First Line Treatment with Venetoclax and Ibrutinib Induction Followed By Obinutuzumab Intensification Exclusively in CLL/SLL Patients Not in Complete Remission and/or with Detectable Bone Marrow Minimal Residual Disease (NEXT STEP trial)

Background Keeping the balance between long-term efficacy and toxicity of treatment in patients with chronic lymphocytic leukemia (CLL) is of utmost importance. Ibrutinib impacts BCR/adhesion signaling resulting in efficient lymph node (LN) responses and prolonged disease control despite a lack of deep remissions. Venetoclax directly kills CLL cells by antagonizing the pro-survival Bcl-2 protein leading to deep remissions (undetectable minimal residual disease (uMRD)) in the blood and bone marrow (BM) but incomplete LN clearance. Synergy between these agents is shown in our relapsed/refractory CLL HOVON 141 study with complete remission (CR) rates of 69% and blood uMRD rate of 55% after 12 full dose combination cycles with acceptable toxicity (abstract submitted; Niemann et al.). Extrapolating these data, we hypothesize that a fixed duration of a combination of venetoclax and ibrutinib will result in a substantial proportion of patients in CR and with undetectable MRD, who will have very good outcome after treatment cessation. Yet, not all patients will achieve this level of disease clearance and therefore, intensification approaches are of interest. A prior study has shown that addition of the CD20 antibody obinutuzumab lead to considerably higher uMRD rates when added after 1 year of prior ibrutinib monotherapy than when given simultaneously (BM uMRD rate of 50% versus 6% respectively; Hillmen et al. 2018). This suggests an opportunity for treatment intensification in the subset of patients who do not respond optimally to initial I+V combination treatment. In CLL, 3 compartments exist with putative differential sensitivity for targeted agents. Although the predictive role of residual leukemia cells in blood and bone marrow, as measured by MRD is increasingly appreciated, the biological and prognostic relevance of residual LN, which is often observed in venetoclax treated patients, is uncertain. 18F-fluorodeoxyglucose (FDG) PET-CT is widely used for response evaluation of lymphoma, but has not proven its value in CLL. (Conte et al. 2014) However, radiomics with computational processing of the PET/CT may provide biologic and clinical relevant information on the characteristics of residual LN and warrants exploration for guidance of treatment intensification as an MRD proxy for spleen and LN. (Lee et al. 2018) Objectives To evaluate the efficacy of 6 cycles ibrutinib+obinutuzumab in converting patients who are not in CR or who have detectable MRD after 12 cycles of ibrutinib+venetoclax to a CR with uMRD (BM). Moreover, PET/CT with radiomics is employed to assess clearance of CLL from LN and spleen. Primary endpoint CR with uMRD (BM) 3 months after end of intensification with ibrutinib+obinutuzumab in patients who are not in CR and/or uMRD on combination ibrutinib/venetoclax. Design The trial is designed as a single arm phase 2 study for treatment naïve CLL patients requiring treatment according to IWCLL criteria. 85 patients will be included. Study Treatment Patients will receive 3 lead-in cycles of ibrutinib 420 mg/day. Here-after, patients will continue with 13 induction cycles (including one bridging cycle) combining ibrutinib 420 mg/day and venetoclax 400 mg/day including a ramp up of 5-weeks starting in cycle 4 day 1. Patients with measurable disease at evaluation after 15 cycles will continue with 6 intensification cycles of ibrutinib/obinutuzumab. day 1, 2, 8, 15 for the first cycle and with obinutuzumab day 1 for the following 5 cycles in combination with ibrutinib (Figure 1). Major inclusion criteria Treatment naïve CLL or SLL patients requiring treatment by iwCLL WHO performance status 0-3 Adequate BM function defined as: Hb > 8 g/dLNeutrophil count ≥75 x 109/LPlatelet count ≥ 50,000 /μLcreatinine clearance ≥ 30ml/min Major exclusion criteria Active fungal, bacterial, and/or viral infection that requires systemic therapy; Patients requiring treatment with strong cytochrome P450 (CYP) 3A inhibitor or with vitamin K antagonists Statistical methods For the primary endpoint analyses, all patients registered and eligible for intensification treatment with ibrutinib+obinutuzumab (not in complete remission and/or uMRD) will be included. Perspective This trial helps in personalizing CLL treatment by selecting sequential time limited therapies guided by MRD. Figure 1 Disclosures Levin: Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Niemann:Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Abbvie: Consultancy, Other: Travel grant, Research Funding. Kater:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax Combination of ibrutinib and obinutuzumab

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PreVent-ACaLL Short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping

Blood ◽

10.1182/blood-2019-121907 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4304-4304

Author(s):

Caspar Da Cunha-Bang ◽

Rudy Agius ◽

Arnon P. Kater ◽

Mark-David Levin ◽

Anders Österborg ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Severe Infection ◽

