Matteo Molica

How tyrosine kinase inhibitors impair metabolism and endocrine system function: A systematic updated review

Tyrosine kinase inhibitors (TKIs) advent has deeply changed the outcome of chronic myeloid leukemia (CML) patients, with improved rates of response and overall survival. However, for this success some patients paid the price of a number of peculiar side effects, the so-called off-target side effects, specific for each one TKI. These effects are due to non-selective inhibition of other tyrosine kinase receptors, such as PDGFR, c-KIT, Src, VEGF. Consequences of this inhibition, some metabolic changes during the treatment with TKIs are reported. Aim of present review is to report metabolic changes and potential mechanisms involved in the pathogenesis related to imatinib, second (nilotinib and dasatinib) and third generation (bosutinib and ponatinib) TKIs.

Baff serum level predicts time to first treatment in early chronic lymphocytic leukemia

We analyzed the correlation between well‐established biological parameters of prognostic relevance in B‐cell chronic lymphocytic leukemia (CLL) [i.e. mutational status of the immunoglobulin heavy chain variable region (IgVH), ZAP‐70 and CD38 expression] and serum levels of B cell–activating factor (BAFF of the TNF family) by evaluating the impact of these variables on the time to first treatment (TFT) in a series of 169 previously untreated CLL patients in Binet stage A. Higher levels of BAFF were more frequently associated with female gender (P = 0.02), younger age (P = 0.01), Rai stage 0 (P = 0.002), higher platelet count (P = 0.005), mutated IgVH disease (P = 0.002), higher occurrence of normal cytogenetic profile or presence of 13q deletion (P = 0.02), low ZAP‐70‐ (P = 0.003), and CD38‐expression (P = 0.02). Maximally selected log‐rank statistic plot identified a serum BAFF concentration of 0.313 ng/mL as the best cut‐off (P < 0.0001). This threshold recognized two subsets of patients with different TFT (P < 0.0001). Because in multivariate analysis soluble BAFF [Hazard ratio (HR), 8.23; confidence Interval (CI) 95%,3.0–22.6, P < 0.0001] and mutational status of IgVH (HR = 2.60; CI 95% 1.10–6.14, P = 0.03) maintained the discriminating power their combined effect on clinical outcome was assessed. When three groups were considered: ( 1 ) low‐risk (n = 93), patients with concordant IgVHmut and higher soluble BAFF; ( 2 ) intermediate‐risk (n = 50), patients with IgVHmut and low BAFF levels or IgVHunmut and soluble higher BAFF;( 3 ) high‐risk (n = 26), patients with concordant IgVH unmut and low soluble BAFF, the 2‐yr TFTs were, respectively, 95%, 85%, and 41% (P < 0.0001). In conclusion, our results indicate that in early B‐cell CLL, the biological profile including among other parameters soluble BAFF may provide a useful insight into the complex interrelationship of prognostic variables.

Age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival

We applied Charlson comorbidity index (CCI) stratification on a large cohort of chronic myeloid leukemia (CML) very elderly patients (>75 years) treated with imatinib, in order to observe the impact of concomitant diseases on both compliance and outcome. One hundred and eighty-one patients were recruited by 21 Italian centers. There were 95 males and 86 females, median age 78.6 years (range 75-93.6). According to Sokal score, 106 patients were classified as intermediate risk and 55 as high risk (not available in 20 patients). According to CCI stratification, 71 patients had score 0 and 110 a score ≥ 1. Imatinib standard dose was reduced at start of therapy (200-300 mg/day) in 68 patients independently from the evaluation of baseline comorbidities, but based only on physician judgement: 43.6% of these patients had score 0 compared to 34% of patients who had score ≥ 1. Significant differences were found in terms of subsequent dose reduction (39% of patients with score 0 compared to 53% of patients with score ≥ 1) and in terms of drug discontinuation due to toxicity (35% of patients with score 0 vs 65% of patients with score ≥ 1). We did not find significant differences as regards occurrence of hematologic side effects, probably as a consequence of the initial dose reduction: 39% of patients with score 0 experienced grade 3/4 hematologic toxicity (most commonly anemia) compared to 42% of patients with score ≥ 1. Independently from the initial dose, comorbidities again did not have an impact on development of grade 3/4 non-hematologic side effects (most commonly skin rash, muscle cramps and fluid retention): 62% of patients with score 0 compared to 52.5% of patients with score ≥ 1. Notwithstanding the reduced dose and the weight of comorbidities we did not find significant differences but only a trend in terms of efficacy: 66% of patients with score 0 achieved a CCyR compared to 54% of patients with score ≥ 1. Comorbidities appeared to have an impact on median OS (40.8 months for patients with score 0 vs 20.16 months for patients with score ≥ 1) on EFS and on non-CML death rate. Our results suggest that treatment of very elderly CML patients might be influenced by personal physician perception: evaluation at baseline of comorbidities according to CCI should improve initial decision-making in this subset of patients.

