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Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, n = 118), 2L ( n = 127) and ≥3L ( n = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients' clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3-4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL.

Checkpoint inhibitors have significantly changed the prognosis of patients with relapsing refractory classical Hodgkin's lymphoma (cHL), demonstrating excellent results in heavily pretreated patients. However, there is still limited data on the real-world experience with PD-1 inhibitors in cHL. Within the context of the Apulian hematological network (Rete Ematologica Pugliese, REP), we performed a retrospective, multicenter analysis of 66 patients with relapsing refractory cHL who had received PD-1 inhibitors in the non-trial setting. Forty-three patients (65%) were treated with nivolumab and 23 (35%) with pembrolizumab. Thirty-one (47%) and 8 (12%) patients underwent autologous or allogeneic stem cell transplantation prior to checkpoint inhibitor therapy, respectively. The median number of lines of treatment attempted prior to PD-1 inhibitor therapy was 4 (range, 3 to 7). All patients had received brentuximab vedotin prior to checkpoint inhibitor therapy. The overall response rate to PD-1 inhibitors therapy was 70% (47% complete remission (CR) and 23% partial remission (PR)). Twenty-four immune-related adverse events (19 (80%) grades 1-2; 5 (20%) grades 3-4) were documented (4 gastrointestinal, 4 hepatic, 6 fever, 4 hematological, 3 dermatological, 3 allergic rhinitis). Toxicity resolved in all patients, and there were no deaths attributed to checkpoint inhibitor therapy. After a median follow-up of 26 months (range 3-72 months), 54 patients (82%) are alive, and 12 (18%) died. The cause of death was attributed to disease progression in 9 patients and sepsis in 3 patients. After PD-1 inhibitor therapy, 22 patients (33%) relapsed or progressed. The overall survival and progression-free survival at 5 years were 65% and 54%, respectively. This study confirms the efficacy and tolerability of PD-1 inhibitor therapy in relapsed refractory cHL in a real-world setting, demonstrating similar clinical outcomes and toxicity profiles compared to clinical studies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

After FDA and EMA approval of the regimen containing polatuzumab vedotin plus rituximab and bendamustine (PolaBR), eligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients in Italy were granted early access through a Named Patient Program. A multicentric observational retrospective study was conducted focusing on the effectiveness and safety of PolaBR in everyday clinical practice. Fifty-five patients were enrolled. There were 26 females (47.3%), 32 patients were primary refractory and 45 (81.8%) resulted refractory to their last therapy. The decision to add or not bendamustine was at physician's discretion. Thirty-six patients underwent PolaBR, and 19 PolaR. The 2 groups did not differ in most of baseline characteristics. The final overall response rate was 32.7% (18.2% complete response rate), with a best response rate of 49.1%. Median disease-free survival was reached at 12 months, median progression-free survival at 4.9 months and median overall survival at 9 months, respectively. Overall, 88 adverse events (AEs) were registered during treatment in 31 patients, 22 of grade ≥3. Eight cases of neuropathy occurred, all of grades 1-2 and all related to polatuzumab. The two groups of treatment did not differ for effectiveness endpoints but presented statistically significant difference in AEs occurrence, especially in hematological AEs, in AEs of grade equal or greater than 3 and in incidence of neuropathy. Our data add useful information on the effectiveness of Pola(B)R in the setting of heavily pretreated DLBCL and may also suggest a better tolerability in absence of bendamustine without compromise of efficacy., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

