scholarly journals Omission of Staging Bone Marrow Biopsy Does Not Affect Outcomes in Patients with Stage I Extranodal Marginal Zone Lymphoma (EMZL) Treated with Radiation Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2829-2829
Author(s):  
Juan Pablo Alderuccio ◽  
Derek Isrow ◽  
Isildinha M. Reis ◽  
Sunil Iyer ◽  
Jessica Meshman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Radiation Therapy ◽  
Family Member ◽  
Board Of Directors ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Stage I ◽  
Competing Risk ◽  
Advisory Committees ◽  
Significant Difference

INTRODUCTION: Patients with stage I localized extranodal marginal zone lymphoma (EMZL) treated with radiation therapy (RT) have excellent outcomes. Negative bone marrow (BM) biopsy at diagnosis is key to confirm early stage disease. However, BM biopsy is not performed in some patients for various reasons such as comorbidities, patient refusal or physician decision. The aim of this study was to assess the effects of BM status (negative vs. not done) on disease recurrence/progression and survival in EMZL patients presenting with otherwise localized disease by imaging and treated with RT. METHODS: From January 1995 to January 2019, we identified 188 patients with stage I EMZL treated with frontline RT at the University of Miami Health Care System. All patients had biopsy proven EMZL and scans (CT, MRI, and/or PET-CT) at the time of diagnosis. Medical records were reviewed and pertinent information gathered. Relapse/progression was subclassified based on disease location: inside, outside, or inside and outside of the radiation field (RF). The competing risk method and the Gray's test were used in analysis of incidence rates of type of relapse/progression and lymphoma-specific death. The Kaplan-Meier method and the log-rank test were used in analyses of progression-free survival (PFS) and overall survival (OS). RESULTS: Among 188 patients included in this study, 104 (55.3%) were ≤60 years and 135 (71.8%) <70 years. 117 (62.2%) females and 98 (52.1%) non-Hispanic Whites. EMZL location was as follows: Orbit 118 (62.8%), gastric 19 (10.1%), head & neck 14 (7.4%), dural 13 (6.9%), skin 12 (6.4%), and other 12 (6.4%). Most patients had a negative staging BM biopsy (148, 78.7%); however, in 40 (21.3%) patients BM biopsy was not performed. Patients without BM biopsy at diagnosis were mainly >60 years (26, 65%). Radiation doses broadly varied but most patients (176, 93.6%) received ≥30 Gy. 183 patients (97.3%) achieved complete response (CR) following RT with 2 (1.1%) achieving partial response (PR), 2 (1.1%) stable disease and 1 (0.5%) demonstrating disease progression. Among 176 patients receiving ≥30 Gy RT, 173 (98.2%) achieved CR. With a median follow-up of 6.2 years (range 0.3-22.3 years) the 10 years-PFS was 64.4% (95%CI:54.9%-72.5%). No difference in PFS was observed by location of disease or BM biopsy (negative vs. not done). Patients treated with ≥30Gy had statistically significantly longer PFS compared to patients treated with <30Gy, whether or not BM biopsy was done. There were 52 progression events, including 5 inside RF (4 relapses/1 progression), 6 inside & outside (5 relapses/1 progression), 25 outside alone (24 relapses/1 progression), and 16 non-lymphoma deaths. Taking into account non-lymphoma death as a competing risk, the 5-year incidence of lymphoma relapse/progression was 2.9% (95%CI:1.1-6.3%) inside RF, 3.4% (95%CI:1.2-7.3%) inside & outside RF and 9.8% (5.8-15.0%) outside RF. Importantly, there was no higher cumulative incidence of each type of relapse/progression relative to RF (inside p=0.2490, inside & outside p=0.1617, and outside alone p=0.3070) in patients without vs. negative staging BM biopsy. There were 23 deaths, 7 attributed to lymphoma. The 10-year OS was 83.3% (95%CI:75.0-89.0%), and there was no difference in OS by EMZL location. Patients without staging BM biopsy had shorter OS (p=0.0062). However, when lymphoma-specific death was analyzed (non-lymphoma death as competing risk) the estimated 10-year cumulative incidence of lymphoma-specific death was 5.3% (2.3%-10.2%) and there was a non-statistically significant difference between patients with and without staging BM biopsy (p=0.5201). The cumulative 10-years incidence of non-lymphoma specific death (lymphoma death as competing risk) was 11.4% (95% CI:6.3%-18.2%). There was a statistically significant difference by BM biopsy status (p=0.0107), with patients without staging BM biopsy having higher incidence of non-lymphoma death compared to negative BM biopsy patients (10-yr rate 26.7% vs 7.9%, respectively), likely due to coexistent comorbidities. CONCLUSION: In this large cohort of patients with stage I EMZL treated with RT we demonstrate for the first time that omission of BM biopsy at diagnosis does not affect lymphoma-specific survival or the incidence of disease relapse/progression overall or by relapse location type, suggesting that diagnostic BM biopsy may not be necessary. Disclosures Alderuccio: Foundation Medicine: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member; Targeted Oncology: Honoraria; Agios: Other: Immediate family member; Puma Biotechnology: Other: Immediate family member; OncLive: Consultancy. Lossos:NIH: Research Funding; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Brian T. Hill ◽  
Deepa Jagadeesh ◽  
Alex V. Mejia Garcia ◽  
Robert M. Dean ◽  
Omer N. Koc ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Proteasome Inhibitors ◽  
Marginal Zone Lymphoma ◽  
Aggressive Lymphoma ◽  
Advisory Committees ◽  
Frontline Treatment

