Association of Azacitidine and Lenalidomide (Combined vs Sequential Treatment) in High-Risk Myelodysplastic Syndromes. Final Results of a Randomized Phase II Multicenter Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2871-2871
Author(s):  
Carlo Finelli ◽  
Cristina Clissa ◽  
Matilde Follo ◽  
Marta Stanzani ◽  
Sarah Parisi ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Disease Progression ◽  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Response To Treatment ◽  
Hematologic Toxicity ◽  
Efficacy And Safety ◽  
Randomized Phase Ii

Abstract Introduction. Azacitidine (AZA) is able to induce hematologic responses in 50-60 % of patients (pts) with Myelodysplastic Syndromes (MDS) and moreover to prolong survival in higher risk MDS pts. Recently, several studies have evaluated the efficacy and safety of combining, in high-risk MDS pts, AZA with Lenalidomide (LEN), either administered concurrently (Sekeres, 2010; 2012), or sequentially (Platzbecker, 2013), in both cases showing promising results, although in a limited number of pts. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in high-risk MDS pts (IPSS score risk: High or INT-2). Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, WHO diagnosis was: RCMD: 2 pts; RCMD-RS: 1 pt ; RAEB-1: 11 pts; RAEB-2: 30 pts; IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts; IPSS cytogenetic risk was: Good: 17 pts; Intermediate: 11 pts; Poor: 14 pts; N.D.: 2 pts. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. At the time of this analysis, enrolment of the planned 44 pts was completed. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining 10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8 (1-28) cycles; in ARM 1: 9 (1-22) cycles, in ARM 2: 8 (1-28) cycles, respectively. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was: CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of 2 (1-8) cycles. Responder pts were: 13/17 (ORR: 76.5 %) in ARM 1 (3 CR; 1 PR; 1 mCR; 4 HI, 4 mCR+HI), and 13/17 (ORR: 76.5 %) in ARM 2 (5 CR; 2 mCR; 4 HI; 2 mCR+HI), respectively. Overall, the median duration of response was 8.5 (2-23) months: 6 (2-19) months in ARM 1; 16 (2-23) months in ARM 2. A grade > 2 non hematologic toxicity was observed in 24/44 (54.5 %) pts (ARM 1: 66.7%; ARM 2: 43.5%). 27/44 pts (61.4 %) (ARM 1: 61.9%; ARM 2: 60.9%) had a dose reduction of LEN because of hematologic or non-hematologic toxicity. 22 pts (50%) died (ARM 1: 47.6%; ARM 2: 52.2%). 14 pts (31.8%) (ARM 1: 23.8%; ARM 2: 39.1%) showed progression to AML. Overall, median survival was 13 (1-28) months; ARM 1: 13 (1-25) months; ARM 2: 14 (2-28) months. Conclusions. Our results confirm the efficacy of both AZA + LEN treatment regimens in high-risk MDS pts. Moreover, at a molecular level, a significant increase of phosphoinositide-specific phospholipase C (PI-PLC) beta1 and/or PI-PLCgamma1 expression was associated with a favourable clinical response to treatment. Responder cases also showed an increase of Beta-globin expression, hinting at a specific contribution of LEN on erythroid activation Disclosures Finelli: Janssen: Other: Speaker; Novartis: Other: Speaker; Celgene: Other: Speaker, Research Funding. Visani:Celgene: Research Funding. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria.

Azacitidine and Lenalidomide (Combined vs Sequential Treatment) in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3169-3169
Author(s):  
Carlo Finelli ◽  
Cristina Clissa ◽  
Matilde Follo ◽  
Marta Stanzani ◽  
Sarah Parisi ◽  
...  
Keyword(s):  
Complete Remission ◽  
Disease Progression ◽  
Phase Ii ◽  
Median Duration ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Hematologic Toxicity ◽  
Efficacy And Safety ◽  
Randomized Phase Ii ◽  
Microrna Profile

