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In: Leukemia, Springer Science and Business Media LLC, Vol. 35, No. 8 ( 2021-08), p. 2332-2345

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-01117-w

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2008023-2

In: Leukemia & Lymphoma, Informa UK Limited, Vol. 59, No. 1 ( 2018-01-02), p. 187-195

Type of Medium: Online Resource

ISSN: 1042-8194 , 1029-2403

URL: Article

DOI: 10.1080/10428194.2017.1321751

Language: English

Publisher: Informa UK Limited

Publication Date: 2018

detail.hit.zdb_id: 2030637-4

In: Leukemia Research, Elsevier BV, Vol. 130 ( 2023-07), p. 107308-

Type of Medium: Online Resource

ISSN: 0145-2126

URL: Article

DOI: 10.1016/j.leukres.2023.107308

Language: English

Publisher: Elsevier BV

Publication Date: 2023

detail.hit.zdb_id: 2008028-1

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2633-2633

Abstract: Tyrosine kinase inhibitor (TKI) therapies have profoundly changed the natural history of chronic myeloid leukemia (CML) and prolonged survival. However, in vitro and in vivo data suggest strongly that the eradication of the most primitive CML stem cells will not be possible by the use of TKI therapies alone. The mechanisms of this inefficiency might involve cell autonomous (activation of alternate signaling, reduced BCR-ABL expression) or non-cell autonomous (niche-related) pathways. It would therefore be of major interest to determine if compounds targeting CML progenitors and stem cells can be used in combination with TKI. Few targeted therapies have been so far shown to be clinicaly acceptable. We have used for this purpose Inecalcitol (19, nor 14 epi 23-yne-1,25 (OH)2D3) (ICC),a vitamin D3 analog, which has been shown to exert antiproliferative effects in several types of cancer cell lines. CD34+ cells isolated from CML patients at diagnosis (n = 15) were tested in clonogenic assays (500 CD34+ cells / dish in triplicate). Interestingly, ICC alone is highly efficient to inhibit the clonogenic growth in the majority of the CML patients at diagnosis (10/ 15 patients). The combination of ICC with either Imatinib Mesylate (IM), Dasatinib (DA) or Nilotinib (NIL) in clonogenic assays showed a synergistic effect for the inhibition of CFC growth (10 - 25% CFC survival) using IM (n = 15 patients). In the same conditions, we have not observed any significant inhibitory effect of IM and ICC combination in cord-blood derived progenitors (n = 3). To determine the effects of these combinations in the most primitive stem cells, we have performed long-term cultures initiating cell (LTC-IC) assays using purified CD34+ cells (4.104 cells / dish) from CML patients with half medium changes each week for 5 weeks. The combination was tested in 6 (ICC+ IM) and 4 (ICC + DA / NIL) CML samples. As a control, CD34+ cells from cord blood were used. In CML samples tested with the combination of either IM / ICC (n = 6) or DA/ NIL and ICC (n = 4), CML LTC-IC derived progenitors were highly inhibited (ICC and IM) or undetectable (ICC and DA or NIL). Short-term cultures of CML CD34+ cells in the presence of 5 growth factors with or without ICC showed that ICC induced the expression of myeloid markers and highly favored the appearance of double positive CD14/CD15 cells. Experiments are underway to determine if ICC interferes with the expression of the components of SHH pathway (Smo, Ptched, Gli). as well as the gene expression profiling of CML cells treated with ICC. Thus, these results establish that ICC, a clinically used derivative of vitamin D3 has a clear activity in CML progenitors by itself and a major synergistic effect with TKI. A clinical phase 2 trial aiming to confirm the synergistic effect of ICC and TKI is ongoing in CML patients treated with imatinib. Citation Format: Ali G. Turhan, Hyacinthe Johnson Ansah, Patricia Hugues, Camille Debord, Remi Delansorne, Agnes Guerci-Bresler, Jean Francois Dufour Lamartinie, Annelise Bennaceur-Griscelli. Vitamin D3 analog inecalcitol synergizes with tyrosine kinase inhibitors (TKI) and selectively inhibit the growth of chronic myeloid leukemia (CML) progenitors: Development of a clinically applicable leukemic stem cell targeting strategy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2633. doi:10.1158/1538-7445.AM2015-2633

