Alessandra Serrao

MDS-specific comorbidity index is useful to identify myelodysplastic patients who can have better outcome with 5-azacitidine

Recently Della Porta and colleagues[1][1] reported on the importance of evaluation of comorbidities at baseline in myelodysplastic syndrome patients (MDS) in order to better tailor treatment strategies according to WPSS stratification. They proposed a prognostic score, the so-called MDS-CI, which

5-Azacitidine efficacy and safety in patients aged >65 years with myelodysplastic syndromes outside clinical trials

Abstract The efficacy and safety of azacitidine in elderly patients (aged >65 years) with myelodysplastic syndromes (MDS) treated outside clinical trials are reported. Thirty-eight patients with MDS received azacitidine (75 mg/m2, schedule 5+2 +2): seven patients were classified as having refractory cytopenia with multilineage dysplasia (RCMD), nine patients with refractory anemia with excess of blasts (RAEB) type 1, 18 patients with RAEB type 2 and four patients with chronic myelomonocytic leukemia type 2 (CMML-2). According to International Working Group (IWG) 2006 criteria, after the first four cycles we detected complete remission in seven patients (CR, 18%), improvement of bone marrow dysplasia and reduction of blast percentage in seven patients (partial response, 18%), stable disease in 20 patients (53%) and progression to acute leukemia in four patients (10%). Median overall survival for all patients treated was 16.4 months. Only mild non-hematologic toxicity was detected (grade 1–2 nausea and pruritus), whereas 55% of patients experienced hematologic side effects (25% grade 3–4 thrombocytopenia and 30% grade 3–4 neutropenia). Our results suggest that advanced age should not preclude effective treatment with azacitidine in non-selected elderly patients wih MDS.

Delayed cytogenetic and major molecular responses associated to increased BMI at baseline in chronic myeloid leukemia patients treated with imatinib

Obesity, measured as body mass index (BMI), has been identified as a possible risk factor for several solid tumors as well as for chronic myeloid leukemia (CML). To date, no correlations have been reported in this latter disease between BMI at baseline and response to targeted therapies. We refer here on the impact of BMI on clinical response in 339 chronic phase (CP) CML patients treated with imatinib and 35 CP-CML patients treated frontline with nilotinib. If compared to patients with low BMI (<18.5-25), patients with increased BMI (>25-40) at diagnosis who received imatinib showed a significantly longer median time to achieve complete cytogenetic response (6.8 months vs 3.3 months, p=0.001), a reduced rate of major molecular response (77% vs 58%, p=0.01) which was also achieved in a longer median time (29 months compared to 14 months, p=0.01). Conversely, no differences were revealed with respect to BMI in patients treated frontline with nilotinib and also patients with increased BMI obtained rapidly CCyR and MMR with an incidence similar to that of underweight/normal weight patients. These results suggest that CML patients with increased weight at baseline should be followed and carefully monitored if treated with standard dose imatinib frontline for a possible early switch.

Evaluation of overall survival according to myelodysplastic syndrome-specific comorbidity index in a large series of myelodysplastic syndromes

We read with interest the article by Della Porta and colleagues[1][1] and the editorial of Prof. Cazzola[2][2] relating to the role of comorbidities in myelodysplastic syndromes (MDS). We have previously published a paper on the role of comorbidities in MDS patients[3][3] and we found it intriguing

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.

Fasting glucose level reduction induced by imatinib in chronic myeloproliferative disease with TEL-PDGFRβ rearrangement and type 1 diabetes.