Abstract Introduction. Azacitidine (AZA) is the standard of care of higher-risk myelodysplastic syndromes (MDS), but the duration of clinical response is limited, and outcome after AZA failure is dismal. Several studies have demonstrated the efficacy and safety of combining AZA with Lenalidomide (LEN), either administered concurrently or sequentially, however the optimum dose and schedule for this combination remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts (IPSS score risk: High or INT-2), and to look for possible biomarkers able to predict response. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts. In 5 pts (11.4%) del(5q) was present. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining 10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8.5 (1-37) cycles; in ARM 1: 9 (1-32) cycles, in ARM 2: 8 (1-37) cycles, respectively. 6 pts (ARM 1: 2; ARM 2: 4) are still on treatment. Pts have been followed for a median of 15 (2-37) months for all subjects, for a median of 32 (18-37) months for survivors. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was: CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of 2 (1-8) cycles. The median duration of hematologic response was 10.5 months. A grade > 2 non hematologic toxicity was observed in 54.5 % of pts, and an emerging (from grade 0-2 to > 2) hematologic toxicity in 27.3% of pts. In 61.4% of pts LEN dose was reduced because of hematologic or non-hematologic toxicity. 32 pts (72.7%) died , and 17 pts (38.6%) showed progression to AML. Median overall survival (OS) was 15 months. No significant differences between the 2 arms were observed, in terms of ORR, CR rate, toxicity, AML incidence and OS, but there was a trend (although still not significant) towards a longer median duration of response in the sequential arm: ARM 1: 6 months; ARM 2: 18 months (p=0.0847). MDS cells showed alterations of the inositide-dependent signalling as well as an altered microRNA profile. In particular, responder cases showed a frequent downregulation of miR-3613 and mir-4668, that were upregulated in non responder cases. Further analyses are ongoing. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR, although the sequential schedule seems to induce more durable responses. Moreover, possible relationships with signal transduction pathways and microRNA profile are under evaluation. Disclosures Finelli: Novartis: Other: Speaker fees; Celgene: Other: Speaker fees; Celgene: Research Funding. Gobbi:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Roche: Honoraria; Takeda: Consultancy; Gilead: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Long-Term Follow Up Of a Randomized Phase II Study Of The JAK2-Selective Inhibitor Fedratinib (SAR302503) In Patients With Myelofibrosis (MF)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4047-4047 ◽  
Author(s):  
Animesh Pardanani ◽  
Ayalew Tefferi ◽  
Catriona HM Jamieson ◽  
Nashat Y Gabrail ◽  
Claudia Lebedinsky ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Hematologic Toxicity ◽  
Costal Margin ◽  
Spleen Volume ◽  
Randomized Phase Ii ◽  
Grade 3

Abstract Background We previously reported that patients with MF enrolled in a randomized Phase II study of fedratinib (SAR302503) (ARD11936; NCT01420770) had clinically meaningful reductions in splenomegaly and improvements in MF-associated constitutional symptoms after 24 weeks of treatment (Haematologica 2013;98:S1113). Here, we report updated efficacy and safety results from this study after 48 weeks of treatment (end of Cycle 12). Methods Patients with intermediate risk-2 or high-risk MF were randomized to receive once-daily fedratinib at doses of 300 mg, 400 mg, or 500 mg, for consecutive 4-weekly cycles, until disease progression or unacceptable toxicity. Eligible patients were aged ≥18 years, with palpable splenomegaly (5 cm below costal margin), and a platelet count ≥50 × 109/L. The primary measure for this study was percent change in spleen volume from baseline at the end of Cycle 3 (Blood 2012:120;Abstract 2837. Haematologica 2013;98:S1113). Endpoints for the current analysis included spleen response (≥35% reduction in spleen volume from baseline, assessed by a blinded independent central review by MRI), safety, and changes in bone marrow fibrosis (BMF). Results A total of 31 patients were randomized and treated: median age 63 years, 52% male, 58% primary MF, 58% high-risk MF, 90% JAK2V617F positive. The median numbers of treatment cycles were 12, 14, and 13 in the 300 mg, 400 mg and 500 mg dose groups, respectively, with median durations of exposure of 48.2, 56.2, and 52.4 weeks. At the cut-off date for this analysis, 21 patients (68%) remained on treatment; the most common reasons for treatment discontinuation were adverse events (AEs) (n=5) and withdrawal of consent (n=2). Overall, 58% (18/31) of patients achieved a spleen response at any time during treatment. The median spleen response duration was >35 weeks at all doses (Table). At Week 48, a spleen response was achieved by 30% (3/10), 80% (8/10), and 45% (5/11) of patients in the 300 mg, 400 mg, and 500 mg groups, respectively. Responses were generally maintained across all treatment groups. From Week 24 to Week 48 two additional patients achieved a spleen response (both in the 400 mg group), while one patient in the 500 mg group did not maintain a response (this patient had a fedratinib dose reduction to 200 mg). Changes in BMF up to Week 48 are being evaluated. The most common non-hematologic AE was diarrhea, with a Grade 3 rate of 13% (4/31 patients) but no Grade 4 cases were recorded. The rates of diarrhea decreased after the first cycle of treatment; from Cycle 2, the incidence of diarrhea (any grade) did not exceed 16% (5/31) at any cycle, and only one case of diarrhea was reported at Week 48 (end of Cycle 12). Anemia was the most-common hematologic toxicity, with a Grade 3 rate of 58% (18/31); no Grade 4 cases were reported. All Grades thrombocytopenia occurred in 55% (17/31) of patients, Grade 3 in three patients, and Grade 4 in two patients. Discontinuation of treatment due to AEs occurred in five patients over the 48 weeks (300 mg [n=2]; 400 mg [n=2]; 500 mg [n=1]), with two cases reported after Week 24 (dyspnea and leukocytosis [400 mg]; anemia and thrombocytopenia [500 mg]). There were 2 deaths (one in the 300 mg group due to unknown reasons [85 days after fedratinib discontinuation] and one in the 500 mg group due to disease progression [36 days after fedratinib discontinuation]). No cases of leukemic transformation were reported. Conclusions This updated analysis of the ARD11936 Phase II trial shows that treatment with fedratinib results in durable reductions in splenomegaly in patients with MF. No additional safety signals were observed with prolonged exposure to fedratinib. This study was sponsored by Sanofi. Disclosures: Pardanani: Sanofi, Bristol Myers Squibb, PharmaMar and JW Pharma: Clinical trial support Other. Jamieson:J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Lebedinsky:Sanofi: Employment. Gao:Sanofi: Employment. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau.