Newly Diagnosed ◽

Risk Of Infection ◽

Advisory Committees ◽

Educational Grant ◽

Travel Grant ◽

Grade 3

Background Patients with Chronic Lymphocytic Leukemia (CLL) have an increased risk of infections both prior to and upon treatment. Infections are the major cause of death for these patients, the 5-year incidence of severe infection prior to treatment is approximately 32 % with a 30-day mortality of 10 % (Andersen et al., Haematologica, 2018). Chemoimmunotherapy is still 1st line standard of treatment for patients without del17p or TP53 mutation despite association with neutropenia, immunesuppression and infections. The combination of BTK inhibitors and the bcl-2 inhibitor venetoclax has demonstrated synergy in vitro and in vivo, while translational data indicate that the CLL-related immune dysfunction can be improved on treatment with reduced risk of infections. Employing the Machine-Learning based CLL treatment infection model (CLL-TIM) that we have developed, patients with a high (>65%) risk of infection and/or need of CLL treatment within 2 years of diagnosis can be identified (CLL-TIM.org). The significant morbidity and mortality due to infections in treatment-naïve CLL warrants trials that challenge the dogma of only treating symptomatic CLL. Thus, we initiated the randomized phase 2 PreVent-ACall trial of 12 weeks acalabrutinib + venetoclax to reduce risk of infections. Methods Design and statistics A phase 2, randomized, open label, multi-center clinical trial for newly diagnosed patients with CLL. Based on the CLL-TIM algorithm, patients with high risk of severe infection and/or treatment within 2 years from diagnosis can be identified. Approximately 20% of newly diagnosed CLL patients will fall into this high-risk group. First patient in trial planned for September 2019, primary outcome expected in 2021. Only patients identified as at high risk, who do not currently fulfil IWCLL treatment criteria are eligible. Patients will be randomized between observation in terms of watch&wait according to IWCLL guidelines or treatment. Primary endpoint Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm after 24 weeks (12 weeks after end of treatment). Study treatment Acalabrutinib 100 mg BID from cycle 1 day 1 for 12 weeks. Venetoclax, ramp up during the first five weeks starting cycle 1 day 1, thereafter 400 mg once daily for a total of 12 weeks counted from cycle 1 day 1. Patients A sample size of 25 patients in each arm, 50 patients in total. Major inclusion criteria CLL according to IWCLL criteria ≤1 year prior to randomizationHigh risk of infection and/or progressive treatment within 2 years according to CLL-TIM algorithmIWCLL treatment indication not fulfilledAdequate bone marrow functionCreatinine clearance above 30 mL/min.ECOG performance status 0-2. Major exclusion criteria Prior CLL treatmentRichter's transformationPrevious autoimmune disease treated with immune suppressionMalignancies other than CLL requiring systemic therapies or considered to impact survivalRequirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonistsHistory of bleeding disorders, current platelet inhibitors / anticoagulant therapyHistory of stroke or intracranial hemorrhage within 6 months Trial registry number EUDRACT NUMBER: 2019-000270-29 Clinicaltrials.gov number: NCT03868722 Perspectives: As infections is a major cause of morbidity and mortality for patients with CLL prior to any treatment, we aim at changing the natural history of immune dysfunction in CLL. The PreVent-ACaLL trial includes an optional extension into a phase 3 part with the primary outcome of grade ≥3 infection-free, CLL treatment-free survival two years after enrollment to address the unmet need of improved immune function in CLL for the first time. Figure Disclosures Da Cunha-Bang: AstraZeneca: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; Roche: Other: Travel Grant. Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Österborg:BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Kancera AB: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Abbvie: Consultancy, Other: Travel grant, Research Funding. OffLabel Disclosure: acalabrutinib and venetoclax in combination for CLL.

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Multiple Myeloma In Complete Remission After Autologous Stem Cell Transplantation: Impact of Bone Marrow Plasma Cell Assessment by Conventional Morphology on Disease Progression

Blood ◽

10.1182/blood.v116.21.2946.2946 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2946-2946

Author(s):

Carlos Fernández de Larrea ◽

Natalia Tovar ◽

María Rozman ◽

Laura Rosiñol ◽

Juan I. Aróstegui ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Stem Cell ◽

