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In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 53-54

Abstract: Context. The perhaps only CMML-specific Randomized Clinical Trial (RCT) established hydroxyurea (HY) as the main treatment (Tx) for advanced proliferative CMML (Wattel Blood 1996). In Europe, the only hypomethylating agent (HMA) approved in CMML is AZA in non proliferative CMML-2. Phase 2 trials reported the activity of decitabine (DAC) in advanced proliferative CMML (Braun Blood 2011, Santini Leukemia 2018). We performed a RCT of DAC (±HY during the first 3 cycles) vs HY alone in those pts. Methods. The DACOTA trial (EudraCT 2014-000200-10) accrued pts with previously untreated (or & lt; 6 weeks of HY), proliferative (WBC ≥ 13x109/L) CMML with advanced disease defined per Wattel et al as presence of extramedullary disease or ≥2 criteria among: BM blasts ≥5%, abnormal karyotype (except -Y), ANC ≥ 16x109/L, Hb & lt; 10 g/dL, platelets & lt; 100 x109/L or splenomegaly & gt; 5 cm below costal margin. Pts were randomized 1:1 to DAC (20 mg/m2/d IV 5d/28d) or HY (1g/d, adjusted on WBC, 28d cycles) and treated until death, AML transformation or progression. The primary endpoint was EFS, events being death, transformation to AML, progression of myeloproliferation after 3+ cycles or progression of blasts and cytopenias after 6+ cycles. Response was assessed with IWG 2006 criteria modified to account for improvement of myeloproliferation, after central morphology review. Intent-to-treat analyses were done considering missing responses as failures. Results. From Oct 2014 to Sep 2019, 217 pts from 47 centers were screened and 170 randomized (84 DAC and 86 HY), including 12 pts (6 DAC and 6 HY) who never started Tx. Median age was 73 years (IQR 68-78). WHO was CMML-NA/1/2 in 2, 114 and 54 pts, respectively (resp). Median WBC 34.9 x109/L (IQR 22.9-55.7). Cytogenetic risk (Such Haematologica 2011) was fav 69%, int 12%, adv 18% NA 1%. Mutations in TET2, SRSF2, ASXL1 and signaling genes (CBL, JAK2, FLT3, KIT, NRAS, KRAS and CSF3R) were present in 64%, 51%, 62% and 57% resp. 72 pts had received HY for a median 27 days prior to randomization. Aside from older age in the HY arm (median 74 vs 71.5y in the DAC arm), there was no imbalance between Tx arms. DAC and HY pts received a median of 5 (IQR 3-12) and 6 (IQR 3-14) cycles, resp. As of 15th June 2020, 5 and 10 DAC and HY pts were still on Tx. Reasons for Tx cessation in the DAC arm were death (n=19), AML transformation (n=16), progression (n=9) , hematological toxicity (n=13) or other (n=21). Reasons for Tx cessation in the HY arm were death (n=14), AML transformation (n=13), progression (n=18), hematological toxicity (n=6) or other (n=20). 126 and 85 pts received 3 and 6 cycles, resp. In the ITT population, ORR at 3 cycles was 56% (7CR, 25 mCR±HI, 15 SD+HI) and 30% (0 CR, 8 mCR±HI, 18 SD+HI) in the DAC and HY arms, resp (p=0.0011) and ORR at 6 cycles was 32% (6 CR, 9 mCR±HI, 12 SD+HI) and 17% (2 CR, 4 mCR±HI, 9 SD+HI) in the DAC and HY arms, resp (p=0.033). Median response duration was 15.9 vs 18.2 months (mos) in the DAC and HY arm, resp (p=0.81). Infection and hemorrhage occurred at least once in 49% and 31% of pts, resp. 55% of DAC pts and 38% of HY pts required hospitalization at least once (p=0.05). Non-heme ≥ grade 2 AEs occurred in 79% and 63% of DAC and HY arms, resp (p=0.03). Grade ≥3 cardiac AEs occurred in 13 DAC and 4 HY pts, resp. With a median follow-up of 13.9 mos, median EFS was 12.6 vs 10.3 mos in the DAC and HY arms, resp (reference DAC arm, HR= 1.14 CI95 0.8-1.64, p= 0.46). Median AML-free survival (AMLFS) was 13.6 and 15.8 mos in the DAC and HY arms resp (p=0.86). Median OS was 18.4 and 23.1 mos in the DAC and HY arms, resp (p=0.72). Considering death and AML transformation as competing risks there was no significant difference in cumulative incidence of AML (p=0.1) or death without transformation (p=0.06) between arms. 30 pts from the HY arm received an HMA (DAC n= 13, AZA n= 16, both=1) after study exit. Censoring at HMA onset in the HY arm, median OS was 18.4 vs 30.4 in the DAC and HY arm, resp (p=0.15). 13 pts were transplanted (DAC n= 10, HY n= 3). There was no interaction between Tx arm and CMML-0/1 vs -2, platelets ≥ vs & lt;100 x109/L and anemia (Hb & lt; 8 g/dL or RBC-TD vs Hb ≥8) on both EFS and OS (all p & gt;0.05). Conclusion. RCTs are feasible in advanced proliferative CMML, which remains an unmet medical need. In these pts, DAC did not provide an overall or event-free survival advantage over HY. HY remains a valid option in advanced proliferative CMML. However, one third of HY pts subsequently received an HMA and more DAC pts achieved a response and were bridged to HSCT. Figure Disclosures Itzykson: Abbvie: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Sanofi: Honoraria; BMS (Celgene): Honoraria; Janssen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncoethix (now Merck): Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Santini:BMS, J & J, Novartis: Honoraria; Acceleron, BMS, Menarini, Novartis: Consultancy; Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Lionel:Abbvie: Consultancy; Takeda: Consultancy; Celgene/BMS: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Luebbert:Janssen: Research Funding. Park:Takeda: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Other: Travel expenses. Stamatoulas Bastard:Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria; Takeda: Consultancy. Solary:Janssen: Research Funding. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. OffLabel Disclosure: Decitabine for CMML with WBC & gt; 13 x109/L.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-138680

