scholarly journals Outcome of 472 Chronic Myeloid Leukemia Patients Treated with Frontline Nilotinib: A Gimema CML WP Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 458-458 ◽  
Author(s):  
Gabriele Gugliotta ◽  
Fausto Castagnetti ◽  
Massimo Breccia ◽  
Alessandra Iurlo ◽  
Mariella D'Adda ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Age Groups ◽  
Advisory Board ◽  
Molecular Response ◽  
First Line ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
First Line Treatment

Abstract BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib showed better efficacy compared to imatinib. The higher rates of deep molecular response with nilotinib may translate in more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit nilotinib use in selected groups of pts (e.g. elderly pts). AIM: To investigate the efficacy and safety, overall and according to age, of first-line treatment with nilotinib in CML pts. METHODS: We analyzed response rates, events and outcome of 472 pts ≥ 18 y of age with CP CML, enrolled in clinical trials of the GIMEMA CML WP with nilotinib frontline. Pts were treated with: nilotinib 300 mg BID (n=276); nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123). The median follow-up was 36 (3-82) months. Pts were further analyzed considering 3 age groups: 18-39 y (98 pts); 40-59 y (217 pts); and ≥ 60 y (157 pts). Definitions: Major molecular response (MR3): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to accelerated/blast phase (AP/BP), or deaths. Arterial thrombotic events (ATEs): peripheral arterial obstructive disease, acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events. RESULTS: Overall, the cumulative incidences of MR3 by 12, 24, and 36 months were 75, 88, and 93%, respectively. The cumulative incidences of MR4 by 12, 24, and 36 months were 38, 63, and 76%, respectively. Events leading to permanent nilotinib discontinuation occurred in 132 (27.9%) pts. ATEs occurred in 33 (7% of pts) ATEs, corresponding to 19.7 ATEs/1000 pt-y. Fifteen (3.1%) pts progressed to AP/BP. Overall, 23 (4.9%) pts died, 11 of them after progression to AP/BP. The estimated 5-year OS was 93%. The sub-analysis according to age showed that: MR3 and MR4 rates were similar across the 3 age groups (cumulative incidences of MR4 by 24 months were 55, 62, and 70% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively; p=0.25). Progressions to AP/BP were: 6.1% in pts 18-39 y, 2.8% in pts 40-59 y, and 1.9% in pts ≥ 60 y. ATEs were: 0 in pts 18-39y, 4.1% (11.7/1000 pt-years) in pts 40-59 y, and 15.3% (41.3/1000 pt-years) in pts ≥ 60 y (no difference in ATEs was found between pts 60-69 y and those ≥ 70 y). The 5-y OS was 91, 97, and 89% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively (p=0.065). Death was always leukemia-related in pts 18-39 y (100%), while it was mainly leukemia-unrelated (75%) in pts ≥ 60 y. SUMMARY/CONCLUSION: Nilotinib as first-line treatment of newly diagnosed CP CML pts showed high rates of deep molecular responses, few progressions to AP/BP, and a high OS. Deep molecular response were similar in all age groups; as expected, ATEs were more frequent in pts > 60 y. These data suggest that: in pts > 60 y, the high efficacy of nilotinib should be weighed against its potential toxicity; in pts < 60 years, nilotinib may be a very good choice, with high efficacy and low toxicity. Disclosures Gugliotta: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Abruzzese:Pfizer: Consultancy; Ariad: Consultancy; Novartis: Research Funding; BMS: Consultancy. Soverini:Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD. Cavo:AbbVie: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: 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; GlaxoSmithKline: 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. Pane:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.

scholarly journals Analysis of Factors Predictive of Risk of Transformation and Time to Transformation in Patients (pts) with Mantle Cell Lymphoma - Cohort Study of 369 Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1526-1526
Author(s):  
Preetesh Jain ◽  
Rashmi Kanagal-Shamanna ◽  
Chi Young Ok ◽  
Gonzalez-Pagan Omarya ◽  
Lucy Navsaria ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Initial Diagnosis ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Ki 67 ◽  
Leukemic Phase ◽  
First Line Treatment

