from which a risk versus dose curve was obtained. The experimental curve identified a 5% risk dose that was congruent with a previously reported clinical value (380 versus 400 mg/m2, respectively); however, 1-2% risk occurred after lower doses than reported. Simulations of gain-of-function polymorphism of carbonyl reductase 3, which converts DOX to its poorly diffusible alcohol metabolite, doxorubicinol (DOXOL), expanded anthracycline pools and caused 5% or 1-2% risk doses to decrease to 330 or 180-230 mg DOX/m2, respectively. These data show there is no safe dose of DOX. Diminishing cardiac exposure to circulating DOX may represent a cardioprotective strategy. We show that DOX slow infusions or liposomal DOX, which reduce cardiac exposure to DOX, caused formation of smaller anthracycline pools, did not generate DOXOL, increased the 5% risk dose to 750-800 mg/m2, and prevented HF risk aggravation by carbonyl reductase polymorphism.

Primary Prevention Strategies for Anthracycline Cardiotoxicity: A Brief Overview.

The clinical use of doxorubicin and other antitumor anthracyclines is limited by a dose-related risk of cardiomyopathy and heart failure which may occur "on treatment" or any time, from months to years, after completing chemotherapy. Dose reductions diminish the incidence of cardiac events attributable to anthracyclines, but heart failure still occurs in some patients exposed to low or moderate anthracycline doses. Because anthracyclines improve the life expectancy of patients with, for example, breast cancer or lymphomas, preventing or diminishing the risk of early or delayed cardiotoxicity is of obvious clinical importance. Here, we briefly review some potential strategies of primary prevention that are based on what we know about the molecular mechanisms of cardiotoxicity, and what can be done, or might be done, to interfere with the pharmacokinetic, pharmacodynamic, and genetic determinants of cardiotoxicity.

Ponatinib Induces a Persistent Molecular Response and Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia with a T315I Mutation following Early Relapse after Allogeneic Transplant.

We describe the case of a patient with a Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with dasatinib plus steroids as the first-line therapy who achieved a molecular complete remission and then underwent a matched, unrelated donor allogeneic transplant. Five months after the transplant, he experienced a disease relapse with an T315I mutation, which was resistant to salvage chemotherapy. Once the details of the T315I mutation were acquired, we initiated ponatinib treatment at a standard dosage and observed a rapid decrease of minimal residual disease (MRD) at molecular assessment. The bone marrow evaluation after 2, 3, 6, 10 and 13 months was negative for MRD. After starting ponatinib, the patient experienced a skin graft-versus-host disease (GVHD), whereas no occurrence of GVHD was observed after transplant, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect, but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib was well tolerated but a thyroid dysfunction mimicking a cardiovascular toxicity was observed and solved with hormonal substitutive treatment.

The concomitant management of cancer therapy and cardiac therapy.

Antitumor drugs have long been known to introduce a measurable risk of cardiovascular events. Cardio-Oncology is the discipline that builds on collaboration between cardiologists and oncologists and aims at screening, preventing or minimizing such a risk. Overt concern about "possible" cardiovascular toxicity might expose cancer patients to the risk of tumor undertreatment and poor oncologic outcome. Careful analysis of risk:benefit balance is therefore central to the management of patients exposed to potentially cardiotoxic drugs. Concomitant or sequential management of cardiac and cancer therapies should also be tailored to the following strengths and weaknesses: i) molecular mechanisms and clinical correlates of cardiotoxicity have been characterized to some extent for anthracyclines but not for other chemotherapeutics or new generation "targeted" drugs, ii) anthracyclines and targeted drugs cause different mechanisms of cardiotoxicity (type I versus type II), and this classification should guide strategies of primary or secondary prevention, iii) with anthracyclines and nonanthracycline chemotherapeutics, cardiovascular events may occur on treatment as well as years or decades after completing chemotherapy, iv) some patients may be predisposed to a higher risk of cardiac events but there is a lack of prospective studies that characterized optimal genetic tests and pharmacologic measures to minimize excess risk, v) clinical toxicity may be preceded by asymptomatic systolic and/or diastolic dysfunction that necessitates innovative mechanism-based pharmacologic treatment, and vi) patient-tailored pharmacologic correction of comorbidities is important for both primary and secondary prevention. Active collaboration of physicians with laboratory scientists is much needed for improving management of cardiovascular sequelae of antitumor therapy. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Rethinking Drugs from Chemistry to Therapeutic Opportunities: Pixantrone beyond Anthracyclines.

Pixantrone (6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione) has been approved by the European Medicines Agency for the treatment of refractory or relapsed non-Hodgkin's lymphoma (NHL). It is popularly referred to as a novel aza-anthracenedione, and as such it is grouped with anthracycline-like drugs. Preclinical development of pixantrone was in fact tailored to retain the same antitumor activity as that of anthracyclines or other anthracenediones while also avoiding cardiotoxicity that dose-limits clinical use of anthracycline-like drugs. Preliminary data in laboratory animals showed that pixantrone was active, primarily in hematologic malignancies, but caused significantly less cardiotoxicity than doxorubicin or mitoxantrone. Pixantrone was cardiac tolerable also in animals pretreated with doxorubicin, which anticipated a therapeutic niche for pixantrone to treat patients with a history of prior exposure to anthracyclines. This is the case for patients with refractory/relapsed NHL. Pixantrone clinical development, regulatory approval, and penetration in clinical practice were nonetheless laborious if not similar to a rocky road. Structural and nominal similarities with mitoxantrone and anthracyclines may have caused a negative influence, possibly leading to a general perception that pixantrone is a "me-too" anthracycline. Recent insights suggest this is not the case. Pixantrone shows pharmacological and toxicological mechanisms of action that are difficult to reconcile with anthracycline-like drugs. Pixantrone is a new drug with its own characteristics. For example, pixantrone causes mis-segregation of genomic material in cancer cells and inhibits formation of toxic anthracycline metabolites in cardiac cells. Understanding the differences between pixantrone and anthracyclines or mitoxantrone may help one to appreciate how it worked in the phase 3 study that led to its approval in Europe and how it might work in many more patients in everyday clinical practice, were it properly perceived as a drug with its own characteristics and therapeutic potential. The road is rocky but not a dead-end.