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 13-13

Abstract: Thrombosis is the major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). Age ≥60 years (y) and/or history of thrombosis labels patients (pts) as high-risk for thrombosis. Yet, thrombosis frequently occurs prior to the diagnosis of PV/ET. In a multicenter study of the East German Study Group (HINC-207; OSHO #091), the interaction between age and time occurrence of the first thrombosis as risk factors for thrombosis after diagnosis was studied. Methods After IRB approvals, JAK2 mutated adults with PV or ET were prospectively enrolled in 9 centers and centrally stratified in a one to two ratio (group A: pts with a history of thrombosis; group B: pts without thrombosis) with a pre-planned minimum of 60:120 pts. Based on a longitudinal and cross-sectional design, clinical and laboratory data at diagnosis, last follow-up, and thrombosis (for group A) were collected. Thrombosis prior to diagnosis was labeled as A1 and thrombosis after diagnosis as A2. Thrombosis risk factors were grouped into age-, previous thrombosis-, thrombosis prior to PV/ET-, cardiovascular (CV)-, thrombophilia-, and disease- (JAK2 allele burden, Hct, and WBC) related. Additionally, therapies [aspirin (ASS), anticoagulation, phlebotomy, and cytoreduction] and data from a study-own patient questionnaire were included. All pts signed informed consent. The primary endpoint was the phenotypic diversity in JAK2-mutated ET and PV pts with or without thrombosis. Results From April to Dec, 2019, 246 pts were recruited. Data on 237 pts (median age 62y; 59% females, 58% PV) are available. At diagnosis, pts in group A (n=71, median age 59.5y) tended to be younger than those in group B (n=166, median age 63y) (p=0.07). Yet, 70.4% thrombotic events (venous: median age 46.5y; arterial: median age 57y) occurred in A1 and correlated with younger age (p=0.03). Only 3 pts developed a second event after diagnosis. These were counted in A2 (n=24, median age at thrombosis: 61y). Overall, thrombosis occurred either prior to or within the first 3y after diagnosis in 63/71 (89%) pts. Age & gt;60y could not be identified as a risk factor for thrombosis or type of thrombosis at any time point. The 5 y probability of no thrombotic event after diagnosis in pts & gt;60y was 90.4% vs. 89.2% for pts & lt;60y (p=0.8) and that of a thrombotic event & gt;3y after diagnosis in pts & gt;60y was 3.7% vs. 4.9% for pts & lt;60y (p=0.7). Similarly, A1 did not correlate with A2 (p=0.3). With 1691 patient-years for the entire cohort, the incidence of thrombosis after PV/ET diagnosis was 0.7 for arterial and 0.6 for venous events per 100 patient-years. Smoking was more prevalent in pts & gt;60y (p=0.003) and was not associated with thrombosis. Irrespective of age, hypertension (65%, p=0.03), hyperlipidemia (19%, p=0.008), and diabetes (16.4%, p=0.05) were frequent and correlated with A2 while atrial fibrillation (p=0.03) and inherited thrombophilia risk factors (p & lt;0.00) with A1. JAK2 allele burden (median 19%) and Hct & gt;45% (median 45%) at diagnosis correlated strongly with age & gt;60y (p=0.005) but not with A, A1, or A2, although Hct & gt;45% at diagnosis correlated with A2 in PV (p=0.001). Surprisingly, a Hct & gt;45% at thrombosis was more frequently present in A1 (55%) vs A2 (30%) (p & lt;0.00). Median WBC at diagnosis was higher in B compared to A (p=0.004), strongly associated with age & gt;60y (p & lt;0.00) but not with A2. WBC & gt;15% at thrombosis did not correlate with A. Age rather than thrombosis was the trigger for cytoreduction [82% hydroxyurea (HU) in B pts & gt;60y vs 53% in A pts & lt;60y] (p & lt;0.00). In PV, ASS did not correlate with thrombosis (25% of pts in B did not receive ASS). Cytoreduction, interval between diagnosis and cytoreduction, nor the duration of exposure correlated with thrombosis. Conclusions: The majority of thrombotic events occurred prior to or within the first 3 years after