INTRODUCTION: Lenalidomide and Rituximab (R2) is an effective frontline treatment regimen for patients (pts) with indolent B-cell lymphoma including follicular lymphoma (FL). Recent phase III data from the RELEVANCE trial comparing R2 to traditional chemoimmunotherapy showed that this regimen is generally well-tolerated and has favorable clinical efficacy [61% overall response, 53% CR rate, 77% 3-year progression free survival (PFS) (Morschhauser, et al)]. Proteasome inhibitors such as bortezomib disrupt NF-KB signaling and have shown clinical activity in indolent NHL. Although randomized trials have failed to demonstrate clinical benefit of adding bortezomib to standard chemoimmunotherapy regimen bendamustine + rituximab (BR) for frontline treatment of FL, the addition of proteasome inhibitors to lenalidomide is a mainstay of treatment for plasma cell neoplasms due to synergistic antitumor effect. The oral proteasome inhibitor ixazomib has less potential for dose-limiting neuropathy than bortezomib, making it an attractive option to incorporate into the R2 regimen. We sought to investigate the safety and efficacy of the addition of ixazomib to R2 for FL and indolent B-cell NHL through a phase I clinical trial of this combination for patients with high risk disease. METHODS: Adult (age ≥ 18) pts with untreated FL or other indolent lymphoma, adequate organ function and performance status were enrolled. To be enrolled, FL patients were required to have stage 2, 3 or 4 disease, with high tumor burden by GELF criteria and/or FLIPI score of 3-5. During 3 x 3 dose escalation, ixazomib was given at a dose of 2 mg (n=3), 3 mg (n=3) or 4 mg (n=12) PO on days 1, 8, and 15 with lenalidomide 20 mg PO on days 1-21 every 28 days. Rituximab was administered at standard dosing on days 1,8,15,21 for cycle 1, once every 28 days for cycles 2-6 and then once every 2 months for cycles 7-12. Treatment was continued for 12 cycles and no maintenance therapy was specified per protocol. All pts received low dose aspirin for venous thromboembolism prophylaxis and acyclovir for prevention of VZV reactivation. Response assessments by CT were performed after cycle 3 and 6 and by PET/CT at the end-of-treatment (cycle 12). RESULTS: 20 pts were enrolled and 18 were eligible for treatment [15 FL (14 grade 1-2, 1 grade 3A), 2 splenic marginal zone lymphoma and 1 nodal marginal zone lymphoma].The median age of treated pts was 61 (range 40-83) years old. 55% of patients were female. Stage at diagnosis was II (n =2), III (n = 4) and IV (n = 12). For FL pts, FLIPI scores at enrollment were low (n=2), intermediate (n = 5) and high risk (n=8) and FLIPI-2 scores were low (n=3), intermediate (n = 2) and high risk (n=10). There were no dose limiting toxicities during 3 x 3 dose escalation. Grade (G) 1/2 and G3/4 treatment-related hematologic adverse events (AEs) included neutropenia (6%, 28%), thrombocytopenia (16.7%, 5.6%) and anemia (16.7%, 0%). The most common treatment-related AEs included nausea/vomiting (44% G1, 11% G2), diarrhea, (50% G1, 22% G2, 5% G3), rash (33% G1, 6% G2, 11%G3), peripheral neuropathy (22% G1, 6% G2), myalgia/arthralgia (17% G1, 17% G2), and infection (33% G2, 17% G3). There was one pulmonary embolism and no cases of febrile neutropenia. As of June, 2020, median follow-up among living pts was 21 months. 4 pts discontinued treatment due to disease progression; 2 with transformation to aggressive lymphoma. Of the transformed cases, one subject died on study due to progression disease and one developed CNS disease on study treatment but proceeded to autologous stem cell transplant. The best overall response rate was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. 18-month Kaplan-Meier estimates of PFS and overall survival were 71% and 94%, respectively (Figure). CONCLUSION: R2 can safely be combined with at the target dose of 4 mg of ixazomib for treatment-naïve indolent NHL patients. Non-hematologic AEs were generally consistent with known toxicity of each component of therapy. CR rate and PFS were was similar to the outcomes reported in the RELEVANCE trial despite enrolling high risk patient. R2 may serve as backbone for future studies of novel treatment combinations for high risk FL after thorough evaluation for occult transformation to aggressive lymphoma. Disclosures Hill: Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jagadeesh:MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Smith:Takeda: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Ixazomib is off-label for treatment of NHL

scholarly journals Distinct Clinical and Biological Implications of Various DNTMT3A Mutations in Myeloid Neoplasms

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2872-2872
Author(s):  
Suresh Kumar Balasubramanian ◽  
Mai Ali ◽  
Taha Bat ◽  
Bhumika Patel ◽  
Bartlomiej P Przychodzen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Clinical Features ◽  
Bone Marrow Failure ◽  
Missense Mutations ◽  
Negative Consequences ◽  
Wild Type ◽  
Advisory Committees ◽  
Myeloid Neoplasms ◽  
Significant Difference