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2015-2633

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2015

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 22 ( 2019-11-15), p. 6606-6613

Abstract: Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation. Patients and Methods: We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML. Results: A total of 218 patients with de novo chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1–64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in BCR-ABL1 levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%–59%] at 6 months, and 50% (95% CI, 43%–57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415–0.972] and P = 0.008 (HR, 0.556; 95% CI, 0.360–0.858), respectively. Conclusions: We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with de novo chronic phase CML. See related commentary by Yan et al., p. 6561

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-18-3373

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2019

detail.hit.zdb_id: 1225457-5

detail.hit.zdb_id: 2036787-9

In: British Journal of Haematology, Wiley, Vol. 195, No. 3 ( 2021-11), p. 469-471

Type of Medium: Online Resource

ISSN: 0007-1048 , 1365-2141

URL: Issue

URL: Article

DOI: 10.1111/bjh.v195.3

DOI: 10.1111/bjh.17761

Language: English

Publisher: Wiley

Publication Date: 2021

detail.hit.zdb_id: 1475751-5

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 134-134

Abstract: Background: Combination of Pegylated-Interferon alpha (Peg-IFNa) 2a and imatinib (IM) has been reported to significantly induce higher rates of molecular responses (including undetectable BCR-ABL transcript) over IM alone, as frontline therapy for CP-CML patients (pts) in a randomized phase 3 trial (SPIRIT, Preudhomme et al, NEJM 2010). Second generation TKIs such as dasatinib (DASISION, Kantarjian et al, NEJM 2010) enhance the speed and depth of molecular response (MR) in comparison to IM. Phase II trial using nilotinib and PegIFNa2a has recently reported high rates of deep molecular response (MR4.5) within 24 months (Nicolini FE et al, Lancet Haematology 2015). Aims: To determine the efficacy and safety of the combination of dasatinib and Peg-IFNa2b in CP-CML frontline. (EUDRACT Number: 2012-003389-42, Dasa-PegIFN trial). Methods: Newly diagnosed Ph+ CP-CML pts less than 65-year-old started dasatinib 100 mg/day. At 3 months, they were assigned to receive Peg-IFNa2b associated to dasatinib when platelets (plt) 〉 100 X 109/L, Neutrophils (ANC) 〉 1.5 X 109/L) and lymphocytes 〈 4.0 X 109/L counts were achieved. Otherwise, dasatinib was continued alone in the study according to the current international ELN guidelines. The maximum duration of the combination dasatinib and Peg-IFNa2b is 21 months. The primary endpoint is the cumulative rate of Molecular Response 4.5log (MR4.5 defined as BCR-ABL1/ABL1IS≤0.0032%) at 12 months. Molecular analyses were centralized and expressed according to the international scale (IS). Secondary endpoints included efficacy (cytogenetic and molecular responses at several time-points) and safety endpoints. Preliminary results are reported here. Results: 81 pts were enrolled between October 2013 and July 2014. All pts will have completed the 12 months follow-up time-point in August 2015. 79/81pts were included in the analysis (1 pt died of a CML-related haemorrhage before receiving dasatinib, 1 screening failure (masked Ph)). Median age was 48 (20-65) years. 