Complete Remission ◽

Board Of Directors ◽

Research Funding ◽

Bone Marrow Aspirate ◽

Advisory Committees ◽

Bone Marrow Plasma ◽

Serum And Urine

Abstract Abstract 2946 Background: The achievement of complete remission (CR) is the crucial step for a long-lasting response and prolonged survival after autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). The European Group for Blood and Marrow Transplantation (EBMT) criteria for CR include the negativity of serum and urine immunofixation (IFE) and less than 5% of bone marrow plasma cells (BMPCs). Additionally, the International Myeloma Working Group (IMWG) has even proposed a stringent CR category, which requires to rule out the clonal nature of the BMPCs. However, few studies have addressed this issue in patients with MM and negative IFE. The aim of the present study was to determine the impact of plasma cell count in the bone marrow aspirate on the long-term outcome of patients with MM with negative IFE after ASCT. Methods: Thirty-five patients (16M/19F; median age at ASCT 55 years, range 26–68) with MM who underwent ASCT from March 1994 to December 2008, were studied. All patients had achieved a negative serum and urine IFE after high dose therapy with melphalan-based regimens. Bone marrow aspirate was performed when negative serum and urine IFE was achieved and at least three months from ASCT (median 3.24 months). The analysis was based on microscopic revision for May-Grünwald-Giemsa stained bone marrow smears performed according to standard procedures. BMPC percentage was calculated independently by two observers counting 500 bone marrow total nucleated cells in random areas from two different slides (1000 cells on each patient). Results: Median BMPCs percentage was 0.8 (range 0.1–5.8). Only two patients had more than 3% BPMCs. These results are in contrast with a recent report from the Mayo Clinic group, where 14% of the patients with MM and negative IFE had 5% or more BMPCs. In univariate Cox-model regression analysis, the number of BMPCs significantly correlated with progression-free survival (PFS)(p=0.021) with no impact on overall survival (OS)(p=0.92). This statistical significance on PFS was retained in the multivariate analysis, when baseline prognostic factors such as age, hemoglobin level, serum creatinine, β2-microglobulin and Durie-Salmon stage were added to the model (p=0.003). To establish the best predictive cut-off for progression and survival, a receptor-operator curve (ROC) analysis was developed. It showed the value of 1.5% BMPCs, with a sensitivity of 53%, specificity of 90% and area under the curve of 0.66 for predicting progression. Ten patients had more than 1.5% BMPC, and 25 equal or less than 1.5% BMPC. Median PFS was 8.5 years (CI 95% 2.6 to 14.3) and was not reached in patients with ≤1.5% BMPCs versus 3.1 years in patients with >1.5% BMPCs, with a hazard ratio probability to progression of 3.02 (CI 95% 1.18 to 9.71)(p=0.016) in the group with more than 1.5% of BMPCs (Figure 1). Median OS was not reached in patients with ≤1.5% compared with a median of 9.7 years in those with more than 1.5% BMPCs (p=0.195) (Figure 2). It is likely that serological CR with very low percentage of BMPCs (i.e. ≤1.5%) is equivalent to negative MRD assessed by MFC or molecular studies. In fact, all 8 patients in continued CR between 9 and 16 years beyond ASCT (“operational cures”) are in the group with ≤1.5% BMPCs, while all patients in the group with >1.5% BPMC have relapsed within the first 9 years from ASCT (Figure 1). Conclusion: The percentage of BMPCs in patients with MM in CR after ASCT is a strong predictor of progression. Bone marrow morphology examination is an easy, inexpensive, and non-time consuming test and it should be the first step in the estimation of the residual tumor mass in patients with MM in CR after ASCT. Disclosures: Rosiñol: Janssen-Cilag: 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. Cibeira:Janssen-Cilag: 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. Blade:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Inhibition of SUV39H Methyltransferase As a Potent Therapeutic Target in Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.1771.1771 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1771-1771 ◽

Cited By ~ 3

Author(s):

Julie Devin ◽

Elena Viziteu ◽

Laurie Herviou ◽

Anja Seckinger ◽

Grandmougin Camille ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Advisory Committees ◽

Myeloma Cells ◽

Normal Bone ◽

Significant Toxicity ◽

Wide Range ◽

Travel Grant

Abstract Epigenetics is characterized by a wide range of changes that are reversible and orchestrate gene expression. Recent studies have shown that epigenetic modifications play a role in multiple myeloma (MM) by silencing various cancer-related genes. We investigated the epigenetic genes differentially expressed between normal bone marrow plasma cells (BMPC ; N=5) and MM plasma cells from patients (N=206). Using SAM (Significance Analysis of Microarrays) analysis, only 12 genes significantly differentially expressed between BMPC and MM cells (ratio > 2 and FDR (false discovery rate) < 5%) were identified, including the SUV39H1 histone methyltransferase. SUV39H1 and SUV39H2 are regulators of chromatin organization. SUV39H1-dependent trimethylation of H3K9 is essential for maintenance of both pericentromeric and telomeric heterochromatin. SUV39H1 deficiency reduced cell viability severely and is associated to heterochromatin decompaction, loss of silencing, genome instability, and a wide range of defects in cell cycle, cell growth, and meiosis. SUV39H1-mediated H3K9me has been linked to gene silencing of the tumor suppressor genes, such as p15INK4B and E-cadherin, in acute myeloid leukemia (AML). Therefore, it is highly possible that the default function of SUV39H1 is to maintain genome stability by limiting the acute activation of oncogenes while its dysregulation could cause tumor formation. We reported that high SUV39H1 expression, in MM cells, is associated with a poor prognosis in two independent cohorts of patients (Heidelberg-Montpellier cohort - N=206 and UAMS-TT2 cohort - N=345). SUV39H1 expression was downregulated by conditional shRNA expression through lentiviral delivery. SUV39H1 knock down significantly inhibits H3K9me3, growth of myeloma cells, induces apoptosis, cell cycle deregulation, reactive oxygen species production and spontaneous accumulation of DNA double strand breaks. According to these results, SUV39H1 depletion sensitizes myeloma cells to melphalan. Chaetocin is a selective inhibitor of SUV39H1. We identified that chaetocin has anti-myeloma effects at low nanomolar doses (range: 4 to 17 nM), on 11 different human myeloma cell lines, that are representative of the molecular heterogeneity of the patients, in association with H3K9 trimethylation inhibition. Furthermore, this significant toxicity of chaetocin in MM was confirmed on primary myeloma cells of 5 patients cocultured with their bone marrow microenvironment without significant toxicity on normal bone marrow cells and hematopoietic stem cells. Interestingly, the IC50 doses of chaetocin in MM were 50 fold lower compared to results published in AML, suggesting H3K9 histone methyltransferases could be a potent therapeutic target in MM. Disclosures Seckinger: EngMab AG: Research Funding; Takeda: Other: Travel grant. Goldschmidt:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau. Hose:EngMab AG: Research Funding; Takeda: Other: Travel grant.