Abstract DNMT3A, a member of the DNA methyltransferases family along with DNMT1 and DNMT3B, is located on chromosome 2p23. Recurrent somatic mutations in DNMT3A are typically heterozygous and found mostly in non-CBF AML, less frequently in MDS and MPN. DNMT3A mutations are reported with other common myeloid mutations including NPM1, FLT3 and IDH1/2. The most canonical DNMT3A mutations are missense alteration in the R882 codon, accounting for >60% of all DNMT3A mutations and they imply dominant negative consequences. Overall, DNMT3A mutations carry a poor prognosis compared to the AML or MDS with wild type (WT) DNMT3A, although data within different subgroups (e.g., incorporating cytogenetic profiles) are conflicting. We hypothesized that molecular consequence of R882 mutations will differ from those of other somatic alterations of DNMT3A and may also result in distinct clinical features and outcomes. To test this theory, we analyzed a cohort of 1174 patients with myeloid neoplasias including 32% AML, 33% MDS, 13% MDS/MPN, 6% MPN and 16% other bone marrow failure disorders. These cases were subjected to multiamplicon targeted deep NGS including all ORFs of DNMT3A and other recurrently mutated genes. After application of various bioanalytic algorithms, confirmatory sequencing and thus stringent exclusion of all artifacts and germline alterations, we identified 140 somatic mutant cases (12% of the cohort), including 89 missense mutations (53 at R882, 19 at R693 and 17 other non-canonical missense alterations) and 51 truncations/frame shifts (all heterozygous). There was an age-related increase in the incidence of DNMT3A mutations, with the peak occurrence at 35-40 yrs. of age. Mutations in DNMT3A were most common in AML (54% in primary (p) AML, 8% in secondary (s) AML) followed by MDS (28%), MDS/MPN (4%), MPN (3%) and other bone marrow failure disorders (3%). Mutation in the R693 codon and truncating mutations were most commonly associated with MDS (p=.013) and sAML (p=.0013) whereas mutation occurring in codon R882 and other non-canonical missense mutations were frequently associated with pAML (p=.00001). For the whole cohort, DNMT3A mutations were most frequently associated with NPM1 (21% vs 8%, p=.014), FLT3 (24% vs. 2%, p=.0001), and IDH1/2 (26% vs. 8%, p=.001), compared to wild type DNMT3A. However, PRC2 complex mutations were less likely to occur in the context of DNMT3A mutations (6% vs. 24%, p=.0006). Canonical R882 mutation was commonly associated with FLT3 (p=.03) mutations, while truncating mutations were not (p=.03). Analyses of clonal hierarchy by ranking of VAF values demonstrated that 53% of DNMT3A mutations were dominant (mean VAF 39%, range 5-93%) (n=74/140). When DNMT3A mutations were dominant, IDH 1/2 (14%), TET2 (9%), ASXL (5%), PRC2 complex (3%) and BCOR (3%) mutations were common secondary events. In subgroup analyses, 55% of mutations in the R693 codon were dominant compared to 45% in R882 and 47% in truncating mutations. TET2 mutations were the most common associated secondary hits in dominant R693 mutations (n=10) compared to truncating (n=24) and R882 mutations (n=23) (40% vs. 8% vs. none, p=.0001). When DNMT3A mutations are secondary (mean VAF 34%, range 1-60%), as in 47% of our cases (n=66/140), then the common first hits were TET2 (10%), U2AF1 (8%) and cohesin complex (RAD21, SMC3, STAG2) mutations (6%). Dominant DNMT3A mutations correlated with MDS/MPN (60%, p=.007), while secondary DNMT3A mutations correlated with sAML (73%, p=.001). DNMT3A mutant myeloid neoplasms showed worse survival (p<.0001) compared to WT cases. Among different subgroups, there was significant difference in OS between R882, R693, truncating and other non-canonical missense mutations (p=.013). The R882 mutations had worse survival compared to other DNMT3A mutations (p=.003). Non-canonical mutations (truncating and other missense) vs. canonical mutations (R882 and R693) had better survival (p<.04). Survival for mutant R882 DNMT3A was worse compared to truncating mutations (p=.005) while there was no difference between R693 and truncating mutations. Among AML cases, R882 mutations vs. other mutations had worse survival (p=.01) while in MDS and MDS/MPN there was no significant difference in OS. DNTMT3A mutations often occur as founder lesion in AML. Our study shows that different types of mutations other than canonical R882 alterations may have a differential impact on OS and distinct clinical features. Disclosures Carraway: Celgene Corporation: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Value of Minimal Residual Disease (MRD) Negative Status at Response Evaluation in Chronic Lymphocytic Leukemia (CLL): Combined Analysis of Two Phase III Studies of the German CLL Study Group (GCLLSG)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 23-23 ◽  
Author(s):  
Gabor Kovacs ◽  
Sebastian Boettcher ◽  
Jasmin Bahlo ◽  
Sandra Kluth ◽  
Matthias Ritgen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Bone Marrow Involvement ◽  
Phase Iii ◽  
Two Phase ◽  
Advisory Committees ◽  
Significant Difference ◽  
Travel Grant

Abstract Introduction: Within clinical trials in CLL, response assessment is based on the NCI 1996 guidelines or its update, the iwCLL 2008 guidelines, respectively. Whereas detailed response criteria with clear cut-off values are provided for the assessment of most parameters, a few parameters such as splenomegaly are not defined quantitatively in the guidelines. In addition, the detection of MRD, which was recommended for clinical trials but not formally included in the definition of response, is gaining increasing importance. Both MRD negativity (with a threshold of <10-4 leukemic cells per leukocytes) and the occurrence of a complete response (CR) predict long progression free survival (PFS). In order to investigate the value of MRD with respect to clinical response, the MRD status was explored in patients (pts) with CR and partial remission (PR) in two phase III trials of the GCLLSG. Furthermore, we evaluated the relevance of residual splenomegaly, lymphadenopathy or bone marrow involvement in MRD negative (-) pts with clinical PR. Patients and Methods: 542 pts from two prospective phase III trials of the GCLLSG (CLL8 trial: fludarabine and cyclophosphamide without (FC) or with rituximab (FCR); CLL10 trial: FCR vs bendamustine and rituximab (BR)) were included in the analysis (Figure 1). The comprehensive dataset included MRD results from peripheral blood at final restaging (RE) (2 months after the end of last treatment cycle), bone marrow (BM), clinical and radiological assessment for organomegaly and lymphadenopathy. Clinical response was defined according to the iwCLL 2008 guidelines. Splenomegaly was determined by physical and radiological examination. Moreover, different cut-off values defining splenomegaly by CT or ultrasound (longest diameter >12 cm and >14 cm) were investigated. PFS was analyzed using Kaplan-Meier methodology, and survival curves were compared using two-sided log-rank tests. Additionally hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Significance was set at a p value<0.05. No adjustments for multiple testing were performed. Results: 542 pts were included in the analysis. Their median age was 61 years, median CIRS score 2 (range 0-6), median follow up time 45.9 months (mo) (range 5.5-96.1). 121 pts (22.3%) received FC, 283 (52.2%) FCR and 138 (25.5%) BR. 13.3% of pts had Binet stage A, 52.3 % stage B and 34.4% stage C disease. Among 514 pts with IGHV results, 63.0% had an unmutated status. In 524 pts FISH was available, del(17p) was only found in 1.3% (exclusion criterion in CLL10 trial), del(11q) in 25.0%, 12+ in 10.1%, normal in 25.4%, and del(13q) in 38.2% of the pts. MRD negativity was achieved in 81.8% (175/214) of pts with CR and in 47.9% (157/328) of the pts with PR, respectively. There was a statistically significant difference in PFS between MRD- CRs and MRD positive (+) CRs (69.2 mo vs 40.4 mo; HR 0.445, 95% CI=0.282-0.703, p=0.001). Additionally, there was a statistically significant difference between MRD- PRs and MRD+ CRs (61.7 mo vs 40.4 mo; HR 0.537, 95% CI=0.340-0.847, p=0.008). No statistically significant difference between MRD- CRs and MRD- PRs was detected (69.2 mo vs. 61.7 mo; HR 0.822, 95% CI=0.572-1.182, p=0.29) (Figure 2). Of the 157 pts presenting with an MRD- PR, 106 pts were evaluable for remaining CLL involvement: 48 pts (45.3%) had a splenomegaly, 12 (11.3%) lymphadenopathy, 19 (17.9%) bone marrow involvement as the sole abnormality. Only 25.5% (27) of the pts had more than one abnormality. There was no statistically significant difference in PFS between MRD- PRs with single splenomegaly and MRD- CRs (not reached (NR) vs 69.2 mo; HR 0.737, 95% CI=0.387-1.404, p=0.4). Moreover, patients with MRD- PRs and single splenomegaly had a statistically significant longer PFS than MRD+ CR pts (NR vs 40.4 mo; HR 0.348, 95% CI=0.172-0.701, p=0.003). (Figure 3) The difference was independent of the cut-off values used for splenomegaly (12 cm or 14 cm) (p=0.001 and p=0.03). Conclusion: MRD negativity determined in the peripheral blood after end of treatment is a potent predictor of treatment efficacy regardless of the clinical response assessment. The persistence of splenomegaly as sole abnormality post treatment in MRD- patients has no negative influence on PFS. More data are needed to prove the relevance of residual BM involvement and lymphadenopathy in MRD- PR pts. These results support the use of MRD for response evaluation. Figure 1 Figure 1. Disclosures Boettcher: Roche: Honoraria, Research Funding, Travel grant Other. Ritgen:Roche: Honoraria, Research Funding, Travel grant Other. Cramer:Mundipharma: Travel grant, Travel grant Other; Roche: Travel grant Other. Maurer:Mundipharma: Travel grant Other. Doehner:Roche: Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding. Kneba:Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Fischer:Roche: Travel grant Other. Hallek:Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Eichhorst:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant Other; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Off Label Use: The Combination of Bendamustine and Rituximab is not approved for frontline chemoimmunotherapy of CLL.

