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Lombardy represents the largest region of Italy by population, with almost 10 million residents, a dimension similar to a medium size country like Sweden or Belgium. The CML subcommittee of the Lombardy Hematology Network (REL-CML) conducted a study at the beginning of 2023. Prevalence was calculated by direct input from the 21 centers participating in REL-CML. Tyrosine Kinase Inhibitors (TKI) prescription records collected from the ARIA regional registry were used to estimate the number of CML patients followed in smaller centers not participating in REL-CML. A total of 2285 patients were registered, representing a prevalence of 0.23 ‰. These data were compared to a similar census conducted in 2005, at the beginning of the TKI era, where a prevalence of 0.029‰ was calculated. This indicates that an almost 10 times increase took place during this period of time. Imatinib represents the most frequently prescribed first-line TKI; its use in 2022 still represented 75% of total first line prescriptions. An increased concentration of the care of CML patients in specialized REL centers with a decreased dispersion of patients in small centers was also evident over this 18 year period of time. Nineteen % of patients discontinued treatment, highlighting persisting logistical and biological challenges; one some recommendations on CML management are included to this aim., (© 2024 The Author(s). Hematological Oncology published by John Wiley & Sons Ltd.)

Purpose: We assessed the prognostic value of F-18 fluorodeoxyglucose (FDG) uptake in the bone marrow of patients with multiple myeloma (MM) in comparison with Tc-99m methoxy-isobutyl-isonitrile (MIBI)., Methods: The extent and intensity of FDG and MIBI uptake in the bone marrow of 18 patients with a recent diagnosis of MM were assessed by visual score and by calculating the mean SUV (mSUV) for FDG and the femora/thigh ratio (TG/BKG, [Target/Background ratio]) for MIBI images. These parameters were correlated with clinical indexes of disease using hemoglobin and beta-2-microglobulin levels and plasma cell infiltrate (PCI) percentage. The mean values of the visual score, mSUV, and TG/BKG levels were compared in patients deceased after a relatively short follow-up (n = 9; group A) and in patients with a longer survival or were alive at the end of the study (n = 9; group B)., Results: Significant correlations of mSUV and TG/BKG values with PCI percentages and beta-2-microglobulin were found (P < 0.05). The extent of FDG and MIBI bone marrow uptake was greater in patients of group A (P < 0.01). Higher values of mSUV (P < 0.01) and TG/BKG (P < 0.05) were also observed in patients of group A. These results were consistent with the differences (not statistically significant) in hemoglobin, albumin, beta-2-microglobulin levels, and PCI percentages observed in the 2 groups., Conclusion: Our study demonstrates that an increase of FDG bone marrow uptake may predict a more aggressive disease, as much as MIBI uptake. Therefore, an additional analysis of FDG bone marrow images should be performed in patients undergoing PET studies during the initial staging of MM.

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.

Various clinical prognostic scoring systems (PSSs) have been suggested as means of selecting high-risk chronic idiopathic myelofibrosis (CIMF) patients at diagnosis. The WHO has recently proposed strict diagnostic criteria for CIMF, and the European consensus for bone marrow fibrosis (BMF) grading recommends 4 classes. It has been suggested that BMF grading may play a prognostic role in CIMF, but it has never been compared with the other PSSs in the same patients. We tested a prognostic model for overall survival (OS) based on the WHO criteria and BMF grading in 113 consecutive patients with chronic myeloproliferative disorders (98 with CIMF and 15 with postpolycythemic myelofibrosis), and compared the findings with those of PSSs. The results showed that our model is significantly associated with different OSs and, unlike the other PSSs, clearly discriminates the OS of intermediate- and high-risk patients.

We examined microvessel density (MVD) and immunohistochemical expression of vascular endothelial growth factor (VEGF) in the bone marrow biopsy specimens of 98 patients with Philadelphia chromosome-negative (Ph-) chronic myeloproliferative disorders (CMPDs). There were significantly more MVD "hot spots" in chronic idiopathic myelofibrosis (CIMF; mean +/- SD, 25.6 +/- 6.3) and polycythemia vera (PV; 20.7 +/- 10.2) cases than in essential thrombocythemia (ET) cases (10.1 +/- 4.5) and normal control (NC) samples (7.5 +/- 3.6) (P < .05). Similar results were found using a semiquantitative method (P < .0001). A calculated VEGF index (VEGF(i)) was higher in CIMF (0.29 +/- 0.15) and PV (0.28 +/- 0.20) cases than in ET (0.12 +/- 0.05) and NC (0.08 +/- 0.04) cases (P < .0001). MVD and VEGF(i) were higher in the myelofibrotic phases of CIMF and PV. There was a direct correlation between VEGF(i) and MVD when considering the Ph- CMPDs together (r = 0.67; P < .001) and when considering PV (r = 0.79; P < .001) and CIMF (r = 0.40; P = .013) as individual entities. Our data could provide a rationale for directly targeting VEGF or endothelial cells in CIMF and PV.