scholarly journals Addition of Lenalidomide (LEN) to Azacitidine (AZA) (Combined vs Sequential Treatment) in High-Risk Myelodysplastic Syndromes (MDS): A Randomized Phase II Multicenter Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4648-4648 ◽  
Author(s):  
Carlo Finelli ◽  
Cristina Clissa ◽  
Matilde Y Follo ◽  
Marta Stanzani ◽  
Paolo Avanzini ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Single Agent ◽  
Sequential Treatment ◽  
Refractory Anemia ◽  
Hematologic Toxicity ◽  
Mutational Status ◽  
Randomized Phase Ii

Abstract Introduction. Azacitidine (AZA) as single agent has been shown to improve overall survival in high-risk myelodysplastic syndromes (MDS), with an overall response rate (ORR) of 50-60% (Silverman 2002; 2006; Fenaux 2009). However as a significant proportion of patients (pts) do not respond to treatment, and moreover, as the the duration of therapeutic response to AZA is limited, several attempts have been made to associate AZA with other drugs, with the aim to improve the outcome. In particular, the addition of lenalidomide (LEN) to AZA, either administered concurrently (Sekeres, 2010; 2012), or sequentially (Platzbecker, 2013), has shown promising results, although these data await confirmation by larger series of pts. The aim of this study was to evaluate the efficacy (ORR) and safety of the combination vs the sequential use of AZA and LEN in high-risk MDS pts. Moreover, as in previous studies we demonstrated that the increase in PI-PLCβ1 gene expression during AZA treatment is related to haematological response and frequently anticipates the response (Follo, 2009; 2012), another aim of our study was to assess the evaluation of PI-PLCβ1 expression as early predictive biomarker of response also with the association of AZA and LEN, and to look for other possible biomarkers able to predict response, as the mutational status assessed by next generation sequency (NGS). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (according to WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The treatment for both arms was planned for 8 cycles (32 weeks) in the absence of disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 40 pts (23 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, WHO diagnosis was: Refractory Cytopenia with Multilineage Dysplasia (RCMD): 3 pts; Refractory Anemia with Excess of Blasts-1 (RAEB-1): 9 pts; RAEB-2: 23 pts; MDS-unclassified (MDS-U): 5 pts; IPSS risk was: Intermediate-2: 29 pts; High: 6 pts; not determined (N.D.) (because of lack of cytogenetic data): 5 pts. (all with RAEB-2). IPSS cytogenetic risk was: intermediate in 10 pts and high in 9 pts (3 with complex karyotypes and 6 with isolated -7 or 7q-). 5 pts showed del5q (in 3 cases in the context of a complex karyotype, and in 1 case associated with another single additional cytogenetic alteration). 2 pts had therapy-related MDS. 21 pts (52.5%) were transfusion-dependent at baseline. 19 pts were randomly assigned to ARM 1, and 21 pts to ARM 2. At the time of this analysis, 22/40 pts (55%) completed ≥ 6 cycles of treatment, and are evaluable for response. 13/22 pts (59,1%) showed a favourable response to treatment, following the International Working Group (IWG) criteria (Cheson, 2006): 2 pts achieved Complete Remission (CR), 2 pts attained Partial Remission (PR), 2 pts showed Marrow Complete Remission (mCR), and 7 pts obtained Hematological Improvement (HI), while the 9 non responder pts maintained a Stable Disease (SD). Responder pts were 7/10 (70%) in ARM 1 (2 CR; 1 PR; 4 HI), and 6/12 (50%) in ARM 2 (1 CR; 1 PR; 2 mCR; 2 HI), respectively. Median time to first response: 2 (2-7) months. A significant toxicity (grade > 2) was observed in 10/40 (25%) pts. 15/40 pts (37,5%) had a dose reduction of LEN because of hematologic or non-hematologic toxicity. 8 pts (20%) early discontinued therapy before completing the planned 8 cycles, because of prolonged thrombocytopenia (1 pt), death (3 pts), evolution into acute myeloid leukemia (AML) (2 pts) and withdrawal of consent (2 pts), respectively. Causes of death were: febrile neutropenia, myocardial infarction and sudden death, respectively . Conclusions. Our results, although preliminary, seem to confirm the feasibility of the association of AZA and LEN in high-risk MDS pts. More data are needed in order to compare the efficacy and safety of combined vs sequential treatment and vs AZA monotherapy. Moreover, possible relationships with signal transduction pathways and with mutational status are under evaluation. Disclosures Finelli: Celgene: Research Funding, Speaker Other; Novartis: Speaker, Speaker Other; Janssen: Speaker, Speaker Other. Off Label Use: Lenalidomide in higher-risk MDS and AML. Cavo:Celgene: Consultancy, Honoraria, Speakers Bureau.