Introduction: A fraction of pts with classic variant MCL can transform to an aggressive histology (blastoid/pleomorphic) MCL. Outcomes of transformed pts are inferior to that of denovo blastoid variant MCL and classic variant MCL who never transformed (CNT) Jain P et al ASH 2018. Application of routinely available clinical variables at initial diagnosis to predict the future risk for transformation or time to transformation is an unmet need in MCL. Methods: We analyzed charts from 369 pts with MCL (293 were CNT and 76 were transformed MCL). Statistical analysis was performed from baseline pt characteristics collected from the time of initial diagnosis in CNT group and at the time of initial diagnosis of classic variant MCL who later transformed (t-MCL). Time to transformation (TTT) was calculated from initial diagnosis to the date of transformation in those who transformed and last follow up in those who never transformed. Univariate and multivariate logistic regression modeled the risk of transformation. Classification and regression tree (CART) analysis was performed to identify optimal cut off in categorical variables predictive of TTT. Results: Among the 369 pts, the median age was 62 yrs (range 34-90), 79% were males. Ki-67% values were available in 133 pts (36% of total) and median Ki-67% was 25% (range 1-80). 84% had initial bone marrow involvement and 12% had leukemic phase at diagnosis. The median follow up was 58.5 months and the median overall survival (OS) was 94.8 months and 47% were alive at the time of this analysis. Compared to pts in the CNT group, pts in t-MCL group exhibited differences in following baseline characteristics - higher values of median Ki-67% (30% vs 20% in t-MCL; p=0.04), higher LDH levels, higher proportions of pts with high risk simplified MIPI risk score, leukemic phase at initial diagnosis, complex karyotype and lower hemoglobin and lower proportion of pts achieving complete remission (CR) after first line treatment (78% in t-MCL vs 86% in CNT). In addition, first line treatments received by both groups were similar - R-HCVAD based, R-chemo based, ibrutinib based, chemotherapy alone and miscellaneous. Logistic regression model showed factors associated with the risk of transformation. In univariate analysis, higher risk was significantly associated with Ki-67% as a continuous variable - OR 1.03 (95% CI 1.01-1.05; p=0.006), leukemic phase at diagnosis, high risk MIPI score, complex cytogenetics. First line treatment with ibrutinib compared to R-HCVAD, autologous stem cell transplant SCT at any time point and higher number of nodal sites were associated with decreased risk of transformation. In multivariate analysis (MVA), higher number of nodal sites and SCT were associated with decreased risk of transformation. The median time to transformation in months for those who transformed was 39 (range 5-240 months) while in CNT it was 51 months (1-257 months). We further identified that incremental Ki-67% was significantly associated with TTT and OS (Figure-1A-B). Using CART analysis we identified Ki-67% ≥60 is significantly associated with shorter TTT (HR, 6.26; 95% CI 2.58-15.21; p &lt;0.001-1C). In addition, shorter TTT was associated with elevated LDH, high risk MIPI score, CNS involvement at baseline, higher WBC counts, leukemic phase MCL, complex cytogenetics and R-chemotherapy as first line treatment while longer TTT was associated with higher number of nodal sites, SCT at any time point, higher hemoglobin, CR after initial treatment (Figure-1D) and increased number of lines of treatment before transformation. In MVA, higher number of nodal sites, CR after initial treatment was predictive of longer TTT while CNS involvement at baseline and bone marrow involvement at baseline were predictive of shorter TTT. Further analysis on gene signature, type of treatments, response, VH gene mutation, Sox-11 status, somatic mutation status are ongoing and will be reported. Conclusions: This is the first analysis showing an association of routinely available clinical variables in determining risk for transformation of MCL and TTT. Routinely available variables such as incremental Ki-67%, LDH levels, number of nodal sites, ibrutinib based treatments, SCT, CR after first line treatment and leukemic phase at diagnosis reliably predicted for time to transformation in MCL. Disclosures Lee: Seattle Genetics, Inc.: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding. Nastoupil:Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Champlin:Sanofi-Genzyme: Research Funding; Actinium: Consultancy; Johnson and Johnson: Consultancy. Neelapu:Cellectis: Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; BMS: Research Funding; Acerta: Research Funding; Incyte: Consultancy; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Cell Medica: Consultancy; Karus: Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Allogene: Consultancy. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria; MoreHealth: Consultancy, Equity Ownership; Pharmacyclics: Honoraria, Research Funding; Acerta Pharma: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding.

scholarly journals Achieving the Deep Molecular Response Levels Required for an Imatinib Discontinuation Trial Is Strongly Associated with the BCR-ABL Level at the First Qualifying Timepoint

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4561-4561 ◽  
Author(s):  
Susan Branford ◽  
David M Ross ◽  
David T Yeung ◽  
Jodi Braley ◽  
Timothy P. Hughes
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Molecular Response ◽  
First Line ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
Landmark Analyses ◽  
Tki Treatment