The standard management for relapsed or refractory classical Hodgkin lymphoma (cHL) is salvage therapy followed by autologous stem cell transplantation (ASCT). This strategy allows almost 50% of patients to be cured. Post-ASCT maintenance treatment with brentuximab vedotin (BV) confers improved progression-free survival (PFS) to cHL patients at high risk of relapse. We investigated the outcome of 105 cHL patients receiving post-ASCT BV maintenance in the real-life setting of 23 Italian hematology centers. This population included naïve patients and those previously exposed to BV. Median follow-up was 20 months. Patients presented a median of two lines of treatment pre-ASCT, with 51% receiving BV. Twenty-nine percent of patients had at least two high-risk factors (refractory disease, complete response [CR] less than 12 months, extranodal disease at relapse), while 16% presented none. At PET-CT, a Deauville score (DS) of 1-3 was reported in 75% and 78% of pre- and post-ASCT evaluations, respectively. Grade 3-4 adverse events (AEs), mainly peripheral neuropathy, were observed in 16% of patients. Three-year PFS and overall survival (OS) were 62% and 86%, respectively. According to BV exposure, 3-year PFS and OS were 54% and 71%, respectively, for naïve and 77% and 96%, respectively, for previously exposed patients. Refractory disease (hazard ratio [HR] 4.46; p = 0.003) and post-ASCT DS 4-5 (HR 3.14; p = 0.005) were the only two factors significantly associated with PFS reduction in multivariable analysis. Post-ASCT BV maintenance is an effective, safe treatment option for cHL naïve patients and those previously exposed to BV., (© 2021 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Background: Nowadays minimal residual disease (MRD) and log-reduction of leukemic cells are poorly investigated in elderly patients with acute myeloid leukemia (AML) treated with hypometilating agents (HMAs). Studies focusing on MRD in elderly AML patients who received HMAs are scant and devoid of rigorous criteria for both enrollment and monitoring. Log-reduction has never been investigated in these patients. Thus, the purpose of our study was to compare the prognostic impact of MRD and log-reduction of leukemic cells at the optimal time of assessment in older AML patients., Methods: Elderly patients who completed at least six cycles of HMAs and showed suitable leukemia-associated immunophenotypes (LAIPs) for the MRD and log-reduction assessment by flow cytometry were enrolled in the study., Results: After comparing the times of assessment C4 (4-cycles) and C6 (6-cycles), C6 has been chosen as optimal. Patients who achieved MRD negativity or 2-log-reduction of leukemic cells at C6 had a significantly longer DFS. Particularly, results of 2-log-reduction were confirmed a multivariate analysis. Patients with MRD negativity or 2-log reduction of leukemic cells showed an improvement of their OS, although not significantly., Conclusions: Our data confirmed the predictive role of MRD and 2-log reduction also in older AML patients treated with HMAs., (© 2021 International Clinical Cytometry Society.)

Introduction: In patients with primary immune thrombocytopenia (ITP), a short course of steroids is routinely given as first-line therapy. However, the response is often transient and additional therapy is usually needed. Thrombopoietin receptor agonists (TPO-RAs) are frequently used as second-line therapy, although there is little clinical guidance on the timing of their administration and on tapering/discontinuation of the drug. To provide clinical recommendations, we used the Delphi technique to obtain consensus for statements regarding administration and on tapering/discontinuation of second-line TPO-RAs among a group of Italian clinicians with expertise in management of ITP., Methods: The Delphi process was used to obtain agreement on five statements regarding initiation and on tapering/discontinuation of second-line TPO-RAs. Agreement was considered when 75% of participants approved the statement. Eleven experts participated in the voting., Results: Full consensus was reached for three of the five statements. The experts held that an early switch from corticosteroids to a TPO-RA has the dual advantage of sparing patients from corticosteroid abuse and improve long-term clinical outcomes. All felt that dose reduction of TPO-RAs can be considered in patients with a stable response and platelet count >100 × 10 9 /L that is maintained for at least 6 months in the absence of concomitant treatments, although there was less agreement in patients with a platelet count >50 × 10 9 /L. Near consensus was reached regarding the statement that early treatment with a TPO-RA is associated with an increase in clinically significant partial or complete response. The experts also agreed that optimization of tapering and discontinuation of TPO-RA therapy in selected patients can improve the quality of life., Conclusion: The present consensus can help to provide guidance on use of TPO-RAs in daily practice in patients with ITP., Plain Language Summary: Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia There is little guidance on the timing of administration and tapering/discontinuation of thrombopoietin receptor agonists (TPO-RAs) in patients with primary immune thrombocytopenia (ITP).The Delphi technique was used to obtain consensus for five statements.The present consensus among Italian clinicians aims to provide guidance on second-line use of TPO-RAs for patients with ITP in daily practice., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CM received honoraria from Amgen and Novartis for serving on advisory boards; SS received honoraria from CSL, AMGEN, Novartis, Novo Nordisk, SOBI, and Bayer; ZF received honoraria and funding from Novartis, Amgen, and Grifols; PF received honoraria from Novartis; FB received consultation honoraria from Amgen, Novartis, and Momenta; BC received honoraria from Novartis and Amgen; BA has received honoraria from Amgen, Novartis, Novo Nordisk, Bayer, and Takeda; GG, SPR, BE, CF, CG, RE, VA have no conflict of interest to declare., (© The Author(s), 2021.)

