Background: Thrombopoietin receptor-agonists (TPO-RAs), eltrombopag (ELT) and romiplostim, are effective drugs licensed for relapsed/refractory ITP, leading to 70-80% response rates. As they ...stimulate the Mpl receptor on megakaryocytes, increasing platelet production, their effect is expected to be dependent on their continuous administration. However, durable remissions after TPO-RAs discontinuation have been described in 10-30% of patients (pts). This evidence pointed out a possible curative role for these agents, suggesting a mode of action that goes beyond the mere increase of platelet count, and interferes with the immune dysregulation underlying the disease, which worsens as ITP becomes chronic. The aim of this prospective study is to explore the role of ELT given for a defined period of time as second-line treatment in pts with newly diagnosed (ND) or persistent (P) ITP, thus interfering with the pathogenesis of the disease at an early stage, either offering a possible curative option for pts or a steroid-sparing drug as a bridge to chronic phase (CP).
Methods: Pts aged ≥18 years with ND or P ITP not responsive or in relapse after standard first-line therapy, with active disease (platelet count <30x109/L or steroids/IVIG dependence to maintain a platelet count ≥30x109/L and/or avoid bleeding) were included. The study was divided into a period of treatment (PT), during which pts received ELT at a starting dose of 50 mg/day, then adjusted according to platelet count, for 24 weeks, a period of tapering and discontinuation (PTD) (week 25 - 32), and a period of observation (PO) (week 33 - 52). Complete response (CR) was defined as a platelet count ≥100x109/L; response (R) as a platelet count ≥30x109/L and at least doubling of baseline count. Only pts in R or CR at the end of week 24 entered the PTD. The primary end-point was the proportion of pts who, being in remission at the end of PT, were able to taper down and discontinue ELT, maintaining the remission for all the PO, without requiring any concomitant therapies. Secondary objectives included the relationship between baseline TPO serum level and response to treatment, exploring modifications of immunological parameters across study phases and their correlation with responses.
Results: Between 24/02/16 and 05/05/2018, 55 pts were enrolled by 10 GIMEMA Italian Centers. 3 pts didn't meet the inclusion criteria and 1 was excluded from study population because of protocol violation. Of the 51 evaluable pts, 31 (61%) were females. Median age was 65 years (range 21-90). 22 pts (44%) had ND ITP. Median baseline platelet count was 19x109/L (range 1-227). At the time of data cut-off, 10 pts were still in PT and 1 was not evaluable. Out of the remaining 40 pts, 2 were discontinued for reasons other than failure, and were excluded from response analysis. Of the 38 evaluable pts, at the end of 6 months of therapy 14 (37%) were in CR and 12 (32%) in R, with an ORR of 69%; 12 pts were non responders. All the 26 responders started the PTD. Of the 18 pts who completed the PTD, 7 maintained the response (ORR 39%), with 5 CR (28%) and 2 R (11%). At time of data cut-off, 11/26 pts have not completed yet the PO. 15/26 pts were evaluable at the end of the PO: 3 maintained the response (ORR 20%), with 1 CR and 2 R. 12 pts relapsed: 11 during the PTD and 1 during the PO. 17 pts (33%) reported a total of 58 adverse events (AEs), 8 pts (16%) reported a total of 11 grade ≥3 AEs. 4 AEs were considered treatment related, only 1 of them was grade ≥3 (deep vein thrombosis). 2 pts (3.9%) died during the study, for reasons not related to treatment.
Conclusions: These preliminary data confirm the previously reported efficacy of ELT in primary ITP, with an ORR of 69%. Almost 40% of pts maintained the response at the end of PTD, which is slightly higher than expected. These data suggest that the use of ELT at an earlier phase of the disease (ND or P ITP) is a more effective approach and that 6 months of therapy is a sufficient period to think about ELT tapering and discontinuation. Long-term remission was achieved in 20% of pts, but probably this data is biased by the fact that at the time of data cut-off only a small proportion of pts completed the PO, also considering that only 1 pt lost the response during the PO. For pts who don't maintain the response, ELT can still be a steroid-sparing agent used as a bridge to CP or other treatment options. This analysis is too early to define a correlation between the response and immunological parameters (including TPO levels).
