Publications by authors named "Giuseppe Auteri"

24 Publications

  • Page 1 of 1

Real-world use of thrombopoietin receptor agonists in elderly patients with primary immune thrombocytopenia.

Blood 2021 Apr 22. Epub 2021 Apr 22.

(Institute of Hematology, Bologna, Italy.

The efficacy and safety of thrombopoietin-receptor agonists (TRAs) in elderly patients with primary immune thrombocytopenia (ITP) is uncertain. In 384 ITP patients treated with TRAs when aged ≥60 years, we investigated TRAs response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROT). After 3 months, 82.5% and 74.3% of eltrombopag and romiplostim-treated patients achieved a response, respectively (p=0.09); 66.7% maintained the response (median follow-up: 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; while no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. During TRA, 34 major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, and were associated with thrombosis history (SHR: 2.04, p=0.05) and platelet count <20x109/L at TRA start (SHR: 1.69, p=0.04), respectively. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but one during persisting TRA treatment (incidence rate: 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRA; 53 (13.8%) patients maintained SROT, which was associated with TRA discontinuation in complete response (p<0.001). Very old age (≥75, 41.1%) was associated with more frequent TRAs start in persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in elderly ITP patients, with no fatal haemorrhages and with SROT in a significant portion of patients; in patients with thrombosis history caution is warranted and a careful risk/benefit balance should be carried out.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021010735DOI Listing
April 2021

Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome.

Cancer 2021 Apr 1. Epub 2021 Apr 1.

Unit of Hematology and Clinical Immunology, University of Padua, Padua, Italy.

Background: After ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities.

Methods: The authors performed a subanalysis of an observational, retrospective study (RUX-MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival.

Results: A total of 219 patients (31.2%) discontinued ruxolitinib for ≥14 days and survived for ≥30 days. In 60 patients (27.4%), ruxolitinib was rechallenged for ≥14 days (RUX-again patients), whereas 159 patients (72.6%) discontinued it permanently (RUX-stop patients). The baseline characteristics of the 2 cohorts were comparable, but discontinuation due to a lack/loss of spleen response was lower in RUX-again patients (P = .004). In comparison with the disease status at the first ruxolitinib stop, at its restart, there was a significant increase in patients with large splenomegaly (P < .001) and a high Total Symptom Score (TSS; P < .001). During the rechallenge, 44.6% and 48.3% of the patients had spleen and symptom improvements, respectively, with a significant increase in the number of patients with a TSS reduction (P = .01). Although the use of a ruxolitinib dose > 10 mg twice daily predicted better spleen (P = .05) and symptom improvements (P = .02), the reasons for/duration of ruxolitinib discontinuation and the use of other therapies before rechallenge were not associated with rechallenge efficacy. At 1 and 2 years, 33.3% and 48.3% of RUX-again patients, respectively, had permanently discontinued ruxolitinib. The median overall survival was 27.9 months, and it was significantly longer for RUX-again patients (P = .004).

Conclusions: Ruxolitinib rechallenge was mainly used in intolerant patients; there were clinical improvements and a possible survival advantage in many cases, but there was a substantial rate of permanent discontinuation. Ruxolitinib rechallenge should be balanced against newer therapeutic possibilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33541DOI Listing
April 2021

Eltrombopag second-line therapy in adult patients with primary immune thrombocytopenia in an attempt to achieve sustained remission off-treatment: results of a phase II, multicentre, prospective study.

Br J Haematol 2021 Apr 22;193(2):386-396. Epub 2021 Feb 22.

Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

Up to 30% immune thrombocytopenia (ITP) patients achieve a sustained remission off-treatment (SROT) after discontinuation of thrombopoietin receptor agonists (TPO-RAs). Factors predictive of response are lacking. Patients aged ≥18 years with newly diagnosed or persistent ITP were treated with eltrombopag for 24 weeks. Primary end-point was SROT: the proportion of responders that were able to taper and discontinue eltrombopag maintaining the response during a period of observation (PO) of six months. Secondary end-points included the association between some immunological parameters (TPO serum levels, cytokines and lymphocyte subsets) and response. Fifty-one patients were evaluable. Primary end-point was achieved in 13/51 (25%) treated patients and 13/34 (38%) patients who started the tapering. Baseline TPO levels were not associated with response at week 24 nor with SROT. Higher baseline levels of IL-10, IL-4, TNF-α and osteopontin were negative factors predictive of response (P = 0·001, 0·008, 0·02 and 0·03 respectively). This study confirms that SROT is feasible for a proportion of ITP patients treated with eltrombopag. Some biological parameters were predictive of response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17334DOI Listing
April 2021

Impact of comorbidities and body mass index on the outcome of polycythemia vera patients.

Hematol Oncol 2021 Feb 15. Epub 2021 Feb 15.

IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.

In 816 patients with 2016 World Health Organization-defined polycythemia vera (PV) enrolled in a multicenter retrospective study, we investigated the predictive value of Charlson comorbidity index (CCI) and body mass index (BMI) on thrombosis, progression to post-PV myelofibrosis (PPV-MF) and survival. Patients were subgrouped according to CCI = 0 (58.1%, no comorbidities) or CCI ≥ 1 (41.9%) and according to normal/underweight (BMI < 25, 54.5%) or overweight/obesity (BMI ≥ 25, 45.5%) at PV diagnosis. BMI was available for 529 patients. Patients with CCI ≥ 1 were older and more frequently presented cardiovascular risk factors compared to patients with CCI = 0 (p < 0.001), while overweight/obese patients were more frequently males (p < 0.001). Cumulative incidence of thromboses with death as competing risk was 13.3% at 10 years. Multivariable analysis with death as competing risk showed that previous thromboses (subdistribution hazard ratio [SHR]: 2.1, p = 0.01) and hypertension (SHR: 1.77, p = 0.04) were significantly associated with a higher thrombotic risk, while BMI ≥ 25 lost statistical significance (SHR: 1.69, p = 0.05) and CCI ≥ 1 was excluded after evaluation of goodness of fit. After a median follow-up of 6.1 years, progression to PPV-MF occurred in 44 patients, and 75 patients died. BMI ≥ 25 was associated with a lower probability of progression to PPV-MF (SHR: 0.38, CI95%: 0.15-0.94, p = 0.04) and better survival (hazard ratio [HR]: 0.42, CI95%: 0.18-0.97, p = 0.04). CCI ≥ 1 did not affect progression to PPV-MF (p = 0.44) or survival (p = 0.71).  The evaluation of CCI and BMI may improve the prognostic definition of PV. In patients with hypertension an accurate evaluation of thrombotic risk is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2843DOI Listing
February 2021

Distinct profile of CD34 cells and plasma-derived extracellular vesicles from triple-negative patients with Myelofibrosis reveals potential markers of aggressive disease.

J Exp Clin Cancer Res 2021 Feb 1;40(1):49. Epub 2021 Feb 1.

Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy.

Background: Myelofibrosis (MF) is a clonal disorder of hemopoietic stem/progenitor cells (HSPCs) with high prevalence in elderly patients and mutations in three driver genes (JAK2, MPL, or CALR). Around 10-15% of patients are triple-negative (TN) for the three driver mutations and display significantly worse survival. Circulating extracellular vesicles (EVs) play a role in intercellular signaling and are increased in inflammation and cancer. To identify a biomolecular signature of TN patients, we comparatively evaluated the circulating HSPCs and their functional interplay with the microenvironment focusing on EV analysis.

Methods: Peripheral blood was collected from MF patients (n = 29; JAK2 mutation, n = 23; TN, n = 6) and healthy donors (HD, n = 10). Immunomagnetically isolated CD34 cells were characterized by gene expression profiling analysis (GEP), survival, migration, and clonogenic ability. EVs were purified from platelet-poor plasma by ultracentrifugation, quantified using the Nanosight technology and phenotypically characterized by flow cytometry together with microRNA expression. Migration and survival of CD34 cells from patients were also analyzed after in vitro treatments with selected inflammatory factors, i.e. (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, IL6) or after co-culture with EVs from MF patients/HD.

