Adriano Salaroli

Evaluation of comorbidities at diagnosis predicts outcome in myelodysplastic syndrome patients

Recent data suggest that proper assessment of comorbidities is useful to predict the outcome of MDS patients receiving allogeneic stem cell transplantation. However, the results obtained in this highly selected subset of patients cannot be applied to the whole MDS population. We evaluated the impact of comorbidities in 418 consecutive MDS patients diagnosed at our institute from 1992 to 2005. All patients were classified according to WHO criteria and all received only conservative and supportive treatment. One or more comorbidities were detected in 390 patients (93%) at the time of diagnosis, with a higher incidence in older patients. Cardiac diseases were the most frequent comorbidities (30%) while diabetes and correlated adverse events were the second cause of comorbidity (20%). We applied 3 comorbidity prognostic scores (CCI, HCT-CI and a MDS-CI score proposed by Della Porta et al.). According to CCI score, 253 patients had a score 0, 111 patients had a score 1 and 54 patients had a score >2. According to HCT-CI, 209 patients had a score 0, 105 patients had a score 1 and 106 patients had a score >2. With MDS-CI score, 288 patients had a score 0 and 129 patients had a score >1. We found a significant correlation between survival and stratification according to CCI and MDS-CI scores (p=0.01 and 0.02, respectively), but not according to HCT-CI score. The number of comorbidities as evaluated according to CCI was directly correlated to the development of RBC transfusion-dependency and was associated to a significantly higher risk of death not related to leukemic evolution (HR = 2.12, p ≤ 0.001). Conversely, higher risk of non-leukemic death did not correlate with higher transfusional requirement according to HCT-CI and MDS-CI scores (p = 0.3 and 0.43, respectively). As suggested by Della Porta et al., also in our experience the presence of cardiac, liver, renal, pulmonary diseases and solid tumours was found to independently affect the risk of death in a multivariable Cox regression analysis (p values from <0.01 to 0.004). In conclusion, assessment of comorbidities at diagnosis in MDS patients may improve the ability of therapeutic decisions.

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

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.

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

Suboptimal response to imatinib according to 2006–2009 European LeukaemiaNet criteria: a ‘grey zone’ at 3, 6 and 12 months identifies chronic myeloid leukaemia patients who need early intervention

Barker, J.N., Weisdorf, D.J., DeFor, T.E., Blazar, B.R., McGlave, P.B., Miller, J.S., Verfaillie, C.M. & Wagner, J.E. (2005) Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood, 105, 1343–1347. Barker, J.N., Scaradavou, A. & Stevens, C.E. (2010) Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood, 115, 1843–1849. Blume, K.G., Forman, S.J., O’Donnell, M.R., Doroshow, J.H., Krance, R.A., Nademanee, A.P., Snyder, D.S., Schmidt, G.M., Fahey, J.L., Metter, G.E., Hill, L.R., Findley, D.O. & Sniecinski, I.J. (1987) Total body irradiation and high-dose etoposide: a new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies. Blood, 69, 1015–1020. Brunstein, C.G., Barker, J.N., Weisdorf, D.J., DeFor, T.E., Miller, J.S., Blazar, B.R., McGlave, P.B. & Wagner, J.E. (2007) Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood, 110, 3064–3070. Delaney, C., Gutman, J.A. & Appelbaum, F.R. (2009) Cord blood transplantation for haematological malignancies: conditioning regimens, double cord transplant and infectious complications. British Journal of Haematology, 147, 207–216. Kurtzberg, J., Laughlin, M., Graham, M.L., Smith, C., Olson, J.F., Halperin, E.C., Ciocci, G., Carrier, C., Stevens, C.E. & Rubinstein, P. (1996) Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. New England Journal of Medicine, 335, 157–166. Laughlin, M.J., Barker, J., Bambach, B., Koc, O.N., Rizzieri, D.A., Wagner, J.E., Gerson, S.L., Lazarus, H.M., Cairo, M., Stevens, C.E., Rubinstein, P. & Kurtzberg, J. (2001) Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. New England Journal of Medicine, 344, 1815–1822. MacMillan, M.L., Weisdorf, D.J., Brunstein, C.G., Cao, Q., DeFor, T.E., Verneris, M.R., Blazar, B.R. & Wagner, J.E. (2009) Acute graftversus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood, 113, 2410–2415. Rocha, V. & Broxmeyer, H.E. (2010) New approaches for improving engraftment after cord blood transplantation. Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation, 16, S126–132. Wagner, J.E., Barker, J.N., DeFor, T.E., Baker, K.S., Blazar, B.R., Eide, C., Goldman, A., Kersey, J., Krivit, W., MacMillan, M.L., Orchard, P.J., Peters, C., Weisdorf, D.J., Ramsay, N.K. & Davies, S.M. (2002) Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood, 100, 1611–1618.

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.