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The incidence of non-Hodgkin lymphomas increases with age. Non-pegylated liposomal formulations of doxorubicin (Myocet®®) reduce systemic and cardiac toxicity especially in the elderly, who often have cardiac diseases. We treated 80 patients (mean age 70.9 years) with poor-risk diffuse large B-cell lymphoma with the R-COMP 21 regimen (Myocet®® 50 mg/m2, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, rituximab 375 mg/m2, prednisone 100 mg/day). In all, 82.5%% and 13.7%% patients showed complete and partial responses, respectively. Sixty-two of the 80 patients are alive and disease-free (77.5%%), while 3/80 are alive with active disease and 15 patients (18.7%%) have died (median follow-up: 31 months). The estimated probability of overall survival at 12/24 months from admission was 93.5/87.3%%, respectively. There were no therapy-related cardiac events and the ejection fraction improved (from 51.6 ±± 6.9%% to 54.2 ±± 3.9%%). Grade 3--4 neutropenia occurred in 22%% of patients. We concluded that Myocet®® shows both efficacy and tolerability, mainly at the cardiac level. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the therapeutic activity of recombinant erythropoietin (r-EPO) in association with thalidomide in 30 patients with myelodysplastic syndromes (MDS), previously treated with r-EPO (n.15, group A) or thalidomide (n.15, group B) as single agents, respectively, without any significant benefit on their anemia. Four patients of group A and three of group B (23.3%) achieved an erythroid response, according to International Working Group (IWG) criteria. After 12 weeks, responders of group A continued with thalidomide alone, those of group B with r-EPO alone. All responses were maintained, thus suggesting they were likely due to the second drug adjuncted (thalidomide for group A and r-EPO for group B), rather than to a combined effect. Our results do not support the hypothesis of a synergistic activity for the association of r-EPO and thalidomide on anemia of MDS. It seems, instead, that two populations of patients can be identified, according to their sensitivity to r-EPO or, alternatively, to thalidomide. [Copyright &y& Elsevier]

Four cases of hypereosinophilic syndrome (HES) treated with the tyrosine-kinase inhibitor imatinibmesylate 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. However, its effectiveness and safety profile in real clinical practice should be further assessed. We retrospectively evaluated 130 consecutive RRMM patients treated with KRd between December 2015 and August 2018, in 9 Hematology Departments of Rete Ematologica Pugliese (REP). The overall response rate (ORR) was 79%, with 37% complete response (CR). Treatment with KRd led to an improvement in response regardless of age, refractory disease, and number and type of previous therapies. After a median follow-up of 18 months, median PFS was 24 months and 2y-PFS was 54%. PFS was longer in patients achieving a very good partial response (VGPR) with median PFS of 32.4 months. The relapses after prior autologous transplant (ASCT) positively impact median PFS. Several baseline disease characteristics, such as III ISS scoring or elevated LDH, and prior exposure to lenalidomide were found to negatively impact PFS. Primary refractory or relapsed myeloma patients have been treated with KRd as bridge to ASCT with a great benefit. Thirty-four (83%) reached at least a partial response after KRd and 21 (61%) performed ASCT. In transplanted patients, median PFS was not reached and 2y-PFS was 100%. The treatment discontinuation rate due to adverse events (AEs) was 18%, most commonly for lenalidomide (11%). Overall, in 10% of patients, a KRd dose reduction was necessary at least once (2.5% for carfilzomib and 8% for lenalidomide). The most frequent AE was neutropenia (44%) and anemia (41%). Infections occurred in 14% of patients. Cardiovascular events occurred in 11% of patients. Elderly patients have tolerated therapy very well, without additional side effects compared to younger patients, except for cardiac impairment. Our analysis confirmed that KRd is effective in RRMM patients. It is well tolerated and applicable to the majority of patients outside clinical trials. A longer PFS was shown in patients achieving VGPR, in those lenalidomide naïve and in patients relapsing after previous ASCT. Previous ASCT should not hamper the option for KRd therapy. Accordingly, KRd should be used as bridge regimen to ASCT with remarkable improvement in response and PFS rates. Further clinical studies are needed. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented reporting on three patients with multiple myeloma and showing hyperbilirubinemia without jaundice due to paraprotein interference.