Abstract Background: Discontinuation of tyrosine kinase inhibitor (TKI) treatment for patients (pts) with CML is desirable for both clinical and economical reasons. Two studies, STIM and TWISTER, demonstrated that treatment free remission (TFR) is achievable in a proportion of pts. A qualifying period of 3 years of imatinib and sustained undetectable BCR-ABL with a sensitivity of MR5 or MR4.5 for at least 2 years was required before discontinuation. Due to the very slow clearance of BCR-ABL after an initial rapid reduction in the first year of imatinib, the number of pts meeting discontinuation criteria potentially requires many years of imatinib. New discontinuation studies may require at least 3 years of TKI treatment but are exploring less stringent molecular criteria for discontinuation. The first requirement is the achievement of MR4.5 (≤0.0032%) or even MR4 (≤0.01%), and these responses must be maintained. More potent TKIs when administered as first line or after switch from imatinib are associated with higher rates of deep molecular response, which potentially leads to a greater number of pts who qualify for a discontinuation trial. It is unknown what proportion of imatinib treated pts who have not achieved a deep molecular response at 3 years will subsequently do so, and in which subgroup of patients a switch to a more potent TKI is warranted if TFR is the goal. Aim: Since BCR-ABL levels at milestone response timepoints strongly predict long term molecular response, we determined whether the BCR-ABL level at the first qualifying timepoint for a discontinuation trial (3 years) predicts the achievement of deep molecular response. Method: 528 consecutive chronic phase pts treated with first line imatinib were examined (400, 600 or 800 mg). Those who met the following criteria at 3 years were included: CCyR or 1% BCR-ABL, no MR4.5 and at least 6 months of further imatinib therapy. Only 4 pts did not have CCyR at 3 years and were not included since they also had treatment failure. The cohort is historical so was not confounded by switching to another TKI after 3 years of imatinib. Landmark analyses according to the BCR-ABL response level at 3 years were performed for MR4 and MR4.5. These responses required confirmation at consecutive measurements. Results: 147 pts met the analysis criteria. The median follow up on imatinib after the 3 year landmark was 1.5 years, range 0.75 – 9.8. At 3 years of imatinib the median BCR-ABL was 0.03%, range 0.004% - 1.4%. The cumulative incidence of MR4 for the 116 pts without MR4 at 3 years was 52% by 5 years after the landmark. The cumulative incidence of MR4.5 for the 147 pts was 62% by 5 years after the landmark. Pts were divided into 3 BCR-ABL response levels at the landmark: MR2 (>0.1%) n=45; MMR (>0.01 – 0.1%) n=71; and MR4 (>0.0032 – 0.01%), n=31. Landmark analyses demonstrated that pts with MR2 at 3 years of imatinib had a negligible probability of achieving MR4 and MR4.5 with up to 5 additional years of imatinib, Figure. Only 2 and 1 of these 45 pts reached MR4 and MR4.5, respectively. Furthermore, pts with MMR at 3 years had a significantly lower cumulative incidence of MR4.5 compared to pts with MR4: MMR vs MR4, 61% vs 100% by 5 years after the landmark, P < .0001, Figure. Intuitively, pts with BCR-ABL close to MR4.5 could be predicted to achieve that response. However, the median time to reach MR4.5 for the pts with MR4 at 3 years was at 1.5 years of additional imatinib, demonstrating the very slow kinetics of BCR-ABL clearance. The starting dose of imatinib had no effect on the achievement of MR4 or MR4.5. Only 1 of the 147 pts lost CCyR (pt with MMR at 3 years). Conclusion: This study has further demonstrated that the BCR-ABL value is a powerful predictor of response, not only in the first months of treatment but also at later timepoints when long term management decisions are made. If the aim of therapy is to qualify for TFR studies, our data suggest that pts without an MMR at 3 years of imatinib have minimal chance of reaching the deep molecular responses required, even with up to 5 additional years of imatinib. Pts who switched to nilotinib without MMR in the ENESTcmr trial were indeed more likely to achieve MR4.5 compared to continuing on imatinib (Hughes Blood 2014). In our study, most pts with MR4 at 3 years of imatinib achieved the deep molecular response criteria with 2 additional years of imatinib. These findings may help clinical decisions when considering a switch of treatment to optimize discontinuation options. Figure 1 Figure 1. Disclosures Branford: Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Ross:Novartis: Honoraria, Research Funding; BMS: Honoraria. Yeung:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding.

scholarly journals Disease Characteristics of AML Patients with Germline DDX41 Variants

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3384-3384
Author(s):  
Jennie Vagher ◽  
Shobi Venkatachalam ◽  
Peng Li ◽  
Julie D. Asch ◽  
Bryan D. Huber ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Cultured Skin ◽  
Myeloid Neoplasms ◽  
First Line Treatment

