The use of thrombopoietin-receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP): a “real life” retrospective multicenter experience of the Rete Ematologica Pugliese (REP)

Immune thrombocytopenia (ITP) is a disease which sees one-third of patients failing first and subsequent therapeutic approaches, including splenectomy. Thrombopoietin-receptor agonists (TPO-RAs) are recommended for adults who relapse after splenectomy or who have contraindications for splenectomy. In this multicenter study, a total of 124 patients were retrospectively evaluated: 55 (44.3 %) were treated by romiplostim and 69 (55.6 %) by eltrombopag. Mean age, number of young patients (<60 years), time from primary diagnosis of ITP to TPO-RA treatment, and previous lines of therapy were similar in both groups. The overall response rate was 80 % (44/55) for romiplostim and 94.2 % (65/69) for eltrombopag; the duration of response and the time to response were similar (p = NS). The response rate to both drugs in non-splenectomized patients was higher than that of splenectomized patients (p < 0.05). The mean duration of response was 30 months for romiplostim and 15 months for eltrombopag, due to later commercialization of eltrombopag. Failure was the most frequent cause of discontinuation. Thrombotic events were the most consistent adverse events and were recorded in 2 and 3 % of patients treated by romiplostim and eltrombopag, respectively. In conclusion, romiplostim and eltrombopag are effective in the majority of patients with chronic ITP who failed several lines of therapy; whether TPO-RAs could substitute splenectomy is under discussion and studies are warranted

Brentuximab vedotin as salvage treatment in Hodgkin lymphoma naïve transplant patients or failing ASCT: the real life experience of Rete Ematologica Pugliese (REP)

Brentuximab vedotin (BV) shows a high overall response rate (ORR) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) after autologous transplant (ASCT). The aim of this multicenter study, conducted in nine Hematology Departments of Rete Ematologica Pugliese, was to retrospectively evaluate the efficacy and safety of BV as salvage therapy and as bridge regimen to ASCT or allogeneic transplant (alloSCT) in R/R HL patients. Seventy patients received BV. Forty-five patients (64%) were treated with BV as bridge to transplant:16 (23%) patients as bridge to ASCT and 29 (41%) as bridge to alloSCT. Twenty-five patients (36%), not eligible for transplant, received BV as salvage treatment. The ORR was 59% (CR 26%). The ORR in transplant naïve patients was 75% (CR 31%). In patients treated with BV as bridge to alloSCT, the ORR was 62% (CR 24%). In a multivariate analysis, the ORR was lower in refractory patients (p < 0.005). The 2y-OS was 70%. The median PFS was 17 months. Ten of the 16 (63%) naïve-transplant patients received ASCT, with 50% in CR before ASCT. In the 29 patients treated with BV as bridge to alloSCT, 28 (97%) proceeded to alloSCT with 25% in CR prior to alloSCT. The most common adverse events were peripheral neuropathy (50%), neutropenia (29%) and anemia (12%). These data suggest that BV is well tolerated and very effective in R/R HL, producing a substantial level of CR. BV may also be a key therapeutic agent to achieve good disease control before transplant, improving post- transplant outcomes, also in refractory and heavily pretreated patients, without significant overlapping toxicities with prior therapies

A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients. Final results of the GIMEMA LAL1509 protocol

The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 6410% at 3 months, 641% at 6 months, 640.1% at 12 months, 640.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 &gt;10% at 3 and 6 months, &gt;1% at 12 months, and &gt;0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR

Small-Sized Clone of T Cells in Multiple Myeloma Patient after Auto-SCT: T-LGL Leukemia Type or Clonal T-Cell Aberration?

Second cancers and particularly postransplant lymphoproliferative disorders (PTLDs) are extremely rare in patients undergoing autologous peripheral blood stem cell transplantation (auto-SCT). We report the case of clonally rearranged T-cell expansion which occurred after auto-SCT for Multiple Myeloma (MM). Does asymptomatic clonal T-cell large granular lymphocytic proliferation, in our experience, represent either a secondary cancer after auto-SCT or clonal T cell aberration or derive from expansion of coexisting undetected small-sized clone of T cells