54% of pts were male. Sokal scores were low, intermediate and high in 51%, 32% and 17% of pts respectively. After the first 3 months of therapy (M3), sixty-one patients (77%) started Peg-IFNa2b at the dose of 30 microg/week in association with dasatinib. For these pts after M3, reported hematologic adverse events (AE) were neutropenia (G3/4 n=11; G1/2 n=17), thrombocytopenia (G3/4 n=0; G1/2 n=7), anemia (G3/4 n=0; G1/2 n=7). Extra-hematologic AE were essentially of low grade (overall, G3/4 n=3; G1/2 n=113). According to NCI CTCAE V4.0, most frequent AE were infections (16%), general symptoms (15%), skin lesions (10%), hepato-biliary abnormalities (7.7%), nervous system/headache (7.7%) musculoskeletal pain (7%), psychiatric (7%), GI (6%) disorders. Eight serious AE (SAE) were reported after Peg-IFNa2b initiation: G4 neutropenia n=2, dysthyroitidis n=1, dyspnea n=1, pleural effusion n=1, lymphoid hyperplasia n=1, hemorrhoids n=1, rectal fistula (SUSAR) n=1. Efficacy was analysed according to the intention-to-treat principle (ITT), and considering missing data as no response to avoid inflated results. Overall at M3, 85% of pts had a BCR-ABL1/ABL1 ratio ≤10%. For eligible patients who received combined therapy (n=61), rates of MMR were 16%, 51%, 70%, and 70% (pending n=5) at M3, M6, M9 and M12, including MR4.5 rates 10%, 20%, 30% at M6, M9 and M12 respectively. Eighteen pts (22.7%) were not eligible to receive Peg-IFNa2b. Reasons, according to protocol criteria, were ANC 〈 1.5 X 109/L (n=10), plt 〈 100.0 X 109/L (n=5), lymphocytes 〉 4.0 X 109/L (n=1), absence of complete hematologic response (n=1), non compliance (n=1). Rates of MMR for these pts were 27% at M6, 50 % at M9 (missing n=2), pending data for n=6 at M12. Conclusion: Peg-IFNa2b combined to dasatinib therapy in first line CP-CML induces a high rate of deep molecular response (ie MR4.5) during the first year of therapy. Despite few pending data, results at 12 months are already in line with previous data combining Peg-IFNa and TKI, expecting a potential for an increased rate in therapy cessation attempt. Preliminary data of this phase II trial indicate a manageable toxicity profile for this combination, despite an increased rate of neutropenia. Updated analyses (ITT and per protocol) will be presented for all the pts with at least 12 months follow-up. Disclosures ROY: BMS: Other: CongressTravels/Accomodations, Research Funding, Speakers Bureau; Novartis: Other: Congress Travels/Accomodations, Research Funding, Speakers Bureau; Merck: Other: Peg-Interferon provided in the trial. Guerci-Bresler:Novartis: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau; PFIZER: Speakers Bureau. Giraudier:BMS: Speakers Bureau; Novartis: Other: Congress Travel/Accomodation, Speakers Bureau. Johnson-Ansah:Hybrigenics SA: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau. Amé:Novartis: Speakers Bureau; BMS: Speakers Bureau. Etienne:BMS: Consultancy, Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau. Nicolini:BMS: Other: Travel/Accommodations/Expenses; Novartis: Other: Travel, Accommodations, Expenses; ARIAD: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting or Advisory Role, Speakers Bureau; Novartis: Honoraria, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau. Rea:Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Ianotto:Novartis: Other: Congress Travel/ Accomodations. Legros:ARIAD: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Coiteux:BMS: Speakers Bureau. Hermet:BMS: Speakers Bureau; Novartis: Speakers Bureau. Mahon:BMS: Speakers Bureau; Novartis: Speakers Bureau. Rousselot:ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.134.134

