Mariangela Colombi

Thrombotic and hemorrhagic complications in essential thrombocythemia. A retrospective study of 103 patients

A retrospective study of 103 patients with essential thrombocythemia was carried out to evaluate the incidence of thrombohemorrhagic complications and establish whether there were any correlations between these events and clinical or laboratory data. At onset or during the course of the disease, 26 patients (25.2%) presented thrombotic and 12 (11.6%) hemorrhagic complications: among the latter, six patients had gastrointestinal bleeding during antiaggregant therapy. No significant correlations were observed between thrombohemorrhagic complications and platelet count, age, sex, platelet function, bleeding time, or therapeutic regimen. However, there was a statistically significant correlation between a positive patient history for thrombotic events and an increase in thromboses. In agreement with other authors, it is believed that the best approach in asymptomatic patients is strict surveillance without treatment. Chemotherapy and/or treatment with antiaggregant agents should be reserved for symptomatic patients or patients with a positive history for thrombotic events.

Immunoglobulin M Monoclonal Gammopathies of Undetermined Significance and Indolent Waldenstrom's Macroglobulinemia Recognize the Same Determinants of Evolution Into Symptomatic Lymphoid Disorders: Proposal for a Common Prognostic Scoring System

PURPOSE To evaluate the clinicohematologic variables at diagnosis that are prognostically related to neoplastic progression in patients with immunoglobulin M (IgM) monoclonal gammopathies of undetermined significance (MGUS), and indolent Waldenströms macroglobulinemia (IWM), and propose a scoring system to identify subsets of patients at different risk. PATIENTS AND METHODS We evaluated 217 patients with IgM MGUS and 201 with IWM (male-female ratio, 131:86 and 117:84; mean age, 63.7 and 63.6 years, respectively) diagnosed on the basis of serum monoclonal component (MC) levels and bone marrow lymphoplasmacytic infiltration degree. The variables selected by univariate analyses were multivariately investigated; on the basis of their individual relative hazards, a scoring system was devised to identify subsets of patients at different risk of evolution. RESULTS After a median follow-up of 56.1 and 60.2 months, 15 of 217 MGUS and 45 of 201 IWM patients, respectively, required chemotherapy for symptomatic WM (13 and 36), non-Hodgkins lymphoma (2 and 6) and amyloidosis (0 and 3). The median time to evolution (TTE) was not reached for MGUS and was 141.5 months for IWM. The variables adversely related to evolution were qualitatively the same in both groups: MC levels, Hb concentrations and sex. A scoring system based on these parameters identified three risk groups with highly significant differences in TTE in both groups (P < .0001). CONCLUSION MGUS and IWM identify disease entities with different propensities for symptomatic neoplastic evolution. As both have the same prognostic determinants of progression, we propose a practical scoring system that, identifying different risks of malignant evolution, may allow an individualized clinical approach.

Second malignancies in essential thrombocythemia (ET): a retrospective analysis of 331 patients with long-term follow-up from a single institution

Abstract Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by an indolent clinical course, with a median survival exceeding 20 years. A minority of patients undergo thrombohemorrhagic complications, which might be prevented by cytoreductive treatment in high risk categories. Alkylating agents (ALK) have been demonstrated to increase the risk of acute leukemia and myelodysplastic syndromes in patients with myeloproliferative disorders, whereas the potential oncogenicity of hydroxyurea (HU) remains a matter of debate. In this study, we retrospectively investigated long-term development of hematological and non-hematological second malignancies in 331 patients with ET, analyzing possible associations with chemotherapy treatments. Median follow-up was 108 months. Of the 194 patients who were treated with chemotherapy, 116 (60%) received only HU, 38 (19·5%) only ALK (busulfan or melphalan) and 40 (20·5%) ALK followed by HU. After a median time of 87 months from the diagnosis of ET, 43 patients developed a second malignancy, hematological in 15 and non-hematological in 28, for an overall cumulative incidence of 13%. According to the type of treatment, second malignancies were documented in 11·2% of patients treated with only HU, in 26·3% of patients who received only ALK, and in 25% of those treated with ALK followed by HU. Ten cases (7·3%) were recorded among the 137 patients who did not receive any treatment. Our analysis revealed a significant association between treatment with alkylating agents and an increased risk of developing second hematological malignancies, whereas no such association was detected with regard to treatment with hydroxyurea single agent in our ET population. In addition, different treatment strategies did not affect the risk of developing second solid cancers.