scholarly journals Comparison of Two Different Therapeutic Regimens with Azacitidine and Lenalidomide (Combined versus Sequential) in Higher-Risk Myelodysplastic Syndromes. Update of Long-Term Results of a Randomized Phase II Multicenter Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4365-4365 ◽  
Author(s):  
Carlo Finelli ◽  
Cristina Clissa ◽  
Matilde Y Follo ◽  
Sarah Parisi ◽  
Miriam Fogli ◽  
...  
Keyword(s):  
Complete Remission ◽  
Disease Progression ◽  
Board Of Directors ◽  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Haematological Toxicity ◽  
Advisory Committees ◽  
Haematological Response ◽  
Randomized Phase Ii

Abstract Introduction. The association of Azacitidine (AZA) and Lenalidomide (LEN), either administered concurrently (Sekeres, 2010; 2012; 2017), or sequentially (Platzbecker, 2013; Di Nardo 2015; Mittelman 2016; Narayan 2016) has proven effective in Myelodysplastic Syndromes (MDS), however the optimum dose and schedule remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the IWG criteria (Cheson, 2006). Secondary endpoints: a) rate of CR; b) duration of responses; c) overall survival (OS). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS with IPSS risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles. For responder patients the same treatment was continued until disease progression or unacceptable toxicity. Results. From March 2013, 44 pts (27 males), median age: 72 (48-83 yrs) were enrolled, from 13 hematologic Centers. At baseline, IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts. In 5 pts (11.4%) del(5q) was present (additional cytogenetic alterations: 1 in 1 pt, and > 1 in 4 pts , respectively). 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. Treatment was given for a median of 8.5 (1-52) cycles; in ARM 1: 9 (1-51) cycles; in ARM 2: 8 (1-52) cycles, respectively. Median follow-up: 15 (2-54) months; 47 (37-54) months for survivors. 10/44 pts (22.7%) did not complete at least 6 cycles of treatment for causes other than disease progression (6 pts for adverse events, 2 pts for consent withdrawal and 2 pts for medical decision), and were not considered evaluable for response. Among the 34/44 pts (77.3%) evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. Intention-to-treat (ITT) analysis: ORR: 59.1%. First response was observed after a median of 2 (1-8) cycles. The Best Response achieved was: CR: 8 pts (23.5%) (ITT: 18.1%), PR: 1 pt (2.9%) (ITT: 2.2%), mCR: 3 pts (8.8%) (ITT: 6.8%), HI: 8 pts (23.5%) (ITT: 18.1%), mCR+HI: 6 pts (17.6%) (ITT: 13.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). Among the 27 pts (21 evaluable for response) with an abnormal karyotype at baseline, ORR was 66.7% (ITT: 51.8%) and 4 pts achieved complete cytogenetic response. Median duration of hematologic response: 10.5 months. 34 pts (77,3%) died , and 17 pts (38.6%) showed progression to AML. Grade >2 non haematological toxicity: 54.5%. Median OS: 15 months. No significant differences between the 2 arms were observed, in terms of ORR (ARM 1: 76.5%, ITT: 61.9%; ARM 2: 76.5%, ITT: 56.5%), CR rate (ARM 1: 17.6%, ITT: 14.3%; ARM 2: 29.4%, ITT: 21.7%), grade >2 non haematological toxicity (ARM 1: 66.7%; ARM 2: 43.5%), AML incidence (ARM 1: 28.6%; ARM 2: 47.8%) and OS (ARM 1: 14 months; ARM 2: 16 months), but the median response duration was significantly longer in ARM 2 (18 months) as compared to ARM 1 (6 months) (p=0.0459). At the time of last analysis, 5/44 (11.4%) patients, 1/21 (4.8%) in ARM 1, and 4/23 (17.4%) in ARM 2, were still maintaining the haematological response, and were still in treatment, after 54, 54, 52, 51 and 37 months, and after 52, 51, 33, 48 and 35 cycles of therapy, respectively. The changes observed during treatment in mutational status of inositide-specific genes and microRNA expression profiling were related to clinical outcome, predicting a negative response to therapy. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR and OS, although pts treated with the sequential regimen showed a significantly longer duration of haematological response. Disclosures Finelli: Celgene: Other: speaker fees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: speaker fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees. Candoni:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau. Gobbi:Novartis: Consultancy; Janssen: Consultancy; Ariad: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees. Rigolin:Gilead: Research Funding. Cavo:GlaxoSmithKline: Honoraria, 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, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase II Study to Determine the Safety and Efficacy of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase (IDO) Enzyme INCB024360 in Patients with Myelodysplastic Syndromes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4653-4653 ◽  
Author(s):  
Rami S Komrokji ◽  
Sheng Wei ◽  
Adam W Mailloux ◽  
Ling Zhang ◽  
Eric Padron ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Disease Progression ◽  
Phase Ii ◽  
Median Duration ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Indoleamine 2,3 Dioxygenase ◽  
The Mean