Abstract Introduction: Germline pathogenic variants in DDX41 represent the most common predisposition to myeloid neoplasms accounting for 1-4% of patients (pts). Myeloid neoplasm with germ line DDX41 mutation is included as a separate entity in the revised 2016 World Health Organization classification of myeloid neoplasms and acute leukemia. The risk to develop any myeloid neoplasm in individuals with pathogenic germline DDX41 variants is modest, estimated to be about 20-30%. The recent inclusion of DDX41 on next generation sequencing panel (NGS) for myeloid neoplasms has led to increase in identification of DDX41 variants. Identification of germline DDX41 variants in MDS/AML pts will inform on donor selection and genetic testing of family members who are potential hematopoietic stem cell transplant (HSCT) donors is critical to eliminate the risk for transmission of a donor derived leukemia. Herein, we describe 10 pts with acute myeloid leukemia who were identified to have a DDX41 variantsince January 2020. Methods Among the pts diagnosed with acute myeloid leukemia in Utah between January 2020 and April 2021, 10 pts were identified to have a DDX41 variant on myeloid NGS panel (peripheral blood or bone marrow) performed at the time of diagnosis (9 pts) or through genetic testing performed on cultured skin fibroblasts (1 pt). When possible, pts with met a genetic counselor and germline genetic testing was performed utilizing DNA obtained from cultured skin fibroblasts through GeneDX Laboratory and Prevention Genetics. DDX41 variants are classified (Table 1) as per the ACMG criteria. Results Of the 10 pts with a DDX41 variant on myeloid NGS panel, 9 (90%) were diagnosed with AML. One pt (10%, Pt 9)) was initially diagnosed as AML and subsequently classified as mixed phenotype T/myeloid leukemia on repeat marrow evaluation after failure of initial induction based on blasts co-expressing cytoplasmic CD3 and MPO. The DDX41 variant was classified as pathogenic and variant of uncertain significance (VUS) in 6 (60%) and 4 (40%) pts, respectively. The variant allele frequency (VAF) of DDX41 variants was above 35% in all pts (Table1). Seven pts had germline testing performed from cultured skin fibroblasts, all were found to have germline DDX41 variants. Three pts did not undergo germline genetic testing, but the VAFs were highly suggestive of germline origin. Baseline demographics and the AML disease characteristics are outlined in Table 1. ELN risk category was unknown in 1 pt (10%), favorable in 1 pt (10%), intermediate in 3 pts (30%) and adverse in 5 pts (50%). Karyotype was normal in6 pts (60%), 20 q deletion in one pt and a complex in 2 pts (20%). Other somatic variants identified on the myeloid NGS panel are outlined in Table 1. First line treatment included intensive chemotherapy in 6 pts (60%) and 4 pts (40%) received hypomethylating agent based (HMA) therapy. Seven pts achieved a complete remission (CR), after first line treatment, of whom 5 received intensive chemo and 2 received HMA based treatment. One pt who received HMA therapy failed to achieve CR or CRi (pt 5), achieved CR after receiving intensive chemo for salvage. One pt failed initial induction with idarubicin and cytarabine (7+3 regimen) and achieved CR after reinduction with cycle 1 A of HyperCVAD. 5 pts relapsed after first line treatment (2 after intensive chemo and 3 after HMA based treatment). At the time of this report, 2 pts received allogeneic stem cell transplant (allo-SCT) both from unrelated donors and 3 pts died. Conclusion: In our experience, AML pts with germline DDX41 variant presented after fifth decade similarly to sporadic AML. Most pts had pathogenic variants in DDX41 (per ACMG), though 3 pts were classified as uncertain variants which represent an area of further knowledge. The majority of the pts had a normal karyotype at diagnosis. A second somatic DDX41 variant was observed in 2 pts. ASXL1 mutations were observed in 3 pts. Inclusion of the DDX41 gene in a myeloid NGS panel is necessary to identify this subset of pts and in addition germline testing should also be considered for all MDS/AML pts with age &lt;40. Multicenter registry-based studies are necessary to further characterize and develop a standardized treatment approach for these individuals and the role of allo-SCT. Figure 1 Figure 1. Disclosures Tashi: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Shami: JSK Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bastion Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chimerix: Research Funding; Takeda: Consultancy; Gilead: Consultancy; BMS: Consultancy; Chimerix: Research Funding; Amgen: Research Funding; Aptevo: Research Funding. Kovacsovics: Stemline: Honoraria; Novartis: Research Funding; Amgen Inc.: Research Funding; Janssen Pharmaceuticals: Research Funding; AbbVie: Research Funding; Jazz Pharmaceutials: Honoraria. Maese: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Tantravahi: Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding; Abbvie Inc.: Research Funding; CTI BioPharma: Research Funding; Novartis: Research Funding; BMS: Research Funding.

scholarly journals Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4112-4112
Author(s):  
Charline Moulin ◽  
Romain Morizot ◽  
Thomas Remen ◽  
Hélène Augé ◽  
Florian Bouclet ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Intermediate Risk ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Long Term Survivors ◽  
First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) with Acute Myeloid Leukemia (AML): Princess Margaret Cancer Centre Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2609-2609
Author(s):  
Muhned Alhumaid ◽  
Georgina S Daher-Reyes ◽  
Wilson Lam ◽  
Arjun Law ◽  
Tracy Murphy ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Age Groups ◽  
Treatment Strategies ◽  
Patient Characteristics ◽  
Cancer Center ◽  
Advisory Committees ◽  
Disease Behavior