FLT3-ITD in acute promyelocytic leukemia: Clinical distinct profile but still controversial prognosis

FLT3 gene, which is located on chromosome 13q12 in humans, ncodes a class III tyrosine kinase receptor (RTKs) and plays an mportant role in the differentiation of hematopoietic stem cells. TKs are characterized by five immunoglobulin – like regions, such s extra-cellular domain, a juxtamembrane (JM) domain, a transembrane region, two intracellular tyrosine kinase domains. The nteraction with specific ligands leads to receptor dimerization ollowed by the subsequent phosphorylation of tyrosine residues ctivating multiple intracellular signaling pathways leading to cell roliferation and activation [1]. Any form of alterations of RTKs, uch as overall expression, amplification or somatic mutations, eterminate an increased and uncontrolled intracellular signaling efinitely causing tumorigenesis [2]. FLT3 mutations including nternal tandem duplications (ITD) in the juxtamembrane domain, hich frequently involve exon 14 and eventually intron 14 or exon 5, have been reported in 30% of patients affected by acute myeloid eukemia (AML) [3]. An additional mutation have been detected n 5–10% of AML which is a point mutation in the tyrosine kinase I domain (TKD) at Asp835 within exon 20 of the FLT3 gene and esides within the activation loops of the kinase domain of the FLT3 rotein [2]. In acute promyelocytic leukemia (APL) the incidence of LT3-ITD mutation was reported with a wide range (12–38%) [4]. everal prognostic factors have been proposed to negatively influnce overall survival (OS), event free survival (EFS) and the risk f relapse in APL patients included older age, high white blood cell ount at diagnosis, bcr3 type of transcript, morphologic microgranlar variant, additional cytogenetic alterations, and the expression f the surface antigens CD34 and CD56 [5]. The role of FLT3-ITD in PL as a prognostic factor for long-term outcome is not yet clarified nd the significance of this genetic alteration remains absolutely ontroversial. Most of the studies published, showed a strong corelation between FLT3-ITD and specific features at baseline, such as igher WBC count, variant morphologic subtype and short type of ranscript. Indeed, not all studies were able to report a clear demon-

Systematic review of dasatinib in chronic myeloid leukemia.

Dasatinib is a dual tyrosine kinase inhibitor active against ABL and Src family kinases, and is approved for the treatment of chronic myeloid leukemia (CML) patients in chronic, accelerated, or blast phase with resistance or intolerance to imatinib therapy, for newly diagnosed chronic phase patients, and for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia who have become resistant to or intolerant of other treatments. This review presents clinical data regarding different trials involving CML patients in different phases of the disease. Six-year follow-up of the Phase III dose-optimization study are described, showing overall survival of 71% with the current approved dose of 100 mg once daily. Three-year results of the randomized Phase III DASISION (DASatinib vs Imatinib Study In Treatment-Naïve CML patients) trial confirmed that dasatinib 100 mg once daily was superior to standard-dose imatinib in terms of achieving a faster and deeper molecular response, with similar activity regardless of baseline prognostic score.

Vitamin D insufficiency predicts time to first treatment (TFT) in early chronic lymphocytic leukemia (CLL).

Although vitamin D insufficiency is related to inferior prognosis in some cancers, limited data exist in hematologic malignancies. We evaluated the relationship between 25(OH)D serum levels and time to first treatment (TFT), a disease-specific end point, in 130 previously untreated Binet stage A chronic lymphocytic leukemia (CLL) patients. Measurement of 25(OH)D was performed by means of a direct, competitive chemiluminescence immunoassay using the DiaSorin LIAISON 25(OH)D TOTAL assay (DiaSorin, Inc., Stillwater, Minnesota). Overall, 41 patients (31.5%) had severe vitamin D insufficiency (<10 ng/mL), 66 (50.7%) had mild to moderate insufficiency (10-24 ng/mL), and 23 (17.6%) had 25(OH)D levels within the optimal range (25-80 ng/mL), with no relationship with between the season of sample collection and 25(OH)D level (P=0.188). A patient stratification according to these 3 groups led to significant difference in terms of TFT, with vitamin D insufficient patients having the shortest TFT (P=0.02). With respect to continuous 25(OH)D levels and clinical outcome, TFT was shorter as 25(OH)D decreased until a value of 13.5 ng/mL at which point the association of 25(OH)D and TFT remained constant. As a matter of fact, the 25(OH)D value of 13.5 ng/mL identified two patients subsets with different TFT risk (HR=1.91; 95% CI=1.06-3.44; P=0.03). In multivariate analysis the variable entering the model at a significant level were mutational status of IgVH (P<0.0001), serum thymidine kinase (P=0.02) and absolute lymphocyte count (P=0.03). Thus confirming the Mayo clinic experience, our data provide further evidence that 25(OH)D levels may be an important host factor influencing TFT of Binet stage A patients. Whether normalizing vitamin D levels may delay disease-progression of patients with early disease will require testing in future trials.