Pregnancy and β-thalassemia: an Italian multicenter experience

Background: Recent advances in the management of thalassemia have significantly improved life expectancy and quality of life of patients with this hemoglobinopathy, with a consequent increase in their reproductive potential and desire to have children. Design and Methods: We describe the methods of conception and delivery, as well as the course and outcome of pregnancy including transfusions, iron overload and chelation in 46 women with thalassemia major (58 pregnancies) and in 11 women with thalassemia intermedia (17 pregnancies). Conception was achieved after gonadotrophin-induced ovulation in 33 of the women with thalassemia major and spontaneously in all of those with thalassemia intermedia. Results: Among the women with thalassemia major, 91% of the pregnancies resulted in successful delivery of 45 singleton live-born neonates, five sets of twins and one set of triplets. No secondary complications of iron overload developed or worsened during pregnancy. When considering only the singleton pregnancies, the proportion of babies with intrauterine growth retardation did not differ from that reported in the general Italian population. The high prevalence of pre-term births (32.7%) was mostly related to multiple pregnancies and precautionary reasons. Pregnancy was safe in most women with thalassemia major or intermedia. However, women with thalassemia intermedia who had never previously been transfused or who had received only minimal transfusion therapy were at risk of severe alloimmune anemia if blood transfusions were required during pregnancy. Conclusions: Provided that a multidisciplinary team is available, pregnancy is possible, safe and usually has a favorable outcome in patients with thalassemia. In women with hypogonadotropic hypogonadism, gonadal function is usually intact and fertility is usually retrievable

Myocardial iron overload assessed by magnetic resonance imaging (MRI)T2* in multi-transfused patients with thalassemia and acquired anemias

Background: Cardiac complications secondary to iron overload remain a significant matter in patients with transfusion dependent anemias. Patients and methods: To evaluate cardiac siderosis, Magnetic resonance imaging T2* (MRI T2*) was performed in 3 cohorts of transfusion dependent patients: 99 with thalassemia major (TM), 20 with thalassemia intermedia (TI), and 10 with acquired anemias (AA). Serum ferritin was measured and all patients underwent echocardiographic evaluation. Results: In TM patients cardiac T2* pathologic values (below 20 ms) were found in 37 patients. Serum ferritin was negatively associated with age (r = -0.32, p = 0.001) and weakly with T2* values (r = -0.19, p = 0.057). A positive correlation was found between T2* and LVEF (r = 0.27, p = 0.006). Out of 37 patients with T2* < 20 ms, 18 (48%) had serum ferritin values < 1000 ng/ml. In TI cohort, 3 patients had cardiac T2* pathologic values. In AA cohort, pathologic T2* values were found in 2 patients, who received 234 and 199 PRBC units, respectively, and were both on chelation therapy (in one patient ferritin value was 399 ng/ml). T2* values were negatively associated, but not significantly, with the number of PRBC transfused (r = -0.53, p = 0.07). Conclusion: In our experience, 37% of TM patients had a myocardial iron overload assessed by MRI T2*; this value is higher than in TI patients. Serum ferritin measurement was a poor predictor of myocardial siderosis. In patients with AA, more than 200 PRBC units transfused were required to induce cardiac hemosiderosis, in spite of chelation therapy and, in one patient, of normal ferritin values. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved

Azacitidine in the treatment of older patients affected by acute myeloid leukemia: A report by the Rete Ematologica Pugliese (REP)

The optimal treatment of older patients (>65 years) with acute myeloid leukemia (AML) remains challenging in daily clinical practice; a choice has to be made between intensive chemotherapy and best supportive care. To guide physicians, several prognostic factors have been identified and risk scores developed. Recently, the DNA methyltransferase inhibitor azacitidine has become available for use in MDS and AML patients with up to 30% bone marrow blasts. However, limited data are available on the outcome of older unfit AML patients, regardless of their bone marrow blast count. We retrospectively analyzed the outcome of 90 newly diagnosed older unfit AML patients in 9 Institutions from the Apulia Region (REP). Responder patients (evaluation performed after 4 cycles of treatment even in cases of primary failure) showed a better overall survival than non responders (23 vs 6 months, p< .001). ECOG PS ≥ 2 seems to be correlated with OS in multivariate analysis, while neither primary treatment failure (documented after 2 cycles) nor bone marrow blast count were correlated with a worse overall survival either at univariate (22 vs 29 months, p= .ns; 16 vs 19 months, p= .ns) or multivariate analysis. Overall, the results of our retrospective analysis seem to confirm the efficacy of AZA treatment for this unfit AML patients setting, in terms of both CR and OS, regardless of the bone marrow blasts count, while primary treatment failure should not lead to a discontinuation of treatment