Results: The absolute numbers of circulating CD34 cells were massively increased in TN patients. We found that TN CD34 cells show in vitro defective functions and are unresponsive to the inflammatory microenvironment. Of note, the plasma levels of crucial inflammatory cytokines are mostly within the normal range in TN patients. Compared to JAK2-mutated patients, the GEP of TN CD34 cells revealed distinct signatures in key pathways such as survival, cell adhesion, and inflammation. Importantly, we observed the presence of mitochondrial components within plasma EVs and a distinct phenotype in TN-derived EVs compared to the JAK2-mutated MF patients and HD counterparts. Notably, TN EVs promoted the survival of TN CD34 cells. Along with a specific microRNA signature, the circulating EVs from TN patients are enriched with miR-361-5p.

Conclusions: Distinct EV-driven signals from the microenvironment are capable to promote the TN malignant hemopoiesis and their further investigation paves the way toward novel therapeutic approaches for rare MF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13046-020-01776-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849077PMC
February 2021

Second primary malignancy in myelofibrosis patients treated with ruxolitinib.

Br J Haematol 2021 Apr 21;193(2):356-368. Epub 2020 Nov 21.

Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, Italy.

Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non-melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real-world context. Median follow-up from starting RUX was 2·9 years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22-4·60, P = 0·01] and thrombocytosis> 400 × 10 /l at RUX start (HR:1·98, 95%CI: 1·10-4·60, P = 0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24-7·92, P = 0·02) and duration of hydroxycarbamide and RUX therapy > 5 years (HR: 3·20, 95%CI: 1·17-8·75, P = 0·02 and HR: 2·93, 95%CI: 1·39-6·17, P = 0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11-5·25, P = 0·03), platelet > 400 × 10 /l (HR: 3·30, 95%CI: 1·67-6·50, P = 0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48-8·14, P = 0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17192DOI Listing
April 2021

Cytogenetic study in primary myelofibrosis at diagnosis: Clinical and histological association and impact on survival according to WHO 2017 classification in an Italian multicenter series.

Hematol Oncol 2021 Feb 4;39(1):123-128. Epub 2020 Oct 4.

Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

We analyzed cytogenetic data at diagnosis in 395 primary myelofibrosis (PMF) patients to evaluate any possible association between karyotype and WHO 2017 classification and its impact on prognosis. All the cases were diagnosed and followed at five Italian Hematological Centers between November 1983 and December 2016. An abnormal karyotype (AK) was found in 69 patients and clustered differently according to bone marrow fibrosis grade as it was found in 31 (27.0%) cases with overt fibrotic and 38 (13.6%) with pre-fibrotic PMF (p = 0.001). Sex, anemia, thrombocytopenia, circulating blasts ≥1%, higher lactate dehydrogenase, and International Prognostic Scoring System risk classes were all significantly associated with karyotype. At a median follow-up of >6 years, 101 deaths were recorded. Survival was different between AK and normal karyotype (NK) patients with an estimated median overall survival (OS) of 11.6 and 25.7 years, respectively (p = 0.0148). In conclusion, in our cohort around 20% of patients had an AK, more frequently in subjects with an advanced bone marrow fibrosis grade and clinical-laboratory features indicative of a more aggressive disease. This study shows that an AK confers a more severe clinical phenotype and impacts adversely on OS, thus representing an additional parameter to be considered in the evaluation of PMF prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2808DOI Listing
February 2021

The role of circulating monocytes and JAK inhibition in the infectious-driven inflammatory response of myelofibrosis.

Oncoimmunology 2020 06 23;9(1):1782575. Epub 2020 Jun 23.