Abstract Introduction: Recent studies emphasized the role of immune dysregulation and innate immune activation in the pathogenesis of myelodysplastic syndromes (MDS). The expansion of T-regulatory cells, namely effector memory cells (Treg EM), in MDS correlates with worse outcome. The expansion of inflammatory hematopoietic suppressive cells called myeloid-derived suppressor cells (MDSC) is sufficient to perturb hematopoiesis and result in the development of MDS in a mouse model. INCB024360 is an oral inhibitor of the enzyme indoleamine 2,3-dioxygenase (IDO) which catalyzes the degradation of tryptophan (Trp) to Kynurenine (Kyn). Increased expression of IDO1 was an independent prognostic variable for survival in patients with acute myeloid leukemia (AML). Preclinical data suggests that IDO1 inhibition by INCB024360 will increase T cell proliferation, and decrease T reg cells and will decrease MDSC suppressive activity. We report the results of a phase II clinical study with laboratory correlatives exploring the potential role of INCB024360 for the treatment of MDS patients. Methods: This was a phase II, 2-step design to explore the activity and pharmacodynamics of INCB024360 in previously treated MDS patients. All patients signed informed consent. All patients with WHO defined MDS and AML with a myeloblast percentage between 20-30% (RAEB-t by FAB) were included. All risk categories by international prognostic scoring systems (IPSS) were allowed. The study excluded patients with viral hepatitis, HIV infection, prior solid organ or hematopoietic stem cell transplant or active autoimmune disease. The primary endpoint was overall response rate by the International Working Group criteria (IWG 2006). The secondary endpoints included IDO suppression measured intracellular by flowcytometry, change in Treg EM % with treatment and the percentage of bone marrow MDSC change after treatment with INCB024360 . All patients were treated with 600 mg oral twice a day for 16 weeks unless clear evidence of disease progression or toxicity was evident. Descriptive statistics were used to report baseline characteristics and response rates. The paired t-test was used to compare means. The study was registered at clinicaltrials.gov NCT01822691. Results: Between August 2013 and January 2014, 15 patients were enrolled at Moffitt Cancer Center. The median age was 72 years the majority of whom were white (93%) and male gender (80%). Seven patients were RCMD WHO subtype, 3 RAEB-I and RAEB-II each, and 1 RARS and MDS/MPN each. The IPSS risk was low 27% (4), intermediate-1 47% (7) and intermediate-2 27% (4). By the revised IPSS, 5 patients were intermediate risk (33%), 2 (13%) high and very high risk respectively. Two thirds were intermediate-2 or high risk by global MD Anderson risk model. The median number of prior therapies was 3 (2-10) and all patients had prior azacitidine therapy. The best response was stable disease in 12 (80%); 3 (20%) patients experienced disease progression and no hematological improvement was observed. The median duration of follow up was 10 months, median duration on study treatment 3.9 months, and median overall survival was not reached. Two patients progressed to AML. The treatment was relatively well tolerated; no treatment-emergent grade 3/4 adverse events were reported. One patient developed hypothyroidism and adrenal insufficiency (grade 2) and one patient had a low testosterone level. Mean IDO expression measured intracellular in mononuclear bone marrow cells was 39% at baseline compared to 26% after treatment (n=9, p 0.4). Mean BFU-E recovery improved from 72 to 191 colonies/106 (n=5, p value 0.036) and mean CFU-GM from 62 to180 colonies/106 (n=6, p 0.5). The mean MDSC % (CD33Lin-HLA cells) was 29.5% at baseline compared to 27.6% after treatment (n=9, p 0.7) however most patients experienced some reduction in MDSC%. The mean T Reg EM cell % changed from 9.6% at screening to 7.4% at end of treatment. (n=14, p 0.8) Conclusions: INCB024360 was relatively well tolerated in MDS patients. At the current dosages tested no significant clinical activity was observed. No significant decrease in intracellular IDO expression was observed. No significant decrease in MDSC and T reg EM as potential mechanism of action were observed. . Disclosures Komrokji: Incyte Corporation: Consultancy, Research Funding. Padron:Incyte: Honoraria, Research Funding. Tinsley:Incyte: Speakers Bureau.