Dear Editor, A minority of patients with chronic myeloproliferative disease have constitutive activation of the gene for PDGFRβ; this is usually caused by t(5;12)(q33;p13) translocation associated with a TEL-PDGFRβ fusion gene encoding for a tyrosine kinase receptor which can be inhibited by imatinib. Several reports [1–3] have suggested that imatinib can affect fasting glucose (FG) level in CML or gastrointestinal stromal tumors (GIST) patients with type II diabetes. Here, we report a patient with TELPDGFRβ rearrangement affected by concomitant type 1 diabetes who was treated with imatinib at 400 mg daily and experienced symptomatic FG reduction requiring insulin dose decrease. A 27-year-old male referred to our institute for asymptomatic isolated leukocytosis (35×10/l). While peripheral blood molecular evaluation for BCR-ABL rearrangement was negative, conventional cytogenetic analysis showed a t(5;12)(q33;q13) in 13 out of 22 metaphases analyzed. Qualitative molecular analysis detected TEL-PDGFRβ rearrangement both in bone marrow and peripheral blood. The patient was diagnosed with type 1 diabetes at 24 years of age, requiring insulin replacement therapy. The patient was then started on imatinib 400 mg daily and achieved complete hematologic response after 1 month. To control FG level, before starting imatinib, the patient required a total of 66 IU insulin per day. Following imatinib treatment, the patient soon obtained an optimal control of FG: during week 7 of imatinib therapy, he developed symptomatic hypoglycemia with a glucose level of 45 mg/dL. For this reason, insulin therapy was reduced in the following weeks from 20 to 10 IU at breakfast, from 15 to 7 IU at lunch, and to 12 IU of long-acting insulin before going to sleep (total, 29 UI per day). FG declined from a median value of 182 mg/dl before starting imatinib to a median of 138 mg/dl on imatinib. No weight increment or loss occurred during the first 5 months of therapy. During this period, the glycated hemoglobin decreased from 7.2 to 5 %. The subsequent controls showed glycated hemoglobin level in the normal range. As far as we know, this is the first case described in literature of in vivo control of type 1 diabetes in a patient on imatinib, requiring reduction of insulin therapy. This evidence is also in line with our previously reported experience on the improvement of fasting glucose in patients with CML and type 2 diabetes treated with imatinib and with the evidence of decreased glucose uptake by gastrointestinal stromal c-KIT-positive tumors after imatinib treatment [4, 5]. Imatinib might affect glucose homeostasis resulting in a reduced necessity for antidiabetic treatment in some diabetic patients, and hypoglycemia might be exacerbated in patients with GIST exhibiting symptoms of non-islet cell-induced hypoglycemia [4, 6]. The molecular mechanisms underlying the A. Salaroli :G. Loglisci :A. Serrao :G. Alimena :M. Breccia Department of Biotechnologies and Cellular Hematology, Sapienza University, Rome, Italy

Prognostic features of patients with myelodysplastic syndromes aged < 50 years: update of a single-institution experience

Abstract Fewer than 10% of patients with myelodysplastic syndromes (MDS) are younger than 50 years. A series of 91 younger patients (median age 44 years with female prevalence) are reported and compared with elderly patients. Frequent karyotypic changes were trisomy 8 (9.8%) and monosomy 7 (5%). Twenty-three patients had occupational exposure to potential mutagens (benzene and solvents), with a male predominance, higher frequency of refractory cytopenia with multilineage dysplasia (RCMD) (52%) and higher frequency of monosomy 7 (21.7%). At a median follow-up of 72 months, 22 patients (24%) evolved to acute leukemia, with higher frequency being observed among the exposed cohort (39% vs. 19% non-exposed). Unfavorable factors for overall survival were: age > 40 years, > 5% of blasts, trilinear bone marrow involvement and intermediate–high World Health Organization Prognostic Scoring System (WPSS) risk. The present results suggest that younger MDS could be identified as a distinct subset. For patients belonging to the low/intermediate-I risk group, due to a low transformation rate, aggressive approaches should rarely be recommended.