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3059-3059

Abstract: Ecto-nicotinamide Adenine Dinucleotide Oxidase 2 (ENOX2) or Tumor-Associated Nicotinamide Adenine Dinucleotide Oxidase (tNOX), plays a major role as a membrane hydroxyquinone oxidase catalyzing the conversion of reduced NADH to the oxidized NAD+ .Cellular NAD+/NADH ratio plays a major role in the regulation of several metabolic pathways such cell cycle and apoptosis. The membrane NAD+/NADH ratio has been shown to be involved membrane lipid and sphingomyelin metabolism. Several lines of experimental data indicate that ENOX2, as compared to ENOX1 isoform, is preferentially expressed in cancer cells and ENOX2 is also secreted in the serum of patients with cancer and representing a surrogate marker for cancer progression as well as a drug target. The expression of ENOX2 in CML has not been studied so far. To this end, we have analyzed the expression of ENOX2 by Western blots in 40 patients with CML at diagnosis and compared this expression to that of control cells from healthy donors (n= 30). ENOX2 expression was found to be highly increased ( x 6.6 fold) in primary leukemic cells and this was highly significant ( p= 0.0081). To determine if ENOX2 expression is related directly to BCR-ABL expression, we have analyzed the expression of ENOX2 in UT7 cell line and its BCR-ABL-expressing counterparts UT7-11. As compared to parental UT7, ENOX2 expression was highly increased in UT7 cells expressing either native or T315I-mutated BCR-ABL. This increase was also documented in DOX- inducible cell line BaF/p210 sin1.55 in which activation of BCR-ABL expression correlated with ENOX2 expression. The expression of ENOX2 in CML cells was a tyrosine kinase-dependent event as demonstrated by Western blot experiments showing that ENOX2 expression was reduced UT7/11 cell line treated with Imatinib mesylate (1 microM) for 6, 18 and 24 hours whereas there was no change in ENOX2 expression in similarly treated parental UT7 cell line. As ENOX2 is a protein secreted from tumor cells, we have analyzed the levels of ENOX2 in the plasma of CML patients at diagnosis as compared to controls. A series of 41 patients with CML as compared to plasma from 28 healthy donors were analyzed by ELISA. This analysis showed a highly significant increase of ENOX2 protein levels in the plasma of patients with CML (mean levels of 800 pg/ml in CML versus 500 pg/ml, Mann-Whitney U-Test, p 〈 0.0001). There was no correlation between ENOX2 levels and leukocyte numbers at diagnosis. In order to determine the potential clinical value of ENOX2 expression in different phases of the disease, ENOX2 expression in CML CD34+ cells was compared to healthy donor samples in microarray dataset GSE 4170. CML patients in chronic phase overexpressed ENOX2 in CD34+ cells as compared to control (two-sided test with Welch correction p-value=0.00054). Gene expression pattern matching correlating ENOX2 in CML CD34+ cells was determined in three phases of the disease. Pavlidis template matching algorithm used with ENOX2 as predictor allowed to discover 301 genes correlated with CML in chronic phase. Unsupervised principal component analysis performed with ENOX2 pattern matching gene expression profile allowed us to discriminate the 3 phases of CML in CD34+ cell compartment in a highly significant manner (p-value 6.75E-15). Functional enrichment performed with ENOX2 pattern matching on Gene Ontology Biological Process database revealed implication of different pathways of cell signaling such as: Rho GTPase, MAPKs, GPCR, RAS and NOTCH pathways, the latter being connected to stem cell biology. This analysis also showed implication of metabolic functions such as carbohydrate homeostasis. Other functionalities that could act on hematopoiesis have been also highlighted by this analysis such as proliferation, integrin-mediated signaling, and circadian rhythm. Finally genes related to angiogenesis have been also found to be implicated in ENOX2 signalling such as placental growth factor (PLGF) also EPHB3 which is a receptor tyrosine kinase implicated in cell migration. Overall these results suggest that ENOX2 pathway plays a major role in the pathogenesis of CML and represents, to the best of our knowledge, the first surrogate secreted tumor marker in CML. ENOX2 expression correlates with disease progression and experiments are underway to determine the use of ENOX2 as a drug target in CML and T315I-mutated CML stem cells. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3059.3059

