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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: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 75, No. 05 ( 1996), p. 862-863

Type of Medium: Online Resource

ISSN: 0340-6245 , 2567-689X

URL: Article

DOI: 10.1055/s-0038-1650383

Language: English

Publisher: Georg Thieme Verlag KG

Publication Date: 1996

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: Leukemia Research, Elsevier BV, Vol. 39, No. 4 ( 2015-04), p. 453-461

Type of Medium: Online Resource

ISSN: 0145-2126

URL: Article

DOI: 10.1016/j.leukres.2015.01.008

Language: English

Publisher: Elsevier BV

Publication Date: 2015

detail.hit.zdb_id: 2008028-1

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: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 556-556

Abstract: The French group, GOELAMS, performed a multicenter phase III randomized open trial to evaluate whether adding androgens to post-remission induction therapy was associated with an improved outcome in elderly pts with de novo AML. All patients received the ICL induction protocol (idarubicin 8mg/m2 day1–5, cytarabine 100mg/m2 day1–7 & lomustine 200mg/m2 day1). Patients in complete or partial remission received maintenance therapy consisting in 6 reinduction courses (idarubicin 8mg/m2 day1, cytarabine 100mg/m2 day1–5.), once every 3 months, with a continuous regimen of methotrexate and 6-mercaptopurine in-between these. At diagnosis, patients were randomized to receive (AndroG arm) or not (Control arm) norethandrolone 10 to 20 mg per day, according to body weight. Androgen was started after recovery from aplasia, between day-20 and day-30 following induction chemotherapy, and was to be continued during the 2-year maintenance therapy period if a complete or partial remission was achieved following induction chemotherapy. The two arms were well-balanced for known prognostic factors. Between June 2002 and January 2005, 330 patients with de novo AML and age 60 y (median 70, range 60–86) were included. Pts with acute promyelocytic leukemia were not included. At diagnosis, ECOG was 0–1, 2, 3–4 in 270, 55, and 5 cases; WBC count was & lt; 4 G/L, & gt; 30 G/L, & gt; 100 G/L in 141, 85, and 33 pts. Of note, 61% of the pts with a WBC count & lt; 4 G/L were males, and 52% of males had a low WBC count vs 33% of females (p & lt;0.001). Centrally reviewed cytogenetics was available in 308 cases (high-risk, 78; int-risk, 185; low-risk, 15; failures, 30). Median follow-up from induction chemotherapy was 1.1 y (1st quartile, 0.34 y; 3rd quartile, 2.91 y) for the overall group, and 3.6 y (1st quartile, 3.2 y; 3rd quartile, 4.3 y) for pts alive at last news. Complete remission, on days 40 and 80, was achieved by 56% vs 52%, and 83% vs 79% of the pts in Control and AndroG arms, respectively. Twelve pts from the AndroG arm did not receive norethandrolone. Fine & Gray competing-risk model was used to estimate 5-year relapse incidence and the effect of norethandrolone on this endpoint. As for relapse, the potential benefit of norethandrolone on 5-year leukemia-free survival (LFS), event-free survival (EFS), and overall survival (OS) was analyzed on an intention-to-treat basis, using univariate and multivariate adjusted models. S-Plus2000Pro software was used for all analyses. Results: Crude univariate analyses regarding the effect of androgen randomization on 5-year relapse incidence, LFS, EFS and OS are listed in Table 1. Table 1 Full time period from diagnosis HR, hazard ratio; CI, confidence interval; Cox p-val, p-value of Cox regression model. Endpoints Control AndroG Gray test p-val HR; 95%CI Cox p-val Relapse 66% 54% 0.21 -- -- LFS 23% 33% -- 0.79; 0.58–1.09 0.15 EFS 16% 22% -- 0.95; 0.75–1.22 0.69 OS 19% 26% -- 0.96; 0.74–1.23 0.72 Of note, the effect of norethandrolone on relapse incidence, LFS, EFS, and OS, was violating the proportional hazards assumption (scaled Schoenfeld residuals analysis). Since the 2 hazards rate functions crossed each other, which would result in ineffective comparisons if using log-rank tests, time-dependent models were considered. For all these endpoints, as estimates for the 2 arms were not significantly different during the first year, but diverged during the following years, favoring the AndroG arm (Table 2, Figure 1), a step-function at 1 year from diagnosis was considered. Table 2 Time period starting 1 year from diagnosis Endpoints Control AndroG Gray test p-val HR; 95%CI Cox p-val Relapse 55% 33% & lt; 0.01 -- -- LFS 37% 54% -- 0.56; 0.33–0.94 0.028 EFS 32% 52% -- 0.57; 0.36–0.89 0.013 OS 37% 60% -- 0.63; 0.41–0.96 0.034 Figure Figure Thus, for pts alive and in complete remission at 1 year from diagnosis, relapse incidence was lower, while LFS, EFS and OS were higher in the AndroG arm, even after adjusting for other significant covariates (p=0.029 Relapse; p=0.038 LFS; p=0.028 EFS; p=0.029 OS). Moreover, the beneficial effect of norethandrolone was more pronounced in males, and in pts having WBC count & lt; 4 G/L as shown in Figure 2 for the LFS. Figure Figure Conclusion: addition of low-dose norethandrolone to maintenance chemotherapy is associated with an improved outcome in elderly pts with AML; especially in those achieving CR and remaining in remission for at least a year. Improved outcome was observed with androgen in males and/or in pts with low proliferative disease.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.556.556

