Cristina Bucelli

Effects of first- and second-generation tyrosine kinase inhibitor therapy on glucose and lipid metabolism in chronic myeloid leukemia patients: a real clinical problem?

Background Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of patients with chronic myeloid leukemia (CML). They have a distinct toxicity profile that includes glycometabolic alterations: i.e. diabetes mellitus (DM), impaired fasting glucose (IFG), and the metabolic syndrome (MS). The aim of this study was to evaluate the prevalence of these alterations in a cohort of CML-chronic phase patients treated with imatinib, dasatinib or nilotinib. Methods The study involved 168 consecutive CML-chronic phase patients with no history of DM/IFG or MS. Anthropometric and metabolic parameters were assessed, and DM/IFG and MS were diagnosed based on the criteria of the American Diabetes Association and the National Cholesterol Education Program-Adult Treatment Panel III, respectively. Results The nilotinib group had significantly higher levels of fasting plasma glucose, insulin, C-peptide, insulin resistance, and total and LDL cholesterol than the imatinib and dasatinib groups. DM/IFG were identified in 25% of the imatinib- and dasatinib-treated patients, and 33% of those in the nilotinib cohort (p = 0.39 vs imatinib and p = 0.69 vs dasatinib). A diagnosis of MS was made in 42.4% of the imatinib-treated patients, 37.5% of the dasatinib-treated patients, and 36.1% of the nilotinib-treated patients (p = 0.46 vs imatinib and p = 0.34 vs dasatinib). Conclusions Treatment with nilotinib does not seem to induce DM/IFG or the MS to a significantly higher extent than imatinib or dasatinib, though it causes a worse glycometabolic profile. These findings suggest the need for a close monitoring of glucose and lipid metabolism and a multidisciplinary approach in patients treated with nilotinib.

Imatinib and ruxolitinib association: first experience in two patients

We report the first case of 2 patients with a previous diagnosis of post-polycythemic (PV) myelofibrosis who developed chronic myeloid leukemia (CML) seven years later, both treated with an association of a tyrosine-kinase inhibitor (imatinib) and a JAK1/JAK2 inhibitor (ruxolitinib). In 1992, a 46-

Imatinib and polypharmacy in very old patients with chronic myeloid leukemia: effects on response rate, toxicity and outcome

Background About 40% of all patients with chronic myeloid leukemia are currently old or very old. They are effectively treated with imatinib, even though underrepresented in clinical studies. Furthermore, as it happens in the general population, they often receive multiple drugs for associated chronic illnesses. Aim of this study was to assess whether or not in imatinib-treated patients aged >75 years the exposure to polypharmacy (5 drugs or more) had an impact on cytogenetic and molecular response rates, event-free and overall survival, as well as on hematological or extra-hematological toxicity. Methods 296 patients at 35 Italian hematological institutions were evaluated. Results Polypharmacy was reported in 107 patients (36.1%), and drugs more frequently used were antiplatelets, diuretics, proton pump inhibitors, ACE-inhibitors, beta-blockers, calcium channel blockers, angiotensin II receptors blockers, statins, oral hypoglycemic drugs and alpha blockers. Complete cytogenetic response was obtained in 174 patients (58.8%), 78 (26.4%) within 6 month, 63 (21.3%) between 7 and 12 months. Major molecular response was obtained in 153 patients (51.7%), 64 (21.6%) within the 12 month. One hundred and twenty-eight cases (43.2%) of hematological toxicity were recorded, together with 167 cases (56.4%) of extra-hematological toxicity. Comparing patients exposed to polypharmacy to those without, no difference was observed pertaining to the dosage of imatinib, cytogenetic and molecular responses and hematological and extra-hematological toxicity. Conclusion Notwithstanding the several interactions reported in the literature between imatinib and some of the medications considered herewith, this fact does not seem to have a clinical impact on response rate and outcome.

Transient elastography spleen stiffness measurements in primary myelofibrosis patients: a pilot study in a single centre.

Keywords: primary myelofibrosis; bone marrow fibrosis; transient elastography; spleen stiffness; ruxolitinib

The hOCT1 and ABCB1 polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia

First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of hOCT1 (rs683369 [c.480C>G]) and ABCB1 (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, hOCT1 and ABCB1 polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, in contrast to data obtained in patients treated with imatinib, hOCT1 and ABCB1 polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.