the diagnosis of JAK2 mutated PV/ET and were associated with CV-risk factors rather than older age. Phenotypic features such as Hct & gt;45%, high WBC, and JAK2 allele burden were associated with age & gt;60y and less with thrombosis. Their value as surrogate markers for therapeutic interventions to reduce thrombosis needs to be critically evaluated in larger series. Whether adequate PV/ET- or CV-risk- treatments account for the low rate of CV events after diagnosis (despite a higher incidence of CV-risk factors) compared to the general population could not be answered due to study design and needs to be addressed prospectively. Disclosures Al-Ali: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-139366

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 5945-5945

Abstract: Introduction: Prognosis of patients (pts) with high risk acute lymphatic leukemia (ALL) in first complete remission (CR) or ALL 〉 CR1 is poor. For years, myeloablative conditioning followed by allogeneic stem cell transplantation (HCT) was the only curative treatment option for eligible pts. Over the past years, reduced intensity conditioning (RIC) regimens have been introduced to provide a curative treatment for elderly pts or ones with comorbidities ineligible for myeloablative chemotherapy. In this retrospective survey we analyzed the outcomes of ALL pts not eligible for conventional myeloablative HCT who were treated with RIC-HCT. Patients and Methods: Twenty-eight (55% male, 45% female) consecutive pts, who underwent RIC-HCT from sibling (MRD) or unrelated donors (MUD) between 2003 and 2013 in our institution were analyzed. The median age at transplantation was 58 (range 23 to 71) years. The conditioning regimen consisted of Fludarabine 30 mg/m2 from days -4 to -2 and a 200 cGy total body irradiation on days -1 or 0 before HCT. Reasons for RIC HCT as opposite to myeloablative chemotherapy was age over 50 years for MUD, and age over 55 years for MRD HCT. Eight (28.5%) pts were younger than 50 years and had comorbidities, making them ineligible for a myeloablative conditioning regimen. Median follow up was 2.4 years for pts alive. Three pts (10.7%) underwent second HCT, one after early transplant failure and two after late rejections. Six HCTs (19.4%) were performed from sibling donors, 17 (54.8%) from human leukocyte antigen (HLA) matched unrelated donors and eight (25.8%) from HLA mismatched ( 〉 1 allele) donors. Eight of our patients (28.5%) were Philadelphia chromosome (Ph) positive. Results: After two years the overall survival (OS) was 49±10% and event-free survival (EFS) was 40.5±9.4% with a non-relapse mortality incidence of 34±9.6%. The cumulative incidence of relapse (CIR) amounted 37±9.6% at two years. There was no statistically significant difference in two years OS in pts after RIC-MRD vs RIC-MUD, however CIR was higher in pts with MRD than in pts with MUD, though without reaching statistical significance. Patients in CR1 had higher two years OS 63.1+12.1 compared to patients in CR2 or worse 42.4+14.8 though without reaching statistical significance. Noteworthy, six of eight patients in the high-risk Ph+ cohort are still alive and only one of them relapsed after HCT. Of the three pts who underwent second HCT, one died due to Graft versus Host Disease (GvHD) eight months after the second transplantation. The other pts are still in persistent CR seven and two years after the second HCT. Conclusion: RIC-HCT can be used in pts with ALL and is certainly a curative option for pts with higher age (up to 71 years) or severe comorbidities. In the high-risk Ph+ cohort we observed remission rates of 62.5%. Prospective studies are needed to define the role of RIC-HCT in high risk ALL or in remission after relapse even if only an one antigen mismatch unrelated donor is available. Disclosures Jaekel: Novartis: Honoraria. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Niederwieser:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.5945.5945