Thrombotic and haemorrhagic complications are the main causes of morbidity in Essential Thrombocythemia (ET). We investigated the clinical and laboratory characteristics associated with the occurrence of these events with the aim of identifying subgroups of patients who might benefit from anti-aggregant and/or cytoreductive therapy. The study involved 306 consecutive ET patients (median age 58 years and median follow-up 96 months); the investigated variables were age, gender, platelet count, previous history of thrombotic or haemorrhagic events, disease duration and cardiovascular risk factors. Forty-six patients (15%) experienced thrombotic complications during the follow-up: 26/64 patients with a previous history of thrombosis (40.6%) and 20/242 patients without (8.3%; p < 0.0001). Thirty-one patients (10%) experienced major haemorrhagic complications, mainly gastrointestinal tract bleeding: 3 with and 28 without a history of haemorrhagic events (p = 0.052). When the patients with a negative history of thrombosis were stratified on the basis of the number of cardiovascular risk factors (none vs. one vs. more than one), there was a significant correlation with the occurrence of thrombotic events (p < 0.05). ET patients with a positive history of thrombosis are at high risk of thrombotic complications, and should receive cytoreductive and anti-aggregant treatment. Asymptomatic patients with a negative thrombotic history and no cardiovascular risk factors are at low risk, and should not be treated. Patients with a negative thrombotic history and one or more cardiovascular risk factors are at intermediate risk, and should be treated with anti-aggregant and/or cytoreductive therapy. The need for treatment should be periodically re-evaluated. Age and platelet count, generally accepted as very important risk factors for thrombosis, did not seem in our series associated with an increased risk for thrombosis., (2007 John Wiley & Sons, Ltd.)

The aim of this multicenter GIMEMA study was to correlate autoimmune complications (AIC) in B-cell chronic lymphocytic leukemia (B-CLL) with stage and therapy. Autoimmune hemolytic anemia (129/194 cases) and autoimmune thrombocytopenia (35/194 cases) were typically present in advanced and multi-treated disease. Age over the median, stage C and first and second line therapy were identified as independent risk factors by multivariate analysis. In contrast, non-hematologic AIC (30/194 cases) and the presence of serological markers of autoimmunity were mostly observed in early B-CLL, suggesting different pathogenic mechanisms underlying hematologic and non-hematologic autoimmune phenomena in B-CLL.

Hydroxyurea is a usually well-tolerated cytostatic agent, but its side effects include cutaneous lesions that appear after several years of maintenance therapy with hydroxyurea. The reported incidence of such adverse reactions varies from 10 to 35%; in our Center it is 2%. We describe a patient with essential thrombocythemia who presented with ulcers of the hands only 15 days after hydroxyurea treatment.

To evaluate the clinical usefulness of IL-2 in myelodysplastic syndromes (MDS) the in vitro effects of interleukin-2 (IL-2) on blast cell proliferation, clonogenic activity, cytokine release and cell mediated cytotoxicity were examined in 49 MDS patients. Morphological analyses of bone marrow (BM) cytospin preparations showed a significant decrease in the number of blast cells in MDS after incubation with IL-2. Incubation of bone marrow mononuclear cells (BMMNCs) with IL-2 induced a significant increase in the number of CFU-GM in comparison with untreated controls. gamma-IFN and GM-CSF, but not alpha-TNF were found to be released in significant amounts by the BMMNCs cultured with IL-2. No significant differences in the surface phenotypes of fresh lymphocytes were observed between the normal and MDS subjects. After incubation with IL-2, we observed a significant increase in the number of CD3-/CD56+ cells in both normal and MDS subjects. Peripheral blood (PB) and BM NK activity against K562 was significantly greater in MDS after stimulation with IL-2. These data suggest the clinical usefulness of IL-2 in a large subgroup of patients as it may reduce the percentage of blasts and increase clonogenic capacity and cell-mediated cytotoxicity.