Objective and Methods: In order to assess the efficacy of brentuximab vedotin (Bv) in combination with bendamustine (B) in multiple relapsed or refractory (RR) classic Hodgkin lymphoma (cHL), medical records of 47 patients treated with BvB in second relapse or beyond were reviewed., Results: The median number of previous treatments was 2 (1-4). Bv was given at 1.8 mg/kg on day 1 and bendamustine at 90 mg/m 2 on days 1 and 2 of a 21-day cycle. The median number of BvB cycles was 4 (2-7), and all patients were evaluable for efficacy. The CR and OR rates were 49% and 79%, respectively; 67% of responding patients and 2 in stable disease proceeded to a SCT procedure. After a median follow-up of 19 months (5-47), median PFS was 18 months (95%CI: 23-29), and the 2-year OS was 72%. Significantly longer PFS and OS were observed in patients attaining a major clinical response to treatment and in those who received consolidation with SCT. Fifteen (32%) patients experienced severe (G > 2) toxicity. The main toxicities were neutropenia (23%), gastrointestinal (10%), peripheral sensory neuropathy (11%), and infection (4%)., Conclusion: Our real-world results suggest that BvB is an effective third-line rescue and bridge-to-transplant regimen for RR-cHL patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The assessment of minimal residual disease (MRD) by flow cytometry (FC) has a prognostic impact in acute myeloid leukemia (AML), despite the low sensitivity in predicting relapse. Nonetheless, the role of leukemic-associated immunophenotypes (LAIPs)-related specificity on the sensitivity of MRD has not been clarified yet. In this respect, we accomplished this study., Methods: LAIP-frequencies of bone marrow samples from healthy donors and patients after treatment were quantified and subdivided in "categories of specificity" named as: "strong," "good," and "weak." At the following, the diagnostic performance of MRD was investigated in terms of sensitivity, specificity, predictive values, likelihood ratio (LR)., Results: "Strong" LAIPs were identified by CD7, CD2, CD4, and CD56 markers while "weak" LAIPs, independently of coexpressed markers, were mainly observed in CD33+ cells. MRD identified patients with significantly low DFS and OS but showed a low sensitivity in predicting relapse. Interestingly, majority of recurrences was noticed in patients with two LAIPs and lacking of "strong" LAIPs or only with one "good" LAIP. Thus, only patients showing one "strong" or two "good" LAIPs were considered suitable for MRD monitoring and selected to be further investigated. In this subset, positive MRD predicted a poor prognosis. Moreover, a higher sensitivity, negative predictive value (NPV) and LR- were observed after comparison with the previous series., Conclusions: These data highlight the relevant role of LAIP classification in "categories of specificity" in improving the sensitivity of MRD as assessed by FC., (© 2019 International Clinical Cytometry Society.)

Thrombopoietin receptor agonists (TPO-RAs) are currently indicated for continuous treatment of chronic primary immune thrombocytopenia (ITP). However, there is growing evidence that TPO-RAs can also trigger sustained response in 10-30% of cases after treatment tapering and discontinuation. Therefore, at least for selected responding patients, it might be rational to plan TPO-RA interruption to exploit off-treatment response. Intriguingly, complete or partial responses with TPO-RAs are frequently observed when treatments are initiated early, suggesting that unknown immune-related mechanisms may be involved in this phenomenon. The sustained responses observed after interruption of TPO-RAs may be interpreted as a recovery of immunological tolerance; thus, the re-establishment of immunological equilibrium might be primarily responsible for the observed off-treatment effect. Importantly, these findings may indicate that anticipated TPO-RA usage can lead to improved responses, and that optimized tapering and interruption in selected patients can furthermore improve prognoses. On the base of this rationale, a series of real-life considerations have been generated by a panel of Experts to elucidate possible novel criteria and modalities to identify subgroups of patients who can benefit from tapering and/or discontinuation of TPO-RAs. Towards this aim, the results of a survey of ITP experts are herein reported, reflecting a snapshot of current real-life experience on early discontinuation of TPO-RA-based therapy. The present manuscript also highlights the importance of future translational studies on novel prognostic and predictive biomarkers that can stratify patients and facilitate the clinical choice for second-line treatment of ITP., Competing Interests: Declaration of Competing Interest The authors declare potential conflict of interest with Novartis Corp., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Optimization of chemotherapy regimens in the treatment of multiple myeloma (MM) has led to increase the frequency of cases with complete response (CR). Nonetheless, many MM patients still experience relapse, suggesting that CR represents a suboptimal response criteria, and that new therapeutic strategies are needed after single transplant. However, the role of double autologous stem cell transplant (ASCT) as new adjunctive strategy remains to be elucidated. Indeed, we investigated the role of minimal residual disease (MRD) and log-reduction of plasma cells (PCs) as predictors of outcome and in quantifying the degree of tumor reduction after any ASCT., Methods: MRD and log-reduction were assessed by a six-color flow cytometry (FC) at different time-points: post induction, post first-, and post-second ASCT., Results: A significant difference was evidenced among the three time points for both log-reduction (P < 0.001) and MRD (P = 0.005). MRD levels after double ASCT were lower than MRD levels achieved after single ASCT (P = 0.005) and after induction (P < 0.001). Frequency of MRD positive patients after double ASCT was significantly lower rather than after the first ASCT (P = 0.008) and after induction (P = 0.004). Interestingly, a significant reduction of PFS was observed in patients with an unfavorable-risk cytogenetic (P < 0.001) and patients with MRD over 0.01% (P = 0.001) as well as log-reduction lower than 2.57 (P = 0.018) after double ASCT., Conclusions: Our results show that a better clearance of myeloma cells is observed after the double ASCT, and a longer PFS is associated with a lower MRD. © 2018 International Clinical Cytometry Society., (© 2018 International Clinical Cytometry Society.)

In patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), the anti-thrombotic and/or cytoreductive treatment in the follow-up may affect the evaluation of the pro-thrombotic weight of the clinical and biological characteristics at diagnosis. In order to avoid this potential confounding effect, we investigated the relationship between prior thrombosis (PrTh: thrombosis occurred before diagnosis and before treatment) and the characteristics at diagnosis in 977 thrombocythemic patients with MPN, reclassified according to the WHO 2008 criteria. PrTh occurred in 194 (19.9%) patients, with similar rates in the different MPNs. In multivariate analysis, PrTh rate was significantly related to minor thrombocytosis (platelets ≤700×10(9)/L), leukocytosis (leukocytes >10×10(9)/L), higher hematocrit (HCT >45%), JAK2 V617F mutation, older age, and cardiovascular risk factors (CVRFs). The highest PrTh rate (33.9%) was associated with the coexistence of minor thrombocytosis and leukocytosis. Of note, the inverse relationship between PrTh rate and platelet count is consistent with the hemostatic paradox of thrombocytosis. In conclusion, this analysis in MPN patients disclosed the unbiased characteristics at diagnosis with a pro-thrombotic effect. Moreover, it suggests that the optimal control of blood cells counts, and CVRFs might be of utmost importance in the prevention of thrombosis during the follow-up., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: The randomized HD2000 trial compared six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), four escalated plus two standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and six cycles of COPP-EBV-CAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin; CEC) in patients with advanced-stage Hodgkin lymphoma. After a median follow-up of 42 months, patients who received BEACOPP were reported to have experienced better progression-free survival (PFS) but not better overall survival (OS) results than those receiving ABVD. We here report a post hoc analysis of this trial after a median follow-up of 10 years., Patients and Methods: Three hundred seven patients were enrolled, 295 of whom were evaluable. At the time of our analysis, the median follow-up for the entire group was 120 months (range, 4 to 169 months)., Results: The 10-year PFS results for the ABVD, BEACOPP, and CEC arms were 69%, 75%, and 76%, respectively; corresponding OS results were 85%, 84%, and 86%. Overall, 13 second malignancies were reported: one in the ABVD arm and six each in the BEACOPP and CEC arms. The cumulative risk of developing second malignancies at 10 years was 0.9%, 6.6%, and 6% with ABVD, BEACOPP, and CEC, respectively; the risk with either BEACOPP or CEC was significantly higher than that reported with ABVD (P = .027 and .02, respectively)., Conclusion: With these mature results, we confirm that patients with advanced Hodgkin lymphoma have similar OS results when treated with ABVD, BEACOPP, or CEC. However, with longer follow-up, we were not able to confirm the superiority of BEACOPP over ABVD in terms of PFS, mainly because of higher mortality rates resulting from second malignancies observed after treatment with BEACOPP and CEC., (© 2015 by American Society of Clinical Oncology.)

High-dose chemotherapy (HDT) with autologous stem cell transplantation is the standard of care for relapsed/refractory (RR) Hodgkin lymphoma (HL). Given that HDT may cure a sizeable proportion of patients refractory to first salvage, development of newer conditioning regimens remains a priority. We present the results of a novel HDT regimen in which carmustine was substituted by a third-generation chloroethylnitrosourea, fotemustine, with improved pharmacokinetics and safety (FEAM; fotemustine, etoposide, cytarabine, melphalan) in 122 patients with RR-HL accrued into a prospective registry-based study. Application of FEAM resulted in a 2-year progression-free survival (PFS) of 73·8% [95% confidence interval (CI), 0·64-0·81] with median PFS, overall survival and time to progression yet to be reached. The 2-year risk of progression adjusted for the competitive risk of death was 19·4% (95% CI, 0·12-0·27) for the entire patient population. Most previously established independent risk factors, except for fluorodeoxyglucose ((18) (F) FDG)-uptake, were unable to predict for disease progression and survival after FEAM. Although 32% of patients had (18) (F) FDG-positrin emission tomography-positive lesions before HDT, the 2-year risk of progression adjusted for competitive risk of death was 19·4% (95% CI; 0·12-0·27). No unusual acute toxicities or early/late pulmonary adverse events were registered. FEAM emerges as an ideal HDT regimen for RR-HL patients typically pre-exposed to lung-damaging treatments., (© 2015 John Wiley & Sons Ltd.)