Poor prognosis in non-villous splenic marginal zone cell lymphoma is associated with p53 mutations

We have recently reported a series of 15 non‐villous splenic marginal zone lymphoma patients, six of whom showed p53 mutations (40%). This molecular alteration did not correlate with any particular clinico‐pathologic feature at diagnosis. After a median follow‐up of 56 months, four cases evolved into aggressive fatal non‐Hodgkins lymphoma (NHL) and two had refractory progressive disease; interestingly, p53 mutations were demonstrated in five of these patients at diagnosis. As the patients with wild‐type p53 presented responsive or indolent disease, this genetic alteration may be an early marker of aggressive transformation or refractoriness. p53 evaluation at diagnosis could be advisable in this particular subset of NHL.

Treatment of Indolent B-Cell Nonfollicular Lymphomas: Final Results of the LL01 Randomized Trial of the Gruppo Italiano per lo Studio dei Linfomi

PURPOSE To evaluate the effect of epirubicin on therapeutic response and survival in patients with indolent nonfollicular B-cell lymphomas (INFL) treated with pulsed high-dose chlorambucil. PATIENTS AND METHODS A total of 170 untreated patients with advanced/active INFL were randomly assigned to receive either eight cycles of high-dose chlorambucil (15 mg/m2/d) plus prednisone (100 mg/d) for 5 days (HD-CHL-P; arm A) or eight cycles of HD-CHL-P plus epirubicin 60 mg/m2 intravenous on day 1 (arm B). The responding patients were randomly assigned to either maintenance therapy with interferon alfa (IFNalpha-2a; 3 MU, three times weekly) for 12 months or observation. RESULTS There were 160 assessable patients (82 males, 78 females; median age, 63 years; range, 33 to 77 years); 77 patients were assigned to arm A, and 83 were assigned to arm B. Induction therapy led to 47 complete responses (CRs; 29.4%) and 68 partial responses (PRs; 42.5%), with no significant difference between the two arms (60 CR + PR in arm A [77.9%] and 55 CR + PR in arm B [66.3%]; P =.07). After a median follow-up of 38 months (range, 2 to 103 months), there was no between-group difference in overall survival (OS; P =.45), failure-free survival (P =.07), or progression-free survival (PFS; P =.5). Eighty-eight patients were randomly assigned to either IFNalpha-2a (n = 43) or observation (n = 45), without any difference in 3-year PFS (44% and 42%, respectively). Univariate analysis showed that OS was influenced by age, anemia, serum lactate dehydrogenase levels, and International Prognostic Index distribution; multivariate analysis identified age and anemia as having influence on OS. CONCLUSION HD-CHL-P treatment outcome in INFL patients was good (50% 3-year PFS, minimal toxicity, and low costs); epirubicin did not add any advantage. One-year IFNalpha maintenance treatment did not prolong response duration.

Diagnostic role and prognostic significance of a simplified immunophenotypic classification of mature B cell chronic lymphoid leukemias

We verified the diagnostic and prognostic role of a simplified immunophenotypic classification (IC) in a series of 258 patients (M/F: 1.4; median age: 64 years; median follow-up: 64 months; 75 deaths) with mature B cell lymphoid leukemias (MBC-LL) for whom no histopathological diagnosis was available because of minimal or no lymph node involvement. The IC was based on the reactivity of three pivotal immunophenotypic markers: CD5, CD23 and SIg intensity. On the basis of different expression patterns, we identified four diagnostic clusters (C) characterized by distinct clinico-biological features and different prognoses: C1 (149 patients) identified most classical B cell chronic lymphocytic leukemias (CLL-type cluster; SIgdim/CD5+/CD23+); C2, 38 patients whose clinico-hematological characteristics were intermediate between C1 and C3 (CLL-variant cluster; SIgbright/CD5+/CD23+/−or SIgdim/CD5−/−/CD23 indifferent); C3 (16 patients) most situations consistent with mantle cell lymphoma in leukemic phase (MCL-type cluster; SIgbright/CD5+/CD23−); and C4, 55 cases, most of whom were consistent with leukemic phase lymphoplasmacytic/splenic marginal zone lymphomas (LP/S-type cluster; SIgbright/CD5−/+/CD23 indifferent). At univariate survival analysis, prognosis worsened from C1 to C4, C2 and C3 (P = 0.0001), and this was maintained at multivariate analysis (P = 0.006), together with CD11c expression (P = 0.0043), age at diagnosis (cut-off 70 years; P = 0.0008) and platelet count (cut-off 140 × 109/l; P = 0.0034). Besides recognising the two well-known situations of classic B-CLL and MCL, our IC identified situations with distinct prognostic and/or clinical behaviors.