Department of Experimental, Institute of Hematology "L. E A. "Seràgnoli", Diagnostic and Specialty Medicine, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Myelofibrosis (MF) is characterized by chronic inflammation and hyper-activation of the JAK-STAT pathway. Infections are one of the main causes of morbidity/mortality. Therapy with Ruxolitinib (RUX), a JAK1/2 inhibitor, may further increase the infectious risk. Monocytes are critical players in inflammation/immunity through cytokine production and release of bioactive extracellular vesicles. However, the functional behavior of MF monocytes, particularly during RUX therapy, is still unclear. In this study, we found that monocytes from JAK2V617F-mutated MF patients show an altered expression of chemokine (CCR2, CXCR3, CCR5) and cytokine (TNF-α-R, IL10-R, IL1β-R, IL6-R) receptors. Furthermore, their ability to produce and secrete free and extracellular vesicles-linked cytokines (IL1β, TNF-α, IL6, IL10) under lipopolysaccharides (LPS) stimulation is severely impaired. Interestingly, monocytes from RUX-treated patients show normal level of chemokine, IL10, IL1β, and IL6 receptors together with a restored ability to produce intracellular and to secrete extracellular vesicles-linked cytokines after LPS stimulation. Conversely, RUX therapy does not normalize TNF-R1/2 receptors expression and the LPS-driven secretion of free pro/anti-inflammatory cytokines. Accordingly, upon LPS stimulation, RUX treatment of monocytes from MF patients increases their secretion of extracellular vesicles-linked cytokines but inhibits the secretion of free pro/anti-inflammatory cytokines. In conclusion, we demonstrated that in MF the infection-driven response of circulating monocytes is defective. Importantly, RUX promotes their infection-driven cytokine production suggesting that infections following RUX therapy may not be due to monocyte failure. These findings contribute to better interpreting the immune vulnerability of MF and to envisaging strategies to improve the infection-driven immune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1782575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458658PMC
June 2020

Disease-Specific Derangement of Circulating Endocannabinoids and -Acylethanolamines in Myeloproliferative Neoplasms.

Int J Mol Sci 2020 May 11;21(9). Epub 2020 May 11.

Institute of Hematology "L. e A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine (DIMES), School of Medicine, University of Bologna, 40138 Bologna, Italy.

Growing evidence highlights the endocannabinoid (EC) system involvement in cancer progression. Lipid mediators of this system are secreted by hematopoietic cells, including the ECs 2-arachidonoyl-glycerol (2AG) and arachidonoyl-ethanolamide (AEA), the 2AG metabolite 1AG, and members of N-acylethanolamine (NAE) family-palmitoyl-ethanolamide (PEA) and oleoyl-ethanolamide (OEA). However, the relevance of the EC system in myeloproliferative neoplasms (MPN) was never investigated. We explored the EC plasma profile in 55 MPN patients, including myelofibrosis (MF; = 41), polycythemia vera (PV; = 9), and essential thrombocythemia (ET; = 5) subclasses and in 10 healthy controls (HC). AEA, PEA, OEA, 2AG, and 1AG plasma levels were measured by LC-MS/MS. Overall considered, MPN patients displayed similar EC and NAE levels compared to HC. Nonetheless, AEA levels in MPN were directly associated with the platelet count. MF patients showed higher levels of the sum of 2AG and 1AG compared to ET and PV patients, higher OEA/AEA ratios compared to HC and ET patients, and higher OEA/PEA ratios compared to HC. Furthermore, the sum of 2AG and 1AG positively correlated with variant allele frequency and splenomegaly in MF and was elevated in high-risk PV patients compared to in low-risk PV patients. In conclusion, our work revealed specific alterations of ECs and NAE plasma profile in MPN subclasses and potentially relevant associations with disease severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21093399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246996PMC
May 2020

Risk factors for progression to blast phase and outcome in 589 patients with myelofibrosis treated with ruxolitinib: Real-world data.

Hematol Oncol 2020 Aug 20;38(3):372-380. Epub 2020 Apr 20.

Department of Scienze Mediche, Chirurgiche e Tecnologie Avanzate "G.F. Ingrassia", University of Catania, Catania, Italy.