Serum level of CD26 predicts time to first treatment in early B-chronic lymphocytic leukemia

We analyzed the correlation between well‐established biological parameters of prognostic relevance in B‐cell chronic lymphocytic leukemia (CLL) [i.e. mutational status of the immunoglobulin heavy chain variable region (IgVH), ZAP‐70‐ and CD38‐expression] and serum levels of CD26 (dipeptidyl peptidase IV, DPP IV) by evaluating the impact of these variables on the time to first treatment (TFT) in a series of 69 previously untreated Binet stage A B‐cell CLL patients. By using a commercial ELISA we found that with exception of a borderline significance for ZAP‐70 (P = 0.07) and CD38 (P = 0.08), circulating levels of CD26 did not correlate with either Rai substages (P = 0.520) or other biomarker [β2‐microglobulin (P = 0.933), LDH (P = 0.101), mutational status of IgVH (P = 0.320)]. Maximally selected log‐rank statistic plots identified a CD26 serum concentration of 371 ng/mL as the best cut‐off. This threshold allowed the identification of two subsets of patients with CD26 serum levels higher and lower that 371 ng/mL respectively, whose clinical outcome was different with respect to TFT (i.e. 46% and 71% at 5 yr respectively; P = 0.005). Along with higher serum levels of CD26, the univariate Cox proportional hazard model identified absence of mutation in IgVH (P < 0.0001) as predictor of shorter TFT. As in multivariate analysis all these parameters maintained their discriminating power (mutational status of IgVH,P < 0.0001; soluble CD26, P = 0.02) their combined effect on clinical outcome was assessed. When three groups were considered: (1) Low‐risk group (n = 31), patients with concordant IgVHmut and low level of soluble CD26; (2) intermediate risk group (n = 26), patients with discordant pattern; (3) high‐risk group (n = 12), patients with concordant IgVHunmut and high level of soluble CD26, differences in the TFT were statistically significant, with a TFT at 5 yr of respectively 88%, 51% and 43% (P < 0.0001). Our results indicate that in early B‐cell CLL biological profile including among other parameters soluble CD26 may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, CD26 along with mutational status of IgVH can be adequately used to predict clinical behavior of patients with low risk disease.

Monoclonal B-cell lymphocytosis: a reappraisal of its clinical implications

Abstract Monoclonal B-cell lymphocytosis (MBL) is a recently defined medical condition that displays biological similarities to chronic lymphocytic leukemia (CLL), the most common subtype of adult leukemia in the Western world. MBL may be diagnosed in individuals with a normal lymphocyte count via a screening assay (screening MBL) or through the clinical evaluation of lymphocytosis (clinical MBL). Clinical MBL, which resembles CLL with a good prognosis, has attracted considerable interest because of its clinical and biological implications. The biological profile of clinical MBL appears indistinguishable from that of CLL for a large variety of markers. Differential diagnosis between clinical MBL and CLL is mainly based on peripheral blood B-cell counts. The 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria changed the definition of CLL to a B-cell count ≥ 5.0 × 109/L to eliminate overlap between CLL and MBL. However, this cut-off is arbitrary, and recent studies suggest that a B-cell count of 10.0–11.0 × 109/L may represent the threshold that best predicts time to first treatment. After a diagnosis of clinical MBL, patients should be educated about appropriate monitoring and follow-up keeping in mind that, with time and counseling, most patients will understand that clinical MBL and CLL represent a continuum.

Discontinuation of alpha-interferon treatment in patients with chronic myeloid leukemia in long-lasting complete molecular response

To evaluate follow-up after α-interferon (IFN) discontinuation, 23 patients with chronic myeloid leukemia (CML) in stable complete molecular response (CMolR) with IFN were revisited. After a median IFN treatment of 105.8 months (IR 56.1 – 127.3), all patients discontinued IFN for prolonged CMolR (12), intolerance (8) or planned ABMT (3). After 12.5 months, one patient developed an extramedullar blast crisis. Four patients needed to start imatinib, all achieving again molecular response. Eighteen patients are still off-therapy (median time from IFN discontinuation 125.5 months, IR 86.9–205.3); among these, five are BCR-ABL negative, six present with a sporadic positivity (BCR-ABL ratio < 0.1) and seven show a stable and long-lasting mild positivity (BCR-ABL ratio < 0.5). Patients in prolonged CMolR with IFN have low risk of recurrence after discontinuation; the reappearance of a BCR-ABL positivity < 0.5 did not always precede a relapse, suggesting mechanisms of immunological control induced by IFN.

Improvement of bone marrow fibrosis with ruxolitinib: will this finding change our perception of the drug?

Ruxolitinib, a JAK1 and JAK2 inhibitor, has been tested and approved for the treatment of primary and secondary myelofibrosis. Reduction of spleen volume and improvement of constitutional symptoms and quality of life have been reported as the major findings in sponsored randomized clinical trials. Recent data indicated that the drug improves bone marrow fibrosis and that different targets may be involved in this response. These new data, which require confirmation in prospective trials, may change our perspectives and therapeutic strategies for this disease.