Background Chronic myelomonocytic leukemia (CMML) is an ultrarare stem cell disorder defined by the presence of monocytosis (≥1.0 G/l, ≥10%). Depending on white blood cell (WBC) count, CMML can be divided into a myelodysplastic (MD) (WBC ≤13 G/l) and a myeloproliferative (MP) variant (WBC >13 G/l). Although hypomethylating agents (HMA) have been shown to prolong overall survival (OS) in MDS patients (pts) in prospective, randomized phase III trials, only 6-14 MD-CMML pts were included, and MP-CMML pts were excluded [Silverman 2002; Kantarjian 2006; Fenaux 2009]. EMA approval of azacitidine (AZA) in CMML is thus based on limited experience and restricted to MD-CMML with 10-29% bone marrow blasts (BMB), whereas decitabine (DAC) is not approved for treatment (trt) of CMML in the EU. Smaller analyses and single-arm trials of HMA in CMML exist [Wijermans 2008; Ades 2013; Pleyer 2014; Zeidan 2017; Duchmann 2018; Santini 2018; Coston 2019; Diamantopoulos 2019], but it is still unclear whether HMA provide a benefit in CMML (subgroups) compared with other trts. Aim Evaluate the impact of HMA and hydroxyurea (HU) trt on OS and time to next trt (TTNT). Methods Data were collected from 7 European study groups and 2 US MDS Centers of Excellence; database lock 27.05.19; Assign Data Management and Biostatistics GmbH performed statistical analyses with SAS® 9.3. Of 1657 CMML pts, only those who received trt (n=950), with documented WBC and BMB at 1st line, were included in these analyses (n=845, cohort 1). Pts were stratified according to the EMA approved AZA indication, and inclusion/exclusion criteria of the GFM-DAC-CMML trial assessing DAC +/- HU vs HU (NCT02214407) (diagnosis of CMML, no prior trt [except supportive care, erythropoietin or ≤6 weeks HU], WBC ≥13 G/l and ≥2 of the following: BMB ≥5%, clonal cytogenetic abnormality [other than -Y], hemoglobin <10 g/dL, neutrophil count >16 G/l, platelet count <100 G/L, splenomegaly; pts with ECOG>2 excluded) (n=486; cohort 2). Results In cohort 1, pts receiving HMA 1st line (n=375) had longer OS (19.8 vs 16.3 months [mo], P=0.0102) and TTNT (13.2 vs 6.7 mo, P=0.0001) than pts treated with non-HMA 1st line (n=470). Survival benefit was longer when comparing pts who received HMA (any time) (AZA [n=442], DAC [n=37], both [n=27]) with those that never received HMA (never HMA; n=339) (23.0 vs 13.0 mo, P<0.0001). Median OS was longer for MD-CMML (n=294) vs MP-CMML pts (n=551) (25.5 vs 15.0 mo, P<0.0001). OS was shorter for all pts with 1st line HU preceding any 2nd line trt (9.4 vs 19.6 mo; P<0.0001; Fig A), for MP-CMML pts separately (8.7 vs 15.6 mo, P=0.0001), and for the subset with HU preceding 2nd line HMA (11.6 vs 19.8 mo; P=0.0016; Fig B). The following were significantly less common in pts treated with HMA vs those that were not: diagnosis in the pre-HMA era (8 vs 43%), MP-CMML (48 vs 66%), splenomegaly (27 vs 36%), ECOG≥2 (12 vs 24%), 1 trt line (43 vs 74%). WHO subtype, karyotype, transfusion dependence, LDH, CPSS score, AML transformation and therapy-related CMML were comparable between cohorts. HMA are not approved in the EU for CMML pts with <10% BMB. In this subgroup (n=588), median OS was longer for MD-CMML vs MP-CMML (28.1 vs 17.0 mo, P<0.0001) and for pts who received HMA vs never HMA (26.5 vs 14.8 mo, P=0.0003). Pts with <10% BMB and MD-CMML (n=206) did not seem to benefit from HMA vs non-HMA trt (median OS 28.4 vs 25.3 mo, P=0.9908; Fig C), whereas the MP-CMML subgroup (n=382) did (24.4 vs 13.0 mo, P<0.0001; Fig D). HMA are also unapproved in the EU for MP-CMML pts with ≥10% BMB. In pts with ≥10% BMB (n=257), median OS was longer for MD-CMML vs MP-CMML (19.4 vs 11.2 mo, P=0.0023) and for pts who received HMA vs never HMA (18.3 vs 7.0 mo, P<0.0001). Both MD-CMML (OS 21.7 vs 10.9 mo, p=0.0134; Fig E) and MP-CMML pts (15.6 vs 6.3 mo, P<0.0001; Fig F) benefited from HMA trt vs never HMA. In cohort 2, 1st line trts were HU (n=214), HMA (n=187) and others (n=85). Comparing HMA vs HU 1st line, median OS was 15.6 vs 14.5 mo (P=0.0307) and median TTNT was 8.8 vs 6.5 mo (P=0.0452; Fig G). OS and TTNT were comparable for HU vs other trts (Fig G). Similar observations were made in the larger cohort 1 (Fig H). Conclusions HMA show promising results with survival benefits of +11.4, +10.8 and +9.3 mo in pts with MP-CMML <10%, and MD- or MP-CMML ≥10% BMB. In MP-CMML pts fulfilling GFM-DAC-CMML trial inclusion criteria, survival and TTNT were longest in pts receiving HMA 1st line as compared to HU or other trts. Preceding HU portends poor prognosis (-10.2 mo). Disclosures Pleyer: Abbvie: Other: Advisory board; Novartis: Other: Advisory board; Inflection Point Biomedical Advisors: Other: Advisory board; Celgene: Other: Advisory board; Agios: Other: Advisory board. Leisch:Novartis: Honoraria, Other: Travel support; Bristol-Myers-Squibb: Honoraria; Celgene: Other: Travel support. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Heibl:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Honoraria; Daiichi Sankyo: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Geissler:Novartis: Honoraria; Roche: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria; AOP: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Ratiopharm: Honoraria. Valent:Blueprint: Research Funding; Pfizer: Honoraria; Deciphera: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Medina de Almeida:Novartis: Speakers Bureau; Celgene: Speakers Bureau. Jerez:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Germing:Novartis: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanz:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman - La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen - Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees, Research Funding. Greil:Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Janssen-Cilag: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding. OffLabel Disclosure: Azacitidine is not approved for the treatment of MP-CMML or CMML with <10% BM blasts, decitabine is not approved for treatment of CMML in the EU, hydroxyurea is not approved for the treatment of CMML in the EU.
Background:As life expectancy increases, elderly patients (pts) with immune thrombocytopenia (ITP) are increasingly being encountered in everyday practice. However, the features of ITP in older adults have not been fully elucidated thus far.Aims:To describe real world characteristics at diagnosis and evaluate disease outcome in a group of elderly pts (> 65 years) with primary ITP as compared to younger pts (>16 years‐ 65 years), using data from the national database (ITP registry) operated under the auspices of the Hellenic Society of Hematology.Methods:The Greek ITP registry recruits pts (n = 1317, to date) nationally through a network of 21 sites. In the present study we retrospectively analyzed data from pts with primary ITP aged over 16 years, who were diagnosed from 1979 to 2018.Results:The total number of evaluable pts was 843. Pts were divided in 2 groups based on age: Group‐1 consisted of 540 pts aged 16–65 years and Group‐2 of 303 pts aged > 65 years. The mean age at diagnosis was 36 years (16.1–64.7) in Group‐1 and 76 years (65.1–99) in Group‐2. The female to male ratio in Group‐1 was 1.9 and in Group‐2 1.1 (P = 0.0012). The median platelet count at diagnosis was significantly higher in Group‐1 (16x109/L, interquartile range: 8–35.7x109/L) than in Group‐2 (12x109/L, interquartile range: 5–29x109/L; P = 0.0014). As expected, significant fewer pts in Group‐1 had co‐morbidities as compared to Group‐2 (54.3% and 87.1%, respectively; P < 0.0001). Concurrently used medications, including vitamin K antagonists, platelet antagonists, other anticoagulants or non‐steroidal anti‐inflammatory drugs were more frequently reported in Group‐1 than in Group‐2 pts (P < 0.0001). Bleeding manifestations at diagnosis were observed at a similar frequency between the two groups, with the exception of menometrorrhagia which was significantly more frequent in Group‐1 that in Group‐2 pts, as expected (P < 0.0001). Bone marrow examination was performed more frequently in Group‐1 pts, whereas antiphospholipid antibody, platelet associated antibody, antinuclear antibody, HIV and hepatitis C testing were more frequently performed in Group‐2 pts. Treatment was given in 88% of Group‐1 and in 91% of Group‐2 patients at diagnosis. Overall response rate did not differ between the two Groups. A similar proportion of Group‐1 and Group‐2 patients were treated with corticosteroids, intravenous IgG or both, rituximab, anti‐D immunoglobulin or thrombopoietin receptor agonists, whereas significant more Group‐1 pts underwent splenectomy (P < 0.0001). Follow‐up of at least 1 year from diagnosis revealed that a similar proportion of Group‐1 and Group‐2 patients had developed chronic ITP. During follow‐up, 2 Group‐1 pts and 11 Group‐2 pts died (1.4% and 12%, respectively; P = 0.0003). Three deaths in Group‐2 were considered to be related to ITP.Summary/Conclusion:Elderly pts (Group‐1) presented with lower platelet counts at diagnosis had a higher frequency of comorbidities and used more often anti‐platetet and anticoagulant agents. However, neither the frequency nor the location of bleeding differed between Group‐1 (younger pts) and Group‐2 pts. Age influenced the choice of diagnostic procedures but not that of treatment, with the exception of splenectomy which was performed at significantly lower rate in Goup‐2 pts. Neither the treatment response nor the frequency of chronic ITP differed between Group‐1 and Group‐2 pts. 27% of deaths in Group‐2 pts were ITP‐related, whereas none in Group‐1 pts, thereby underscoring the need for age‐adapted management in elderly pts with ITP.