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1803-1803

Abstract: Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a median age of approximately 60 years (Hoglund M 2013). However, little is known about outcomes in CML in adolescents and young adults. In the literature there are few reports involving only patients enrolled in trials aged from 15 to 30 years (Cortes J 2012, Kalmanti L 2013). We report here the characteristics and outcomes in 78 unselected adolescents and young adults ranging from 18 to 25 years with newly diagnosed CML in chronic (n=73) or in accelerated phase (n=5) in the tyrosine kinase inhibitor (TKI) era from 13 Fi-LMC centers being in possession with local databases. The median follow-up is 56 months (0-144) after diagnosis. Sokal scores were low in 41 (56%) patients, intermediate in 10 (13%), and high in 13 (17%) and unknown in 9 (14%) patients. Five patients had a CCA/Ph+ but were in CP cytologically, at diagnosis. Initial TKI were imatinib alone (n=55) or in combination with IFN (n=3), nilotinib alone (n=5) or in combination (n=1), dasatinib alone (n=10) or in combination (n=1) or ponatinib (n=1). One patient died before treatment initiation from brain hemorrhage, and initial treatment is unknown in one patient. Only 38/76 (50%) of patients remained under TKI first-line at latest follow-up. The reasons of first-line discontinuation were blast crisis (n=3); according to ELN criteria, cytogenetic failures (n=10), molecular failures (n=5), molecular warnings (n=8), mutation (n=1); intolerance (n=6), FDA notification in EPIC study (n=1). The second-line therapies were imatinib (n=2), IFN in combination with aracytine (n=1), nilotinib (n=13), dasatinib (n=13), high-dose chemotherapy alone (n=1) or followed by allogeneic bone marrow transplantation (n=4). 13 patients discontinued their second line TKI for blastic transformations (n=2), cytogenetic failures (n=4), molecular failures (n=2), molecular warning (n=1), mutation (n=1) and intolerance (n=3). The third-line therapies were imatinib (n=1), nilotinib (n=2), dasatinib (n=5), ponatinib (n=1), chemotherapy alone (n=1), allo-transplantation (n=1). Only 25/78 (32%) of patients were included in a trial. Only one patient experimented a 4th line of TKI (ponatinib). We compared characteristics and outcome of the 2 groups of patients, enrolled in first line versus unenrolled (Table 1). There were significantly more men included than women. Accelerated phases and CCA/Ph+ were observed only in the unenrolled group. The overall survival is shown in Figure 1A. Blastic transformation, failure of TKI defined as ELN 2013 recommendations and death were used to calculate the EFS curve (Figure 1B). Finally, we designed a curve representing the probability to remain under first-line TKI: 2nd line TKI-Free Survival (Figure 1C). A complete analysis comparing characteristics and outcome between the 2 groups of patients, will be available for ASH presentation. Table 1: Characteristics of patients Total patients n=78 Enrolled patients n=24 Unenrolled patients n=54 P value Ratio H/F (n) 50/28 18/5 22/32 0.0025 Median age (years) 22 23 22 NS CCA/Ph+ (n) 5 0 5 - Phase (C/A) (n) 73/5 24/0 49/5 NS Sokal (L/I/H/U) (n) 41/10/13/9 16/2/5/1 25/8/8/8 NS Median FU (months) (Range) 56 (0-144) 41 (2-114) 63 (0-144) - Interval from D to 1st line TKI (days) 27 29 24 - 1st line TKI (I/N/D/P/NA)(n) 58/6/11/1/2 9/4/10/1/0 49/2/1/0/2 NS Median 1st line TKI duration (months) 27 26 28 - Discontinuations (n) 38 8 30 0.069 Discontinuation reasons (n) Blastic phase Cytogenetic failure Molecular failure Molecular warning Intolerance Pregnancy Sustained CMR FDA notification Mutation 3 10 5 8 6 2 2 1 1 0 3 3 0 0 0 1 1 0 3 7 2 8 6 2 1 0 1 TKI line Number (1/2/3/4)(n) 38/19/10/1 17/5/2/0 24/12/8/1 - Abbreviations: U unknown; FU follow up; D diagnosis; I imatinib; N Nilotinib; D dasatinib; P Ponatinib; TKI Tyrosine Kinase Inhibitor Figure 1: (A) overall survival from diagnosis of enrolled and unenrolled patients. (B) EFS of enrolled and unenrolled patients. Patients in AP were excluded. (C) 2nd line TKI-Free Survival of enrolled and unenrolled patients corresponding to the probability to remain under first-line TKI. Figure 1:. (A) overall survival from diagnosis of enrolled and unenrolled patients. (B) EFS of enrolled and unenrolled patients. Patients in AP were excluded. (C) 2nd line TKI-Free Survival of enrolled and unenrolled patients corresponding to the probability to remain under first-line TKI. Disclosures Nicolini: Novartis: Consultancy. Gardembas:BMS: Honoraria. Etienne:Novartis, BMS, Pfizer, Ariad: Honoraria. Guerci-Bresler:Novartis, BMS, Pfizer: Honoraria. Roy:Novartis: Honoraria; BMS: Honoraria. Legros:Novartis, BMS: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.1803.1803