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Dynamic Changes in Clonal Clearance with Decitabine Therapy in AML and MDS Patients

Blood ◽

10.1182/blood.v126.23.689.689 ◽

2015 ◽

Vol 126 (23) ◽

pp. 689-689

Author(s):

John S. Welch ◽

Allegra Petti ◽

Christopher A. Miller ◽

Daniel C. Link ◽

Matthew J. Walter ◽

...

Keyword(s):

Bone Marrow ◽

Complete Remission ◽

Clinical Response ◽

Exome Sequencing ◽

Board Of Directors ◽

Research Funding ◽

Bone Marrow Cells ◽

Advisory Committees ◽

Clonal Hematopoiesis ◽

Clinical Responses

Abstract To determine how AML subclonal architecture changes during decitabine treatment, and whether specific mutations might correlate with sensitivity vs. resistance to decitabine, we performed exome sequencing at multiple time points during single agent decitabine therapy. We enrolled 69 patients with either AML (age ≥ 60, or with relapsed/refractory disease, N = 45) or MDS (N = 24) on a phase I clinical trial. All subjects were treated with decitabine 20 mg/m2 on days 1-10 of 28 day cycles. With a median follow-up of 13.7 months, the intention to treat clinical response (complete remission with or without complete count recovery: CR/CRi) is 40%, with survival correlating with response (median survival - CR/CRi: 583 days; partial response/stable disease (PR/SD): 260 days; progressive disease (PD) or failure to complete cycle 1: 36 days, p < 0.0001). We performed exome sequencing on unfractionated bone marrow cells at diagnosis (day 0), cycle 1 day 10, cycle 1 day 28, cycle 2 day 28, and, when possible, during remission and at clinical relapse/progression. We have completed sequencing analysis for the first 34 cases (outcomes: 5 CR, 15 CRi, 3 PR, 8 SD, and 3 PD). Several important themes have emerged, as follows: 1) We correlated mutation status at diagnosis with clinical response. All six patients with TP53 mutations obtained clinical CR or CRi, and exome analysis demonstrated near complete elimination of the TP53- associated founding clones by the end of cycle 2 (p < 0.03). Long-term outcomes were similar in these patients compared with other patients who achieved CR/CRi: four patients relapsed after 8, 9, 10, or 17 cycles; 1 patient is doing well post-transplant; and one patient died of an infectious complication after cycle 2. No other mutations were significantly associated with clinical response or with consistent mutation clearance. 2) We observed a reduction in blast counts, which preceded mutation elimination in fourteen cases with CR, CRi or PR. This suggests that decitabine may induce morphological blast differentiation in vivo prior to mutation elimination. 3) In eight of nine cases with a clinical response followed by relapse, clinical progression was associated with expansion of a pre-existing subclone. We have not yet observed any recurrent mutations that reliably predict whether a subclone will contribute to relapse. Intriguingly, in two of these cases, the relapse-associated subclone was detectable at diagnosis and was eliminated more slowly than the founding clone mutations, suggesting that this subclone harbored intrinsic decitabine-resistance. 4) Complete remission can occur with concomitant non-malignant, clonal hematopoiesis. In three cases with a CR, a new clonal population was selected for during the remission. In two of these cases, there were no shared mutations between the founding clone and the emergent, non-malignant, clonal hematopoiesis, suggesting that these clones were unrelated. 5) Mutational architecture is generally stable, but differential chemo-sensitivity can be detected even between subclones in the same patient. In ten cases with PR or SD, we observed minimal shifts within the mutational burden over the course of eight weeks, suggesting that "clonal drift" is a relatively slow process. However, in four cases with SD, what appeared clinically to be simple persistent disease was in fact a dynamic elimination of one subclone, and its replacement by a different subclone. Similarly, in three cases with CRi, we observed rapid clearance of a subclone with slower clearance of the founding clone, again suggesting differential chemo-sensitivity among subclones. 6) Finally, we correlated pharmacologic markers with clinical outcomes. We observed no correlation between steady-state plasma decitabine levels and clinical responses. Using Illumina 450k methylation arrays, we observed a correlation between response and the extent of decitabine-induced hypomethylation in total bone marrow cells that persisted on cycle 1 day 28 (p < 0.01), but not on cycle 1 day 10 (p < 0.1). In summary, these data reveal that response to decitabine is associated with morphologic blast clearance before mutations are eliminated, that relapse is associated with subclonal outgrowth that may be identified early in the treatment course, and that TP53 mutations may be predictive of rapid clinical responses, although, like most responses to decitabine, these are not necessarily durable. Disclosures Off Label Use: Decitabine treatment of AML.. Uy:Novartis: Research Funding. Oh:CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Abboud:Novartis: Research Funding; Gerson Lehman Group: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Merck: Research Funding; Teva Pharmaceuticals: Research Funding. Cashen:Celgene: Speakers Bureau. Schroeder:Celgene: Other: Azacitidine provided for this trial by Celgene; Incyte: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.

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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 ◽

10.1182/blood.v124.21.23.23 ◽

2014 ◽

Vol 124 (21) ◽

pp. 23-23 ◽

Cited By ~ 2

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.

