Minimal Residual Disease in the Maintenance Setting in Myeloma: Prognostic Significance and Impact of Lenalidomide

Abstract Introduction. Minimal residual disease (MRD) is a powerful predictor of outcome in multiple myeloma (MM). A recent meta-analysis has confirmed this and demonstrated a hazard ratio for PFS of 0.41; 95% CI, 0.36-0.48; P < .001 (Munshi et al, JAMA Oncol, Jan 2017). We have previously demonstrated the prognostic impact of MRD both following ASCT in transplant-eligible (TE) patients and following induction in transplant non-eligible (TNE) patients. There is more limited data on the applicability and significance of MRD assessment in the maintenance setting, largely as a consequence of high rates of drop-off historically within myeloma trials but improved outcomes have seen larger numbers of participants with samples at later timepoints. Patients and Methods. This analysis aims to assess the impact of MRD on PFS amongst patients receiving maintenance or no further therapy in the NCRI Myeloma XI trial. In this study patients were randomised between thalidomide (CTD) and lenalidomide (RCD) based induction therapies. For patients with a sub-optimal response to initial therapy, induction was supplemented with sequenced bortezomib-based induction (CVD). Intensively treated patients then proceeded to an autologous transplant and then responding patients from both intensive and non-intensive arms were subsequently randomised to maintenance with lenalidomide monotherapy, lenalidomide and vorinostat or no further therapy. Bone marrow aspirates were obtained prior to maintenance randomisation (100 days post ASCT for TE and at the end of (sequenced-) induction treatment for TNE) and 6 months post maintenance randomisation. This analysis represents a subset of 389 patients (median age 63.5 years) with an informative post maintenance randomisation bone marrow aspirate. MRD was assessed using flow cytometry (sensitivity 0.004%) with a minimum of 500,000 cells evaluated with six- or eight-colour antibody combinations including CD138/CD38/CD45/CD19/CD56/CD27 in all cases and CD81/CD117 added latterly. Results. Taking the group as a whole, MRD-negativity was demonstrated in 206/389 (55.8%) and this was associated with a significant outcome advantage as the median PFS was >50 months versus 20 months for MRD-positive patients (Fig.1(a), p<0.0001, HR 0.2, 95% CI 0.11-0.37). When the pre-maintenance MRD result was also taken into account, outcome was best for patients achieving negativity post ASCT/end of treatment and remaining MRD-negative and worst for those patients who were MRD-positive post ASCT/end of treatment and remained so (Fig 1(b), p<0.0001). Conversions to MRD-negativity were seen in 32% of MRD-positive patients on maintenance compared to 4% of patients randomised to no further therapy (p=0.0045). This conversion is associated with some improvement in outcome, but this group still have inferior outcome relative to those patients achieving MRD-negativity earlier in protocol treatment. Conversions to MRD-positivity were also seen in 24 (9.5%) of 252 patients and the outcome for this patient group was similar to that of the patients who remain MRD-positive throughout (Fig. 1(b)). For those patients that remained MRD-positive, a benefit from maintenance could be demonstrated by a lower level of residual disease relative to those patients on observation (median level of neoplastic plasma cells 0.15% on maintenance vs 0.39%, p=0.04). Conclusions. We would conclude that MRD is a particularly powerful predictor of outcome in the maintenance setting and is clearly a desirable therapeutic goal in this patient group. The hazard ratio of 0.2 demonstrated here appears superior to those demonstrated in previous studies examining post induction or ASCT time-points. Approximately one third of MRD-positive patients receiving maintenance became MRD-negative and maintenance therapy also results in a decrease in disease levels in those patients remaining positive. These results support the role of MRD monitoring in assessment of the efficacy of different maintenance/consolidation strategies within clinical trials. In the longer term, a stratified approach to treatment based on sequential MRD assessments is feasible. The predictive ability of MRD during maintenance will be assessed with respect to overall survival when the primary endpoint matures in September 2017 and presented at the meeting. Disclosures Rawstron: BD biosciences: Patents & Royalties; Gilead: Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Pawlyn: Celgene: Honoraria, Other: Travel support; Janssen: Other: Travel support; Takeda: Honoraria, Other: Travel support. Davies: Bristol-Myers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Jones: Celgene: Honoraria, Other: Travel Support, Research Funding. Kaiser: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy; BMS: Consultancy, Other: Travel expenses; Chugai: Consultancy. Drayson: Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jenner: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support , Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding, Speakers Bureau; Chugai: Membership on an entity's Board of Directors or advisory committees. Gregory: Janssen: Honoraria; Celgene: Consultancy, Honoraria. Jackson: Celgene: Honoraria; J&J: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Chugai: Honoraria. Morgan: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Myers: Consultancy, Honoraria. Owen: Takeda: Honoraria, Other: Travel Support; Janssen: Consultancy, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding.