Introduction: Clinical outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA) are rarely reported as an isolated subgroup. Treatments vary little across age groups, and treatment intensity depends upon comorbid conditions and performance status. Optimal treatment strategies focused on disease behavior, biological factors, and the distinct needs of this subset of AML patients remain elusive. The purpose of this retrospective analysis is to determine the characteristics and outcomes of AYA AML patients treated at a specialized adult leukemia cancer center in comparison to older adults with AML (40-60 years). Methods: A retrospective analysis was performed on all patients treated at Princess Margaret Cancer Center from 2008-2018. Patients with acute promyelocytic leukemia were excluded. Clinical characteristics, treatment strategies, and survival outcomes were recorded for all patients. Overall survival (OS) and disease-free survival (DFS) rates were calculated using the Kaplan-Meier product-limit method and the impact of covariates were assessed using the Log-rank test. Finally, we compared the outcomes of AYA patients treated at our centre between 2015-2018 with older patients. Results: A total of 175 patients aged 18-39 were identified. Patient characteristics are shown in (Table 1). Cytogenetic were available in 163 patients. Based on MRC criteria, 27 (16%) were favorable risk, intermediate in 95 (54%), adverse in 39 (22%), and missing/failed in 14(8%). NPM1 status was available in 110 patients of whom 38 (35%) were positive. FLT3-ITD was available in 67 patients with 24 (36%) positive. Both mutations were present in 13 (54%) patients. There were no significant differences in terms of risk stratification based on cytogenetic and molecular markers based on age (18-29 vs.30-39) (P= 0.98). Most patients 172 (98%) received induction, 157 (91%) with 3+7, and 15 (9%) with FLAG-IDA. Complete remission (CR) was achieved in 133 (77%) after first induction [120 (76%) after 3+7 and 11 (73%) after FLAG-IDA]. Induction related mortality was low (2%). Of the 39 who did not achieve CR, thirty-four patients received re-induction (13 FLAG-IDA, 16 NOVE-HiDAC, 5 others) with CR in 21 (62%). Overall, 154 (89.5%) achieved CR1. Sixty-four (42%) proceeded to hematopoietic stem cell transplantation (HSCT) in CR1. 59 (38%) patients relapsed in CR1 with 8 (12%) relapsing post HSCT. Fifty-five (5 post HSCT) patients received reinduction with 30 (51%) (2 after HSCT) achieving CR2. Fifteen patients received HSCT in CR2. OS and DFS at 2 years were 62% (95% CI 0.53-0.69) and 50% (95% CI 0.41-0.57), respectively. Stratified by cytogenetic risk, OS was 81% for favorable risk, 61% for intermediate, and 50% for adverse risk (P=0.0001), respectively. DFS in these groups was 85%, 57%, and 46 % (P=0.0025), respectively. We further compared outcomes in the 18-29y and 30-39y age groups. The OS was 61.9% compared to 62.5% (P=0.91) and DFS of 52.1% compared to 47% (P=0.65) respectively. On univariate analysis for OS and DFS, cytogenetic risk stratification was the only significant variable (P=0.0004 and P=0.0042). We then compared the outcomes 67 sequential patients aged I8-39 treated from 2014-2018, with those of 176 sequential patients aged 40-60 treated during the same period (table 2). OS at 2 years was not statistically higher in the younger group compared to the older group (66.7% vs. 61.2%, P=0.372). While relapse rate was lower in older patients (15.5% vs. 22.6%, P=0.093), NRM was higher in older patients (29.7% vs. 18.8%,P=0.094). Conclusion: AYA pts. occupy a unique niche amongst AML as a whole. While treatment responses have improved in general, there may be potential for further gains in these patients. Increased tolerance for more intense treatment strategies as well as the incorporation of novel agents into standard treatment protocols may provide a means to optimize care in AYA patients. Finally, research is needed to elucidate biological mechanisms and predictors of disease behavior instead of arbitrary, age-stratified treatment schema. Disclosures McNamara: Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy. Schuh:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Teva Canada Innovation: 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; Agios: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astellas: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Gupta:Incyte: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Second Imatinib Discontinuation Outcomes in Patients Regaining Durable Deep Molecular Response in the Korean Imatinib Discontinuation Study; KID Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 51-52
Author(s):  
Sung-Eun Lee ◽  
Joon Seong Park ◽  
Young Rok Do ◽  
Sung-Hyun Kim ◽  
Dae Young Zang ◽  
...  
Keyword(s):  
Prospective Study ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Close Monitoring ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
Multicenter Prospective Study

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: 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; Sun Pharma.: Research Funding.

scholarly journals The Application of Machine Learning to Improve the Subclassification and Prognostication of Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
Hassan Awada ◽  
Arda Durmaz ◽  
Carmel Gurnari ◽  
Ashwin Kishtagari ◽  
Manja Meggendorfer ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Somatic Mutations ◽  
Cross Validation ◽  
Steering Committee ◽  
Advisory Board ◽  
Advisory Committees ◽  
Genomic Features ◽  
Acute Myeloid

