Background:
Severe thrombocytopenia is an uncommon event in lower risk MDS patients, but it may significantly influence the prognosis. In fact, when it occurs, major bleeding may be a ...life-threatening complication. No licensed pharmacologic approach is nowadays available yet for these patients. Eltrombopag seems to be a very interesting product, but its efficacy and safeness are still to be better demonstrated. Romiplostim could be suitable too, but, at present, its safety is uncertain in MDS patients. Also danazol, an attenuated androgen, seems to have some ability to increase the platelet count in this context.
Patients and methods:
We retrospectively reviewed 17 thrombocytopenic patients affected by MDS, treated with danazol and observed for at least 6 months. Three patients of these had a therapy-related MDS. At the starting time of danazol therapy, the IPSS was “low” or “intermediate-1” in 16 cases; “intermediate-2” in 1 case. The IPSS-R was “very low”, “low” or “intermediate” in 16 cases; “very high” in 1 case. In 14 patients the platelet count was lower than 25x109/L, in the other 3 lower than 40x109/L, but with spontaneous bleeding. The initial dose was 600 mg/day for all the patients. The IWG criteria of response (Cheson 2006) were adopted. The outcomes were observed after 3 and 6 months from the beginning of therapy. Only descriptive statistical analysis was used.
Results:
At the beginning of therapy, the average platelet count of the 17 patients was 22.6 x109/L (S.D. 8.8, range 6-38). After 3 months, the therapy with danazol was ongoing in 16 patients (in 1 case the drug was discontinued due to renal failure). Platelet improvement, according to IWG criteria, was observed in 8 cases (47%). The average platelet count was 45.3x109/L (S.D. 32.9, range 4-133). The only one “high risk” patient did not show response. After 6 months danazol was still ongoing in 11 patients (in 5 cases the drug was stopped for inefficacy). The response according to IWG criteria was evident in 9 patients (52% of the initial 17 patients). The average platelet count was 66x109/L (S.D. 63.9, range 11-218). Adverse events recorded were as follows: increase in transaminases in 3 cases (in 2 of these the dose was reduced to 400 mg/day); severe but reversible renal failure in 1 case (the drug was stopped); moderate increasing of serum creatinine in 1 case (the drug was reduced to 400 mg/day); reversible cutaneous rush (the drug was reduced to 400mg/day); amenorrhea in 1 case (the only fertile woman in the series); weight loss and loss of appetite in 1 case, weight gain in 1 case.
Conclusions
This series confirms the efficacy of danazol to improve platelet count in approximately half of patients with severe thrombocytopenia due to “low-risk” MDS. In all patients with increased platelet count, the response was clinically significant. The response may not be immediate. Actually, there was an improvement of platelet count even after three months of therapy. The toxicity profile of this drug is low. The mechanism of action of danazol in MDS patients remains unclear. Waiting for more information on the efficacy and safety of eltrombopag from the clinical trials in progress, danazol may be a good therapeutic option for these patients.
Off Label Use: Danazol in MDS patients with severe trhombocytopenia.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
In recent years the management of patients (pts) with chronic lymphocytic leukemia (CLL) has benefited from a deeper knowledge of the mechanisms underlying the disease and from the development of ...novel therapeutic approaches. That notwithstanding, local and national accessibility to drugs and tests may lead to distinct “real-world” practices in terms of management of pts that are worth of being recorded and compared to understand the degree of reproducibility and applicability of international guidelines. This could also be relevant for the design of future clinical trials, more tailored to the true patient's needs. To this end, within the GIMEMA cooperative study group the observational retrospective and prospective CLL2121 study (NCT04867915) has been designed with the objective of evaluating the diagnosis and management of CLL in all hematological centers in Italy through the assessment of: 1) the methods and the actual diagnostic/prognostic work-up capacity; 2) the algorithms applied to define disease progression and treatment requirements with respect to national and international guidelines; 3) the clinical and biological variables not strictly associated with CLL, but capable of influencing the clinical course and overall survival; 4) the true incidence of some rarer complications associated with CLL. The study consists of a collection of clinico-biological data from all pts with newly diagnosed CLL, small lymphocytic lymphoma (SLL) or CLL-like monoclonal B-cell lymphocytosis (MBL), according to the iwCLL 2018 criteria in Italy. The retrospective