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Impact of Minimal Residual Disease in Transplant Ineligible Myeloma Patients: Results from the UK NCRI Myeloma XI Trial

Blood ◽

10.1182/blood.v128.22.245.245 ◽

2016 ◽

Vol 128 (22) ◽

pp. 245-245 ◽

Cited By ~ 6

Author(s):

Ruth Mary de Tute ◽

Andy C Rawstron ◽

David A Cairns ◽

Charlotte Pawlyn ◽

Faith E Davies ◽

...

Keyword(s):

Minimal Residual Disease ◽

Research Funding ◽

Residual Disease ◽

Prognostic Significance ◽

Continuous Variable ◽

Powerful Predictor ◽

Qualitative Variable ◽

The Impact ◽

Minimal Residual ◽

Support Research

Abstract Introduction. Minimal residual disease (MRD) is a powerful predictor of outcome in multiple myeloma (MM). We have previously demonstrated, in transplant eligible patients, that the level of MRD as a continuous variable independently predicts both PFS and OS, with approximately a one year median OS benefit per log depletion (J Clin Oncol 2013; 31:2540-7 and Blood 2015; 125:1932-5). The impact of MRD also appears to be independent of therapy received. There is more limited data on the applicability of MRD assessment in transplant ineligible patients, largely as a consequence of low rates of CR historically within this patient cohort. Patients and Methods. In this analysis we have assessed the impact of MRD on PFS amongst patients treated within the non-intensive arm of the NCRI Myeloma XI trial. Patients were randomised between thalidomide (CTDa) and lenalidomide (RCDa) based induction therapies with responding patients being subsequently randomised to maintenance with lenalidomide monotherapy, or no further therapy. Bone marrow aspirates were obtained at the end of induction and this analysis represents a subset of 297 patients (median age 74 years). MRD was assessed using flow cytometry (sensitivity 10-4) with a minimum of 500,000 cells evaluated with six-colour antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in additional cases as required. Results. Overall MRD-negativity was demonstrated in 41/297 (13.8%). When considered according to induction therapy received 25/154 (16.0%) of patients randomized to RCDa were MRD-negative compared to 16/143 (10.8%) of those randomized to CTDa (p=0.24; Fisher's exact test). MRD-negativity was associated with a significant outcome advantage as the median PFS was 34 months versus 18 months for MRD-positive patients (p<0.0001, HR 0.44 [95% confidence interval (CI 0.29-0.67)]). This effect was noted in both RCDa (median PFS 17m v 32m; p=0.001, HR 0.41 [95%CI 0.23-0.69]) and CTDa (median PFS 19m v 34m; p=0.03, HR 0.49 [95%CI 0.26-0.95]). When the impact of MRD was assessed according to induction regimen the outcome of MRD-negative and MRD-positive patients was similar with both regimens (see figure). The impact of MRD was also assessed as a continuous variable across 5 logs of residual disease. Sequential improvements in outcome with each log reduction were demonstrable. Median PFS for the following disease levels; <0.01%, 0.01 - <0.1%, 0.1% - <1%, 1% - <10% and >/=10% were 34, 26, 16, 14 and 9 months respectively (p<0.0001). This pattern was demonstrable in both RCDa and CTDa treated patients (p<0.0001 for both). Multivariate analysis confirmed the independent predictive value of MRD both as a qualitative and continuous quantitative variable (p<0.0001 for both). In both instances achieving an immunofixation-negative CR was not a significant prognostic variable when included in the model with MRD. Conclusions. We would conclude that MRD is a powerful predictor of outcome in transplant ineligible patients and is a meaningful therapeutic goal in this patient group. In contrast to conventional CR it retains independent prognostic significance both as a quantitative and qualitative variable. This data further supports the role of MRD as a primary endpoint and surrogate marker for survival in future clinical trials. Figure. Figure. Disclosures Rawstron: Janssen: Research Funding; BD Biosciences: Other: Remuneration; Gilead: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Genzyme: Honoraria; AbbVie: Honoraria; Roche: Honoraria; Celegene: Honoraria. Pawlyn:Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda Oncology: Consultancy. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support; Chugai: Consultancy. Jones:Celgene: Honoraria, Research Funding. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jenner:Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: Travel support. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jackson:MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment. Owen:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel support; Janssen: Consultancy, Other: Travel support.