Genetic mutations (somatic or germline), cytogenetic abnormalities and their combinations contribute to the heterogeneity of acute myeloid leukemia (AML) phenotypes. To date, prototypic founder lesions [e.g., t(8;21), inv(16), t(15;17)] define only a fraction of AML subgroups with specific prognoses. Indeed, in a larger proportion of AML patients, somatic mutations or cytogenetic abnormalities potentially serve as driver lesions in combination with numerous acquired secondary hits. However, their combinatorial complexity can preclude the resolution of distinct genomic classifications and overlap across classical pathomorphologic AML subtypes, including de novo/primary (pAML) and secondary AML (sAML) evolving from an antecedent myeloid neoplasm (MN). These prognostically discrete AML subtypes are themselves nonspecific due to variable understanding of their pathogenetic links, especially in cases without overt dysplasia. Without dysplasia, reliance is mainly on anamnestic clinical information that might be unavailable or cannot be correctly assigned due to a short prodromal history of antecedent MN. We explored the potential of genomic markers to sub-classify AML objectively and provide unbiased personalized prognostication, irrespective of the clinicopathological information, and thus become a standard in AML assessment. We collected and analyzed genomic data from a multicenter cohort of 6788 AML patients using standard and machine learning (ML) methods. A total of 13,879 somatic mutations were identified and used to predict traditional pathomorphologic AML classifications. Logistic regression modeling (LRM) detected mutations in CEBPA (both monoallelic "CEBPAMo" and biallelic "CEBPABi"), DNMT3A, FLT3ITD, FLT3TKD, GATA2, IDH1, IDH2R140, NRAS, NPM1 and WT1 being enriched in pAML while mutations in ASXL1, RUNX1, SF3B1, SRSF2, U2AF1, -5/del(5q), -7/del(7q), -17/del(17P), del(20q), +8 and complex karyotype being prevalent in sAML. Despite these significant findings, the genomic profiles of pAML vs. sAML identified by LRM resulted in only 74% cross-validation accuracy of the predictive performance when used to re-assign them. Therefore, we applied Bayesian Latent Class Analysis that identified 4 unique genomic clusters of distinct prognoses [low risk (LR), intermediate-low risk (Int-Lo), intermediate-high risk (Int-Hi) and high risk (HR) of poor survival) that were validated by survival analysis. To link each prognostic group to pathogenetic features, we generated a random forest (RF) model that extracted invariant genomic features driving each group and resulted in 97% cross-validation accuracy when used for prognostication. The model's globally most important genomic features, quantified by mean decrease in accuracy, included NPM1MT, RUNX1MT, ASXL1MT, SRSF2MT, TP53MT, -5/del(5q), DNMT3AMT, -17/del(17p), BCOR/L1MT and others. The LR group was characterized by the highest prevalence of normal cytogenetics (88%) and NPM1MT (100%; 86% with VAF&gt;20%) with co-occurring DNMT3AMT (52%), FLT3ITD-MT (27%; 91% with VAF &lt;50%), IDH2R140-MT (16%, while absent IDH2R172-MT), and depletion or absence of ASXL1MT, EZH2MT, RUNX1MT, TP53MT and complex cytogenetics. Int-Lo had a higher percentage of abnormal cytogenetics cases than LR, the highest frequency of CEBPABi-MT (9%), IDH2R172K-MT (4%), FLT3ITD-MT (14%) and FLT3TKD-MT (6%) occurring without NPM1MT, while absence of NPM1MT, ASXL1MT, RUNX1MT and TP53MT. Int-Hi had the highest frequency of ASXL1MT (39%), BCOR/L1MT (16%), DNMT3AMT without NPM1MT (19%), EZH2MT (9%), RUNX1MT (52%), SF3B1MT (7%), SRSF2MT (38%) and U2AF1MT (12%). Finally, HR had the highest prevalence of abnormal cytogenetics (96%), -5/del(5q) (68%), -7del(7q) (35%), -17del(17p) (31%) and the highest odds of complex karyotype (76%) as well as TP53MT (70%). The model was then internally and externally validated using a cohort of 203 AML cases from the MD Anderson Cancer Center. The RF prognostication model and group-specific survival estimates will be available via a web-based open-access resource. In conclusion, the heterogeneity inherent in the genomic changes across nearly 7000 AML patients is too vast for traditional prediction methods. Using newer ML methods, however, we were able to decipher a set of prognostic subgroups predictive of survival, allowing us to move AML into the era of personalized medicine. Disclosures Advani: OBI: Research Funding; Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; Takeda: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; BMS: Consultancy, Honoraria, Research Funding. Carraway:Novartis: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); Stemline: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Jazz: Consultancy, Speakers Bureau. Saunthararajah:EpiDestiny: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kantarjian:Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Abbvie: Honoraria, Research Funding; Aptitute Health: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Adaptive biotechnologies: Honoraria; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria. Kadia:Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Cyclacel: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; JAZZ: Honoraria, Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Amgen: Research Funding. Sekeres:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

Major Improvement of Invasive Aspergillosis Outcome Is Not Enough to Improve Overall Survival In Allogeneic Hematopoietic Stem Cell Transplant Recipients: Results From a Single-Center Retrospective Analysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1244-1244
Author(s):  
Géraldine Salmeron ◽  
Raphaël Porcher ◽  
Anne Bergeron ◽  
Marie Robin ◽  
Regis Peffault de Latour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Risk Of Death ◽  
First Line Treatment