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 137-137

Abstract: Context: The Tyrosine Kinase Inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) increasing dramatically the survival of CML patients and leading to a residual disease with a sustained and deep molecular response. In this subset of very good responder patients, the attempts of stopping treatment in different clinical trials were successfully achieved without relapse. The Swedish team in the EURO-SKI protocol already reported cases of musculoskeletal pain occurring after cessation of TKI (Richter et al., JCO, 2014). Since several clinical trials regarding TKI discontinuation have been also run in France, we decided to retrospectively collect data using the pharmacovigilance system of the different Trials collected prospectively. Method: 428 patients from STIM2 (n=204) and EURO-SKI (n=224) trials were systematically analyzed from the case report from each trial. For the EURO-SKI only French patients were included. Statistical analysis was performed using Stata 13 software (StataCorp LP, College Station, TX, US). Comparisons between the independent groups were realized using the Chi-squared or Fisher's exact tests for categorical variables, and using Student t-test or Mann-Whitney test for quantitative. Multivariate analyses were performed to take into account adjustment on covariates fixed according to univariate results and clinically relevance. Results: Among the 428 patients the main characteristics were as follow i,e; 208 (48.6%) men and 220 (51.4%) women, with a median age of 77.5 years (24-93). Sokal scores (n=449) were low in 187 (41.6%) patients, intermediate in 188 (41.9%) patients and high in 74 (16.5%) patients. A withdrawal TKI syndrome (WS) was reported for 102 (23.8%) patients (100 after imatinib and 2 after nilotinib). 2). The WS consists in bone and articular pains and arthritis and affects the upper limbs, shoulders and cervical rachis, with a grade 1 or 2 in most patients and grade 3 in 22% of patients . The prevalence of WS depends on the trials, 34.8% in EURO-SKI group and 13.8% in STIM2 group (p 〈 0.001). The WS was treated by non-steroidal anti-inflammatory drugs, corticosteroids or by local infiltration. The median duration of WS was 7 months (range: 3-30 months, 24 exploitable cases). We did not observe any difference between WS group and the group without painful syndrome in terms of sex ratio (p=0.92), age (p=0.33), sokal score (p=0.15), BCR-ABL transcript (p=0.42) or duration of CML (p=0.24). However the median duration of TKI therapy appeared longer in this subgroup (median: 88.8 months vs 79.8 months (p=0.02). There was no biological inflammatory syndrome and the results of medical imaging were inconclusive. However, a medical history of osteoarticular pains or disease appeared as predisposing to withdrawal syndrome (22.9% in WS group vs 9.8% in control group; p=0.002). Finally the two factors, duration of treatment and medical history were confirmed using multivariate analysis (RR=1.73 and 1.76 respectively). Among 19 exploitable cases suffering CML relapse and requiring further TKI treatment, pain disappeared in 7 patients (37%) within a median period of 3.5 weeks. Conclusion: About 23% of patients who stopped TKIs experienced a TKI WS and all TKI seems to be concerned. The predisposing factors were a medical history of osteoarticular pain or disease, and the duration of treatment. So patients and physicians should be aware and recommendations should be proposed for patients who have treated longtime with a history of arthritis. Disclosures Legros: Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rousselot:Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Rea:Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Mahon:Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.137.137