Abstract: 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 (1.3mg/m2 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. [Copyright &y& Elsevier]

Summary. Thirteen patients with low-to-intermediate risk myelodysplastic syndrome (MDS) received recombinant erythropoietin (r-EPO) at the single, weekly dose of 40·000 U for at least 8 weeks. Five patients (38·4%) achieved a major erythroid response (increased haemoglobin levels > 2 g/dl and/or transfusion independence), which is currently maintained after 3–11 months, without modification of r-EPO dose. This study suggests that 40·000 U r-EPO given once a week may be at least as effective as the more frequent (daily or three times a week) administrations of the drug usually employed in MDS patients. [ABSTRACT FROM AUTHOR]

Lenalidomide is approved for the treatment of transfusion-dependent (TD) del(5q) myelodysplastic syndromes (MDS). However, few data are available in patients with transfusion-independent (TI) del(5q) MDS. In the first, observational, part of this 2-part study, we assessed the impact of transfusion dependence on overall survival (OS) and non-leukemic death in untreated del(5q) MDS patients who were TD (n = 136), TI with hemoglobin (Hb) ≥10 mg/dL (n = 88), or TI with Hb <10 mg/dL (n = 96). In the second, interventional, part we assessed the quality-of- life (QoL) benefits and clinical efficacy of lenalidomide (10 mg/day) in 12 patients with TI del(5q) MDS and Hb <10 mg/ dL. In the untreated population, OS was significantly longer in TI than in TD patients (TI [Hb ≥10 g/dL], 108 months; TI [Hb <10 g/dL], 77 months; TD, 44 months). Transfusion dependence also negatively impacted non-leukemic death rates. In the interventional part of the study, baseline Hb levels were found to correlate significantly with physical (R = 0.666, P = 0.035) and fatigue (R = 0.604, P = 0.049) QoL scores. Median physical QoL scores improved significantly after 12 weeks’ treatment with lenalidomide (+12.5; P = 0.020). Evaluable TI patients experienced early increases in Hb levels, and all attained an erythroid response. Our findings suggest that TI patients with moderate anemia may benefit from early treatment with lenalidomide. [ABSTRACT FROM AUTHOR]

Background: The clinical presentation of myelodysplastic syndromes is highly variable and so accurate prediction of outcomes in these patients is crucial. We aimed to assess whether self-reported fatigue severity predicts overall survival beyond gold-standard prognostic indices in patients with higher-risk myelodysplastic syndromes.Methods: We did a multicentre, prospective, observational, cohort study of patients from 37 centres in Europe, USA, and east Asia. Adults (≥18 years) with myelodysplastic syndromes were consecutively enrolled within 6 months of diagnosis with an intermediate-2-risk or high-risk score according to the International Prognostic Scoring System (IPSS). Patients were enrolled irrespective of older age, comorbidities, performance status, and progression from a lower IPSS risk score category. All patients had to complete a quality of life assessment at baseline. With use of univariate and then multivariate Cox proportional hazards regression analysis, we constructed a multivariate model of how prognostic variables, including IPSS and fatigue score from the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-core 30, predicted overall survival. The primary endpoint was overall survival by baseline self-reported fatigue scale ratings. This study was registered with ClinicalTrials.gov, number NCT00809575.Findings: Between Nov 10, 2008, and Aug 13, 2012, we enrolled 280 patients with a median age of 71 years (IQR 64-77). The median follow-up was 15 months (IQR 8-27), and the last patient was assessed Feb 16, 2015. The median overall survival from diagnosis was 17 months (95% CI 15-19). In univariate analysis, the baseline factors that were significantly associated with reduced overall survival were increasing age, transfusion dependency (defined as having received at least one red blood cell transfusion every 8 weeks over a period of 4 months), Eastern Cooperative Oncology Group (ECOG) performance status of two or more, increased white blood cell count, high-risk IPSS score, and higher self-reported fatigue severity. In multivariate analysis, baseline factors independently associated with reduced overall survival were high-risk IPSS score (hazard ratio [HR] 2·525, 95% CI 1·357-4·697; p=0·0035) and a higher score for fatigue (1·110, 1·040-1·170, for every ten points of fatigue deterioration; p=0·0007). In further multivariate models for survival, including either the WHO-based prognostic scoring system or the revised version of the IPSS classification, fatigue remained a statistically significant independent prognostic factor with a HR of 1·120 (1·050-1·180, p=0.0003) and a HR of 1·130 (1·060-1·190, p=0·0002), respectively.Interpretation: In patients with newly diagnosed higher-risk myelodysplastic syndromes, self-reported fatigue severity provides prognostic information for survival independent from gold-standard risk classifications. Our findings suggest that fatigue assessment should be included in routine diagnostic investigation for these patients and considered as a standard baseline stratification factor in future randomised controlled trials.Funding: Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL). [ABSTRACT FROM AUTHOR]

The primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher-risk myelodysplastic syndromes ( MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life ( Qo L) and overall symptom burden in these patients. The analyses were conducted in 280 higher-risk MDS patients. Pre-treatment patient-reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy ( FACIT)- Fatigue scale and Qo L was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire- Core 30 ( EORTC QLQ- C30). Female gender ( P = 0·018), poor performance status (i.e., ECOG of 2-4) ( P < 0·001) and lower levels of haemoglobin ( Hb) ( P = 0·026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global Qo L scores of patients with the highest versus those with the lowest levels of fatigue were 29·2 [standard deviation ( SD), 18·3] and 69·0 ( SD, 18·8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient-reported fatigue severity revealed the effects of disease burden on overall Qo L more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue. [ABSTRACT FROM AUTHOR]

Background In the absence of randomized, controlled trial data to support iron chelation therapy in transfusion-dependent patients with myelodysplastic syndromes ( MDS), continued evidence from large prospective clinical trials evaluating the efficacy and safety of iron chelation therapy in this patient population is warranted. Methods The safety and efficacy of deferasirox was examined in a prospective, open-label, single-arm, multicenter trial of transfusion-dependent patients with International Prognostic Scoring System low- or intermediate-1-risk MDS and evidence of transfusion-related iron overload. The effects of deferasirox therapy on hematological response and disease progression were also examined. Results Of 159 participants enrolled from 37 Italian centers, 152 received ≥1 dose of deferasirox (initiated at 10-20 mg/kg/day and titrated as appropriate), and 68 completed the study. Of 84 patients who discontinued deferasirox therapy, 22 died during the trial, and 28 withdrew due to an adverse event ( AE). Fourteen treatment-related grade 3 AEs occurred in 11 patients, whereas no grade 4 or 5 drug-related AEs were reported. Significant risks for dropout were a higher serum ferritin level at baseline, a higher MDS-Specific Comorbidity Index, and a shorter diagnosis-enrollment interval. Median serum ferritin level fell from 1966 ng/mL to 1475 ng/mL ( P < 0.0001). The cumulative incidence of transfusion independence, adjusted for death and disease progression, was 2.6%, 12.3%, and 15.5% after 6, 9, and 12 months, respectively. Conclusions Deferasirox therapy in transfusion-dependent patients with MDS was moderately well tolerated and effectively lowered serum ferritin levels. Positive hematological responses were observed, and a subset of patients achieved transfusion independence. [ABSTRACT FROM AUTHOR]

In lower-risk myelodysplastic syndromes (MDS) with del(5q), lenalidomide induces erythroid responses associated with better survival. In a phase II, single-arm trial, 45 patients with anemia and lower-risk del(5q) MDS received lenalidomide 10 mg/day to evaluate quality of life (QoL) changes, measured by QOL-E, safety, responses and survival. Lenalidomide was well tolerated, with 80% completing ≥ 24 weeks of treatment. Earlier study discontinuation was related to disease progression ( n = 5), death ( n = 1) and withdrawal of consent ( n = 3). Within 24 weeks, 82% obtained erythroid responses, durable in 69% at 52 weeks. Cytogenetic responses occurred in 29 patients (64%), with 10 patients achieving a complete cytogenetic response. QoL-E scores correlated with hemoglobin levels and improved in erythroid responders. Erythroid responders had an 86% reduced risk of disease progression and an 80% reduction in mortality risk compared with non-responders. These findings corroborate earlier studies and give further support to the use of lenalidomide in lower-risk MDS and del(5q). [ABSTRACT FROM AUTHOR]