Sequential Treatment with Rituximab and CHOP Chemotherapy in B-Cell PTLD - Moving Forward to a First Standard of Care: Results From a Prospective International Multicenter Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 100-100 ◽  
Author(s):  
Ralf Trappe ◽  
Sylvain Choquet ◽  
Stephan H.K. Oertel ◽  
Veronique Leblond ◽  
Daan Dierickx ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Risk Stratification ◽  
Disease Progression ◽  
Early Treatment ◽  
Interim Analysis ◽  
Research Funding ◽  
Low Risk ◽  
Sequential Treatment ◽  
Risk Patients

Abstract Abstract 100 Purpose: This trial aimed to investigate the efficacy and safety of sequential treatment with rituximab and CHOP-21 in patients with PTLD unresponsive to reduction of immunosuppression. Methods: An ongoing prospective, multicenter, international phase II trial was initiated in January 2003. Initially patients were treated with a fixed sequence of rituximab at days 1, 8, 15 and 22 (4R) followed by four cycles of CHOP-21 combined with G-CSF support starting 4 weeks after the last dose of rituximab (sequential treatment, ST). Based on the results of an earlier interim analysis showing that the response to rituximab predicts OS the trial was amended in 2007 introducing risk stratification according to the response to 4R (risk stratified sequential treatment, RSST). In RSST patients achieving a complete remission after 4R (low risk) continue with four 3-weekly courses of rituximab monotherapy while patients in PR, SD or PD (high risk) are followed by four cycles of R-CHOP-21 + G-CSF. Results: This is a scheduled interim analysis after inclusion of a total of 104 patients. The median follow up is 34.0 months for ST (64 pts.) and 9.1 months for RSST (40 pts.). 61 ST and 35 RSST patients were diagnosed with monomorphic PTLD, 3/5 with polymorphic PTLD. 27/23 patients were kidney, 3/0 kidney+pancreas, 15/8 liver, 13/6 heart, 6/3 lung or heart+lung transplant recipients. Median age at diagnosis of PTLD was 53/60 years (mean age: 48/56 years). 59%/58% of patients had an advanced stage of disease (Ann Arbor III/IV) and 49%/47% of tumors were EBV positive. 75%/75% of patients had late PTLD (i.e. later than 1 year after transplantation). LDH was elevated in 71%/64% of patients, respectively. The overall response rate (ORR) to 4 initial courses of rituximab monotherapy (4R, N=104) was 54% with a CR-rate of 32% and the subsequent completion of treatment with CHOP or R-CHOP allowed a clear increase of the response (p<0.0001, Fig. 1). With ST the final ORR was 89% (CR rate: 69%). 86%, 75% and 75% of patients were without disease progression at one, two and three years, respectively (Fig. 2a). Disease free survival was 87%, 78% and 70% at one, two and three years. There were 6 early treatment associated deaths (9%) resulting from infections (1 from CMV-colitis, 1 from PcP-pneumonia, 1 from fulminant hepatitis, 3 from sepsis) and 2/64 patients died from refractory PTLD. Two further patients died due to hemorrhage during treatment. With RSST the ORR was 90% and 73% achieved a complete remission. 90% of patients were without disease progression at one year (Fig. 2a). There was one early treatment related death due to infection (2.5%). This patient died from sepsis secondary to intestinal perforation in response to R-CHOP treatment. 2/40 patients died from refractory PTLD. With 1 event in 16 patients in both, the ST and the RSST-arms, subsequent consolidation with rituximab monotherapy (RSST) seems not to be inferior to consolidation with 4 cycles of CHOP (ST) in patients with a CR after 4R. Up to now there is no difference in toxicity between CHOP and R-CHOP in ST/RSST. Patients failing to achieve a complete remission with 4R (72 patients) seem to benefit from the subsequent escalation from CHOP to R-CHOP (Fig. 2b). Conclusions: This is the largest prospective study in PTLD. Sequential treatment with rituximab and CHOP-21 + G-CSF is well tolerated and highly effective with a treatment related mortality of less than 10% and an efficacy of up to 90%. In comparison to historic series of rituximab monotherapy, significantly more patients achieve a CR with sequential treatment and time to progression (TTP) is very much prolonged. In comparison to historic series of CHOP, sequential treatment is much better tolerated. This may result from a lower tumor burden and a better patient fitness at the time chemotherapy is applied. Introduction of risk stratification according to the response to 4 courses of rituximab monotherapy might further improve these results restricting chemotherapy related toxicity to high risk patients while these data suggest that low risk patients can effectively be treated with extended rituximab monotherapy. Thus, risk stratified sequential treatment (RSST) might further improve OS in this difficult to treat disease. Disclosures: Trappe: Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding; AMGEN GmbH: Research Funding. Choquet:Hoffmann La Roche Ltd.: Consultancy, Honoraria. Oertel:Hoffmann La Roche Ltd.: Employment, Equity Ownership. Leblond:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding. Ekman:Hoffmann La Roche Ltd.: Honoraria. Dührsen:Hoffmann La Roche Ltd.: Honoraria, Research Funding. Salles:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding. Morschhauser:Hoffmann La Roche Ltd.: Honoraria. Riess:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding; AMGEN GmBH: Consultancy, Honoraria, Research Funding.