Abstract Abstract 1244 Background. Voriconazole (V) treatment has been shown to improve the 12 week (W) survival rate of hematological patients (pts) with invasive aspergillosis (IA), including recipients of allogeneic hematopoietic stem cell transplants (HSCT). We investigated whether this early survival advantage could translate into a significant increase in overall survival. Methods. We retrospectively reviewed all consecutive pts who received a transplant between Sept. 1997 and Dec. 2008 at Saint-Louis Hospital and were diagnosed as having IA. The temporal origin of the study was the date of IA diagnosis for each patient. Factors associated with survival were analyzed using Cox proportional hazard models. Separate models were estimated for survival up to 12 W and for survival between 12 W and 24 months (M) in pts surviving longer than 12 W. The deaths of pts with and without IA were analyzed with a competing risk framework. Cumulative incidence curves were compared using Gray's tests. Results. Our study examined 89 IA pts. The median follow-up was 70 M (range, 11–130 M). Two pts did not receive any antifungal treatment and were excluded from subsequent analyses. Of the 87 pts, 42 received first-line V and 45 primarily received a lipid formulation of amphotericin B (n=25), amphotericin B deoxycholate (n=10), caspofungin (n=8) or itraconazole (n=2). The primary characteristics of pts with IA and their causes of death, separated by V as first-line treatment, are shown in the table below. The median survival was 2.6 M, and the overall survival at 24 M was 19% (95% CI 12–30 M) (see figure). Overall, the survival rates of the two groups were significantly different (P= 0.010). However, the differences in survival were quite dramatic prior to 10 M, whereas both survival curves became very close after one year. At 18 M, the numbers of surviving pts were almost identical in the two groups [19% (95% CI: 11–34%) in pts who did not receive V as first-line treatment vs. 21% (95% CI 11–38%) in pts who did]. Pts who did not receive V as a first-line treatment displayed a higher probability of dying from IA than those who did (P=0.004), whereas opposite results were found for mortality in pts without IA (P=0.006). The 24-M cumulative incidence of death from IA was 47% (95% CI 31–61%) in the no V group and 19% (95% CI 9–33%) in the group treated with V. The 24-M cumulative incidence of death in pts without IA was 4% (95% CI 7–14%) in the no V group and 27% (95% CI 14–42%) in pts treated with V. The probability of death from another cause, with IA, was similar in both groups (29% vs. 36% at 24 M; P=0.46). After adjusting for donor type, conditioning regimen, progressive GVHD at diagnosis of IA and cumulated steroid dose (mg/kg) in the W preceding IA diagnosis, administration of V as first-line treatment was found to decrease the risk of death during the first 12 W by approximately 70% [HR=0.31 (95% CI 0.16–0.60); P=0.0005]. Conversely, analysis of mortality between 12 W and 24 M failed to identify any significant predictor of risk of death; however, only 24 pts died during this period. Conclusions. The finding that first-line treatment with V, which is associated with a tremendous improvement in IA outcome, does not translate into an increase in overall survival (even in the context of early diagnosis) is striking. Diagnosis of IA following HSCT, whatever the outcome, appears to be a strong marker for poor long-term prognosis. Disclosures: Bergeron: Pfizer: Speakers Bureau, none; Merck: Speakers Bureau, none; Schering: Speakers Bureau, none. Sulahian:Pfizer: Research Funding, non; Merck: Research Funding, none. Ribaud:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, none; Schering: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, none; Gilead: Speakers Bureau, none.

Clinicopathological Features of Nodular Sclerosis-Type Classical Hodgkin Lymphoma In the Elderly: Multicenter Study of Hodgkin Lymphoma In Japan

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2677-2677
Author(s):  
Naoko Asano ◽  
Tomohiro Kinoshita ◽  
Koichi Ohshima ◽  
Tadashi Yoshino ◽  
Nozomi Niitsu ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
The Elderly ◽  
Clinicopathological Features ◽  
Line Treatment ◽  
Classical Hodgkin Lymphoma ◽  
First Line ◽  
Advisory Committees ◽  
First Line Treatment

Abstract Abstract 2677 Background: Classical Hodgkin lymphoma (CHL), which is characterized by the presence of Hodgkin and Reed Sternberg (H-RS) cells in a background of non-neoplastic inflammatory cells, is divided into four histological subgroups, nodular sclerosis (NSCHL), mixed cellularity (MCCHL), lymphocyte-rich, and lymphocyte depletion. While NSCHL in young adults is characterized by a mediastinal mass and good prognosis, the clinicopathological characteristics of NSCHL in the elderly (NSCHL-e) remain uncertain. Patients and methods: Enrolled patients were diagnosed with CHL between 1986 and 2006 as part of the Hodgkin Lymphoma's Multicenter Study Group. To better characterize NSCHL-e, we compared the clinicopathological profiles of 84 NSCHL-e patients aged 50 or over with 237 NSCHL-y patients aged 49 or younger and 302 with MCCHL. Results: The total of 743 CHL patients consisted of 496 men and 247 women with a median age of 48 years (range, 15– 89 years). The pathological diagnoses were NSCHL in 324 patients (43%) and MCCHL in 303 (41%). NSCHL patients showed a bimodal age distribution, with an initial peak in their 20s and a second small peak in their 60s. We categorized the former as NSCHL-y (49 or younger) and the latter as NSCHL-e (50 and over). NSCHL-e patients were characterized by male predominance and a more advanced clinical stage (53%) than NSCHL-y. Immunophenotypically, H-RS cells had the prototypic immunophenotype of CD15+ CD30+ and Pax5+. NSCHL-e cases showed a significantly higher rate of CD20 (24%) than NSCHL-y (8%, P = 0.001). Furthermore, H-RS cells in 29 of 75 (39%) patients with NSCHL-e were positive for EBV RNA transcripts by in situ hybridization, whereas only 7% of NSCHL-y cases were EBER-positive (P < 0.0001) (Table). Regarding NSCHL-e and MCCHL, no significant difference between these patients was seen in clinical characteristics. Immunophenotypically, NSCHL-e patients showed significantly higher rates for CD3 and TIA-1, while MCCHL patients showed higher EBV positivity (75%). Fifty-five of 63 patients received systemic multi-agent chemotherapy as first-line treatment, consisting of doxorubicin, bleomycin, vinblastine, and dacarbacin (ABVD) in 38 patients; CHOP in 8; C-MOPP in 8; and BEACOPP in 1. Overall, 51 patients responded to first-line treatment, 39 with complete response and 12 with partial response. Disease-specific survival of NSCHL-e was poorer than that of NSCHL-y (P < 0.001) but similar to that of MCCHL (P = 0.43) (Figure). Conclusion: NSCHL-e is characterized by an unfavorable prognosis and different clinicopathological features to NSCHL-y, which is considered as typical NSCHL. A number of cases of NSCHL-e might have been associated with MCCHL, with most being EBV-positive. These results suggest the limitations of current histological subgroupings for CHL. Disclosures: Matsushita: Pfizer CO.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Co.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Predictors of Early Relapse Following Initial Therapy for Systemic Immunoglobulin Light Chain Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2082-2082
Author(s):  
Nidhi Tandon ◽  
Surbhi Sidana ◽  
Morie A. Gertz ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Initial Therapy ◽  
Al Amyloidosis ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Early Relapse ◽  
First Line Treatment