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. 134, No. Supplement_1 ( 2019-11-13), p. 494-494

Abstract: The combination of 2GTKI+pegylated IFN-α (Peg-IFN) is an attractive approach for first-line treatment of CP CML, inducing high rates of deep molecular responses in phase II trials. Thus, we evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82). Newly diagnosed CP CML pts ≤65 y, without prior history of arterial occlusion were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone for 30 days (M-1→M0) 30 μg/wk as priming, prior to NIL 300 mg BID + Peg-IFN 30 μg/wk 2 wks, upgraded to 45 μg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone for 4 more years unless pts enter treatment-free remission (TFR). The primary endpoint is the rate of MR4.5 by 1 y. As a secondary endpoint, pts reaching MR4.5 ≥2 y are allowed to stop NIL and enter a TFR phase in both arms. The trigger for treatment resumption is loss of MMR. All molecular assessments are centralised, quantifications are expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Two hundred pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. Median follow-up is 43.8 (34.3-55.9) Mo. Results are analysed in intention-to-treat. Sokal and EUTOS LTS scores were H in 25% and 2.5%, Int. in 33% and 16.5% and L in 42% and 81% pts respectively equally balanced. Median age is 46 (18-66) y, 18 pts (9%) had ACAs, all pts have a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (in B) and 88% of pts in A and 90.4% of pts in B at M1. CCyR rates at M3 were 63% vs 75% in A and B (p=ns), and BCR-ABL1 ≤1% at M6 were 87% in A vs 93% in B (p=ns). By M12, the rates of MMR were 68.1% vs 70.1% (p=0.44), MR4 were 34% vs 47.5% (p=0.041), MR4.5 were 15.9% vs 21.5% (p=0.049), MR5 11.7% vs 23.71% (p=0.023), in A vs B respectively. By M36 the rates of MMR were 83% vs 86.6% (p=0.31), MR4 were 70.2% vs 71.13% (p=0.50), MR4.5 were 37.2% vs 49.5% (p=0.05), MR5 33% vs 42.3% (p=0.12), in A vs B respectively The overall cumulative incidence of MR4.5 is superior in B (54.6 [43.7-65.5] %) vs A (44 [31.5-54]%) close to significance (unilateral Fisher test, p=0.05, see Figure). Seven patients were mutated by Sanger in A (5 Y253, 1 E255K, 1 T315I) vs 2 in B (2 T315I). One pt (A) progressed toward AP and then myeloid BC with a Y253H mutation, is still alive in CMR on Ponatinib. Twenty nine (29%) pts were withdrawn from study in A (toxicity 9, cancer 3, resistance 14, investigator decision 2, lost for FU 1) vs 26 (26%) pts for B (toxicity 13, resistance 8, investigator decision 5), 1 pt died from cervix cancer (A). Median overall doses of NIL delivered by M36 were 600 mg/d in both arms (p=ns). The median overall dose of Peg-IFN delivered in B by M24 was 37.5 mg/wk. The overall rate of grade 3-4 hematologic toxicities was 22%; with 2% and 7% thrombocytopenia, 4% and 6% neutropenia, and 1% and 1% pancytopenia in A vs B respectively. Major grade 3-4 non-hematologic toxicities consisted in 9% of cardiac disorders in A (2 coronaropathies, 1 myocardial infarction, 2 thoracic pains, 2 atrial fibrillation, 1 bradycardia, 1 palpitations, 1 pericarditis) vs 8% in B (2 coronaropathies, 1 myocardial infarction, 3 atrial fibrillation, 1 palpitations, 1 pericarditis), 4% vascular disorders in A (1 thrombophlebitis + PE, 1 transient ischemic attack, 1 PAOD, 1 carotid stenosis) vs 3% in B (1 thrombophlebitis, 1 PAOD, 1 transient ischemic attack). Three % of gastro-intestinal disorders were observed in A (2 pancreatitis, 1 anal fissure) vs 6% in B (2 pancreatitis, 1 anal fissure, 1 abdominal pain, 2 cholecystectomies); 5% auto-immune disorders in B (1 recurrent pericarditis, 2 hemolytic anemia, 1 ITP, 1 thyroiditis); 5 and 8 pregnancies (2 pts + 3 partner Arm 1, 3 pts + 5 partner Arm B), despite recommended contraceptive methods. Secondary tumours were diagnosed in 4% (1 breast, 1 cervix, 1 thyroid, 1 neuroendocrine) in A vs 2% of pts (1 neuroendocrine and 1 testis) in B. Of note 8% psychiatric episodes were reported in B pts (2 unsuccessful suicide attempts), vs 2% in A. We observed 9% lipase elevations in A, 6% in B, 2% cholestatic episodes in A, 6% in B; 3% of transaminase elevations in A vs 2% in B. Infections were detected in 3% A vs 7% in B. The combination of NIL + Peg-IFN seems to provide somewhat higher MR4.5 rates by M36 in newly diagnosed CP CML pts without inducing significant higher toxicities than NIL alone. Whether this will translate in higher TFR rates is under evaluation. Final updated results at M36 will be presented Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Novartis: Research Funding, Speakers Bureau; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Huguet:Servier: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Charbonnier:Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy; Pfizer: Consultancy. Legros:Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria. Coiteux:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy. Roy:Incyte Biosciences: Consultancy. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Quittet:Novartis: Honoraria, Speakers Bureau. Ame:Incyte Biosciences: Honoraria, Speakers Bureau. Rea:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria; BMS: Honoraria. Dulucq:Novartis: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. OffLabel Disclosure: Pegylated Interferon alpha 2 a is not licensed in this setting