In acute myeloid leukemia (AML), the detection of minimal residual disease (MRD) as well as the degree of log clearance similarly identifies patients with poor prognosis. No comparison was provided between the two approaches in order to identify the best one to monitor follow-up patients. In this study, MRD and clearance were assessed by both multiparameter flow cytometry (MFC) and WT1 expression at different time points on 45 AML patients achieving complete remission. Our results by WT1 expression showed that log clearance lower than 1.96 after induction predicted the recurrence better than MRD higher than 77.0 copies WT1/10(4) ABL. Conversely, on MFC, MRD higher than 0.2 % after consolidation was more predictive than log clearance below 2.64. At univariate and multivariate analysis, positive MRD values and log clearance below the optimal cutoffs were associated with a shorter disease-free survival (DFS). At the univariate analysis, positive MRD values were also associated with overall survival (OS). Therefore, post-induction log clearance by WT1 and post-consolidation MRD by MFC represented the most informative approaches to identify the relapse. At the optimal timing of assessment, positive MRD and log-clearance values lower than calculated thresholds similarly predicted an adverse prognosis in AML.

This retrospective study of the thrombocythemia Italian registry (RIT) documented that 71 (30.6%) out of 232 ET patients experienced 88 cardiovascular adverse events (CV-AEs) during anagrelide treatment (522 pt-y). The rate of CV-AEs was: 24.1% for palpitations, 4.3% for angina, 3.5% for arterial hypertension, 3.0% for congestive heart failure, 1.8% for arrhythmia, 0.9% for AMI, 0.4% for pericardial effusion. CV-AEs led to treatment discontinuation in nine (3.9%) patients, while in the remaining cases they were managed by pharmacological intervention and/or patient life style improvement. CV-AEs had no relationship with patient characteristics (including older age). A significant relationship was found only with a higher anagrelide induction dose. In the absence of any agreed protocol, a cardiovascular instrumental evaluation (CV-IE) was performed in 102 (44%) patients before commencement of anagrelide (with higher rate after the anagrelide/Xagrid EMA approval of 2004), and in 84 (36%) patients during treatment. Patients with and without CV-IEs, who resulted completely balanced for all their characteristics, did not significantly differ in the occurrence of CV-AEs. In conclusion, this study on ET patients treated with anagrelide shows that CV-AEs, equally distributed in younger and older subjects, were mostly mild and easily manageable, allowing safe treatment continuation in the majority of cases. Moreover, routinely performing a CV-IE did not appear to anticipate the occurrence of CV-AEs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The incidence of acute myeloid leukemia (AML) increases with age, but results of intensive chemotherapy in elderly patients are disappointing. Non-pegylated liposomal formulations of doxorubicin (Myocet™) have been developed with the aim of reducing systemic and cardiac toxicity especially in the elderly. We evaluated the efficacy and toxicity profiles of fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) regimen given in association with Myocet™ in 35 patients with AML, median age 69 years (range 61-83 years). Nineteen (54.3%) had newly-diagnosed AML, twelve (34.3%) patients had secondary AML (ten with Myelodisplastic Syndrome, two with Primary Myelofibrosis) and 4 (11.4%) patients had had a late relapse (>12 months) of AML. Complete remission (CR) and partial remission (PR) were obtained in twenty-two (63%) and 3 (8.5%) patients, respectively. Seven (20%) patients showed a resistant disease. There were 3 early deaths (8.5%). Six patients (17%) experienced severe cardiovascular toxicity. The median overall survival (OS) was 12 months (range 1-52 months) with a median disease-free survival (DFS) of 20 months (range 1-48 months). One-year and two-year DFS were 78.9% and 26.7%, respectively. This study demonstrates that in elderly patients with AML, FLAG-Myocet combination shows promising efficacy response with acceptable toxicity, enabling most patients to receive further treatments, including transplantation procedures.