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Palandri:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zaja:Amgen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Sandoz: Honoraria.
Clofarabine (CLO) and cyclophosphamide (CY) combinations were tested in late stage refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) with disappointing results and high-grade toxicity. We ...designed a sequential 5-day combination of CLO 40 mg/m
2
/d plus CY 400 mg/m
2
/d as first salvage for Philadelphia-negative ALL patients refractory or relapsed until 24 months from complete remission (CR). Primary endpoint was an overall response rate (ORR) ≥ 40%. Among 26 study patients (median age 40.5 years) ORR was 57.6% (CR with complete n = 8 or incomplete n = 7 hematologic recovery). Despite severe myelotoxicity, no dose-limiting toxicity suggested de-intensification of CLO schedule. With a median follow-up of 17.0 months, median and 1-year overall and disease-free survival were 6.5 months and 28.6%, and 3.7 months and 28.1%, respectively. This association was tolerable and more effective in patients younger than 40 years with B-precursor ALL, longer first CR, not previously transplanted and achieving CR with full hematological recovery.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The activity and safety of a regimen combining lenalidomide with fludarabine and cyclophosphamide (FC) was investigated in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). ...Treatment consisted of six monthly courses of the FC regimen combined with 14 days of lenalidomide given at the starting dose of 2.5 mg during course 1. The maximum tolerated dose of lenalidomide was 5 mg. Forty patients were assessed for response, 66% were IGHV unmutated, 45% showed deletion 11q or 17p. The overall response and complete remission rates were 62.5% and 22.5%, respectively, the median progression-free and overall survival (OS) were 19 and 45 months, respectively. Grade 3-4 granulocytopenia was observed in 65% of cases, severe infections in 7.5%, the lenalidomide-related toxicity was mild. In conclusion, the results of this study demonstrate that low-dose lenalidomide associated with the FC schedule is an effective treatment for R/R patients with CLL, associated with an acceptable safety profile.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
•HD-DXM allows a better initial response than PDN, but less long-lasting over time, useful when a rapid platelet increase is required.•PDN seems to increase long-lasting responses but exhibits a less ...safe profile than HD-DXM.
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A debate exists regarding which type of corticosteroids (standard-dose prednisone PDN or high-dose dexamethasone HD-DXM) is the best first-line treatment for adult patients with newly diagnosed untreated primary immune thrombocytopenia (pITP). An ad hoc study compared PDN with HD-DXM in newly diagnosed untreated patients with pITP (aged ≥18 but ≤80 years, platelet count of ≤20 or >20 but <50 × 109/L, and bleeding score of ≥8). Patients were randomised to receive PDN 1 mg/kg per day from days 0 to 28 (Arm A) or HD-DXM 40 mg per day for 4 days, every 14 days, for 3 consecutive courses (Arm B). Fifty-nine of 113 patients (52.2%) were randomized to Arm A and 54 of 113 (47.8%) to Arm B. In evaluable patients, total initial responses (complete response CR, partial response PR, minimal response MR) were 44 of 56 (78.57%) in Arm A and 46 of 49 (93.88%) in Arm B at days 42 and 46, respectively (P = 0.0284). Total final responses (at day 180 from initial response) were 26 of 43 (60.47%) in Arm A and 23 of 39 (58.97%) in Arm B (P = 0.8907). Total persistent responses (at 12 months from initial response) were 25 of 31 (80.65%) in Arm A and 20 of 36 (55.56%) in Arm B (P = 0.0292). Seven relapses occurred. Median follow-up was 44.4 months. Overall survival was 100% at 48 months, overall disease-free survival was 81.11% at 48 months from day 180. PDN and pulsed HD-DXM were well tolerated; HD-DXM allows effective initial responses but less long lasting than PDN. This trial was registered at www.clinicaltrials.gov as #NCT00657410.