part aims at including all cases followed at the participating centers with a diagnosis between January 2010 and September 2021, while the prospective part will include all pts with a documented diagnosis of CLL, SLL or MBL between September 2021 and September 2025. In this pilot analysis of the study, we examined pts' demographics, diagnosis, treatment line and type. Data were collected using the REDCap electronic data capture platform, analyzed using the SAS software v.9.4 and reported as numbers and frequencies. Between 2 November 2021 and 28 June 2023, 3294 eligible pts were enrolled in 75 hematology centers (out of the total of 110 centers who will be activated during the study) across the entire Italian territory. At the time of the present report, 3033 pts had clinical data available for our preliminary analysis. The vast majority of pts registered (N=2599, 85.7%) belonged to the retrospective cohort while only a minority (N=434, 14.3%) to the prospective cohort. Pts had a median age of 68 years ranging from 29 to 97; 60% of pts were males. 2630 pts (86.8%) had a diagnosis of CLL, 187 (6.2%) of SLL and 214 (7.0%) of MBL (2 missing information). Among those with available results 112 pts (12.6%) were TP53 mutated, 526 (45.6%) del(13q) positive, 174 (14.9%) del(11q) positive, 142 (11.9%) del(17p) positive and 226 (20.4%) presented a trisomy 12. The majority of pts (57.6%) were untreated, while 42.4% have been treated. Within the latter subset, 67.3% of pts have received one line of therapy, 21.4% 2 lines of therapy, 11.3% ≥3 lines of therapy. The most common therapeutic regimens were the combination of chemotherapy with an anti-CD20 antibody (39.3%), mainly rituximab, and those based on BTK inhibitors (33.3%), mainly ibrutinib. Chemotherapy alone was used in 12% of pts. Only 5% of pts was treated with the BCL2 inhibitor venetoclax. In the remaining 10% of pts, other approaches were used. This is the initial report of a nation-based real-world data collection aimed at describing the biological and clinical features of pts diagnosed with CLL in virtually all Italian hematology centers starting from 2010. The pattern of treatments highlighted in our preliminary analysis, with a wide use of the watch & wait policy and of chemoimmunotherapy, will help understand how the introduction of novel therapies impacted treatment habits also in light of the timing of the local reimbursement policy. The different time of drug access in Italy, typically delayed after the EU approval, may also have affected the limited use of venetoclax-based treatment. The continuous accrual of pts in this study will allow to obtain a close-to-registry vision of CLL management in Italy over time, in terms of coverage of the entire country but enriched with the granularity of the data and flexibility of the collection typical of a real-world study.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Background
The p53 protein is an onco-suppressor protein encoded by the TP53 gene, which is mutated in 5-10% of cases of de novo myelodysplastic syndromes (MDS). In 75% of cases TP53 mutations lead ...to store the p53 protein within the nucleus of the neoplastic cells. TP53 mutations were shown to have an unfavorable prognostic impact in patients with MDS. The immunohistochemical (IHC) expression of p53 in bone marrow (BM) biopsy has in itself negative impact on prognosis in low risk MDS, especially in MDS with isolated del(5q) category. However, the p53 cut-off value related to prognosis has not been established with accuracy, ranging between 1 and 5% in different reports. Moreover, no data are available on the possible prognostic impact of p53 BM expression and cut-off levels in patients with higher risk MDS.
Aim
To evaluate the prognostic value of IHC expression of p53in BM biopsies from patients with intermediate, high and very high R-IPSS risk MDS
Methods
BM biopsies performed at diagnosis in patients with intermediate, high and very high R-IPSS risk MDS with a follow up of at least three years were revised and screened for IHC p53 expression. Percentage of p53 expression was evaluated by two independent pathologists (L.B.; M.T.), and related to patient survival. Only cells with strong p53 staining were counted as positive. The statistical evaluations were carried out with the logistic analysis and the influence of p53 expression on survival was analyzed by Cox regression. A ROC analysis was carried out using theYouden method to analyze the optimal cut-off value influencing the survival. The verification was performed with the positive and negative predictive values (respectively PPV and NPV), the sensibility and the specificity with their respective 95% confidence intervals (95%CI). Survivorships were estimated with the Kaplan-Meier product limit method, followed by the logrank test, and by the Cox proportional-hazard regression. The association among categorical variables was evaluated by Fisher exact test.