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Switching to Nilotinib Is Associated with Continued Deeper Molecular Responses in CML-CP Patients with Minimal Residual Disease After ≥ 2 Years On Imatinib: Enestcmr 2-Year Follow-up Results

Blood ◽

10.1182/blood.v120.21.694.694 ◽

2012 ◽

Vol 120 (21) ◽

pp. 694-694 ◽

Cited By ~ 2

Author(s):

Timothy P. Hughes ◽

Jeffrey H. Lipton ◽

Nelson Spector ◽

Brian Leber ◽

Ricardo Pasquini ◽

...

Keyword(s):

Board Of Directors ◽

Minimal Residual Disease ◽

Research Funding ◽

Residual Disease ◽

Molecular Response ◽

Advisory Committees ◽

Molecular Responses ◽

The Difference ◽

Minimal Residual

Abstract Abstract 694 Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up. Methods: Patients with Ph+ CML-CP who had achieved complete cytogenetic responses but still had persistent BCR-ABL positivity by real-time quantitative polymerase chain reaction (RQ-PCR) after ≥ 2 years on imatinib were eligible. Patients (n = 207) were randomized to switch to nilotinib 400 mg twice daily (BID; n = 104) or to continue on the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103). Rates of MMR, MR4 (BCR-ABL ≤ 0.01% according to the International Scale [IS], corresponding to a 4-log reduction), MR4.5 (BCR-ABL ≤ 0.0032%IS, corresponding to 4.5-log reduction), and undetectable BCR-ABL via RQ-PCR with ≥ 4.5-log sensitivity were measured. Results: Among all randomized patients (intent-to-treat population), significantly more patients treated with nilotinib continued to achieve undetectable BCR-ABL by 24 mo (32.7% on nilotinib vs 16.5% on imatinib; P =.005; Table).The difference between the arms in achievement of this endpoint increased between 1 and 2 years (from 12.4% to 16.2%). The median time to MR4.5 and undetectable BCR-ABL was also significantly faster on nilotinib than on imatinib (P = .005 and .003, respectively). Cumulative rates of MR4.5 and undetectable BCR-ABL continued to be higher with nilotinib in patients without those responses at baseline, and the difference between arms appeared to increase over time. The safety profiles for nilotinib and imatinib were consistent with prior studies. By 24 mo, no patients in either arm progressed to accelerated phase/blast crisis. No patients on nilotinib died since the 12-mo analysis; 1 patient on imatinib died from metastatic prostate cancer in follow-up after discontinuation from the study. Conclusions: Switching to nilotinib led to significantly faster, deeper molecular responses in patients with minimal residual disease on long-term imatinib therapy. Since the 12-mo analysis, rates of deep molecular response (MR4.5 and undetectable BCR-ABL) have remained significantly higher in patients who did not have the response at baseline and were switched to nilotinib (vs those remaining on imatinib). In fact, the difference in favor of nilotinib increased between 1 and 2 years. These results suggest that switching to the more potent, selective tyrosine kinase inhibitor nilotinib is beneficial in patients with minimal residual disease after long-term imatinib therapy. Achievement of these deeper molecular responses (MR4.5 and undetectable BCR-ABL) after switching to nilotinib may enable a greater proportion of CML-CP patients to be eligible for future discontinuation studies. Cumulative rates of confirmed undetectable BCR-ABL by 24 mo will be presented as the confirmation assessments for several responders were not available at the time of this analysis. Disclosures: Hughes: Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding. Lipton:Novartis: Consultancy, Research Funding, Speakers Bureau. Spector:Novarits: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy. Leber:Novartis: Advisory Board Other, Honoraria, Speakers Bureau. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Purkayastha:Novartis Pharmaceuticals Corp: Employment. Collins:Novartis Pharmaceuticals Corp: Employment. Szczudlo:Novartis Pharmaceuticals Corp: Employment. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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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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Phase III Study of Daratumumab/rhuph20 (nsc- 810307) + Lenalidomide or Lenalidomide As Post-Autologous Stem Cell Transplant Maintenance Therapyin Patients with Multiple Myeloma (mm) Using Minimal Residual Disease Todirect Therapy Duration (DRAMMATIC study): SWOG s1803