scholarly journals Serum TARC Concentration Kinetic in Classical Hodgkin Lymphoma during First-Line Treatment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4500-4500
Author(s):  
Ilaria Romano ◽  
Benedetta Puccini ◽  
Leonardo Signori ◽  
Michela Zizza ◽  
Giacomo Coltro ◽  
...  
Keyword(s):  
Treatment Response ◽  
Board Of Directors ◽  
Stage I ◽  
Stage Ii ◽  
Categorical Variables ◽  
Line Treatment ◽  
First Line ◽  
Advisory Committees ◽  
Significant Difference ◽  
First Line Treatment

Abstract Introduction: Thymus and activation-regulated chemokine (TARC) has been recently identified as a promising predictor of response in patients (pts) with classical Hodgkin's Lymphoma (HL). A correlation between treatment response and early sTARC reduction in HL pts treated with PET-adapted strategy was reported (Guidetti A, Leuk Res, 2017; Viviani S, Hematol Oncol, 2020). In the current study, we analyzed the kinetic of sTARC in HL pts during first-line treatment, with the aim to evaluate its potential predictive value. Methods: We prospectively collected plasma samples of naïve HL pts. Pts were stratified according to GHSG risk categories. Localized HL were treated with 2-4 cycles of ABVD followed by involved field radiotherapy (IFRT); advanced HL underwent 6 cycles of ABVD. Pts with a positive PET-2 switched to an intensification treatment. Pts with positive end of treatment PET (EOT-PET) were treated with BeGEV followed by autologous stem cell transplantation (ASCT). sTARC levels were measured with a commercial TARC ELISA kit (R & D Systems, Minneapolis, US) according to manufactory instructions. Samples were collected immediately before treatment on day 1 of each ABVD cycle, before IFRT in localized stages, on day 1 of each cycle of salvage therapy, including ASCT, and 1 month after EOT. Samples were analyzed in duplicate. Statistical analysis was performed using IBM SPSS Statistic v.27 and GraphPad PRISM v.8; Continuous variables were compared by Mann-Whitney U test, categorical variables by χ 2 test. Statistical significance was defined as P=.05. Results: Of 43 pts enrolled in the study, 4 pts were excluded due to missing samples, and for 3 PET-2 positive pts data were unavailable at time of this analysis; overall evaluable pts were 36. Median age was 33.5 yr (range 17−65), 58% pts were male. B-symptoms were present in 50% of pts. Fourteen pts (39%) were early stage (IA, IB, IIA), 22 pts (61%) were advanced stage (IIB, III, IV). Four pts (11%) were refractory, documented by EOT-PET positivity. For the purposes of this analysis, pts were stratified in two subgroups including stage I pts (11%) and stage II-IV (89%). Median baseline sTARC was 35,454 pg/ml (range 273−183,225); levels were significantly lower in stage I compared to stages II-IV (524 vs 50,606 pg/ml, P=.001). Median sTARC after 2 ABVD cycles (sTARC-2) was 482 pg/ml (range 97−2,071) in the whole population, with a median logarithmic reduction (logRED) vs baseline of 1.83 (range -0.26−3.12). In stage II-IV a significant decrease of sTARC-2 (median 493 pg/ml; range 97−2,071), with a median logRED of 1.94 (range 0.73−3.12), was observed, unlike in stage I where sTARC-2 remained stable (median 393 pg/ml; range 279−805); median logRED -0.03 (range -0.27 to 0.57) (Fig 1A). We then compared sTARC in chemorefractory and chemosensitive stage II-IV pts. We observed an almost significant difference (P=.077) by considering baseline sTARC in the two groups, respectively 95,236 pg/ml (range 53,502−135,787) in chemorefractory and 35,454 pg/ml (range 5,475−183,225) in chemosensitive pts. However, sTARC-2 and the logRED of sTARC-2 were not significantly different between the two groups: 654 pg/ml (range 97−1,564) vs 463 (range 150−2,071) and 2.1 (range 1.6−3.1) vs 2.0 (range -0.7−2.6), respectively. Finally, sTARC measurements after PET-2 and before EOT-PET, and their log variation (logΔ) as compared to sTARC-2, were assessed in chemorefractory and chemosensitive subgroups. In refractory pts, a progressive increase of sTARC was observed: median sTARC was 32,202 pg/ml (range 14,362−71,807) at the time of biohumoral relapse compared to 373 pg/ml (range 166−1,102) in responding pts (P=.001). The corresponding log∆ values were -1.5 (range -2.9 to -1.1) and 0.1 (range -0.3−0.6) (P=.001), respectively (Fig 2B). Conclusions: The current study, with the limitations of small pts number, provides an analysis of sTARC prognostic implications in pts with HL. While sTARC is of limited value in pts with stage I disease, the kinetic of sTARC variation in pts with stage II-IV HL resulted well correlated with treatment response as assessed by EOT-PET. Specifically, an increase of sTARC during treatment after sTARC-2 may predict refractoriness at later cycles. Larger studies are needed to confirm that monitoring of sTARC in stage II-IV HL during treatment might provide prognostic and therapeutic insights. Supported by Legato Zottola, University of Florence Figure 1 Figure 1. Disclosures Puccini: Takeda: Membership on an entity's Board of Directors or advisory committees. Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees. Nassi: Incyte: Consultancy; Takeda: Consultancy; Roche: Consultancy; Kyowa Kirin: Consultancy.