Abstract Introduction Immunoglobulin light chain amyloidosis (AL Amyloidosis) is a monoclonal plasma cell proliferative disorder that is characterized by tissue deposits of misfolded insoluble κ or λ light chain derived amyloid fibrils, leading to organ dysfunction. The prognosis of patients depends on the number and severity of organ involvement, especially cardiac involvement. Autologous stem cell transplant (ASCT), if eligible, alkylator (melphalan) and novel drugs like proteasome inhibitors (PI) and immunomodulators (IMiD) have improved the overall survival (OS) during the past decades. But still, nearly half of the patients die within a year of diagnosis. We analyzed the factors predicting early relapse / progression or death (within 12 months) after first line therapy for systemic AL amyloidosis. Methods Clinical and laboratory data of all consecutive patients with systemic AL amyloidosis seen at Mayo Clinic within 90 days of their diagnosis, between 2006 and 2015, was collected by chart review and analyzed retrospectively. Patients who died within 3 months of starting the first line treatment were excluded from analysis. Early relapse (ER) was defined as relapse / progression requiring treatment change / re-institution or death within 12 months of starting first line treatment. Patients in the cohort with ER were compared with patients with a follow up of more than 12 months who had a relapse / progression beyond 12 months or had continuing response at the time of analysis. Categorical variables were analyzed using chi - square and Fisher's exact test and continuous variables using Kruskal- Wallis test and Wilcoxon rank sum test. Multivariate analysis was done using logistic regression model. Results Seven hundred and eighty six patients with newly diagnosed systemic AL amyloidosis met the study criteria and were included in the analysis. Among these, 230 (29.3%) patients had ER within 12 months of starting initial therapy while 556 (70.7%) patients either relapsed after 1 year or had continuing response at the time of analysis. Baseline demographics, organ involvement and type of first line therapy are presented in Table1. The median estimated follow up for the entire cohort from start of initial therapy was 62.9 months (95% CI; 59.9, 67.3). The variables included in the univariate and multivariate analyses for factors predicting ER were age at diagnosis (≤ vs > 70 years ), revised mayo stage (I and II vs III and IV), bone marrow plasma cell percentage (BMPC; ≤ 10% vs > 10%), presence of any chromosomal abnormalities, trisomies or IgH translocations by fluorescence in situ hybridization (FISH), multiorgan involvement [(>1 vs 1) (heart, liver, kidney, gastrointestinal tract, autonomic neuropathy), incorporation of ASCT in initial therapy. In univariate analysis, mayo stage (p<0.0001), multiorgan involvement (p=0.0008) and inclusion of ASCT as part of initial therapy (p<0.0001) were significantly associated with ER, while age (p=0.06), BMPC(p=0.9), FISH abnormalities (p=0.2) were not. However, in multivariate analysis, only mayo stage (III + IV vs I + II; p=0.01) and non-inclusion of ASCT in first line treatment (p=0.0001) were significantly predictive of ER. Conclusions Despite the introduction of ASCT and novel drugs, the early mortality in systemic AL amyloidosis remains high. This study demonstrates that patients with ER are older with higher prevalence of cardiac involvement and multiorgan involvement and higher Mayo stage (III and IV). Incorporation of ASCT as part of the initial therapy was associated with reduced early relapse, but it is difficult to separate the influence of the eligibility for ASCT from the effect of ASCT itself. This will help us in characterizing these patients to better understand their mechanisms of resistance to therapy and gives an insight to the type of initial therapy that benefits them. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; pfizer: Research Funding. Kapoor:Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding.

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