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 10 ( 2023-04-01), p. 1888-1897

Abstract: Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML). PATIENTS AND METHODS Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m 2 /d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression. RESULTS One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 10 9 /L and 31.2 × 10 9 /L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant inte raction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System–mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients ( P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm ( P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04). CONCLUSION Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407 ).

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.22.00437

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2023

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1790-1793

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157265

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 485-485

Abstract: Abstract 485 Transfusional iron overload (TIO) contributes considerably to treatment-related morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Data on post-HCT treatment of secondary hemochromatosis are limited. The results of an open-label, single arm, multi-center trial evaluating the efficacy and safety of the iron chelator deferasirox (DEX) in recipients of HCT with TIO are presented. Patients and methods: The study was conducted in 6 German centers. The primary objective was to evaluate if DEX could provide clinically acceptable chelation in a target pool of 76 adult patients (pts) with TIO 3–12 months after related/unrelated HCT irrespective of conditioning regimens. TIO was defined as a serum ferritin (SF) ≥1000ng/ml without active inflammation (CRP 〈 10mg/l), and a history of 〉 20 units of red blood cell transfusions (RBC) or 100mL/kg of prepacked red blood cells. Main exclusion criteria were ANC 〈 1000/mm3, transaminases (TA) 〉 5xULN, and serum creatinine (Cr) 〉 1.5xULN. DEX 30 minutes prior to lunch was started with 10 mg/kg/d over 52 weeks or until SF 〈 500ng/ml was reached. Subsequent dose adjustments were performed in steps of 5–10 mg/kg/d based on SF and safety assessments. DEX was reduced by 10mg/kg if Cr increased by 〉 33% of baseline (BL) or was 〉 1.5xULN. DEX had to be interrupted if any toxicity 〉 grade 2 according to the NCI common toxicity criteria (CTC) occurred. An independent Data Safety Monitoring Board reviewed safety data on an ongoing basis. Surrogate markers monitored were SF, serum transferrin and transferrin saturation (TS). Results: After a median of 168 days after HCT, 47 (62%) males and 29 (38%) females [median age 56 y] were included. Cyclosporine was taken by 54 (71%) pts. Median number of RBC prior to study entry was 37 units. Post-HCT, 14 (18.4%) pts received transfusions. Post-HCT HFE genotype was mutated in 27/67(40%) pts (heterozygote-H63D,n=13; heterozygote-C282Y,n=7; heterozygote for other mutations, n=6; homozygote-H63D,n=1). At BL, median SF and TS were 2045ng/ml and 56% respectively at a median CRP of 2.7 mg/l. SF correlated with TS (r=0.5, p 〈 .0001), and the number of RBC (p=0.01). DEX was started with a median daily dose of 625mg. From BL to the end of study (EOS), mean daily dose was 629 (9 mg/kg/day) with a median of 503.7mg. SF declined steadily with a median of 957ng/ml at EOS representing a 53% reduction from BL (p 〈 .0001). An initial rise in TS with a median of 92% at a median of 7 weeks was followed by a steady decrease reaching a median of 44.4% at EOS. Over time, stable trough serum cyclosporine levels per patient were measured irrespective of DEX dose. Hb improved under treatment with a median Hb of 12.7g/dl at EOS representing a 12.4% increase from BL. Chronic GvHD was documented in 34 (44.7%) pts (limited 79%; extensive 21%). DEX was discontinued in 8 (9.3%) pts due to relapse/progression of hematologic disease and in one patient (1.3%) due to anemia. Overall, in 1008 safety assessments performed, leucopenia, neutropenia, thrombocytopenia, and TA elevations 〉 grade 2 were 1.6%, 2.3%, 5.5%, and 2.8% respectively. Main non-hematologic adverse events (AEs) were gastrointestinal (GIT) (nausea, vomiting, diarrhea) (16.9%); infections (15.1%); skin (rash, erythema) (4.4%). Cr values above BL were observed in 41 (54%) pts. At EOS, median Cr was above BL by a median of 10 μmol/l. AEs were mostly mild to moderate, transient, and dose-related. On study, a median of 2 drug dosage adjustments/interruptions were made mainly for Cr elevation (27%), GIT-AEs (15%), TA elevation (10.4%), and skin AEs (3.8%). Study drug was permanently discontinued because of GIT-AEs in 3 (4%), skin AEs in 3 (4%), TA in 2 (2.6%), and Cr in 2 (2.6%) pts. Conclusions: A highly significant reduction in serum ferritin could be induced with deferasirox after allogeneic HCT with an acceptable safety profile. Stable trough serum cyclosporine levels could be maintained over time irrespective of the daily dose of deferasirox. Our results indicate that a daily dose of 7.5–10mg/kg is effective, and well tolerated in a complex cohort with TIO after allogeneic HCT. Disclosures: Al-Ali: Novartis: Honoraria. Lieder:Novartis Germany: Employment. Albrecht:Novartis Germany: Employment. Leismann:Novartis Germany: Employment. Bug:Novartis Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant Other. Kroeger:Novartis Germany: Honoraria, Research Funding. Platzbecker:Novartis Germany: Advisory Board Other, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.485.485