The impact of ruxolitinib therapy on evolution to blast phase (BP) in patients with myelofibrosis (MF) is still uncertain. In 589 MF patients treated with ruxolitinib, we investigated incidence and risk factors for BP and we described outcome according to disease characteristics and treatment strategy. After a median follow-up from ruxolitinib start of 3 years (range 0.1-7.6), 65 (11%) patients transformed to BP during (93.8%) or after treatment. BP incidence rate was 3.7 per 100 patient-years, comparably in primary and secondary MF (PMF/SMF) but significantly lower in intermediate-1 risk patients (2.3 vs 5.6 per 100 patient-years in intermediate-2/high-risk patients, P < .001). In PMF and SMF cohorts, previous interferon therapy seemed to correlate with a lower probability of BP (HR 0.13, P = .001 and HR 0.22, P = .02, respectively). In SMF, also platelet count <150 × 10 /l (HR 2.4, P = .03) and peripheral blasts ≥3% (HR 3.3, P = .004) were significantly associated with higher risk of BP. High-risk category according to dynamic International Prognostic Score System (DIPSS) and myelofibrosis secondary to PV and ET Collaboration Prognostic Model (MYSEC-PM predicted BP in patients with PMF and SMF, respectively. Median survival after BP was 0.2 (95% CI: 0.1-0.3) years. Therapy for BP included hypomethylating agents (12.3%), induction chemotherapy (9.2%), allogeneic transplant (6.2%) or supportive care (72.3%). Patients treated with supportive therapy had a median survival of 6 weeks, while 73% of the few transplanted patients were alive at a median follow-up of 2 years. Progression to BP occurs in a significant fraction of ruxolitinib-treated patients and is associated with DIPSS and MYSEC-PM risk in PMF and SMF, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2737DOI Listing
August 2020

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis.

Cancer 2020 03 20;126(6):1243-1252. Epub 2019 Dec 20.

Unit of Hematology and Clinical Immunology, University of Padua, Padua, Italy.

Background: After discontinuing ruxolitinib, the outcome of patients with myelofibrosis reportedly has been poor. The authors investigated whether disease characteristics before the receipt of ruxolitinib may predict drug discontinuation in patients with myelofibrosis and whether reasons for drug discontinuation, disease phase at discontinuation, and salvage therapies may influence the outcome.

Methods: A centralized electronic clinical database was created in 20 European hematology centers, including clinical and laboratory data for 524 patients who received ruxolitinib for myelofibrosis.

Results: At 3 years, 40.8% of patients had stopped ruxolitinib. Baseline predictors of drug discontinuation were: intermediate-2-risk/high-risk category (Dynamic International Prognostic Score System), a platelet count <100 ×10 per liter, transfusion dependency, and unfavorable karyotype. At last contact, 268 patients (51.1%) had discontinued therapy, and the median drug exposure was 17.5 months. Fifty patients (18.7%) died while taking ruxolitinib. The reasons for discontinuation in the remaining 218 patients were the lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib-related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib-unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%). The median survival after ruxolitinib was 13.2 months and was significantly better in the 167 patients who discontinued ruxolitinib in chronic phase (27.5 vs 3.9 months for those who discontinued in blast phase; P < .001). No survival differences were observed among patients who discontinued ruxolitinib in chronic phase because of lack of response, loss of response, or ruxolitinib-related adverse events. The use of investigational agents and/or ruxolitinib rechallenge were associated with improved outcome.

Conclusions: The survival of patients with myelofibrosis after discontinuation of ruxolitinib is poor, particularly for those who discontinue in blast phase. Salvage therapies can improve outcome, emphasizing the need for novel therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32664DOI Listing
March 2020

Management of elderly patients with immune thrombocytopenia: Real-world evidence from 451 patients older than 60 years.

Thromb Res 2020 01 21;185:88-95. Epub 2019 Nov 21.

Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

Introduction: Primary Immune thrombocytopenia (ITP) in the elderly is a major clinical challenge which is increasingly frequent due to global ageing population.

Materials And Methods: To describe baseline ITP features, management, and outcome, a centralized electronic database was established, including data of 451 patients aged ≥60 years that were treated from 2000 onwards and were observed for ≥1 year (total observation of 2704 patient-years).