•An improved pegaspargase-modified MRD and risk-oriented regimen was prospectively tested in adults aged 18-65 years with Ph– ALL/LL.•Three-year survival rates were >60% with HCT or chemotherapy, ...further improved by MRD negativity and age ≤40 years.
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Pediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia chromosome–negative acute lymphoblastic leukemia/lymphoma (Ph– ALL/LL). In LAL1913 trial, the Gruppo Italiano Malattie EMatologiche dell’Adulto added pegaspargase 2000 IU/m2 to courses 1, 2, 5, and 6 of an 8-block protocol for patients aged from 18 to 65 years, with dose reductions in patients aged >55 years. Responders were risk stratified for allogeneic hematopoietic cell transplantation (HCT) or maintenance per clinical characteristics and minimal residual disease (MRD). Of 203 study patients (median age, 39.8 years), 91% achieved a complete remission. The 3-year overall survival, event-free, and disease-free survival (DFS) rates were 66.7%, 57.7%, and 63.3%, respectively, fulfilling the primary study end point of a 2-year DFS >55%. Although based on the intention-to-treat, the DFS being 74% and 50% in the chemotherapy (n = 94) and HCT (n = 91) assignment cohorts, respectively, a time-dependent analysis proved the value of HCT in patients who were eligible (DFS HCT 70% vs no HCT 26%; P <.0001). In multivariate analysis, age and MRD were independent factors predicting DFS rates of 86% (age ≤ 40 and MRD-negative), 64%-65% (MRD-positive or age > 40) and 25% (age > 40 and MRD-positive); P < .0001. Grade ≥2 pegaspargase toxicity was mainly observed at course 1, contributing to induction death in 2 patients but was rare thereafter. This program improved outcomes of patients with Ph– ALL/LL aged up to 65 years in a multicenter national setting. This trial was registered at www.clinicaltrials.gov as #NCT02067143.
Clinical diagnosis of IFI is difficult ,due to lack of sensitive and specific diagnostic tools. An assessment of trends concerning the prevalence of IFI is a challenge and postmortem data may be ...useful to monitor the local epidemiology ,the frequency and the disease patterns.
The aim of this retrospective analysis is to determinate the local epidemiology and the prevalence at autopsy of IFI, occurring in hematological malignancies at a single center over a eleven years period.
We have retrospectively reviewed 161 patients – median age 62,5 yrs, range 22 -83 - with hematological malignancies, who underwent autopsy between 2002 -2012. Acute Myeloid Leukemia (AML) were 77, Acute Lymphoid Leukemia (ALL) 11, Lymphoproliferative disorders (LPD) 56 and other disorders 17. Acute leukemia pts received systemic antifungal prophilaxis, whereas the others not absorbable prophilaxis. None patients received transplant procedures. An experienced pathologist evaluated the organ involvement and the IFI pathologic pattern. Fisher's Exact test was used to recognize the IFI prevalence, the main occurring pathogens and the involved site; a p-value of <0.05 was considered statistically significant.
The analysis of 161 consecutive autopsies identified 40 pts.(25%)resulting to have IFI; of these, 22 were AML (55%) ,6 ALL (15%),11LPD (28%) and 1 other. Aspergillus spp. infection was detected in 20 cases (50%), Mucor spp in 8 (20%) and Candida spp. in 12 (30%). Moulds were prevalent in acute leukemia pts. and Aspergillus spp. is the leading pathogen with respect to Candida and Mucor spp. (p 0,0396),with a statistically significant prevalence in ALL (p 0,0186).The site more involved resulted lung (p 0.0002). Whereas the standardized EORTC/MSG criteria applied in vivo were conclusive for IFI in 6 pts ( 15%) only, the postmortem findings revealed fungal infections in further 34 pts (85%).
This analysis confirms that the IFI diagnosis is still an unresolved issue in hematological malignancies. Acute leukemias remain the subset with the higher prevalence of mould infections. As in other largest studies, in our experience Aspergillus spp and lung proved to be the most recurrent pathogen and site of involvement. At now, the diagnostic methods are not still completely able to identify the underlying IFI, thus the autopsy rate should be increased to achieve a better knowledge of epidemiology and to critically review previous misdiagnosis.