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A New Simplified Prognostic Index Integrating the Type of Extra-Nodal Involvement and Age for Ann Arbor Stage IV Hodgkin Lymphoma Patients Diagnosed at TEP-Scanner Era: A Retrospective Analysis from Lymphoma Study Association (LYSA) Centers

Blood ◽

10.1182/blood-2018-99-118578 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1629-1629

Author(s):

Camille Golfier ◽

Delphine Maucort-Boulch ◽

Emmanuelle Nicolas-Virelizier ◽

Cedric Rossi ◽

Pierre Sesques ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Prognostic Index ◽

Stage Iv ◽

Advisory Board ◽

Liver Involvement ◽

Advisory Committees ◽

Pet Ct

Abstract Purpose International Prognostic Index (IPS) is the most widely used risk stratification index for advanced stage Hodgkin's lymphoma (HL). The use of (18F)-fluorodeoxyglucose PET/CT at diagnosis allows a better characterization of extra-nodal involvement (ENI). We investigated if the type of ENI could affect the prognosis of stage IV HL patients diagnosed with PET/CT and if a specific prognostic index could be defined for these patients (pts). Patients and methods We retrospectively analyzed 220 stage IV HL patients treated from 2005 to 2015 in three LYSA centers. We considered the local investigator interpretation based on the nuclear medicine physician PET/CT report. Regarding ENI, six subgroups were identified: involvement of lung and/or pericard and/or pleural, liver, diffuse and/or focal bone involvement, digestive system, and other involvements; we also considered bone marrow involvement based on the results of bone marrow biopsy. The main outcome was event free survival (EFS) defined by relapse, progression, death from any cause and initiation of a new therapy. For prognostication, we first evaluated the six variables of IPS-6 (corresponding to IPS without "stage IV" item) in this population. ENI was tested adjusted on the retained IPS variables. Univariate and multivariate Cox models were used to assess their prognostic ability for EFS. Cross-validation (10-fold) was used to select the more robust variables avoiding optimism. The finally selected variables constituted a score that was tested on overall survival (OS). Results Among the 220 stage IV patients, 135 (61%) were male. Median age was 33 years (range, 16-86) and 72 pts (33%) were ≥45 years. 130 pts (59%) presented constitutional symptoms. Nodular sclerosis subtype was observed in 163 pts (74%), mixed cellularity subtype in 25 pts (11%) and 47/157 pts (30%) presented EBV-positive HL. For biological parameters of IPS, 158 pts (80%) had low albumin level <4g/dL, 66 pts (30%) hemoglobin values <10.5g/dL, white blood cell (WBC) count was >15G/L in 42pts (19%) and lymphocyte count <600/mm3 in 75 pts (34%). The IPS-6 score was 0-2 in 93 pts (47%) and ≥3 in 104 pts (53%). ENI distribution according to PET/CT was: diffuse and/or focal bone involvement (155 pts, 71%), lung-pericard-pleural (94 pts, 43%), liver (37pts, 17%), digestive system (11 pts, 5%), 38 pts (17%) had other ENI; bone marrow involvement according to biopsy concerned 40 pts (21%). Only 1 extra-nodal site was involved in 49% of pts, 2 sites in 33%, 3 sites in 16% and 4 sites in 2%. With a median follow-up of 4.8 years, the 5-year EFS and OS rates were 73% and 89.9%, respectively for the whole cohort. The IPS-6 remained a strong prognostic index in our cohort. Patients with an IPS-0-2 and 3-6 had a 5-year EFS rate of 81.8% and 64% (p=0.008), respectively. The evaluation in univariate analysis of the prognostic value of each individual variable of IPS showed that only age influenced EFS (p=0.002) but albumin level (p=0.92), hemoglobin level (p=0.28), lymphocyte count (p=0.16), WBC count (p=0.10) and sex (p=0.21) had no significant prognostic effect. Regarding ENI, all 6 subgroups were studied: liver involvement was the only extra-nodal site with prognostic impact (HR=1.67 [0.92-3.04], p=0.093) in univariate analysis. We then performed a multivariate analysis integrating age and liver involvement: age was significantly associated with EFS (HR=2.20 [1.32-3.65], p=0.002); liver involvement also presented an influence on EFS (HR=1.72 [0.94-3.13], p=0.076). Thus, we developed a prognostic index with these two variables that defined two distinct risk groups: low risk (age <45 years or no liver involvement, N=206 pts, 94%) and high risk (age ≥45 years and liver involvement, N=14 pts, 6%) (HR=5.09 [2.64-9.85], p<10-3). 5-year EFS rates were respectively 76.8% and 17.9% (Figure 1A). This model also influenced OS with a 5-year OS rate of 91.8% and 61.4% for low and high risk groups, respectively (Figure 1B). Conclusions: For stage IV HL defined by PET/CT, we developed a simple prognostic score based on age (≥45y) and liver involvement that identify a subgroup of patients with a poor outcome. These findings need to be validated in independent cohorts. Based on these results, whether HL pathogenesis differs by ENI sites should be investigated. Disclosures Bachy: Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Honoraria. Karlin:Celgene: 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, Other: travel support; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Sarkozy:ROCHE: Consultancy. Traverse-Glehen:Takeda: Research Funding; Astra Zeneca: Other: Travel. Salles:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Servier: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria; BMS: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Janssen: Honoraria, Other: Advisory Board; Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Epizyme: Honoraria; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Merck: Honoraria; Servier: Honoraria; Takeda: Honoraria. Casasnovas:Takeda: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy; Roche: Consultancy, Research Funding; Bristol-Meyers Squibb: Consultancy; Merck: Consultancy. Ghesquieres:Celgene: Consultancy; Gilead: Consultancy; Sanofi: Consultancy.