Isolated central nervous system relapse after nine years of complete molecular remission in a lymphoid blast crisis of chronic myeloid leukemia treated with imatinib

Extramedullary blast crisis (BC) of chronic myeloid leukemia CML) has been observed in 7–10% of patients, with or withut other manifestation of disease progression [1]. Cerebrospinal nvolvement as a site of extramedullary BC is rare, but since the dvent of imatinib as first-line treatment for CML, there have een several reports describing patients with isolated central nerous system (CNS) involvement [1–5], because the drug poorly enetrates the blood-brain barrier. Here we report a case of a ymphoid BC, developed under IFN therapy, which reached comlete molecular remission with imatinib and presented an isolated elapse of the same disease in CNS after nine years of imatinib herapy. A 71-year-old female was diagnosed with Philadelphia+ CML in anuary 2001 and was initially treated with interferon (IFN ) at he maximum tolerated dose of 5 MU/day. After 6 months of treatent, she developed a sudden leucocytosis (WBC 52 × 109 /l). At hat time bone marrow examination showed a total infiltration by 0% blast cells: immunophenotypic analysis revealed a blastic poplation, which was positive for the following superficial antigens: D34, CD79-a, CD19 and CD38, CD13, CD33, CD66-C, TdT+, and egative for CD10, CD20, leading to a diagnosis of lymphoid BC. ytogenetic analysis at the time of acute transformation showed uplication of Ph+ chromosome in 20 analysed metaphases. Cererospinal fluid (CSF) analysis at that time did not reveal evidence of isease. The patient was started on imatinib at the dose of 600 mg aily and achieved a complete haematological response after 1onth and a complete cytogenetic response (CCR) after 3 months. complete molecular response (CMR) was reached after 3 years f treatment (ratio BCR-ABL1/ABL1 < 0.001IS), with imatinib being ontinued at 400 mg/day for the following nine years, without any ign of toxicity. In September 2010, the patient suddenly develped left hypoacusia, left lower limb weakness and right visual loss. MRI showed a solid tissue around the left facial nerve. Optical xamination revealed bilateral papilloedema. Bone marrow examnation confirmed CCR and RQ-PCR showed a residual disease with BCR-ABL1/ABL1 ratio of 0.2%IS. CSF analysis demonstrated high cell ount (1,300 cells/mm3): cytological examination revealed lymhoblast infiltration. Immunophenotypic analysis performed on SF showed the same phenotype detected at diagnosis (positivty for CD34, CD79-a, CD19 and CD38, CD13, CD33, CD66-C, TdT, egativity for CD10, CD20) and FISH analysis detected duplicaion of Ph+ chromosome. RQ-PCR performed on CSF showed a CR-ABL1/ABL1 ratio of 120% IS. A diagnosis of extramedullary BC

Impact of exclusion criteria for the DASISION and ENESTnd trials in the front-line treatment of a 'real-life' patient population with chronic myeloid leukaemia.

Both Dasision and ENESTnd trials had many exclusion criteria, with a possible selection bias compared with the real‐life. To address the impact of this bias on the first‐line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase chronic myeloid leukaemia (CML) patients [M/F 108/99, median age 58.8 years, interquartile range 42.3–70.2] treated with front‐line imatinib from June 2002 to June 2013 at our Institution, and evaluated how many of them would have been excluded from enrolment in the two trials. Twenty‐eight patients (13.5%) should have been excluded by both trials because of polycomorbidities (12), severe cardiomyopathy (five), age > 80 with frailty (three), drug abuse (two) or other severe concomitant diseases (six). In addition, eight patients should have been excluded by Dasision due to isolated chronic obstructive broncopulmonar disease, and 19 patients should have been excluded by ENESTnd due to isolated diabetes (10), arrhythmia (four), acute myocardial infarction > 6 months before CML diagnosis (two), chronic pancreatic disease (two) and peripheral arterial obstructive disease (one). On the whole, 36 patients (17.4%) would have been excluded by Dasision trial and 47 (22.7%) by ENESTnd trial. The patients potentially not eligible for both trials were significantly older and with imatinib had a worse outcome compared with patients potentially eligible. Our data highlight that an automatic transposition of results available in clinical controlled trials into the frontline real‐life management of CML patients should be regarded with caution. Copyright

Dasatinib combined with weekly administration of vincristine as effective therapy in sudden or resistant Ph+ lymphoid blast crisis of chronic myeloid leukaemia

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