scholarly journals Splenic Marginal Zone Lymphoma: A U.S Population-Based Survival Analysis (1997-2016)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4014-4014
Author(s):  
Jorge Florindez ◽  
Juan Pablo Alderuccio ◽  
Izidore S. Lossos
Keyword(s):  
Family Member ◽  
Survival Data ◽  
Marginal Zone ◽  
Stage Iv ◽  
Population Based ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Seer Database ◽  
Advisory Committees ◽  
Ann Arbor

INTRODUCTION: Splenic marginal zone lymphoma (SMZL) is a rare and indolent form of NHL with no standard treatment due to scarcity of clinical trials. Watch and wait approach, single agent rituximab or with chemotherapy and splenectomy are valid treatment approaches. No population-based studies examining the impact of chemotherapy and splenectomy on survival of SMZL patients are available. Thus, we decided to compare survival outcomes by clinical factors in SMZL patients deposited in the SEER database, emphasizing in the role of splenectomy on survival outcomes. METHODS: Retrospective analysis of SMZL cases in the SEER database from 1997 to 2016.SEER collects cancer incidence and survival data from population-based cancer registries covering 34% of the U.S. population. PATIENTS: SEER database was queried for SMZL patients at all ages from 1997 to 2016. Cases without histologic confirmation or no survival data were excluded. Demographic and clinical variables (age, sex, race, ethnicity, B-symptoms, Ann-Arbor stage, DLBCL transformation, first malignancy, chemotherapy with or without rituximab, splenectomy and radiotherapy) were summarized by descriptive statistics. Logistic regression used to determine variables associated with splenectomy. Overall survival (OS) and Cancer-specific survival (CSS) were the major end-points, estimated by Kaplan-Meier method. Cox regression used to calculate Hazard Ratios. RESULTS: 2212 patients met inclusion criteria, with a median age of 68yo (25-96). Patient characteristics were a follows: males (n=1152, 52.1%); whites (n=1991, 90.0%), blacks (112, 5.1%); Non-Hispanics (n=2049, 92.6%); B-symptoms (n=461, 20.8%); first malignancy (n=1754, 79.3%); Ann-Arbor Stage I (429, 19.4%), Stage IV (n=1351, 61.1%); DLBCL transformation (n=84, 3.8%). Adjusted Odds ratio (aOR) were used to compare splenectomy versus non-splenectomy treated patients: ≥60yo (aOR 0.49;0.40-0.62), males (aOR 0.77;0.64-0.93). Median survival of all the patients was 120 months (95%CI:111-132); On univariate analysis: shorter OS was significantly associated with age ≥60(HR 3.55;2.87-4.38) and non-first malignancy(HR 1.6;1.36-1.88), while shorter CSS was significantly associated with age ≥60(HR 1.76;1.33-2.34), B-symptoms (HR 1.93;1.44-2.60), Stage IV (HR 1.62;1.15-2.28), DLBCL transformation (HR 2.27;1.55-3.33) and treatment with chemotherapy (HR 1.54;1.22-1.94). On multivariate analysis, shorter OS was significantly associated with age ≥60(HR 3.52;2.83-4.37), male sex (HR 1.15;1.00-1.33), B-symptoms (HR 1.23;1.01-1.51) and non-first malignancy (HR 1.42;1.20-1.67). Shorter CSS was significantly associated with age ≥60(HR 2.15;1.61-2.87), Hispanic ethnicity (HR 1.44;1.00-2.07), B-symptoms (HR 1.77;1.30-2.39), DLBCL transformation (HR 2.03;1.38-2.99) and treatment with chemotherapy (HR 1.38;1.07-1.77). Ann Arbor staging and splenectomy were not associated with OS or CSS. CONCLUSIONS: Older age, Hispanic ethnicity, B-symptoms, DLBCL transformation, and treatment with chemotherapy were associated with poor lymphoma-specific survival. Although, age<60 and female gender were associated higher odds to undergo splenectomy, splenectomy had no impact on the risk of lymphoma-related death or OS. This retrospective study demonstrates that chemotherapy treatment (excluding rituximab) was associated with inferior outcomes in SMZL, while advanced Ann-Arbor stage was not associated with shorter survival as is observed in other indolent lymphomas that commonly present at advanced stage. Table Disclosures Alderuccio: Targeted Oncology: Honoraria; Foundation Medicine: Other: Immediate family member; Agios: Other: Immediate family member; Puma Biotechnology: Other: Immediate family member; OncLive: Consultancy; Inovio Pharmaceuticals: Other: Immediate family member. Lossos:NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees.