Phase II Trial of Initial Safety and Toxicity Prior to the Phase III Trial of Lenalidomide Versus Observation Alone in Patients with Asymptomatic High-Risk Smoldering Multiple Myeloma (E3A06): A Trial Coordinated by the Eastern Cooperative Oncology Group

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4079-4079 ◽  
Author(s):  
Sagar Lonial ◽  
Susanna Jacobus ◽  
Matthias Weiss ◽  
Rafael Fonseca ◽  
Madhav V. Dhodapkar ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Research Funding ◽  
Plasma Cells ◽  
Phase Ii Trial ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Trial Testing ◽  
Grade 3 ◽  
Smoldering Myeloma

Abstract Abstract 4079 The treatment and natural history of asymptomatic or smoldering myeloma has been an area of intense preclinical and clinical study. Historical attempts to treat these patients have not demonstrated significant benefit, likely as a consequence of limited therapeutic options as well lack of attention to the vast heterogeneity contained within the diagnosis of smoldering myeloma. More recent risk criteria from both US and Spanish investigators have identified a cohort of smoldering myeloma patients at high risk for progression to myeloma in a short time. Recently the PETHEMA group has conducted a randomized clinical trial testing lenalidomide and dexamethasone vs observation among high risk smoldering patients and has demonstrated a clear benefit in terms of progression free survival and hints towards improvement in overall survival favoring early intervention. To further evaluate the potential benefit of early intervention in a high risk smoldering cohort, the ECOG myeloma group designed a phase II trial testing the safety and efficacy of single agent lenalidomide with the intent of broadening to a randomized phase III trial if toxicity was acceptable. We report here on the safety portion of the phase II trial. The phase II group of patients received lenalidomide at a dose of 25 mg days 1–21 every 28 days to evaluate the early toxicity and tolerance of this dosing. The dose of lenalidomide could be adjusted based on toxicity using a defined dose-modification guideline in the protocol. The primary endpoint for the safety study was the rate of any treatment-related grade 4–5 non-hematologic toxicity plus grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events) observed within 6 cycles of treatment. The goal was to enroll 34 patients; if 9 or more patients experience toxicity as defined, then the study would not continue. In terms of eligibility, patients were to be diagnosed with asymptomatic high-risk smoldering multiple myeloma (SMM) within the past 12 months, as confirmed by both of the following: bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells and an abnormal serum free light chain ratio (<0.125 or >8.0) by serum FLC assay. Further, patients must have measurable levels of monoclonal protein (M-protein): >=1g/dL on serum protein electrophoresis or >=200 mg of monoclonal protein on a 24 hour urine protein electrophoresis. Patients must have no lytic lesions on skeletal surveys and no hypercalcemia. Among the 36 patients enrolled in the phase II study, 56% were female, and 44% were 65 years and older. Treatment and toxicity data at a minimum through cycle 6 is complete as of August 2, 2102. The last patient enrolled completed cycle 6 treatment on June 7, 2012. The median treatment duration of the entire cohort is 9 cycles (range 1–18 cycles), with 86% of patients completing at least 6 cycles of treatment. Ten patients are off treatment for the following reasons: disease progression (n=1), AE/complication (n=5), death (n=1) and patient withdrawal/refusal (n=3); 5 of the 10 patients ended treatment before completing 6 cycles. Of 36 patients assessed for toxicity, 8 patients [22.2%, 90% CI: (11.6%-36.5%)] experienced worst grade treatment-related non-hematologic toxicity of grade 3 or higher. Separately, 6 patients experienced unrelated non-hematologic toxicity of grade 3 or higher. Three patients [8.3%, 90% CI: (2.3%-20.2%)] experienced a serious adverse event as defined for the purposes of the phase II toxicity analysis (treatment-related grade 4–5 non-hematologic toxicity or grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events). Based upon this analysis of the study, the phase II portion of the trial met the prespecified safety benchmark established to allow for phase III expansion, and accrual to the phase III portion of this study will begin. Efficacy data will be presented at the time of presentation. Disclosures: Lonial: Novartis: Consultancy; Millennium: Consultancy; Onyx: Consultancy; BMS: Consultancy; Celgene Corp: Consultancy; Merck: Consultancy. Off Label Use: Lenalidomide is not approved for treatment of smoldering MM. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy; Binding site: Consultancy; Millenium: Consultancy; AMGEN: Consultancy; Celgene : Research Funding; Onyx: Research Funding; prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties. Dhodapkar:Celgene: Research Funding; KHK: Research Funding.

scholarly journals Microenvironment Profiling in Myelodysplastic Syndromes and Its Relationship to Clonal Hematopoiesis and Disease Progression

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4650-4650
Author(s):  
Antonieta Molero Yordi ◽  
Bárbara Tazón ◽  
Laura Gallur ◽  
Silvia Saumell ◽  
Tamara Jimenez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Disease Progression ◽  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Statistical Significance ◽  
Advisory Committees ◽  
Heterogeneous Distribution