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2808-2808

Abstract: Enhanced progenitor proliferation, bone marrow (BM) hypervascularization and disturbed immune regulation contribute to the pathogenesis of myelodysplastic syndromes (MDS). Inhibition of mammalian-target of rapamycin (mTor) by temsirolimus (TEM) might be a promising strategy to target these disease-specific cellular alterations. We report on the effects of single agent TEM on the clinical course as well as on immune composition and BM vascularization of MDS patients treated within the prospective, multicenter “TEMDS”-trial (NCT01111448). Patients, Materials and Methods Twenty patients being either IPSS low/int-1 MDS (n = 9) or IPSS int-2/high after azacitidine failure were treated with TEM at a dose of 25 mg/week in the absence of toxicity or disease progression. BM was reevaluated after 4 months of treatment with the option of TEM continuation for a maximum of 12 months in responding patients. Translational research within this study included flowcytometry-based measurement of changes in T-cell composition as well as determination of cytokine levels and BM-vascularization prior to and after TEM. Results Of 20 patients treated, 15 discontinued TEM treatment prematurely due to intolerable side effects (n = 11), infectious complications (n = 3), or progression to AML (n = 1). Fatigue, stomatitis and profound leukopenia were the most frequent adverse events. A total of 13 severe adverse events were encountered in 10 patients and 1 patient died of infectious complications during TEM treatment. Of the 5 patients who were treated for at least 4 months and underwent regular BM reevaluation, none showed signs of response according to IWG criteria. TEM treatment resulted in a remarkable, although non-significant, decrease in total number of lymphocytes in the pB (pre: 74.6%, post: 48.4%, p = 0,083) and BM (pre: 23.5% post: 20.1%, p = 0.123). Within the T-helper cell compartment a trend towards an increase in regulatory T-cell (Treg) frequency was observed (pB: pre: 6.0 %, post: 6.4 %, p = 0.083). Moreover, the balance between naive (CD45RA+/CD45RO-) and activated/memory (CD45RA-/CD45RO+) Treg shifted significantly in favor of the latter (p = 0.004). Plasma analysis in BM and pB revealed, that these changes were obviously not mediated by alterations in TGFβ plasma levels. In a total of 12 assessable patients, a significant (p = 0.006) decrease of BM vascularization was observed after treatment with TEM for a median of 5 weeks (Fig. 1). There were, however, no changes in the medullary or peripheral blood VEGF concentration (data not shown). Conclusions Selective inhibition of the mTOR signaling cascade in MDS patients results in specific alterations of the composition of T-cell subsets as well as BM vascularization. Given the absence of any hematological response we suggest that these drug-induced modifications cannot alter the natural course of the disease. Disclosures: Wermke: Pfizer: Research Funding. Off Label Use: Temsirolimus is licensend for the treatment of MCL and RCC but not MDS. Platzbecker:Pfizer: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2808.2808