Blood ◽

10.1182/blood-2020-142913 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 21-22

Author(s):

Amrita Krishnan ◽

Antje Hoering ◽

Parameswaran Hari ◽

Rachael Sexton ◽

Robert Z. Orlowski

Keyword(s):

Multiple Myeloma ◽

North America ◽

Board Of Directors ◽

Minimal Residual Disease ◽

Research Funding ◽

Residual Disease ◽

Phase Iii ◽

Advisory Committees ◽

Optimal Duration ◽

Minimal Residual

Background:Lenalidomide(Len) maintenance following autologous transplantation(ASCT) for multiple myeloma has improved progression free survival (PFS)and overall survival compared with placebo. Optimal duration of maintenance is unknown with considerable inter-trial variability. Depth of remission correlates with PFS, with patients (pts) in a minimal residual disease negative state (MRD) to a sensitivity of 10 -5 having a better PFS. Therefore, Len combinations that lead to higher MRD negativity rates are under study. The anti CD38 antibody Daratumumab in combination with lenalidomide in newly diagnosed MM pts showed a higher MRD negativity rates in the MAIA trial (NEJM2019). SWOGS1803 is testing this regimen as maintenance following ASCT while also assessing the optimal duration of maintenance in patients who achieve MRD negativity. Methods:Pts 18-75 years, with MM within 12 months of induction and without progression from diagnosis are eligible. Prior daratumumab therapy is allowed. Enrollment may be before or after ASCT with transplant being within 18 months from initial registration. Within 180 days from ASCT pts will undergo first randomization to Len or Len plus subcutaneous daratumumab/rHuPH20 maintenance (Len Dara). MRD will be assessed prior to start of maintenance and then annually. Randomized treatment will continue for two years at which time repeat MRD will be assessed for pts in VGPR or better. Pts who are MRD negative will undergo second randomization to either continue maintenance on their assigned arm or discontinue maintenance. The continued maintenance arm will stay on therapy for 7 years or until disease progression or unacceptable toxicity.(see schema) The primary objective of the trial is to compare OS between the two treatment arms (Len vs. LenDara). Secondary objectives include comparisons of overall response rate, PFS, and MRD negativity rate between the treatment arms. The objectives of the second randomization are to compare OS of MRD negative pts who continue maintenance on each arm vs. those who discontinue. An early read out of the trial will be the 24 month MRD analysis after all pts have been accrued. A total of 1100 pts will be accrued to initial step 1 to allow for a 5% drop out and allow 950 pts for the second randomization. As of Aug 1, 171 pts are enrolled for screening among whom 133 have been randomized. Figure 1 Disclosures Krishnan: BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Consultancy; Sutro: Membership on an entity's Board of Directors or advisory committees; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Regeneron: Consultancy. Hari:Incyte Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy. Orlowski:STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Minimal Residual Disease Evaluation Using 8-Color Flow Cytometry Predicts Risk of Relapse in High-Risk and/or Young Myeloma Patients Who Receive Bortezomib Consolidation after Frontline Tandem Transplantation