An unusual type of myeloid sarcoma localization following myelofibrosis: A case report and literature review

Myeloid Sarcoma (MS) is a rare malignancy that can present as an isolated disease or more frequently in association with or following acute myeloid leukemia or other myeloid neoplasms and rarely following myelofibrosis. Since molecular pathogenesis and prognostic factors of MS are not well understood, its prognosis remains poor even in the era of novel agents and target therapies. We report the case of a patient with MS following myelofibrosis with multiple subcutaneous, cutaneous and muscle localizations; the latter has been reported in the literature as anecdotal. In this way we aimed to enhance the understanding of this disease.

Prognostic significance of a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in primary myelofibrosis patients

To evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications.

Reactive follicular hyperplasia on dasatinib treatment for chronic myeloid leukemia

Dear Editor, Dasatinib (DAS) is an oral dual Abl and Src tyrosine kinase inhibitor licensed in the treatment of chronic myeloid leukemia (CML) [1, 2] and is well known to exert an immunomodulatory effect both in vivo and in vitro [3]. DAS shows a distinct toxicity profile among which a previously unrecognized adverse event (AE) is represented by persistent lymphadenopathy with reactive follicular hyperplasia (FLH). Recently, lymphadenopathy with morphologic features of reactive FLH has been described in two small series of longtermDAS-treated CML patients [4, 5], which globally encompass twelve patients, even though only three in the first-line setting. In addition, only in a few patients complete FLHmorphologic and immunophenotypic features were reported. Herein, we describe two cases of patients with chronic phase (CP)-CML, intermediate risk according to Sokal score, and e14a2 transcript type, who presented with unexplained lymphadenopathy during front-line DAS therapy. Case 1: in October 2012, a 30-year-old man was diagnosed with CP-CML and he was front-line treated with DAS 100 mg QD, rapidly obtaining a major and subsequently a deep molecular response. DAS was well tolerated but approximately after 48months, bilateral cervical lymphadenopathy appeared. At a subsequent ultrasound examination, multiple enlarged lymph nodes were detected both in the cervical and submandibular area. Case 2: in April 2016, a 49-year-old man was diagnosed with CP-CML and he was front-line treated with DAS 100 mg QD. The drug was well tolerated and after 12 months of therapy he obtained a major molecular response. Nevertheless, in April 2017 a swelling at the angle of the left mandible and concomitant bilateral cervical, preauricular, and sovraclavear lymphadenopathy appeared. At a subsequent ultrasound examination, multiple enlarged lymph nodes were detected both in the cervical and left submandibular area. For both patients, no generalized lymphadenopathy was noted and no constitutional symptoms were reported. As screening for active viral infection was negative and no signs of local or systemic infectious disease were detected, an excisional biopsy was performed, showing in both cases enlarged lymph nodes with overall preserved architecture, marked follicular hyperplasia with evident reactive germinal centers (CD10+, BCL6+, BCL2and very high Ki-67 immunoreactivity), and moderate expansion of the paracortical T-zone in which a predominance of small CD3+, CD5+ T lymphocytes was identifiable together with scattered enlarged CD45+, CD30−/+, CD15−, and CD20+/− immunoblasts (Fig. 1). In situ hybridization for EBV-encoded RNA was negative. A diagnosis of FLH was made, ruling out an extramedullary blastic transformation of CML. Then, both patients definitely discontinued DAS and started ponatinib at a daily dose of 15 mg, achieving complete clinical resolution of lymphadenopathy. For what concerns FLH pathogenesis, it should be underlined that Lyn, a Src family protein, is expressed in B lymphocytes and regulates their activity via Akt/PKB signaling pathway. Thus, DAS inhibitory impact on Src kinases and the consequent upregulation of Akt/PKB pathway could contribute to the B lymphocytes proliferation and FLH development. * Alessandra Iurlo aiurlo@policlinico.mi.it

Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients

Second-generation tyrosine kinase inhibitors (2G-TKIs) dasatinib and nilotinib produced historical rates of about 50% complete cytogenetic response (CCyR) and about 40% major molecular response (MMR) in chronic myeloid leukaemia (CML) patients failing imatinib. Direct comparisons between dasatinib and nilotinib are lacking, and few studies addressed the dynamics of deep molecular response (DMR) in a “real-life” setting. We retrospectively analyzed 163 patients receiving dasatinib (n = 95) or nilotinib (n = 68) as second-line therapy after imatinib. The two cohorts were comparable for diseases characteristics, although there was a higher rate of dasatinib use in imatinib-resistant and of nilotinib in intolerant patients. Overall, 75% patients not in CCyR and 60% patients not in MMR at 2G-TKI start attained this response. DMR was achieved by 61 patients (37.4%), with estimated rate of stable DMR at 5 years of 24%. After a median follow-up of 48 months, 60% of patients persisted on their second-line treatment. Rates and kinetics of cytogenetic and molecular responses, progression-free and overall survival were similar for dasatinib and nilotinib. In a “real-life” setting, dasatinib and nilotinib resulted equally effective and safe after imatinib failure, determining high rates of CCyR and MMR, and a significant chance of stable DMR, a prerequisite for treatment discontinuation.

Low-Dose Ponatinib in Intolerant Chronic Myeloid Leukemia Patients: A Safe and Effective Option

Ponatinib is an oral third-generation tyrosine kinase inhibitor (TKI) and the only one able to overcome the gatekeeper T315I mutation [1, 2]. Currently, it is registered at a daily dose of 45 mg for the treatment of chronic myeloid leukemia (CML) patients in chronic phase (CP), accelerated, or blast phase of the disease, or of Philadelphiapositive (Ph?) acute lymphoblastic leukemia (ALL) resistant to a second-generation TKI, and for whom imatinib is no longer indicated or for patients carrying the T315I mutation [3]. The efficacy of this drug is well-known, but as it represents a chronic therapy in the same way of the other TKIs, some warnings emerged concerning its safety profile when used at the registered dose. In particular, in the phase II PACE trial serious arterial thrombotic events (ATEs) were observed in 9% of patients at 15 months’ follow-up [1]. Consequently, after October 2013 the dose of ponatinib was reduced from 45 mg to 30 mg/day in patients who had achieved the primary endpoint [2]. Furthermore, each 15 mg/day reduction in average daily dose was predicted to lead to * 40% reduction in risk of ATEs [4]. In general, very limited data have been reported in the literature so far on ponatinib use as a second-line treatment after resistance [5] and/or intolerance to a previous line of therapy in CP-CML. Herein, we report a small series of seven CP-CML patients who have all been treated with ponatinib at a daily dose of 15 mg because of intolerance to their prior TKIs (Table 1). At baseline the Sokal risk was intermediate in five patients, low in one patient and high in another. According to the EUTOS score, all patients were low risk, except one. Among significant comorbidities, diabetes and hypertension were present in one patient each. All patients were receiving dasatinib 100 mg/day before ponatinib start, five in the front-line and two in the secondline setting because of resistance to prior imatinib. Median time from diagnosis to ponatinib treatment was 3.6 years (range 1–19.3). The best response achieved before the switch to ponatinib was a major molecular response (MMR) in five patients and a deep molecular response (MR4) in the remaining cases. All patients switched to ponatinib because of intolerance to dasatinib: in detail, this happened because of the appearance of reactive follicular hyperplasia in cases no. 1 and 4 [6], recurrence of pleural effusion in cases no. 2, 6 and 7, onset of pulmonary arterial hypertension in case no. 3 and severe uncontrolled autoimmune disorder in patient no. 5. As reported in Table 1, adverse events severity was graded as 2 according to common terminology criteria for adverse events (CTCAE) in all the cases except in patient no. 5, whose autoimmune disorder was graded as 3. With regard to efficacy, at a median follow-up from ponatinib start of 9.9 months (range 4.9–24.0 months) all patients maintained at least the same depth of molecular response they had already achieved even if a low dose of ponatinib was administered. In addition, two patients (no. 5 and 7) increase the depth of molecular response, reaching an MR4. & Alessandra Iurlo alessandra.iurlo@policlinico.mi.it