Results
A total of 60 BM biopsies performed at MDS diagnosis were screened for p53 expression. Themedian age of these 60 patients was 67 years (range 19 - 82). Diagnoses, according to WHO, were RCMD in 26/60 (43.3%) cases; RAEB1 in 21/60 (35%) cases; RAEB2 in 13/60 (21.7%) cases. The IPSS-R was intermediate in 43 (71.7%) cases; high in 9 (15%) cases and very high in 8 (13.3%) cases. Cytogenetic risk according to the IPSS-R stratification was: very low in 1(1.6%) case; low in 30 (50%) cases; intermediate in 10 (16.7%) cases; high in 12 (20%) cases; very high in 7 (11.7%) cases. Median overall survival was 41 months. The p53 expression was: < 1% in 39 cases (65.0%), 1% in 5 cases (8.3%), 2% in 6 cases (10.0%), 3% in 2 cases (3.3%), 5% in 3 cases (5.0%),at least 10% in 5 cases (8.3%). Upon analysis, a significant association between percentage of p53 expression and patient survival was found (p=0.013; Hazard Ratio 1.067; 95%CI: 1.014 - 1.124). A cut-off value of 10% p53 expression was associated with outcome (specificity 100%; sensibility 13.5%;PPV 100%; NPV 41.8%). Specifically, as shown in figure 1, a significantly better overall survival was observed in the 55 (91.7%) patients whose BM p53 expression was < 10% compared to the 5 (8.3 %) patients with a BM p53 expression at least 10% (p=0.0038). No association was found between either BM blast countor BM grade of fibrosis and p53 expression.A significant association between the cytogenetic risk according to R-IPSS stratification and the expression of p53was instead found: any single unitary arbitrary increase in the cytogenetic risk score rises by 1600% the odds of a BM p53 expression at least 10% (p=0.015).
Conclusion
In our study population we confirm the unfavorable prognostic significance of BM p53 expression in higher risk MDS patients. Contrary to the reported cut-off values of p53 expression in low risk MDS, in our cohort of higher risk MDS the levels related to prognosis were greater (10% compared with 1 to 5% according to different reports). A tentative explanation for this difference may be that factors other than p53 expression strongly impact on survival in patients with higher risk MDS. Thus the negative prognostic value of p53 only emerges at higher levels of expression. The association between p53 expression and the IPSS-R cytogenetic risk score, if confirmed on a larger cohort, should be evaluated in specific biologic investigations.
Display omitted
No relevant conflicts of interest to declare.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
Purpose
mTOR inhibitor everolimus is used for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC). No reliable predictive biomarker of response is available. Following ...evidences from other solid tumors, we aimed to assess the association between treatment-associated immune system features and everolimus activity.
Methods
We retrospectively explored a correlation with the therapeutic activity of everolimus and tumor-associated immune pathways with ingenuity pathway analysis (IPA), neutrophil-to-lymphocyte ratio (NLR), circulating lymphocytes, and endothelial cells (CECs) in 3 different HR+ mBC studies, including the BALLET phase IIIb study.
Results
The circulating levels of CD3
+
/CD8
+
, CD3
+
/CD4
+
, and overall T lymphocytes were higher in responders versus non-responders at baseline (
p
= 0.017,
p
< 0.001,
p
= 0.034) and after treatment (
p
= 0.01,
p
= 0.003,
p
= 0.023). Reduced CECs, a tumor neoangiogenesis marker, were observed in responders after treatment (
p
< 0.001). Patients with low NLR (≤ 4.4) showed a better progression-free survival compared to patients with high NLR (> 4.4) (
p
= 0.01). IPA showed that the majority of immunity-related genes were found upregulated in responders compared to non-responders before treatment, but not after.