HIF-1α Is Not Essential For The Establishment Of MLL-Leukaemic Stem Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3767-3767
Author(s):  
Deniz Gezer ◽  
Amelie V Guitart ◽  
Milica Vukovic ◽  
Chithra Subramani ◽  
Karen Dunn ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Myeloid Leukaemia ◽  
Progenitor Cells ◽  
Board Of Directors ◽  
Advisory Committees ◽  
Hypoxic Conditions ◽  
Significant Difference

Abstract Haematopoietic stem cells (HSCs) reside in hypoxic niches in the bone marrow (BM) and sustain long-life haematopoiesis. HSCs are largely quiescent, self-renew, undergo apoptosis and generate progenitor cells, which differentiate to multiple blood lineages. The strict regulation of the balance between these fate decisions is essential for haematopoiesis and their dysregulation in HSCs and progenitor cells can result in leukaemic transformation. HSCs and leukemic stem cells (LSCs) are suggested to share the same niche and are in need to adapt to hypoxic conditions. Hypoxia-inducible-factor-1α (HIF-1α) is a key mediator of cellular responses to hypoxia and is important for the maintenance of HSC functions under stressful conditions. Furthermore, in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) HIF-1α is essential for LSC maintenance and ablation or knockdown of HIF-1α leads to exhaustion of established LSCs. The aim of this study was to investigate the requirement for HIF-1α in the generation of pre-LSCs and the establishment of LSCs. To investigate the role of HIF-1α in the generation of pre-LSCs we retrovirally transduced haematopoietic stem and progenitor cells (HSPCs) from either WT or HIF1-αfl/fl Vav-iCre with MLL-ENL retroviruses. Next we performed serial re-plating assays under normoxic and hypoxic conditions to generate pre-LSCs. Surprisingly, WT and HIF-1α deficient HSPCs generated comparable numbers of colonies in normoxia and hypoxia (Fig. 1a). In addition no significant difference was found in the immunophenotypic profile of colonies (Figure 1b). Furthermore, microscopic examination indicated that colonies of all genotypes were dense consistent with their transformed shape (Fig. 1c). WT and HIF-1α-deficient pre-LSCs cultured under normoxia and hypoxia had similar cloning efficiency, which is known to directly correlate with the numbers of LSCs in vivo (Fig. 2). These results indicate that HIF-1α is dispensable for the generation of pre-LSCs. To test the role of HIF-1α in establishment of LSCs from pre-LSCs we transplanted pre-LSCs into lethally irradiated mice together with support BM and monitored the mice for disease development. No significant difference was found in disease latency (Fig. 3a) or frequency of LSCs in peripheral blood, bone marrow or spleens (Fig. 3b) indicating that pre-LSCs lacking HIF-1α can efficiently generate LSCs that cause aggressive AML. In conclusion, we provide genetic evidence that HIF-1α is dispensable for the generation of pre-LSCs and the establishment of LSCs from pre-LSCs. These surprising findings, together with published results indicating that HIF-1α is essential for maintenance of LSCs, imply that HIF-1α has different roles at different stages of leukaemic transformation. Further studies are required to explain the distinct roles of HIF-1α in different stages of leukaemogenesis. Disclosures: Ratcliffe: RedOx: Founder Other. Holyoake:Novartis: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees.

Fluorescence in Situ Hybridization (FISH) abnormalities and Baseline Clinical Features at Diagnosis in African American Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2351-2351
Author(s):  
Megan H Jagosky ◽  
Kyle L Madden ◽  
Blake B Goodbar ◽  
Virginia Thurston ◽  
Manisha Bhutani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
African American ◽  
Board Of Directors ◽  
Clinical Features ◽  
Research Funding ◽  
Advisory Committees ◽  
Significant Difference ◽  
Caucasian Patients ◽  
Caucasian Cohort

Abstract BACKGROUND: Multiple myeloma (MM) is the most common hematologic malignancy in the African American (AA) population with an incidence more than 2-3 times higher than Caucasians [Landgren O et al Blood 2006]. In the pre-novel therapy era, SEER data [1975-2008] indicated better survival outcomes for AA patients with MM. However, with the recent advent of novel drugs for treatment of MM, the survival gap for Caucasian patients with MM has closed [Ailawadhi S et al Br J Haematol 2012]. A recent pooled analysis of diagnostic cytogenetics in 292 AA MM patients [Greenberg et al Blood Cancer J 2015] reported on differences in commonly observed baseline cytogenetic abnormalities (CA) between AA and Caucasian MM patients. The large and diverse population of patients with MM at our institution prompted us to examine diagnostic cytogenetics in our MM patients along with other clinical features. PATIENTS & METHODS: The MM database was interrogated for all patients presenting with MM between January 2012 and February 2016. Baseline clinical and pathology variables were compared between the AA and Caucasian cohorts. Continuous variables were compared using nonparametric rank tests, while incidences and proportions (e.g. CAs including t(11;14), t(4;14), t(14;16), t(14:20), amplification 1q21, monosomy13/del13q and del17p) were compared using Fisher's exact tests. RESULTS: A total of 398 patients were identified for the analysis (African Americans n = 168, Caucasian n = 230). The median age of AA MM patients was significantly younger than Caucasian MM patients (median age 63 years vs. 68 years, p<0.0001), with a similar sex distribution. There was no significant difference in the degree of anemia, renal insufficiency, serum LDH levels, bone marrow flow cytometry, bone marrow cellularity or plasmacytosis in the two cohorts. Although there was a trend toward more ISS I amongst Caucasian MM patients, there was no statistical difference in ISS stages (p = 0.126) and no significant difference in R-ISS stage between the cohorts (p = 0.361). There was 72.7% agreement between the ISS and R-ISS staging (88 of 121 evaluable subjects had the same stage by ISS and R-ISS staging criteria), while 27.3% of the patients were upstaged from Stage I or II by ISS criteria to Stage III by R-ISS criteria. Of those upstaged, 19 patients were in the Caucasian cohort and 14 were in the AA cohort. The magnitude of this upstaging was significant when evaluated with a Generalized McNemar's test (p < 0.001). Additionally, there was a similar incidence of common FISH abnormalities in the AA cohort compared to the Caucasian cohort [Table 1]. CONCLUSIONS: This is the largest single institution report of FISH data in AA MM patients. Unlike previous reports, we show similar clinical, pathological, and cytogenetic features between AA and Caucasian patients with MM at presentation. It is possible that molecular abnormalities not detectable by FISH in our patient cohort could account for differences in our data and the published literature. Table 1 FISH Abnormalities Table 1. FISH Abnormalities Disclosures Bhutani: Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Symanowski:Eli Lilly & Co: Consultancy; Ra Pharma: Consultancy; Caris Life Sciences: Consultancy; Endocyte: Consultancy. Avalos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Usmani:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Pharmacyclics: Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Novartis: Speakers Bureau.