Pregnancy is a high-risk event in women with essential thrombocythemia (ET). This observational study evaluated pregnancy outcome in ET patients focusing on the potential impact of aspirin (ASA) or interferon alpha (IFN) treatment during pregnancy. We retrospectively analyzed 122 pregnancies in 92 women consecutively observed in the last 10 years in 17 centers of the Italian thrombocythemia registry (RIT). The live birth rate was 75.4% (92/122 pregnancies). The risk of spontaneous abortion was 2.5-fold higher than in the control population (P < 0.01). ASA did not affect the live birth rate (71/93, 76.3% vs. 21/29, 72.4%, P = 0.67). However, IFN treatment during pregnancy was associated with a better outcome than was management without IFN (live births 19/20, 95% vs. 73/102, 71.6%, P = 0.025), and this finding was supported by multivariate analysis (OR: 0.10; 95% CI: 0.013-0.846, P = 0.034). The JAK2 V617F mutation was associated with a poorer outcome (fetal losses JAK2 V617F positive 9/25, 36% vs. wild type 2/24, 8.3%, P = 0.037), and this association was still significant after multivariate analysis (OR: 6.19; 95% CI: 1.17-32.61; P = 0.038). No outcome concordance between first and second pregnancies was found (P = 0.30). Maternal complications occurred in 8% of cases. In this retrospective study, in consecutively observed pregnant ET patients, IFN treatment was associated with a higher live birth rate, while ASA treatment was not. In addition, the JAK2 V617F mutation was confirmed to be an adverse prognostic factor., ((c) 2009 Wiley-Liss, Inc.)

We report four patients (mean age 65 yr; range 40-77 yr) affected by acquired pure red cell aplasia (PRCA) complicating chronic lymphoid disorders and treated with anti-CD20 monoclonal antibody rituximab. Three out of four patients were given packed red cell transfusion. Steroids and recombinant erythropoietin (r-Epo) were also administered as first-line therapy without response. After a mean time of 57 d (range 23-62 d) from PRCA diagnosis, all patients received rituximab at a dosage of 375 mg/m(2)/wk for four consecutive weeks. First injection side effects of rituximab were minimal. All patients showed an increase in hemoglobin levels in response to rituximab, in one patient just after the first dose, in another patient after the second and in two other patients after the third dose. Three patients (75%) were considered in complete remission (CR) and one patient (25%) in partial remission 4 wk after the last rituximab infusion, despite a CR was obtained later (16 wk following the beginning of the therapy). Finally, at the last follow-up (mean 18.5 months, range 2-60 months), all patients were alive and in continue CR. Despite very limited in number, these results suggest that rituximab is very effective in the treatment of PRCA complicating B-cell chronic lymphoproliferative disorders.

Thrombotic thrombocytopenic purpura (TTP) is a rare and severe disease characterized by thrombocytopenia, microangiopathic haemolytic anemia, neurological and renal involvement associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. Persistence of high titers of anti-ADAMTS13 autoantibodies predisposes to relapsing TTP. Since relapses are associated with high morbidity and mortality rates, the optimal therapeutic option should be a pre-emptive treatment able to deplete anti-ADAMTS13 autoantibodies and avoid relapses. Five patients who presented with persistence of undetectable ADAMTS13 activity and high titers of autoantibodies, were treated with rituximab as pre-emptive therapy during remission. Four of them were affected by relapsing TTP and one was treated after the first episode. ADAMTS13 activity ranging from 15% to 75% with disappearance of inhibitors was achieved after three months in all patients, and persisted >20% without inhibitors at six months. In three patients disease-free status is still ongoing after 29, 24 and six months, respectively. Relapses were documented in two patients during follow-up: in one patient remission lasted 51 months; while in the other patient relapse occurred after 13 months. Results demonstrated that rituximab used as pre-emptive treatment may be effective in maintaining a sustained remission in patients with anti-ADAMTS13 antibodies in whom other treatments failed to limit the production of inhibitors, and suggests that re-treatment with rituximab should be considered when ADAMTS13 activity decreases and inhibitors reappear into the circulation, to avoid a new relapse.

We investigated the effects of a single s.c. injection of peg-filgrastim in 32 patients with multiple myeloma who underwent autologous stem cell transplantation (AuSCT) as first line treatment. For comparison, 32 myeloma patients with similar characteristics and receiving standard daily administration of filgrastim were matched. Overall, there were no statistically significant differences between peg-filgrastim and filgrastim in terms of tolerability, marrow recovery, severity of neutropenia, incidence and duration of febrile neutropenia, documented infections and transfusions. However, some favourable trends or effects in favour of peg-filgrastim were observed. This was confirmed by a review of the published papers about this topic.