Conclusions
Lymphocytes subpopulations, CECs and NLR could be interesting biomarkers predictive of response to everolimus-based regimens, potentially useful in daily clinical practice to select/monitor everolimus-based treatment in mBC. Further studies to confirm such hypotheses are warranted.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction: Erythropoietin stimulating agents (ESAs) are first-line therapy for International Prognostic Scoring System (IPSS)-low risk myelodysplastic syndrome (MDS) when symptomatic anaemia (Hb ...<10 g/dl) is associated with serum erythropoietin (EPO) <500 mU/mL. Treatment response rate, according to international working group (IWG) response criteria (1- 5), ranges from 40 to 60%.
Attempts have been made to build prognostic scores (integrating transfusion need, erythropoietin level, R-IPSS and ferritin) able to predict response to ESAs (6-7). No data concerning the predictive value of morphological and immunohistochemical analysis on bone marrow biopsy in low risk MDS patients are emerged till now.
Methods: We retrospectively examined 96 IPSS low/int-1 MDS patients treated with ESAs in order to evaluate the morphological and immunohistochemical features of the bone marrow biopsies performed at baseline.
All the patients had hemoglobin (Hb) ≤10 g/dL and serum EPO <500 mU/mL and received EPO alfa or β 40 000-80 000 IU/week for at least 12 weeks. Response to ESAs treatment was evaluated according to IWG 2006 criteria.
A detailed analysis of the morphological features (including quantitative and qualitative changes in the erythroid, myeloid and megakariopoyetic lineages) was performed, together with an immunohistochemical evaluation of p53 expression and CD34-positive blasts percentage.
Results: Sixty-eight percent of the patients were classified as responder while 32% as non-responder. The morphologic profiles of the responder and non-responder did not differ significantly.
A significant correlation was found between the response to the therapy and a percentage of CD34-positive blasts > 3% (univariate analysis: p= .0211).
Moreover p53 expression in less than 1% of the nucleated cells correlated with the treatment response (univariate analysis: p = .0086). These results were also confirmed on multivariate analysis (p= .002).
Fifty-eight percent of patients maintained response to ESAs for the entire duration of the follow up while 42% lost the response (median follow up: 35 months). More than 3% CD34-positive blasts was associated with a higher probability to lose the response to ESAs (p = .00003).
Kaplan-Meier method was than applied to estimate the response duration. Patients with more than 3% CD34-positive blasts showed earlier loss of response in comparison with those with a lower percentage of blasts (p value= .0003; HR=3.9, IC 95% 1.8154-8.6238).
Finally, the expression of p53 in more than ≥ 1% of the nucleated cells correlated with the loss of response before 24 mounts (p value= 0.029).
Conclusions: Our study identifies 2 well-known parameters that could be useful to better predict outcome of ESAs therapy in low risk MDS patients. Therefore role of bone marrow biopsy together with its diagnostic contribution in the clinical evaluation of MDS patients (cellularity, morphologic dysplasia, percentage of CD34-positive blasts, grading of bone marrow fibrosis) could be helpful as a predictive tool in ESAs candidate patients. Further studies based on larger series of patients are needed to confirm these preliminary results.
Reda:Gilead: Consultancy; ABBVIE: Consultancy; Janssen and Cilag: Consultancy; Celgene: Consultancy. Riva:Jannsen and Cilag: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Molteni:Janssen and Cilag: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy; AMGEN: Consultancy. Cortelezzi:abbvie: Consultancy; novartis: Consultancy; roche: Consultancy; janssen: Consultancy.
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IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
The improvement in supportive care and the introduction of new therapeutic agents, including lenalidomide and hypomethylating agents, in myelodysplastic syndromes have improved patients’ outcomes; ...however, at the same time, the frequency and epidemiology of infections have changed. Therefore, the great strides in the indications and use of new treatment strategies for myelodysplastic syndromes need a parallel progress in the best approach to prophylaxis and supportive therapy for infections. Based on the recognition that the above issues represent an unmet clinical need in myelodysplastic syndromes, an Italian expert panel performed a review of the literature and composed a framework of the best recommendations for optimal infection control in patient candidates to receive active treatment for myelodysplastic syndromes. In this consensus document we report the outcomes of that review and of the consensus meetings held during 2017. The issues tackled in the project dealt with: information to be collected from candidates for active treatment for myelodysplastic syndromes; how to monitor the risk of infection; antimicrobial prophylaxis; the role of iron chelation and antiviral/antibacterial vaccinations. For each of these issues, practice recommendations are provided.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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