Uncommon clinical presentation of a lymphocytic lymphoma of intermediate differentiation in a patient with systemic sclerosis.

Summary. The association of systemic sclerosis (SSc) and non‐Hodgkin lymphoma is a rare event and its pathogenetic mechanism remains to be clarified. We describe a previously unreported association of SSc with a lymphocytic lymphoma of intermediate differentiation (IDL), involving the gastrointestinal tract, gallbladder and one salivary gland. Whereas the morphological, immunological and cytogenetic features were typical of IDL, the extensive extranodal involvement and the association with an autoimmune disorder were suggestive of two other lymphomas of mantle lineage: mucosa‐associated lymphoid tissue (MALT) lymphoma and monocytoid B‐cell lymphoma (MBCL).

Conjunctival hemorrhagic events associated with imatinib mesylate.

Imatinib mesylate (IM) is used in the targeted therapy of chronic myelogenous leukemia and gastrointestinal stromal tumors. It is well tolerated and leads to no higher incidence of hemorrhagic events than other therapies. Of 87 patients we treated with IM for a minimum of 3 months, 10 patients (11%) developed unilateral or bilateral conjunctival hemorrhage (CH).No other hemorrhagic events were observed during follow-up, except for CH recurrence in 6 cases (7%). Because there was no other obvious reason for such a high incidence of CH, we hypothesize drug hypersensitivity or ocular irritation induced by IM treatment.Imatinib mesylate (IM) is used in the targeted therapy of chronic myelogenous leukemia and gastrointestinal stromal tumors. It is well tolerated and leads to no higher incidence of hemorrhagic events than other therapies. Of 87 patients we treated with IM for a minimum of 3 months, 10 patients (11%) developed unilateral or bilateral conjunctival hemorrhage (CH).No other hemorrhagic events were observed during follow-up, except for CH recurrence in 6 cases (7%). Because there was no other obvious reason for such a high incidence of CH, we hypothesize drug hypersensitivity or ocular irritation induced by IM treatment.

Prevalence and prognostic significance of sMUC‐1 levels in plasma cell dyscrasias

Summary. High serum Mucin‐1 (sMUC‐1) levels have been shown in patients with adenocarcinoma and multiple myeloma (MM). We evaluated sMUC‐1 levels in 76 patients with MM, 6 with plasma cells leukaemia (PCL) and 89 with monoclonal gammopathy of undetermined significance, to establish prevalence data and verify its possible prognostic role. Of the 171 patients, 27 [16%; 95% confidence interval (CI): 10–21%] had high sMUC‐1 levels compared with healthy subjects (1·5%; 95% CI: 0–4%). Elevated sMUC‐1 levels in MM and PCL patients correlated with anaemia and elevated serum lactate dehydrogenase levels; these patients showed a shorter survival than those with normal sMUC‐1 levels (median overall survival: 25 vs. 49 months, P = 0·003).

Platelet Dysfunction in Acute Megakaryoblastic Leukemia

Platelet function profiles were studied in 3 patients with megakaryoblastic leukemia. All patients had a moderate decrease in platelet counts with abnormal platelet retention. One patient who developed hemorrhagic diathesis had prolonged bleeding time. In all patients platelet aggregation was defective after the addition of ADP, collagen, adrenaline, or U46619, a thromboxane A2 agonist. Malondialdehyde was reduced in all patients, as was platelet serotonin. Plasma beta-thromboglobulin levels were normal in all cases whereas PF4 was markedly elevated in one. Platelet dysfunction was not reversed by clinical remission. These studies confirm that megakaryoblastic leukemia is associated with a thrombocytopathy which may play a role in hemorrhagic diathesis and should be taken into account in the management of these patients.