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. TPS6642-TPS6642

Abstract: TPS6642^ Background: Ruxolitinib, a potent and selective oral JAK1/2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 studies in pts with PMF, PPV-MF, or PET-MF. There is considerable experience in pts who develop thrombocytopenia on study, and ruxolitinib is well-tolerated with dose adjustment. However, there is limited experience in pts with baseline thrombocytopenia as those with low PLTs ( 〈 100 x 10 9 /L) were excluded from the phase 3 protocols. EXPAND (Evaluating RuXolitinib in Patients with Low Baseline PlAtelet CouNts Diagnosed With Myelofibrosis) will evaluate the safety of ruxolitinib and establish the maximum safe starting dose (MSSD) in thrombocytopenic pts with MF. Methods: This is a phase 1b, open-label, dose-finding study (NCT01317875) in pts with PMF, PPV-MF, or PET-MF and baseline PLT 50-100 x 10 9 /L. A Bayesian logistic regression model with escalation with overdose control will be used to guide dose-escalation decisions. The study consists of 2 phases: dose-escalation and safety-expansion. The starting dose is ruxolitinib 5 mg twice daily (BID) with a maximum of 15 mg BID. In the dose-escalation phase, cohorts will be: 5 mg BID, 5 mg am/10 mg pm, 10 mg BID, 10 mg am/15 mg pm, and 15 mg BID; only pts with PLT 75-100 x 10 9 /L (1st stratum) will initially be enrolled. Once safety is established at the first 2 dose levels (5 mg BID; 5 mg am/10 mg pm), pts with PLT 50-75 x 10 9 /L will be included (2nd stratum). Each dose level in the 2nd stratum will be open only if both that dose and the following one are deemed safe in the 1st stratum. In the safety-expansion phase, 20 pts (10 from each stratum) additional to those treated at the MSSD during dose escalation will be treated at the respective MSSD for their stratum. In cohort 1 (n = 4), 3 pts were evaluable as they completed 〉 28 days of treatment; 1/4 pts discontinued after 6 doses due to disease progression. No dose-limiting toxicities were observed. The second cohort (5 mg am/10 mg pm) has completed enrollment (n = 3) and is ongoing.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2012.30.15_suppl.tps6642

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2012

detail.hit.zdb_id: 2005181-5

In: Blood Cells, Molecules, and Diseases, Elsevier BV, Vol. 66 ( 2017-07), p. 11-18

Type of Medium: Online Resource

ISSN: 1079-9796

URL: Article

DOI: 10.1016/j.bcmd.2017.07.003

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 1462186-1

detail.hit.zdb_id: 1237083-6

In: Journal of Health Psychology, SAGE Publications, Vol. 18, No. 7 ( 2013-07), p. 939-949

Abstract: The aim of this study was to determine the effect of art therapy on post-traumatic growth in patients with haematological malignancies in a non-randomised trial ( n = 36, intervention group; n = 129, control group). Art therapy was administered over a period of 22 weeks in small groups. Post-traumatic growth was measured with the Stress-Related Growth Scale. After controlling for the effect of potential confounders, no difference in post-traumatic growth was observed between the intervention and control groups after 22 weeks. There was no evidence for an effect of weekly group sessions with art therapy on post-traumatic growth in patients with haematological malignancies.

Type of Medium: Online Resource

ISSN: 1359-1053 , 1461-7277

URL: Article

DOI: 10.1177/1359105312458332

Language: English

Publisher: SAGE Publications

Publication Date: 2013

detail.hit.zdb_id: 2021897-7

SSG: 5,2