Blood ◽

10.1182/blood-2018-99-112313 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4666-4666

Author(s):

Richard Leblanc ◽

Imran Ahmad ◽

Rafik Terra ◽

Séverine Landais ◽

Céline Nkoue ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Unrelated Donor ◽

Advisory Committees ◽

Highly Sensitive ◽

Minimal Residual ◽

Risk Of Relapse

Abstract Introduction: Multiple myeloma (MM) remains incurable with standard therapies. Allogeneic stem cell transplantation (alloSCT) is the only curative treatment for these patients. We hypothesized that bortezomib (BTZ) consolidation after tandem autologous stem cell transplantation (ASCT) and nonmyeloablative (NMA) alloSCT could improve quality of response while decreasing relapse and cGVHD. We also sought to determine prospectively the predictive value of bone marrow minimal residual disease (MRD) evaluation using a highly sensitive flow cytometry assay. Methods: Newly diagnosed myeloma (NDMM) patients ≤65 years with high-risk (HR) features (based on cytogenetics, ISS 3 or plasma cell leukemia) or ≤50 year regardless of risk status with an 8/8 HLA matched donor are eligible to participate in this prospective trial. After a BTZ-based induction and ASCT, outpatient NMA alloSCT is performed with either fludarabine and cyclophosphamide (sibling donor) or fludarabine and TBI 2 Gy (unrelated donor) followed by peripheral blood stem cells. GVHD prophylaxis consists of tacrolimus and MMF. BTZ is initiated on day +120 post-alloSCT at 1.3 mg/m2 every 2 weeks for 1 year. Response evaluation is based on IMWG criteria. Bone marrow MRD evaluation is performed on 10x106 nucleated cells with highly sensitive (≥10-5) next-generation flow cytometry using the 8-color EuroFlow protocol (CD45, CD38, CD138, CD56, CD19, CD27, CD81, CD117, CyIgκ and CyIgλ) before alloSCT, before BTZ and every 3 months for 2 years. Immunophenotypic complete response (iCR) is defined as stringent CR in addition to 2 consecutive negative MRD results. aGVHD and cGVHD are evaluated prospectively. Results: As of June 29th 2018, 37 patients have been enrolled with a median age of 53 (range: 35-64) years. ISS 3 is found in 43% and HR cytogenetics in 54% (5% del17p, 14% t(4;14), 22% gain 1q21 and 14% >1 HR cytogenetics). Induction consisted of CyBorD (81%) or VTD (19%) for a median of 4 (range: 4-7) cycles. Median times from induction to ASCT and from ASCT to alloSCT were 5.8 and 4.4 months, respectively. Sibling and unrelated donor transplants were performed in 43% and 57%, respectively. KPS and HCT-CI were 90 (range 80-100) and 1 (range 0-3), respectively. Median follow-up is 21 (range 0-39) months after alloSCT. Of enrolled patients, 34 have started BTZ and received 92.5% of planned doses, with no dose reduction needed for toxicity. Observed grade ≥3 non-hematologic toxicities possibly/related to BTZ included diarrhea (n=1), viral hemorrhagic cystitis (2 adenovirus, 1 BK) and nocardial brain abscesses (n=1). Cumulative incidences of grade II-IV and III-IV aGVHD were 26% and 11%. Incidences of all grade, moderate/severe and severe cGVHD at 24 months were 61%, 47% and 10%, respectively, with mostly mouth, skin and liver involvement. Compared to 27 historical controls who did not receive BTZ after tandem transplant, the incidence of moderate/severe cGVHD was much lower in BTZ recipients (47 vs 78%; p=0.002). After reviewing each target organ involvement, mouth and eye cGVHD were significantly less severe with BTZ. Three patients died, one from myeloma progression and 2 from grade III aGVHD, with a 24-month non-relapse mortality of only 8%. BTZ consolidation improved depth of response, increasing ≥CR rate from 64% to 85% and iCR rate from 25% to 59%, regardless of cytogenetic abnormalities (Table 1). Probability of progression-free survival (PFS) at 24 months was 65% (CI 95%: 42-81) while overall survival (OS) was 90% (CI 95%: 70-97; Fig. 1A). The cumulative incidence of progression at 24 months was 28%. Importantly, the presence of ≤50 myeloma cells in the bone marrow 10 months post-alloSCT (after 6 months of BTZ) was associated with a significantly lower probability of progression (15% versus 80%; p=0.03; Fig. 1B). Conclusion: Tandem ASCT-NMA alloSCT followed by BTZ consolidation results in a remarkably high rate of ≥CR, including iCR. For the first time in allogeneic transplant recipients, MRD evaluation using the EuroFlow protocol demonstrates that identification of ≤50 myeloma cells in the bone marrow 10 months after alloSCT/6 months after BTZ seems predictive of a better outcome. If confirmed, this landmark could be used to design future therapeutic interventions in order to decrease the risk of relapse after tandem transplant. Finally, BTZ following alloSCT is safe and may contribute to decrease both incidence and severity of cGVHD. Disclosures Leblanc: Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Cohen:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Kiss:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lachance:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent; Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent. Sauvageau:ExCellThera: Employment, Equity Ownership. Roy:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding.