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Comparison of Acute Myeloid Leukemia Measurable Residual Disease Detection By Flow Cytometry in Peripheral Blood and Bone Marrow

Blood ◽

10.1182/blood-2019-127128 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2729-2729

Author(s):

Colin D. Godwin ◽

Yi Zhou ◽

Megan Othus ◽

Carole M. Shaw ◽

Kelda M. Gardner ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Correlation Coefficient ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Spearman Correlation ◽

Advisory Committees ◽

Measurable Residual Disease ◽

Acute Myeloid

BACKGROUND: The current recommendation against the need for bone marrow aspiration (BMA) in routine follow-of persons with acute myeloid leukemia (AML) in remission preceded the recognition that multiparameter flow cytometry (MFC) is a sensitive and specific means to detect imminent morphologic relapse. Given this recognition, we wondered whether BMA is now necessary, or if concordance between MFC results in peripheral blood (PB) and BMA is such as to make BMA unnecessary, at least for evaluation of measurable residual disease (MRD) by MFC. Previous studies have demonstrated a strong correlation between disease detection by MFC in PB and BMA. Here we examined 724 paired PB and BMA samples from 482 patients to further examine the concordance between PB and BMA blast detection by MFC, particularly among patients in morphologic remission. PATIENTS AND METHODS: We included adults in our institutional AML database, covering 2008-2018. Our Hematopathology database was queried to identify PB and BMA MFC sample pairs with samples considered "paired" if measured within one week of each other. If an individual had multiple pairs, all were included unless otherwise specified. Ten-color MFC was performed routinely on BMA aspirates with a panel of three antibody combinations, with the same antibody combinations applied to PB samples. When identified, the abnormal population was quantified as a percentage of the total CD45+ white cell events. Any level of residual disease was considered positive. Complete remission (CR) and relapse were defined according to the European LeukemiaNet 2017 classification. Relationship between PB and BMA blast % was measured using Spearman's Rank-Order Correlation. Relationship between PB and BMA samples identified as positive or negative is illustrated using 2 X 2 tables (Table 1). RESULTS: Considering all 724 sample pairs, the Spearman correlation coefficient between PB and BMA blast percentage was 0.93, and was 0.91 considering only the first sample pair for each individual patient (n= 482). 315 sample pairs were positive by PB, 97% of which were also positive by BMA while 95% of 409 pairs negative by PB were also negative by BMA. Similar results were seen considering only a patient's first pair. Restricting analysis to patients with pairs obtained between the dates of CR and relapse, the Spearman correlation coefficient was 0.82 with 91% of 35 cases positive in PB also positive in BMA; 93% of 114 pairs negative in PB were also negative in marrow. As a complementary means to compare pairs when AML burden was low, we examined only pairs where the BMA MFC showed <5% blasts. Here, the Spearman correlation coefficient between PB and BMA blasts was 0.83. 90% of 70 positive PB cases were also positive by BMA while 95% of 295 negative PB cases were also negative by BMA. Examining pairs taken from patients in morphologic remission immediately prior to undergoing hematopoietic cell transplant yielded a Spearman correlation coefficient of 0.92, with all 9 PB positive cases also being positive in BMA and 96% of PB negative cases being negative in BMA. CONCLUSIONS: This is the largest cohort of AML PB and BMA sample pairs analyzed by MFC to-date. The percentages of blasts measured in PB and BMA are strongly correlated. In the 365 pairs from patients with MRD-level disease, the predictive value of PB MFC positivity for BMA positivity was 90% (63/70) while the predictive value PB MFC negativity for BMA negativity was 95%. Disclosures Othus: Glycomimetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gardner:Abbvie: Speakers Bureau. Walter:BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Argenx BVBA: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership.

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Interim Analysis of Lenalidomide Consolidation on Minimal Residual Disease in Patients with Chronic Lymphocytic Leukemia Following Initial FCR Chemotherapy - CLL6 Residuum Study of the Australian Leukaemia and Lymphoma Group (ALLG) and the French Innovative Leukemia Organization (FILO)

Blood ◽

10.1182/blood.v128.22.2053.2053 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2053-2053 ◽

Cited By ~ 1

Author(s):

David Gottlieb ◽

Thérèse Aurran ◽

Constantine S. Tam ◽

Mary Sartor ◽

Rémi Letestu ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Consolidation Therapy ◽