scholarly journals A Systematic Review and a Survey Both Reveal Wide Heterogeneity across Trials and Investigators on Time-to-Event Endpoints Definitions in Marginal Zone Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4502-4502
Author(s):  
Côme Bommier ◽  
Emanuele Zucca ◽  
Catherine Thieblemont ◽  
Jérôme Lambert
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Phase 1 ◽  
Marginal Zone Lymphoma ◽  
Time To Event ◽  
Phase 3 ◽  
Advisory Committees ◽  
Free Survival ◽  
Secondary Endpoints

Abstract Background: Marginal zone lymphoma (MZL) is an indolent and heterogeneous B-cell lymphoma. Because of its very indolent course, many time-to-endpoints are used across MZL trials without clear consensus on their definitions. Our aim was to carry out a description of the endpoints used in trials involving MZL patients and to point out the different definitions of time-to-event (TTE) endpoints, both in the literature and among the MZL experts. Methods: We searched over the last 35 years via PubMed, The Cochrane Library, clinicaltrials.gov and clinicaltrialsregister.eu for published and registered clinical trials using the keyword "marginal zone lymphoma". We excluded studies focusing on pediatric populations, cutaneous MZL and on use of allogenic stem cell transplant. Endpoints were reviewed and definitions were analyzed. Afterwards, an online questionnaire was sent to a panel of leading international experts involved in the conduct of lymphoma clinical trials. Experts were selected for their commitment in published phase 2/phase 3 indolent lymphoma trials or for their membership in international lymphoma study groups (International Extranodal Lymphoma Study Group, Lymphoma Research Foundation). The questionnaire proposed 12 criteria to define Progression-free survival (PFS), Event-free survival (EFS), Time to failure (TTF), and Time to next treatment (TTNT). Results: 1192 references were identified by the initial screening. Among the 309 included references (111 published, 198 registered), 213 (69%) were phase 2, 65 (21%) phase 1/2 and 31 (10%) phase 3 trials. The majority of them were open-label (n=295, 95%) non-randomized (n=256, 83%) trials, included all subtypes of MZLs (n=239, 77%), and also non-MZL patients (n=232, 75%). Among phase 1/2 and 2 trials, Overall/complete response rate (ORR/CRR) was the most used primary endpoint (n=196, 70.5%), followed by PFS (n=28, 10.1%); in phase 3 trials PFS was the most used primary endpoint (n=18, 58.1%; ORR/CRR n=6, 19.4%, p&lt;0.001). Overall, the most frequent secondary endpoints were overall survival (OS, n=153, 50%), PFS (n=142, 46%) and ORR/CRR (n=116, 38%). Distribution of endpoints was similar when considering trials with only MZL patients. Time-to-event endpoints definitions were inconsistent across published trials, with up to 9 different definitions of EFS and TTF, and 4 different definitions of Duration of response. A total of 60 MZL experts from 16 different countries (Europe 66%, Northern America 26%, Asia 4%, Oceania 2%, Southern America 2%) took the questionnaire. Forty-nine (82%) of them were clinicians hematologists, and the other were oncologists, radiologists, nuclear medicine physicians, or radiotherapists. Eighty percent and 75% of them had already been primary investigator or coinvestigator in a prospective clinical trial including either MZL-only patients or MZL patients merged with other lymphoma patients, respectively. Among the experts' answers, a total of 23 different definitions of PFS were retrieved, 44 of EFS, 38 of TTF and TTNT. The main divergences concerned the consideration as event of: the add-on of a new therapy and the non-lymphoma related death for PFS; the treatment discontinuation due to adverse events and the add-on of a new therapy for EFS and TTF; the progression of the disease for TTNT. Conclusion: Trials involving MZL patients showed marked heterogeneity both in the choice and definitions of primary and secondary endpoints, thus hampering comparability between trials. This heterogeneity was confirmed through a survey among leading international MZL experts. If PFS and TTNT definitions have been well established by the Food Drug Administration and the European Medicines Agency, a consensus shall be pursued on EFS and TTF definitions within the MZL community. Disclosures Zucca: AstraZeneca: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: 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; Merck: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biomedicine: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Gilead, Kite: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Support. Thieblemont: Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses .

scholarly journals Phase 2 Study of Zanubrutinib (BGB-3111) in Patients with Relapsed/Refractory Marginal Zone Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5256-5256 ◽  
Author(s):  
Stephen Opat ◽  
Robert Marcus ◽  
Craig A. Portell ◽  
William Reed ◽  
Chris Tankersley ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including marginal zone lymphoma (MZL). Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may be co-administered with strong or moderate CYP3A4 inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients with either non-Hodgkin lymphoma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia suggests that zanubrutinib has been generally well tolerated amongst patients with B-cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data from a phase 1 study demonstrated responses in 7 of 9 patients with relapsed/refractory (R/R) MZL treated with zanubrutinib (Tam et al. ASH 2017); the remaining 2 patients had stable disease indicating an encouraging rate of overall disease control. Study Design and Methods: This ongoing global phase 2, single-arm, open-label study (MAGNOLIA; NCT03846427) is examining zanubrutinib monotherapy in patients with R/R MZL who have received 1 or more prior lines of systemic therapy (Figure). Eligible patients must have histologically confirmed diagnosis of MZL including splenic, nodal, and extranodal subtypes, have received prior anti-CD20 antibody therapy, and have measurable disease. Patients must have documented clinical need for therapy as well as adequate marrow and organ function. Patients are treated with oral zanubrutinib at 160 mg twice daily until progressive disease, unacceptable toxicity, or withdrawal of consent. The primary efficacy endpoint is ORR according to the Lugano Classification (Cheson et al. J Clin Oncol. 2014) measured by computed tomography and bone marrow assessment data as determined by an independent review committee (IRC). A 2-sided Clopper-Pearson 95% CI for ORR will be calculated. Key secondary endpoints include ORR by investigator assessment, time to and duration of response, time to treatment discontinuation, progression-free survival (all determined by IRC and investigator assessments), overall survival, safety, and patient-reported outcomes. All patients are tested for the MYD88 mutation at study entry. Recruitment is ongoing. Disclosures Opat: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy. Marcus:Gilead: Consultancy; Roche: Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Other: Travel, Accommodations, Expenses; Roche-Genentech: Honoraria. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding; Kite: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Consultancy; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Research Funding; Pharmacyclics: Consultancy. Reed:BeiGene: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Tankersley:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Trotman:Pharmacyclics: Research Funding; Roche: Research Funding; BeiGene: Research Funding; Janssen: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US