Results: At ITP diagnosis, median age was 71.1 years (age ≥ 75: 42.8%); 237 (53.9%) patients presented with haemorrhages (grade ≥ 3: 7.5%). First-line therapy included prednisone (82.9%), dexamethasone (14.6%), thrombopoietin-receptor agonists (TRAs, 1.3%), and oral immunosuppressive agents (1.1%). Prednisone starting dose ≥1 mg/kg/d (p = .01) and dexamethasone 40 mg/d (p < .001) were mainly reserved to patients aged 60-74, who were more treated with rituximab (RTX, p = .02) and splenectomy (p = .03) second-line. Overall response rates to first and second-line therapies were 83.8% and 84.5%, respectively, regardless of age and treatment type/dose. A total of 178 haemorrhages in 101 patients (grade ≥ 3: n. 52, 29.2%; intracranial in 6 patients), 49 thromboses in 43 patients (grade ≥ 3: n. 26, 53.1%) and 115 infections in 94 patients (grade ≥ 3: n. 23, 20%) were observed during follow-up. Incidence rates of complications per 100 patient-years were: 4.5 (haemorrhages, grade ≥ 3: 1.7), 1.7 (thromboses, grade ≥ 3: 0.9), and 3.9 (infections, grade ≥ 3: 0.7). TRAs use were associated with reduced risk of bleeding and infections, while cardiovascular risk factors (particularly, diabetes) significantly predicted thromboses and infections.

Conclusions: Age-adapted treatment strategies are required in elderly and very elderly patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2019.11.026DOI Listing
January 2020

Integrating clinical, morphological, and molecular data to assess prognosis in patients with primary myelofibrosis at diagnosis: A practical approach.

Hematol Oncol 2019 Oct 22;37(4):424-433. Epub 2019 Aug 22.

Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, and Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Currently available prognostic scoring systems in primary myelofibrosis (PMF) do not integrate clinical, histological, and molecular data, or they also required information on "other" mutations that are available in the clinical practice only in a very limited number of laboratories. In the present multicenter study, including 401 PMF patients, an integrated International Prognostic Scoring System (I-IPSS) was developed by combining IPSS, grade of bone marrow fibrosis (GBMF), and driver mutations molecular status (MS) to define PMF prognosis at diagnosis. Four prognostic categories were identified: I-IPSS-low risk (113 patients), I-IPSS-intermediate-1 risk (56 patients), I-IPSS-intermediate-2 risk (154 patients), and I-IPSS-high risk (78 patients). Median overall survival was 26.7 years in I-IPSS-intermediate-1, 10.8 in I-IPSS-intermediate-2, and 6.4 in I-IPSS-high-risk patients (log-rank test <0.0001); instead, it was not reached in the I-IPSS-low-risk cohort because of the extremely low number of registered deaths. The addition of GBMF and MS to IPSS improved the efficacy for predicting the risk of death. Indeed, the sensitivity of I-IPSS was significantly higher (P < .05) than that of IPSS, considering both total deaths and 5- and 10-year mortality. This comprehensive approach allows clinicians to evaluate mutual interactions between IPSS, GBMF, and MS and identify high-risk patients with poor prognosis who may benefit from aggressive treatments. More importantly, this integrated score can be easily applicable worldwide as it only required information that represent the good clinical practice in the management of PMF patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2658DOI Listing
October 2019

Impact of 2016 WHO diagnosis of early and overt primary myelofibrosis on presentation and outcome of 232 patients treated with ruxolitinib.

Hematol Oncol 2019 Oct 7;37(4):418-423. Epub 2019 Jun 7.

Division of Cellular Biotechnologies and Hematology, University Sapienza, Rome, Italy.

The 2016 WHO criteria identified early primary myelofibrosis (PMF) as an individual entity with milder clinical features and better outcome compared with overt PMF. Here, we compared early and overt PMF patients treated with ruxolitinib in terms of baseline clinical/laboratory characteristics, response, and toxicity to treatment. We observed that early-PMF patients achieve better and more stable spleen and symptoms responses, with significantly lower rates of hematological toxicities. No differences in overall and leukemia-free survival were detected between the two cohorts. The application of 2016 WHO criteria is crucial to identify those PMF patients who deserve a stricter monitoring during treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2619DOI Listing
October 2019

Differences in presenting features, outcome and prognostic models in patients with primary myelofibrosis and post-polycythemia vera and/or post-essential thrombocythemia myelofibrosis treated with ruxolitinib. New perspective of the MYSEC-PM in a large multicenter study.