Front Line ◽

Advisory Committees ◽

To Receive ◽

Minimal Residual

Abstract Introduction Patients with residual disease following initial treatment of chronic lymphocyticleukemia(CLL) withfludarabine, cyclophosphamide and rituximab (FCR) chemotherapy have reduced progression free (PFS) and overall survival (OS). The CLL6 RESIDUUM trial is a joint trial of the Australasian Leukaemia and Lymphoma Group (ALLG) and the French CLL branch of the French InnovativeLeukemiaOrganization (FILO) thatanalyzesthe role oflenalidomide(LEN) as consolidation therapy in patients following front-line treatment for CLL who do not enter minimal residual disease (MRD) negative complete remission. Methods CLL patients with CIRS score <6 requiring treatment according to iwCLLcriteria receive 6 cycles of FCR. Following completion of treatment, those with clinical, radiological and/or multiparameterflow cytometry (MFC) evidence of residual CLL in blood or bone marrow are randomized 1:1 to receive 2 years of maintenance treatment with LEN 10 mg daily or observation (OBS). Patients are reviewed for evidence of clinical progression, and peripheral blood and bone marrow are sampled regularly for evidence of MRD. CT scans are performed until resolution of lymphadenopathy and splenomegaly. Flow analysis for MRD is performed at two central laboratories using ERIC accredited methodology to achieve a sensitivity of 10-4. The primary end point of the study is time to progression or death. Results As of end of July 2016, data from 79 patients randomized on the study were analyzedfor the effects of consolidation treatment on blood and marrow MRD. Median duration from randomization was 488 days. There were 63 males and 16 females. Median age was 62 years (range 29 to 81). 37 patients were randomized to receive LEN, 42 to OBS .On the LEN arm 13, 3 and 21 patientsvs 12, 9 and 21 on the OBS arm were in CR, nodular PR and PR respectively at the time of randomization. There were 26 serious adverse events (SAEs) reported in 22 patients. 12 SAEs in 11 patients were attributed to LEN including pneumonia/chest infection (n=4), pulmonary infiltrate (1), prostatitis (1) second primary malignancy (SPM) (1), vomiting (1), neutropenia (1), tumorflare (1), acute kidney injury (1) and anal warts (1). There were 5 SAEs in the OBS arm comprising SPM (2), neutropenia (1), gout (1) and GuillainBarre syndrome(1). Peripheral blood samples were analyzedprior to consolidation and at 3, 6 and 12 months and every 6 months thereafter. MRD levels during consolidation were compared with pre-consolidation levels and categorized as increasing, decreasing, stable detectable or stable undetectable (Fig 1). MRD increased over the period of observation in 38% of patient on the LEN arm and in 62% of patients on the OBS arm (p = 0.032, Χ2). 10 patients (27%) in the LEN arm and 2 patients (5%) in the control arm had decreasing levels of MRD in the blood (p = 0.006, Χ2). There was no difference between consolidation treatments in the percentage of patients with stable blood MRD measurements, whether in the detectable or the undetectable range. The effect of LEN was most apparent in patients in PR at randomization where 5 patients (24%) taking LEN had increasing MRD in the blood compared to 15 patients (71%) on the OBS arm (p = 0.002, Χ2). Bone marrow MRD levels were assessed prior to consolidation and after 12 months in 9 patients in each arm of the study (LEN arm 2 CR, 1 nPR, 6 PR; OBS arm 4 CR, 1 nPR, 4 PR at randomization). Eight patients in the LEN arm and 2 patients in the OBS arm were observed to have a reduction in marrow MRD. There was a significant reduction between the 2 time points in the LEN arm (p=0.022 paired Wilcoxon test) but not in the OBS arm. Four of 9 patients in the LEN arm and 1 patient in the OBS arm achieved marrow MRD values below 10-4 after 1 year on trial. Conclusion LEN consolidation therapy for residual disease after FCR front-line therapy for CLL is associated with improved control of MRD in both blood and bone marrow. A large group of recently randomized patients will provide more data to determine whether these encouraging results will translate into improved progression free and overall survival. Figure 1 Percentage of patients on LEN and OBS arms with increasing, decreasing, stable detectable or stable undetectable MRD. Figure 1. Percentage of patients on LEN and OBS arms with increasing, decreasing, stable detectable or stable undetectable MRD. Disclosures Gottlieb: Indee: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Aurran:Janssen: Honoraria. Tam:Gilead: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Letestu:Roche: Honoraria; Alexion: Honoraria. Levy:Roche: Honoraria; Gilead: Honoraria; Abbive: Honoraria; Janssen: Honoraria. Leblond:Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Mulligan:GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cymbalista:Abbvie: Honoraria; Roche: Honoraria; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Honoraria.

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TCR Clonal Evolution in AML Patients in Morphologic Remission Treated with Anti-PD1 Antibody, Nivolumab

Blood ◽

10.1182/blood.v128.22.2325.2325 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2325-2325 ◽

Cited By ~ 4

Author(s):