scholarly journals Fms-like Tyrosine Kinase 3 Ligand Concentration Kinetic Profile during Induction Is Strongly Predictive of Survivals in AML: Results of the FLAM/Flal Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1484-1484
Author(s):  
Pierre Peterlin ◽  
Joelle Gaschet ◽  
Thierry Guillaume ◽  
Alice Garnier ◽  
Marion Eveillard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Univariate Analysis ◽  
Advisory Committees ◽  
Kinetic Profile ◽  
Significant Difference ◽  
Low Levels ◽  
The Impact ◽  
Bone Marrow Blasts

Abstract The cytokine Fms-like tyrosine kinase 3 ligand (FL) is a key regulator of hematopoiesis. In a previous Phase 1 study testing a radioimmunotherapy regimen for relapsed/refractory acute lymphoblastic leukemia (ALL), responders showed increased soluble FL serum concentration (sFLc) after salvage regimen (Chevallier, Lancet Haematol., 2015). This prospective monocentric study (ClinicalTrials.gov NCT02693899) aimed to assess the impact of sFLc in ALL and acute myeloid leukemia (AML) patients treated according to standard-of-care intensive first-line chemotherapy regimens. Serum samples were collected on days 1, 8, 15, 22 of induction, at days 1, 8, 15 of each intensive consolidation or day 1 of each non intensive consolidation when appropriate, frozen-stored then tested by ELISA (DY308, R&D Systems, Minneapolis, MN). The following outcomes were considered to assess the impact of sFLc: refractory status after induction (≥5% bone marrow blasts or persistent aplasia >45 days), morphologic, immunophenotypic, cytogenetic or molecular relapses, event-free (EFS) and overall survival (OS). All patients provided informed consent. Between May 2016 and January 2018, 80 patients were included. Data were ultimately available for 16 ALL and 62 AML patients. A total of 579 samples were assayed. Analysis of the results disclosed 3 sFLc kinetic profiles during induction i) sustained increase from days 1 to 22 (FLI group), ii) increase from days 1 to 15, then decrease at day 22 (FLD group) and iii) stagnation of low levels all along (<1000 pg/mL from days 1 to 22, FLL group). The 16 evaluable ALL patients were classified as FLI (n=2), FLD (n=7) and FLL (n=7). All reached a cytologic complete remission after induction and only 2 relapses have been documented so far in this group. No impact of sFLc kinetic profile was seen in this context. Conversely, a significant impact of sFLc during induction (but not during consolidation) was observed in AML patients. The median age in this group was 59 years old (range: 29-71, <60 years n=33). The median follow-up for alive patients was 541 days (range: 154-787). sFLc levels were assayed in 244 samples. Twenty-six patients were classified as FLI (42%), 22 as FLD (35%) and 14 as FLL (23%). Median sFLc at days 1, 8, 15, 22 were as follows for the three groups: FLI: 2, 724, 3673, 5753 pg/mL; FLD: 6, 1229, 6019, 684 pg/mL; and FLL: 0, 60, 124, 81 pg/mL. There was no significant difference between the 3 groups regarding age, ELN 2010 risk-stratification (ELNrs), OMS classification, WBC and bone marrow blasts percentages at diagnosis. When comparing the 3 sFLc groups, almost all refractory patients (n=6) were found in the FLL group (n=5, FLD n=1, FLI n=0, p=0.0007). Three cytologic relapses occurred in the FLI group, 7 in the FLD group (cytologic n=4, molecular n=2, immunophenotypic n=1) and 7 in the FLL group (cytologic n=4, molecular n=2, immunophenotypic n=1). There were more relapses in the FLL group (n=7/9 [78%] vs FLD n=7/21 [33%] vs FLI n=3/26 [11.5%], p=0.0009). In univariate analysis, 2-year EFS and OS were significantly better for the FLI group (79.1+-8 vs FLD 54.9%+-11 vs FLL 11.4%+-10,p<0.001; and 80.4%+-8 vs FLD 58.6%+-11 vs FLL 18.6%+-10, p=0.09,respectively). There was a trend for the association of 2-year EFS (but not OS) with ELNrs (favorable:70.9%+-11, vs Int-1+Int-2:57.1%+-10 vs adverse 33%+-13,p=0.06). Stratification of the patients according to the median sFLc level at day +15 (2952pg/mL) also showed significantly different 2 year EFS at 38.2%+-9 for low levels vs 71.8%+-8 for high levels (p=0.02). The same was true for day +22 median sFLc level (1390pg/mL) at 38.9%+-9 vs 73.6%+-8 (p=0.02). Age had no impact on EFS nor OS. In multivariate analysis considering age, ELNrs, sFLc at days 15 and 22 levels, and sFLc kinetic profile during induction, the latter remained the most powerful factor independently associated with EFS (HR: 3.62; 95%CI: 1,65-7,94, p=0,001; ELNrs: HR: 1.74; 95%CI: 0,98-3.10, p=0.05; sFLc at day+15 p=0,37; sFLc at day+22, p=0.24, age p=NS). sFLc kinetic profile was the sole factor that was also independently associated with OS (HR: 2.60; 95%CI: 1.12-6,07, p=0.02). In conclusion, sFLc kinetic profile during induction appears to be a new powerful early prognostic parameter in AML patients. These results need to be validated on a larger cohort of patients and the mechanism by which induction sFLc levels may impact AML outcome remains to be elucidated. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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