Twenty-one patients with multiple myeloma, all relapsed after frontline autologous stem cell transplantation and all relapsed again after or resistant to thalidomide (employed as second line treatment) received bortezomib (1.3 mg/m(2) body surface twice weekly for 2 weeks followed by an interval of 10-12 days) without adjunct of steroids as third line therapy. Three patients died of progressive disease during the first 2 cycles with bortezomib. Eighteen patients received at least 2 cycles and were evaluated for response. According to EBMT criteria, two complete (negative immunofixation) and seven partial (reduction of M-component > 50-75%) remissions were achieved (ITT response rate 42.8%). Duration of response lasted from 2 to 14+ months. Grades 3-4 toxicities (thrombocytopenia, leucopenia, peripheral neuropathy and vasculitis) were observed in seven patients, but no patient interrupted the treatment due to side effects. We conclude that bortezomib alone may induce high quality responses as third line salvage therapy with acceptable toxicity in a significant proportion of homogeneously pre-treated myeloma patients with progressive disease after autologous transplantation and thalidomide.

Thirty-seven anaemic subjects with low-to-intermediate risk myelodysplastic syndrome (MDS) received the highly glycosylated, long-acting erythropoiesis-stimulating molecule darbepoetin-alpha (DPO) at the single, weekly dose of 150 microg s.c. for at least 12 weeks. Fifteen patients (40.5%) achieved an erythroid response (13 major and two minor improvements, respectively, according to International Working Group criteria). Such results are currently maintained after 7-22 months in 13 of the responders, one of whom required iron substitutive therapy during the treatment. One patient relapsed after 4 months. Another responder died after 5 months because of causes unrelated to the treatment. No relevant side-effects were recorded. At multivariate analysis, significant predictive factors of response were baseline serum levels of endogenous erythropoietin <100 IU/l, absent or limited transfusional needs, no excess of blasts and hypoplastic bone marrow. This study suggests that DPO, at the dose and schedule used, can be safely given in low-intermediate risk MDS and may be effective in a significant proportion of these patients.

Four cases of hypereosinophilic syndrome (HES) treated with the tyrosine-kinase inhibitor imatinib-mesylate are reported. The drug was effective in three patients, but a prolonged clinical and hematological remission was obtained only in one patient, due to appearance of resistance or poor tolerability in the other cases. The dose of imatinib necessary to achieve a response ranged from 100 to 600 mg/d. One patient with evidence of a clonal T-cell population did not respond at all. We confirm the efficacy of imatinib in HES, but we also underline that type and duration of response may be variable. This could be due to different pathogenetic mechanisms of the disease in single patients.

Ninety patients with untreated, stage I-II A myeloma, were randomised to receive or not monthly infusions of pamidronate (PMD) for 1 year, without additional therapies. Follow-up ranged from 36 to 72 months (median 51 months). Three years after the start of the treatment, the disease had progressed in 25% of PMD treated patients and in 26.8% of controls (p n.s). Median time-to-progression was 16 and 17.4 months, respectively (p n.s). Among the 21 patients who required chemo-radiotherapy, skeletal events (osteolytic lesions, pathological fractures and/or hypercalcemia) developed in 9/11 (81.8%) controls and in 4/10 (40%) of treated patients (p < 0.01). "Prophylactic" administration of PMD may decrease the development of skeletal events, but does not reduce the rate and the time of disease progression in early-stage myeloma.

Background and Objectives: Recombinant erythropoietin (r-EPO) induces erythroid responses in patients affected by myelodysplastic syndromes (MDS). However, the response rate declines to 10-15% in MDS with substantial transfusion needs. Both in vitro and in vivo studies have suggested that the addition of growth factors (G-CSF, GM-CSF) or interleukin-3 (IL-3) may potentiate the effect of r-EPO on dysplastic erythropoiesis. The aim of this study was to evaluate the effects of the combination of r-EPO with G-CSF, GM-CSF or IL-3 on the anemia of heavily transfusion-dependent MDS patients, previously unresponsive to r-EPO alone., Patients and Methods: Sixty patients with transfusion-dependent MDS, already treated without significant erythroid response with r-EPO alone, were scheduled to receive, for at least 8 weeks, r-EPO subcutaneously at the dose of 300 U/kg t.i.w. in combination with G-CSF (300 microcg s.c. t.i.w., 27 patients), or GM-CSF (300 microcg s.c. t.i.w., 23 patients), or IL-3 (5 microcg/kg s.c. t.i.w., 10 patients), after a two-week pre-phase during which G-CSF, GM-CSF and IL-3 were administered daily at the same dose, as single drugs., Results: Ten patients were not evaluable for erythroid response because of relevant side effects related to GM-CSF or IL-3 administration. Overall, among 50 patients who completed the study, there were 3 erythroid responses (as determined by complete abolition of red-cell transfusions): 1 (4%) in the G-CSF + r-EPO and 2 (10.5%) in the GM-CSF + r-EPO treated groups. No patient responded to the combination of r-EPO + IL-3. All responders had inappropriate serum levels of endogenous EPO and a relatively short disease duration. Both responders to GM-CSF + r-EPO developed acute myeloid leukemia 2-9 months after the start of the combined therapy. A third elderly patient, treated with the same association, developed marrow hypoplasia. A significant increase in leukocyte count occurred in 96% of patients who received r-EPO + G-CSF, 78.9% of those treated with r-EPO + GM-CSF and 66% of subjects receiving r-EPO + IL-3. A significant increase in platelet count was observed in a single patient receiving r-EPO and GM-CSF, while a slight decrease in platelet count with respect to baseline levels occurred in about 20% of patients., Interpretation and Conclusions: Our results suggest that the combination of r-EPO with G-CSF, GM-CSF or IL-3, at least at the doses and schedules employed in the present study, has limited efficacy on the anemia of heavily transfusion-dependent MDS patients previously unresponsive to r-EPO alone. However, in this setting of patients, the combination of G-CSF or GM-CSF + r-EPO may occasionally be effective in subjects with low circulating levels of serum EPO and short disease duration.