In vitro studies suggest that haploinsufficiency is involved in the pathogenesis of myelodysplastic syndromes (MDS). In patients with del5q cytogenetic abnormality, RPS-14 and microRNAs (miRNAs) play a major role. In a multicenter phase II single-arm trial with lenalidomide in anemic primary del5q MDS patients with low- or int-1 risk IPSS, biological changes from baseline were investigated. Gene expression profiling of selected genes was performed (TaqMan® Low Density Array Fluidic card, Applied Biosystems PRISM® 7900HT) and normalized against the expression of the 18S housekeeping gene from a pool of healthy subjects. Thirty-two patients were evaluated at baseline and after 3 and 6 months of treatment. RPS-14, miR-145, and miR-146 were downregulated at baseline and significantly increased during treatment. Nuclear factor kappa B, IL-6, interferon regulatory factor-1, IFNγ-R2, IL-2, and many genes in the apoptotic pathways (TNF, IL-1B, and IL-10) were upregulated at baseline and significantly downregulated during lenalidomide treatment, while forkhead box P3, FAS, IFNγ, IL-12A, and IL-12B were downregulated at baseline and progressively upregulated during treatment. The crucial role of aberrant immunological pathways and haploinsufficiency in the pathogenesis of del5q MDS is confirmed in the present patient setting. Our results indicate that lenalidomide may act through defined immunological pathways in this condition. [ABSTRACT FROM AUTHOR]

A prospective, multicenter, randomized trial comparing pamidronate administration (60--90 mg once a month for 1 year) versus simple observation in 177 patients with asymptomatic myeloma was performed to explore whether the administration of this drug reduces the rate of and/or the time to progression to overt, symptomatic disease. No relevant side effects were recorded in pamidronate-treated patients. With a minimum follow-up of 5 years for live patients, there were 56/89 (62.9%%) progressions in the pamidronate-treated group and 55/88 (62.5%%) within the controls ( p == NS). Median time to progression was 46 and 48 months, respectively ( p == NS). Overall survival was also similar between the two groups. Skeletal-related events at the time of progression were observed in 40/55 (72.7%%) controls, but only in 22/56 (39.2%%) pamidronate-treated patients ( p == 0.009). In conclusion, the administration of pamidronate in asymptomatic myeloma, while reducing bone involvement at progression, did not decrease the risk of transformation and the time to progression into overt myeloma. [ABSTRACT FROM AUTHOR]

Abstract: NF-kB is reported to be constitutively activated in a percentage of high-risk myelodysplastic syndrome carrying cytogenetic aberrations. Only few data are reported on the use of proteasome inhibitors in this subset of patients. We performed a study on efficacy and safety of bortezomib as a single agent in patients with myelodysplastic syndromes (MDS). Bortezomib was administered at 1.3mg/m2 with a 1, 4, 8, 11-day schedule every 28 days, in 19 patients with IPSS low/intermediate 1 or intermediate2/high risk. Six out of 19 patients received all planned eight cycles. Hematologic toxicity was recorded in all patients, especially grade 3/4 neutropenia and grade 3/4 thrombocytopenia; non-hematologic side effects were recorded in 7 patients, but events were all of grade 1/2 toxicity. According to IWG 2006 criteria, 4 out of 19 patients (21%) achieved erythroid response and 9 patients (47%) showed stable disease. In patients with erythroid response bone marrow WT1 levels decreased from a median of 109 copies at baseline to a median of 14 copies at the end of treatment, whereas in patients with stable disease, median WT1 copies increased either in bone marrow and peripheral blood. In conclusion, bortezomib used alone in MDS shows modest hematologic efficacy but appears to affect the WT1 gene expression, which is typically increased in these diseases. [Copyright &y& Elsevier]

Abstract: This was a retrospective, comparative study focused on the extended follow-up of 192 transfusion-dependent patients with myelodysplastic syndromes treated (n. 83) or not treated (n. 109) with recombinant erythropoietin alpha (r-EPO) as single agent during the course of their disease. The results supported the safety of this treatment in the long term and also showed a significant survival advantage (median 52 months vs. 31 months, p <0.0095) in responding patients as compared to non-responding ones or to subjects never treated with r-EPO. At multivariate analysis, response to r-EPO maintained an independent prognostic value on OS. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

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 μg 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. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor of the "British Journal of Haematology," about the use of rituximab as maintenance therapy after autologous transplantation for patients with multiple myeloma.