Semin Hematol 2018 10 5;55(4):248-255. Epub 2018 Jun 5.

Unit of Hematology and Clinical Immunology, University of Padova, Padova, Italy.

Recently, the myelofibrosis secondary to PV and ET prognostic model (MYSEC-PM) was introduced to assess prognosis in myelofibrosis (MF) secondary to polycythemia vera and essential thrombocythemia (post-PV and post-ET MF), replacing the International Prognostic Scoring System (IPSS) and/or Dynamic IPSS (DIPSS) that was applied for primary MF (PMF). In a cohort of 421 ruxolitinib (RUX)-treated patients (post-PV and post-ET MF: 44.2%), we evaluated the following: (1) disease phenotype, responses, and toxicity to RUX; and (2) performance of the MYSEC-PM in post-PV or post-ET MF. While the IPSS failed to correctly stratify post-PV or post-ET MF patients at diagnosis, the MYSEC-PM identified 4 risk categories projected at significantly different survival probability (P < .001). Additionally, the MYSEC-PM maintained a prognostic value in post-PV and post-ET MF also when used over time, at RUX start. Notably, the MYSEC-PM reclassified 41.8% and 13.6% of patients into a lower and higher risk category, respectively. Finally, patients at intermediate-1 risk had significantly higher spleen responses and lower hematological toxicities compared to higher risk patients. Compared to PMF, post-PV and post-ET MF presented a more hyperproliferative disease, with higher leukocyte and/or platelet count and hemoglobin levels both at diagnosis and at RUX start. Despite comparable response rates, post-PV and post-ET MF had lower rate of RUX-induced anemia and thrombocytopenia at 3 and 6 months. The study validates MYSEC-PM in post-PV and post-ET MF prognostication. Post-PV or post-ET MF represents a separate entity compared to PMF in terms of clinical manifestations and toxicity to RUX.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.seminhematol.2018.05.013DOI Listing
October 2018

Impact of comorbidities and body mass index in patients with myelofibrosis treated with ruxolitinib.

Ann Hematol 2019 Apr 4;98(4):889-896. Epub 2018 Dec 4.

Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

Comorbidities defined by the Charlson comorbidity index (CCI) and body mass index (BMI) are significantly associated with outcome in patients who receive continuous treatment with tyrosine kinase inhibitors. We evaluated the impact of CCI and BMI on responses, drug-related toxicities, and outcome in a cohort of 402 patients with myelofibrosis (MF) treated with ruxolitinib in 23 European Hematology Centers. Comorbidities were evaluable in all 402 patients. A higher (≥ 3) CCI did not correlate with a lower spleen reduction at any time (p = 0.68) or symptoms' response (p = 0.11), but influenced the onset of anemia during the first 3 months of treatment and later (p = 0.02 and p = 0.03, respectively) in patients without anemia baseline. BMI was evaluable in 380 patients and did not correlate with differences in spleen and symptoms response (p = 0.57 and p = 0.49, respectively). A higher CCI and a lower BMI correlated also with a reduced overall survival (p < 0.001 and p = 0.02, respectively). The achievement of a spleen response at 6 months could counterbalance the negative impact of comorbidities, while patients who were underweight when starting ruxolitinib and did not achieve a spleen response at 6 months were projected to the worse outcome. In MF patients treated with ruxolitinib, BMI and comorbidities did not influence the achievement of spleen/symptom responses, but they contributed to the early identification of patients who deserve a strict monitoring during treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-018-3569-1DOI Listing
April 2019

Understanding how older age drives decision-making and outcome in Immune Thrombocytopenia. A single centre study on 465 adult patients.

Br J Haematol 2019 02 8;184(3):424-430. Epub 2018 Nov 8.