We have previously reported the absence of mutations within exons 5-9 of the p53 gene in a panel of 30 cases of acute promyelocytic leukemia (APL), which represent the M3 FAB type of acute myeloid leukemia (AML). In the present report, we extend our analysis of p53 gene mutations to 70 cases of AML representative of the other FAB types of the disease, including M1 (16 cases), M2 (20 cases), M4 (17 cases), M5 (12 cases), and M6 (5 cases). DNAs were analyzed for p53 gene mutations in exons 5 to 9 by polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), and direct sequencing of PCR-amplified products. Mutant p53 alleles were detected in 5 of 70 cases; 1 case in exon 5, 2 cases in exon 6, and 2 cases in exon 7. The alterations of the p53 gene were represented by point mutation leading to an amino acid substitution in four cases, and deletion in the remaining case. In four of the five cases, direct sequencing indicated the loss of the normal p53 allele; in the remaining case, two mutations were detected, presumably involving both p53 alleles. Three cases showed mutations at diagnosis; in the remaining two, the mutations were observed in clinical relapse but not at diagnosis. Our results confirm the relatively low incidence of p53 mutations in AML and further support the evidence that p53 plays a role in leukemogenesis through a recessive mechanism (two-hit model) of inactivation of tumor suppressor activity.

B cell chronic lymphocytic leukemia (B-CLL) represents the most frequent adult leukemia in the Western world. The molecular pathogenesis of B-CLL is largely unknown. Although initial reports on small panels of cases had suggested a role for Bcl-1 and Bcl-2 oncogene activation in B-CLL, later investigations failed to confirm these data. Among tumor suppressor genes, p53 mutations have been reported in a fraction of cases. In this study, we have attempted a conclusive definition of the involvement of dominantly acting oncogenes (Bcl-1 and Bcl-2) and tumor suppressor loci (p53, 6q-) in 100 cases of B-CLL selected for their CD5 positivity and Rai's stage (0 to IV). Rearrangements of Bcl-1 and Bcl-2 and deletions of 6q and 17p were analyzed by Southern blot using multiple probes. Mutational analysis (single strand conformation polymorphism and polymerase chain reaction direct sequencing) was used to assay p53 inactivation. No alterations of Bcl-1 or Bcl-2 were detected in the 100 cases tested. Mutations of p53 were found in 10/100 cases without any significant association with clinical stage. Deletions of 6q were present in 4/100 cases. Overall, our data indicate that: 1) contrary to previous reports, Bcl-1 and Bcl-2 rearrangements are not involved in CD5+ B-CLL pathogenesis and 2) p53 mutations are present in 10% of cases at all stages of the disease.

Bone marrow (BM) biopsies from 58 patients with primary myelodysplastic syndrome (MDS) were studied using QBEND10, a monoclonal antibody that recognizes the human progenitor CD34 antigen in routine aldehyde-fixed paraffin-embedded samples. FAB subtypes were RA (5 patients), RARS (9 patients), RAEB (20 patients), RAEBt (11 patients), CMML (3 patients). In addition, 10 MDS patients whose BM biopsies revealed heavy reticulum fibrosis were included. Neither the percentage of CD34+ cells nor the number of CD34+ aggregates (defined as clusters of 3 or more cells) correlated with the presence and morphology of abnormal localizations of immature precursors (ALIP). When all patients were considered, median survival was 69 months in those with less, and 25 months in patients with more than 1% CD34+ cells (P < 0.05). Median survival was 15 months in patients with CD34+ aggregates and 41 months in those without aggregates (P = 0.0017). When RAEB patients were considered median survival was 41 months in those with less than 1%, and 29 months in those with more than 1% CD34+ cells; the 4-year survival chance was 45% in the former and 18.3% in the latter group. Therefore, CD34 positivity of more than 1% identifies a subset of RAEB patients with shorter life expectancy. In addition, leukemic transformation was observed in 11 of 35 patients (31%) with no CD34 aggregates, but in 14 of 23 patients (60%) with aggregates (P < 0.05). CD34 immunostaining, which can be easily performed on routinely prepared BM biopsies, was found to be a powerful prognostic tool for predicting survival and outcome in MDS.

Thirty patients affected by previously untreated high risk myelodysplastic syndromes (MDS) were treated with human recombinant gamma-interferon (r-IFN-gamma): 15 of them with a higher dose (HD) of 0.1 mg/sqm, three times a week and 15 with a lower dose (LD) of 0.01 mg/sqm, three times a week, both doses administered subcutaneously (s.c.). The therapy was fairly well tolerated and few major toxic events were documented. Sustained improvement of one or more clinico-hematologic parameters was observed in 43.3% of the patients (26.6% and 60.0% for the lower and higher dose, respectively). Median survival time from the start of IFN-gamma therapy was 15+ months (range: 1-26) for patients with refractory anemia with excess of blasts (RAEB) versus 5 months (range 2-12) for patients with RAEB in transformation (RAEB-t); 15+ months (range 1-26) for HD patients versus 8 months (range 2-23) for patients treated with LD regimen; 16+ months (range 9-26) for responders versus 7 months (range 1-22) for nonresponders. All these three variables (diagnosis, treatment, and response to treatment) turned out to be statistically significant (p = at least less than 0.01) at Cox's analysis.