Hongtao Liu ◽

Jae-Hyun Park ◽

Noreen Fulton ◽

Kazuma Kiyotani ◽

Yusuke Nakamura ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

T Cell Repertoire ◽

Cell Repertoire ◽

Advisory Committees ◽

Tcr Repertoire ◽

Minimal Residual

Abstract We are conducting a clinical trial titled "Randomized Phase II Study to Assess the Role of Nivolumab as Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients After Chemotherapy" (REMAIN trial) (NCT02275533). A critical barrier in developing immunotherapies is the identification of predictive biomarkers of response to therapy. T lymphocytes play critical roles in response to immunotherapies but their clonality and temporal changes in the T cell repertoire during treatment have not been well investigated. Recent advances in deep sequencing technology make it possible to characterize the T cell receptor (TCR) repertoire generated following immunotherapy. In this study, we characterized T cell repertoire in peripheral blood and/or bone marrow samples of three AML patients on the REMAIN trial before and after nivolumab treatment. Using Illumina MiSeq sequencer and total RNA from each sample, we conducted deep sequencing of TCR-α and -β chains, and calculated the diversity index (inverse Simpson's index) in their CDR3 sequences to assess overall clonality of T cells. We obtained total CDR3 clonotypes of 420,765 ± 155,449 (average ± standard deviation) for TCR-α and 410,786 ± 115,219 for TCR-β per each sample. Interestingly, we found that certain TCR-α and -β clonotypes were drastically enriched in the bone marrow samples after nivolumab treatment. Many of these enriched TCR clonotypes were minimal or undetectable before nivolumab treatment, indicating that nivolumab might induce expansion of anti-AML T cell subclones. Particularly, nivolumab treatment led to marked reduction of TCR diversity indexes in both peripheral blood and bone marrow samples of one AML patient, who had shown a clearance of minimal residual disease as detected by WT1 qRT-PCR. Our results thus far indicate the feasibility of this type of comprehensive analysis of TCR repertoire in the context of immunotherapy for AML. Preliminary results suggest that such analysis may be utilized to predict response of immune checkpoint blockade, and could also be useful to identify high-affinity TCRs for adaptive T cell therapy approaches. Disclosures Liu: BMS: Research Funding; Karyopharm: Research Funding. Odenike:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stock:ADC Therapeutics: Honoraria; Amgen: Honoraria; Gilead Sciences: Honoraria; Sigma-Tau: Honoraria, Research Funding; Royalties for a chapter in Up to Date: Patents & Royalties.

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Heavy and Light Chain Monitoring in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Blood ◽

10.1182/blood-2019-128655 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1852-1852

Author(s):

Noemi Puig ◽

Teresa Contreras ◽

Bruno Paiva ◽

María Teresa Cedena ◽

José J Pérez ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Response Assessment ◽

Advisory Committees ◽

Minimal Residual

Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of bone marrow minimal residual disease (MRD) negativity. However, other methods of disease evaluation in serum such as heavy+light chain (HLC) assessment, with a potential complementary value to the IMWG response criteria, have also been tested. Aim: To evaluate the performance of HLC assay in HRsMM pts at diagnosis and after consolidation, comparing the results with standard serological methods and Next Generation Flow (NGF) for the assessment of bone marrow MRD. Patients and Methods: Ninety HRsMM pts included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and 2 further cycles of consolidation with the same regimen. All pts received maintenance treatment with lenalidomide for up to 2 years. SPEP and IFE were performed using standard procedures. Serum IgGk, IgGl, IgAk and IgAl HLC concentrations were measured using Hevylite (The Binding Site Group Ltd, Birmingham, UK) on a SPA PLUS turbidimeter. HLC concentrations and ratios were considered abnormal if they were outside the 95% reference ranges provided by the manufacturer. MRD was analyzed by flow cytometry following EuroFlow recommendations (sensitivity, 2x10-6). Standard response assignment was carried out as per the IMWG guidelines. Hevylite responses were assigned and HLC-pair suppression was defined as in Michalet et al (Leukemia 2018). Results: Out of 90 HRsMM pts, 75 had monoclonal intact immunoglobulin and samples available at diagnosis (50 IgG and 25 IgA). HLC ratio was abnormal in 98% of IgG pts and in 100% of IgA pts. Response assessment by Hevylite and standard IMWG criteria were available in 62 pts post-consolidation (Table 1). A good agreement was found between the two methods (kappa quadratic weighting = 0,6327 (0,4016 - 0,8638)). Among 46 pts with assigned CR as per the IMWG response criteria, there were 3 and 8 pts in PR and VGPR according to the Hevylite method, respectively. In 62 cases, paired Hevylite and MRD assessment data were available. Concordant results were found in 72.5% of cases (45/62; HLC+/NGF+ in 15 and HLC-/NGF- in 30 cases) while in the remaining 27.4% of cases results were discordant (17/62; HLC-/NGF+ in 6 and HLC+/NGF- in 11 cases). Post-consolidation, 24, 25.8 and 42.3% of the 62 samples were positive by SPEP, NGF and Hevylite, respectively. HLC-pair suppression was identified in 13/62 pts; 10 had severe HLC-pair suppression at the end of consolidation. After a median follow-up of 32 months (8-128), 93% of pts remain alive and progression-free. Three patients that have already progressed had their responses assessed post-consolidation. The first pt was assigned VGPR by the standard IMWG criteria and PR by Hevylite and was MRD positive by NGF; the second pt was assigned CR by IMWG criteria and Hevylite but had severe HLC-pair immunosuppression and was MRD positive by NGF; the third pt was in CR by IMWG and HLC criteria and was MRD positive by MFC. Conclusions: Moderate agreement was found between response assessment by Hevylite and the standard IMWG methods as well as between Hevylite and MRD assessment by NGF. Most discordances were a result of Hevylite detecting disease in samples negative by the standard methods, but longer follow-up is needed to ascertain its clinical value. HLC assessment could have anticipated the progression noted in 2 (out of 3) patients. Disclosures Puig: Takeda, Amgen: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Sanofi and Takeda: Consultancy. Rodriguez Otero:Kite Pharma: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios: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. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Ocio:Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Novartis: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Janssen: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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