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123674

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 672-672

Abstract: Although patients with Acute Promyelocytic Leukaemia (APL or AML M3) and the classical t(15;17) translocation can now benefit from efficient treatments, some 10 to 20% of patients still relapse at 5 years. In order to improve the clinical outcome of APL patients, the early detection of disease reactivation should allow treatment at molecular relapse rather than at complete haematological relapse. To this end accurately defining molecular relapse is compulsory. Recent studies suggest that RQ-PCR methods applied to the detection of minimal residual disease (MRD) could provide such criteria. Our laboratory has established a RQ-PCR method (Cassinat et al., 2001) using Taqman technology. Standard curves are established and the PML-RARa copy number is normalized according to the expression of the housekeeping gene PBGD. A total of 260 APL patients (APL study Group) have been followed from 2000 to 2004 with a total of 970 samples analyzed. Median follow up for all these patients was 24 mths (range: 1–83 mths) with a median number of samples per patient of 6 (range: 1–28). During this period, 38 patients presented at least one positive result after a median negative period of 13 mths and 13 of them relapsed (median follow-up of 17 mths, range from 3 to 43mths). To evaluate the value of this re-positivity, we tried to determine whether a predictive threshold of PML-RARa copy as assessed by RQ-PCR method could allow detecting patients with molecular relapse. At the time of the first positive result, patients were in hematological CR. Patients were grouped according to the normalized PML-RARa copy number and the risk of relapse was studied in each group. No relapse (n= 0/17; 0%) was noted in patients with less than 10 copies (group A). 38% relapses (n= 5/13) in patients with 10 to 102 copies (group B) and 100% relapses (n=8/8) in patients with more than 102 normalized copies (group C). Negative RQ-PCR was reached again in all patients that did not relapse. Interestingly in groups B and C, interval to hematological relapse appeared to be related to the number of PML-RARa copies at first positivity (median interval to relapse was 6 months in group B and 2 months in group C). For 3 positive patients of group B, 3 consecutive samples were analysed until relapse: copy numbers increased exponentially. From these results we conclude that RQ-PCR is a powerful tool to define the molecular relapse in APL patients as it is able to accurately identify two subgroups of patients with either a 100% or no risk of relapse wilts median follow up of 24 mths. These patients with true molecular relapse should probably receive salvage therapy without waiting for the hematological relapse.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V106.11.672.672

Language: English

Publisher: American Society of Hematology

Publication Date: 2005

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7