Institute of Haematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

We analysed the impact of older age on the management of immune thrombocytopenia (ITP) in 465 adult patients diagnosed between 1995 and 2017 and followed at our institution for a minimum of 12 months. Over a follow-up of 4248 patient-years, front-line corticosteroids therapy was required in 334 patients (71·8%), mainly (85·3%) within 1 year from diagnosis. Need for first-, second- and third-line therapy was comparable in younger and older (age ≥65 years, n = 154) patients. Older patients presented more frequently with severe haemorrhages, started therapy with a higher platelet count and received lower dose front-line corticosteroids; thereafter, they were preferentially treated with mild immunosuppressive therapies/thrombopoietin-receptor agonists. Conversely, younger patients were more frequently treated with rituximab and splenectomy, achieving higher rates of complete responses. Incidence rates of ≥grade 2 complications were: 2·87 (haemorrhages), 1·55 (infections) and 0·66 (thromboses) per 100 patient-years. Older age (P = 0·01) and active haemorrhages at diagnosis (P = 0·01) significantly predicted grade ≥2 haemorrhages during follow-up. Older age (P = 0·01), male gender (P = 0·01), and thrombopoietin receptor agonist use (P = 0·02) were significantly associated with a higher probability of thrombosis over time. Older age is a significant driver of diagnostic/therapeutic strategy in ITP resulting in different responses and complications rates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15668DOI Listing
February 2019

Mobilized Peripheral Blood versus Cord Blood: Insight into the Distinct Role of Proinflammatory Cytokines on Survival, Clonogenic Ability, and Migration of CD34 Cells.

Mediators Inflamm 2018 4;2018:5974613. Epub 2018 Jul 4.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Inflammation may play a role in cancer. However, the contribution of cytokine-mediated crosstalk between normal hemopoietic stem/progenitor cells (HSPCs) and their (inflammatory) microenvironment is largely elusive. Here we compared survival, phenotype, and function of neonatal (umbilical cord blood (CB)) and adult (normal G-CSF-mobilized peripheral blood (mPB)) CD34 cells after exposure to combined crucial inflammatory factors such as interleukin- (IL-) 1, IL-6, tumor necrosis factor- (TNF-) , or tissue inhibitor of metalloproteinases-1 (TIMP-1). To mimic bone marrow (BM) niche, coculture experiments with normal BM stromal cells (BMSCs) were also performed. We found that combined inflammatory cytokines increased only the survival of CB-derived CD34 cells by reducing apoptosis. Conversely, selected combinations of inflammatory cytokines (IL-1 + TNF-, IL-6 + TNF-, and IL-1 + TNF- + TIMP-1) mainly enhanced the CXCR4-driven migration of mPB-derived CD34 cells. TNF-, alone or in combination, upregulated CD44 and CD13 expression in both sources. Finally, BMSCs alone increased survival/migration of CB- and mPB-derived CD34 cells at the same extent of the combined inflammatory cytokines; importantly, their copresence did not show additive/synergistic effect. Taken together, these data indicate that combined proinflammatory stimuli promote distinct functional activation of neonatal or adult normal HSPCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/5974613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079419PMC
December 2018

New strategies in myelofibrosis: the evolving paradigm of disease pathogenesis, prognostication and treatment.

Hematol Oncol 2017 Jun 10;35(2):145-150. Epub 2016 Aug 10.

Department of Hematology and Oncology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy.

Myelofibrosis (MF) is the most severe among the classical Philadelphia-negative myeloproliferative neoplasms that also include essential thrombocytemia and polycythemia vera. Myelofibrosis is characterized by numerous genetic lesions, often variously associated with each other, and by an aggressive clinical phenotype leading to severely reduced survival. Also, the inflammatory microenvironment plays a key role in disease initiation and progression. Because of the complexity of its pathogenesis and the variability of clinical features, MF is a disease that requires a personalized approach and remains orphan of curative treatments besides allogeneic transplantation. JAK2 inhibitors have marked a remarkable progress, because they alleviate systemic symptoms and reduce splenomegaly but have a limited effect on survival, on mutation load, and on marrow fibrosis. Here, we review the main contributing factors to MF pathogenesis and prognosis, focusing on how these factors relate to therapeutic choices. We discuss results from ongoing studies of JAK2 inhibitors and report on new therapeutic strategies that proved effective in early preclinical and clinical trials, including combination treatments, antifibrotic agents, and telomerase inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2324DOI Listing
June 2017