In order to investigate what is the best single parameter to predict the leukapheretic yield of circulating CD34+ progenitor cells, we retrospectively analyzed data from 68 patients with hematological malignancies who underwent mobilizing therapy. Three main parameters were monitored: total white blood cell (WBC), CD34+ cells, and monocyte counts in peripheral blood (PB) at the same day and at the preceding day of the apheretic procedure. Linear regression analysis revealed a strong correlation between CD34+ cell value in PB just before harvest and the number of CD34+ cells collected (P < 0.0001), but not at the preceding day. Monocyte PB concentration and absolute WBC count did not correlate with CD34+ cells harvested, at the preceding day of leukapheresis as well as at the same day of the procedure. The number of CD34+ cells in mobilized PB at the same day of harvest evidenced a very good capacity of predicting the value of harvested CD34+ cell number after collection, while WBC and monocyte count displayed quite a wide dispersion of results. In particular, an amount greater than 50/microL of circulating CD34+ cells ensured the best collections. Finally, CD34+ and CFU-GM content evaluated for each apheresis showed a strong reciprocal correlation (r 0.78; P < 0.0001). We conclude that the absolute number of CD34+ cells at the day of leukapheresis is the only parameter for identifying the exact timing for apheresis and predicting the amount of peripheral blood progenitor cells (PBPCs) that will be collected. In this setting, WBC and monocyte counts, at the day of collection or at the preceding day, are not useful tools.

Recombinant erythropoietin (r-EPO) was administered to 37 patients with advanced, transfusion-dependent and chemo-resistant multiple myeloma (MM), at the fixed dose of 10,000/U s.c., 3 times a week, for 2 months. Thirteen patients (35.1%) achieved a significant response in terms of complete abolition of red cell transfusions. Factors significantly predictive of response were: a) inappropriate production of endogenous EPO, as expressed by a reduced observed/predicted ratio; b) presence of a consistent number of circulating erythroid precursors BFU-E; c) low serum levels of tumor necrosis factor (TNF) and interleukin-1 (IL-1), cytokines with inhibitory activity on erythropoiesis; d) a single line of previously received chemotherapy. Renal failure, bone marrow plasma cell infiltration, serum levels of IL-6 and other main clinical and laboratory parameters did not affect significantly the response to r-EPO. High fluorescence reticulocytes (HFR) and soluble transferrin receptor (sTfR) values were useful to detect an early stimulation of erythropoiesis in responders, while a high percentage of circulating hypochromic erythrocytes (HE), as assessed by an automated counter, identified those patients developing functional iron deficiency during r-EPO treatment. We conclude that about one-third of severely anemic patients with advanced MM, unresponsive to chemotherapy, may benefit by r-EPO therapy. The clinical management of these patients can be accomplished using non-invasive parameters, such as sTfR, HFR and HE.

The in vitro inhibitory effect of all-trans retinoic acid (ATRA) on myeloma cell growth may be synergistically potentiated by the activity of dexamethasone (DEX) and alpha-interferon (IFN). We treated 10 patients with advanced, refractory multiple myeloma (MM) using a combination of ATRA (100 mg p.o., once a day for two weeks every month), DEX (40 mg i.v., for 4 days every 4 weeks) and IFN (3 MU s.c., three times a week). Eight patients completed at least three months of treatment and were evaluable for response. Two of them showed a partial response which persists after 15 to 17 months. Three patients experienced a stable plateau phase of 4 to +11 months, with a significant improvement in the performance status and bone pain. Progressive disease was seen in the remaining three patients. We conclude that the association of ATRA, DEX and IFN warrants further consideration in MM patients.