No relevant conflicts of interest to declare.
Summary
Mantle cell lymphoma (MCL) is an aggressive neoplasm with a short survival. Cases with leukaemic MCL and splenomegaly without adenopathies (non‐nodal MCL) may have a more indolent course. To ...gain insights into the biological features underlying this presentation, we investigated the gene expression profile (GEP) and the IGHV mutational status in a cohort of leukaemic MCL cases. Comparison of MCL with other lymphoproliferative disorders (i.e. splenic marginal zone lymphoma, follicular lymphoma, chronic lymphocytic leukaemia) revealed a MCL signature enriched for the following gene categories: mitochondrion, oxidoreductase activity, response to stress, to DNA damage and TP53‐pathway. Furthermore, GEP analysis revealed that non‐nodal MCL cases were characterized by the down‐modulation of the following gene categories: cell projection, actin cytoskeleton organization, cell adhesion (ITGAE, CELSR1, PCDH9) and tumour invasion/progression (PGF, ST14, ETS1, OCIAD1, EZR). Many down‐modulated genes were related to the TP53‐pathway and to DNA damage response. IGHV status proved unmutated in all nodal and mutated in all non‐nodal MCL. Non‐nodal leukaemic MCLs display a peculiar clinical presentation, with distinctive biological features, such as mutated IGHV and a transcriptional profile lacking tumour invasion properties, that might contribute to the absence of nodal involvement and to the less aggressive clinical course.
INTRODUCTION: Essential Thrombocytemia (ET) is the most common of the myeloproliferative neoplasms, vascular complications contribute mostly to both morbidity and mortality. The ability to identify ...thrombotic risk of the individual patient is necessary for a correct therapeutic management. Traditionally, risk stratification for thrombosis in ET pts was based on the respective absence and/or presence of either age >60 years or history of thrombosis. Recently, the IPSET score (International Prognostic Score Of Thrombosis for ET) was developed to better predict the occurrence of thrombotic events in ET patients. Risk factors included in the new score were: age, cardiovascular risk factors, previous thrombosis, presence of JAK 2 V617F mutation.
AIM: to evaluate the validity of IPSET-thrombosis score in a cohort of ET patients from "Gruppo Laziale for Myeloproliferative Ph negative Neoplasms" in predicting thrombosis incidence.
METHODS: from January 1978 to December 2011 we observed 1249 ET patients, median follow up was 105 months (range 12.1-417.7). We were able to retrospectively evaluate all the IPSET risk factors in 680 ET patients and estimated the clinical implication of the IPSET-thrombosis score system. According to the score 27.3 %, 19.1% and 53.5% of pts were stratified in low, intermediate and high risk group respectively.
RESULTS: median age at the time of diagnosis was 61.8 yrs (range 19.9 -94; 64% females), median hemoglobin was 14 g/dl (range 6-20); median leukocyte count was 8.8 x 109/L (range 1,2-57); median platelets count was 812x 109/L (range 108-3582). We observed, during a median follow-up of 200 months, 82 thrombotic events (total incidence 17,89 %). According IPSET-thrombosis risk, in our ET population was documented a statistically different thrombosis free survival (TFS) (Gray test 0.1316): 85%, 78%, 77% in low,intermediate and high risk group respectively. During all the observation period the intermediate and high risk group showed a similar probability of thrombotic events.
CONCLUSIONS: in our retrospective study the IPSET score was able to differentiate the rate of thrombosis events in low-risk (0-1 risk factors) from that of intermediate (>= 2 risk factors) and high risk (>= 3 risk factors) ET pts. Unfortunately the intermediate and high risk groups show a similar incidence of thrombotic events during the whole observation period. We were not able to verify the clinical benefit resulting from the different treatment strategies. Because treatment options in ET pts are tailored according to thrombotic risk, and since we have specified therapeutic indications for patients with low and high risk, it is necessary to validate the score IPSET in a large prospective, long term study to discriminate a true "intermediate" subset of patients for which there are no currently defined therapeutic guidelines.
No relevant conflicts of interest to declare.