Abstract Background: Immune dysregulation and somatic gene mutations are known prognostics factors in myelodysplastic syndromes (MDS). Moreover, impaired cytotoxicity and a decrease in mature natural killer cells (NK) have been related to higher risk characteristics. Also, killer immunoglobulin-like receptor (KIR) expression and haplotype have been associated with overall survival in MDS. The overexpression of inflammatory cytokines, produced by the clonal cell, plays a role in the immune environment. Early MDS presented increase apoptosis, whereas high risk MDS shows a downregulation of pro-apoptotic cytokines indicating decreased immune surveillance. The importance of the interaction of the immune populations and the malignant clone is not entirely understood. The aim of this study was to characterize how the microenvironment regulates the malignant clone and to describe the different immune landscape in MDS bone marrow. Methods: We prospectively studied 50 MDS patients, 12 idiopathic cytopenia of unknown significance (ICUS) and 4 healthy donors (HD). We analyzed different immune cells in bone marrow: NK (CD3CD56+CD16+/CD56+CD16-/CD56-CD16+) and their activating (NKp46, NKp30, NKG2C, NKG2D, NKp44, DNAM) and inhibitory receptors (TIGIT, NKG2A, Irp60, and PD1) as well as their ligands (HLA-ABC, MICA-B, CD155, PD-L1). We also assessed myeloid-derived suppressor cells (MDSC), differentiating granulocytic (Gr-MDSC: CD11b +CD33 +HLA-DR -CD15 +CD14 -) from monocytic (Mo-MDSC: CD11b +CD33 +HLA-DRlow/CD15 +CD14 +). Also, T cells subpopulations in peripheral blood with the following markers (CD3/CD4/ CD8/CCR7/CD45RA/ CD27/CD28/CD279/CD57/CXCR3/CCR6). Molecular analysis by NGS using the Oncomine Myeloid Research Assay (ThermoFisher Scientific) included 40 genes associated with myeloid malignancies. Also, we determined the KIR haplotype by NGS. For the study of cytokines concentrations, we used the Luminex® platform with ThermoFisher commercial kit ProcartaPlex TM Multiplex immunoassay. Results: A total of 66 samples were tested. Patient's median age was 74 years-old and 44% were female (other details in table1). Compared to ICUS, we found in MDS patients a decrease of TCD4+PD1+ T cells (MDS 26.23% vs ICUS 41.23%, p=0.022), effector TCD8+ cells (MDS 15.74% vs ICUS 45.69%, p= 0.02) and in TNK (MDS 1.72% vs ICUS 7.8%, p= 0.04). Regarding NK cells, we observed a decrease in mature NK (CD56dimCD16+) in MDS compared to ICUS, which did not reach statistical significance (MDS 15.25% vs ICUS 79.16%; p=0.104). As for NK receptors, we observed a significant decrease in NKG2C (MDS 4.94%, vs HD 28.35% p=0.039) and KIR2DS4 (MDS 16.56% vs HD 91.18%; p=0.036) expression in MDS. In the study of ligands, a significant loss of MIC-A/B in MDS vs. controls (MDS 0.42% vs HD 6.96%, p=0.034) was detected. Regarding cytotoxicity, a higher expression of perforin in MDS and ICUS compared with HD (35%, 42.65% vs. 11.93% respectively; p=0.033) was showed. A 33% of patients presented with KIR A haplotype, with no differences in the immunological profile between haplotypes. In terms of MDSC, we observed a trend to higher expression in MDS compared to controls (MDS 1.58%, ICUS 0.15% vs HD 0.18% p=0.10). Of these patients, 4 required treatment and 1 progressed to AML. We found mutations in 34 (85%) of MDS, of these, 27 (79.4%) had more than 2, with 38% of patients with abnormal cytogenetic (including 14.7% complex karyotype). Mutated patients had more MDSC than unmutated patients (0.95% vs 0.01%, p=0.001) and a trend to lower CD56dimCD16+ expression in mutated patients compared with unmutated MDS (24.7% vs. 91.57%, respectively, p=0.058). Finally, in the cytokines analysis, an increased level of IL-10 in high-risk compared to low and intermediate patients (2 pg/ml vs. 1 pg/ml, p=0.04) was demonstrated, 16 (53%) had high concentrations of IL10 &gt; 40 pg/ml, 8 (26.6%) had more than 2 mutations and 3 (10%) had a single TP53 mutation. Conclusions: Our analysis showed a heterogeneous distribution of the different immune populations. We found a decreased mature NK and increased MDSC in mutated patients. Further analyses should be performed to describe independent factors that may affect disease progression. Figure 1 Figure 1. Disclosures Molero Yordi: Oryzon Genomics: Consultancy. Salamero: Pfizer: Consultancy; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Diez-Campelo: Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Prosper: Oryzon: Honoraria; BMS-Celgene: Honoraria, Research Funding; Janssen: Honoraria. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Valcarcel: SANOFI: Consultancy, Honoraria, Speakers Bureau; SOBI: Consultancy, Honoraria, Speakers Bureau; JAZZ: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; NOVARTIS: Consultancy, Honoraria, Speakers Bureau; ASTELLAS: Consultancy, Honoraria, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; CELGENE: Consultancy, Honoraria, Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document