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 456-456

Abstract: Abstract 456 Background: The SPIRIT phase III randomized multicenter open-label prospective trial was designed to compare 4-arm, imatinib 400 mg versus imatinib 600 mg versus imatinib 400 mg + cytarabine at a dose of 20 mg/m2/day in cycles of 28 days, versus imatinib 400 mg + PegIFN at an initial dose of 90 μg/week. The planned molecular analysis after 1 year based on the outcome of 636 pts resulted in a highly significant improvement of superior molecular response (SMR) (0.01 % Bcr-Abl/Abl on IS) of the combination imatinib 400mg-PegIFN (N Engl J Med, 2010). Accrual within the imatinib 600 mg and imatinib 400 mg-cytarabine has been stopped. In the initial cohort of 171 pts who had been treated less than 4 months with the 2 combined agents, major molecular response (MMR: 0.1%) rate was 48%, SMR rate was 23%, and undetectable molecular residual disease (UMRD) was 8%. By contrast, in pts receiving the combined agents longer than 12 months, MMR, SMR and UMRD rates were 82%, 49% and 20% respectively. In order to improve tolerability of the combination, initial dose of PegIFN has been reduced to 45μg/week. The current analysis focuses on the tolerability and efficacy of the reduced dose of PegIFN as compared to the initial planned dose of 90μg/week. Patients and methods: As of December 31st 2010, date for closing accrual, 789 pts have been included, 445 pts within the imatinib 400mg and imatinib 400mg+PegIFN arms. The high proportion of PegIFN discontinuation during the first year prompted an amendment that recommended reducing the initial dose down to 45ug/week at enrolment. For these pts the weekly dose of PegIFN was increased up to 90μg after 2 months of treatment with the combination of PegIFN 45μg plus Imatinib 400mg, if the hematological and non-hematological tolerance was acceptable. Out of the 221 pts assigned to imatinib plus PegIFN, 171 received 90μg and 50 received 45μg/week of PegIFN, both groups being similar with a median age of 51 and 48 years respectively. Molecular biology was centralized, samples being collected every 4 months, with a karyotype recommended yearly. Data of parameters of effectiveness and tolerance were collected even after stopping treatment protocol. Adverse events (AE) considered for the analysis are those which led for PegIFN dose adjustment. Results. At the time of the analysis, 30% of pts were still on PegIFN. Table 1 describes the AE which occurred during the two consecutive periods of the trial (before and after the amendment). Hematologic toxicity was predominant within the PegIFN arm (68% pts suffering all grade including 54% with G3-4) leading to 40% of permanent discontinuation of PegIFN. However, only a small proportion of neuropsychiatric syndrome (including depression, chronic fatigue and insomnia) and flu-like syndrome were observed and no cardiac event occurred with PegIFN at the dose of 45μg/week. Rate of all grade hematologic toxicity decreased from 68% to 45% of pts after the amendment. Of interest the reduced dose of PegIFN had a significant impact on the adherence to the treatment. During the first 6 months before and after the amendment, 40% and 10% of pts discontinued PegIFN respectively. Thus after the amendment 90% received at least 6 months of PegIFN. Of note the reduced dose of 45μg/week resulted in a similar response rate as compared to the initial planned dose of 90μg. The MMR rates at 6 months were before and after the amendment 36.3% (95%CI: 29.1–49.3) and 36% (95%CI: 22.0–50.8) respectively. The corresponding number for SMR rates at 6 months were 9.9% (95%CI: 5.9–15.4) and 10% (95%CI: 3.3–21.8) respectively. Finally for 222 pts, imatinib 400mg alone resulted in less responses at 6 months with MMR and SMR rate of 19.3% (95CI: 14.3–25.0) and 5.8% (95CI:3.1–0.7) respectively. The combination of imatinib and PegIFN has been shown in this trial as an effective combination for increasing the rate of molecular responses compared to imatinib alone. The lower dose of PegIFN (45 mg/week) resulted in less early toxicity. It will allow the combination to be given together for a longer period of time and preserve the increased antitumor efficacy. An update with a minimum of 12 months of follow-up of the 50 pts will be presented. Disclosures: Off Label Use: Pegylated form of interferona2a.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.456.456

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Turkish Journal of Hematology, Galenos Yayinevi, Vol. 40, No. 2 ( 2023-5-30), p. 101-117

Type of Medium: Online Resource

ISSN: 1300-7777 , 1308-5263

URL: Journal

URL: Article

DOI: 10.4274/tjh

DOI: 10.4274/tjh.galenos.2023.2022-0339

Language: Unknown

Publisher: Galenos Yayinevi

Publication Date: 2023

detail.hit.zdb_id: 2060411-7

detail.hit.zdb_id: 2455884-9