Introduction: T regulatory cells are immunosuppressive cells considered to play an important role in cancer biology and autoimmunity by suppressing host immune response and autoreactive lymphocytes respectively. Several studies reveal that Treg cells act by suppressing anti-tumor immune response, through the targeting of other immune cells, such as T cells, B cells and dendritic cells. Accumulated data indicate a significant role of T cell dysfunction in the pathogenesis of CLL. Aims: The scope of this study is the analysis of numerical and functional abnormalities of Tregs in B-CLL with the view to elucidate their role in the pathogenesis of the disease. Methods: Treg cells derived from 44 untreated B-CLL patients with a median age 62 and 17 healthy donors were analyzed by Flow cytometry, using the following antibodies: CD45Ro-FITC/CD45RA-PE/CD4-ECD/CD25-PC5/CD127-PC7, CD1a-FITC/CD137-PE/CD4-ECD/CD25-PC5/CD127-PC7, CD95-FITC/cyCD152-PE/CD4-ECD/CD25-PC5/CD127-PC7, beads/FoxP3-PE/CD4-ECD/CD25-PC5/CD127-PC7, Annexin V-FITC/CD4-ECD/CD25-PC5/CD127-PC7. For the functional analysis, peripheral blood was obtained from 20 patients with B-CLL. Mononuclear cells were isolated using Ficoll-Paque gradient centrifugation. CD4+ CD25+ (Treg cells), CD4+ CD25- (T effectοr cells, Teff), CD5+ CD19+ (B-CLL) and CD5- CD19+ (Normal B, NB) cells were separated using magnetic antibody cell sorting. To test the functionality of the assayed Tregs, the isolated cell populations were cultured in a 96-well plate (Tregs, Teff, B-CLL cells, NB cells, B-CLL cells: Tregs in 1:20 ratio, B-CLL cells: Teff in 1:20 ratio, NB cells: Tregs in 1:20 ratio, NB cells: Teff in 1:20 ratio) and their proliferative capacity was measured using the BrdU assay. To further analyze the functional role of Tregs, peripheral blood was obtained from 22 patients with CLL and 22 healthy donors. Mononuclear cells were isolated using Ficoll-Paque gradient centrifugation. CD4+ CD25+ CD127dim/- (Treg cells), CD5+ CD19+ (B-CLL) and CD5- CD19+ (Normal B, NB) cells were separated using magnetic antibody cell sorting and were co-cultured in a 96-well plate in a 1:10 ratio. The apoptosis of B cells was determined by the Annexin V/PI method. Results: FACS analysis of the Treg cells resulted at the following observations: The Treg absolute cell number (cells/μL), estimated either as the number of CD4+ CD25+ CD127- cells or as the number of CD4+ CD25+ FoxP3+ cells, was statistically significantly higher in patients' samples than in controls (CD127- 21.65 vs 7.35, p=0.001; FoxP3+ 20.42 vs 6.5, p= 0.001). Annexin V expression in Treg cells from BCLL patients was significantly lower compared to controls (3.626 vs 38.615, p=0.003). The functional analysis of Treg cells through BrdU assay indicated that CLL Tregs were able to suppress the proliferation of Teff cells (p=0.002) and that Teff cells were in turn able to significantly suppress the proliferation of B-CLL cells (p=0.05). Moreover, FACS analysis through Annexin V/PI method indicated that Treg CLL cells significantly decrease the apoptosis rate of NB cells after their co-culturing, compared to NB cells (p<0,02). On the contrary, healthy donors derived Treg cells significantly increase the apoptosis of B-CLL cells after their co-culturing, compared to B-CLL cells (p<0.025). Interestingly, no significant alterations were observed after culturing NB cells with Tregs from healthy donors and B-CLL cells with Treg CLL cells. Conclusions: In CLL patients, Treg cells are significantly higher and present with lower apoptotic levels compared to healthy donors. The functional analysis indicates that T effector cells suppress the proliferation of B-CLL cells and T effector cells are suppressed by Tregs indicating that the increased number of Tregs observed in CLL contributes indirectly to the proliferation of the CLL clone. These data are further supported by our observations that CLL derived Treg cells appear rather incapable of inducing apoptosis of both NB cells and B-CLL cells, in contrast to normal Tregs, suggesting an immunoediting effect of B-CLL cells on Tregs which negatively affects the functionality of the latter. Therefore, Treg cells in CLL do not efficiently eliminate the abnormal clone and play an important role in the pathogenesis of the disease. The molecular underlying mechanisms need to be further elucidated. Disclosures No relevant conflicts of interest to declare.
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