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Maintenance of Long-Term Undetectable Minimal Residual Disease after Combination of Ibrutinib with Abbreviated Chemotherapy in the Icll-07 Filo Trial

Blood ◽

10.1182/blood-2019-126720 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3038-3038

Author(s):

Anne-Sophie Michallet ◽

Marie-Sarah Dilhuydy ◽

Fabien Subtil ◽

Valérie Rouille ◽

Beatrice Mahe ◽

...

Keyword(s):

Board Of Directors ◽

Minimal Residual Disease ◽

Research Funding ◽

Residual Disease ◽

Limit Of Detection ◽

Randomised Trial ◽

Primary Objective ◽

Advisory Committees ◽

Minimal Residual

Introduction In previously untreated, medically fit patients with chronic lymphocytic leukaemia (CLL) and no 17p deletion, there is current research interest in improving survival outcomes and potentially sparing some patients from the standard 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR). The phase II ICLL-07 (NCT02666898) trial, conducted by the French Innovative Leukemia Organization (FILO), aimed to explore the efficacy of obinutuzumab and ibrutinib treatment induction for 9 months, followed by a minimal residual disease (MRD)-driven strategy. Methods Following assessment at Month 9, patients in complete response (CR) with bone marrow (BM) MRD <0·01% continued only ibrutinib 420 mg po daily for 6 additional months (I arm). Otherwise, patients received 4x4-weekly cycles of fludarabine/cyclophosphamide (FC) and obinutuzumab 1000 mg iv, alongside continuing ibrutinib for 6 additional months (FCGA+I arm). Beyond Month 16, response was clinically assessed every 3 months and MRD in PB until Month 40 and every 6 months during 36 months. MRD assessment was by 8-colour flow cytometry (limit of detection 10-6). The primary objective was to demonstrate a 30% or higher rate of CR with BM MRD <0·01% at Month 16, by intent-to-treat (ITT) analysis. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. ResultsBetween 10/2015 and 05/2017, 135 patients were enrolled. At Month 9, only 8% of patients reached CR with BM MRD <0·01%, and thus, in accordance with the MRD-driven strategy, were included in the I arm and continued only ibrutinib for 6 additional months. Most patients were included in the FCGA+I arm and received 4 cycles of FC and obinutuzumab, alongside continuing ibrutinib for 6 additional months. At Month 16, the ITT rate of CR with BM MRD <0·01% was 62% (84/135; 90% confidence interval [CI] 55−69). Of note, the primary objective was exceeded, and this high ITT rate was achieved with no more than 4 cycles of FC and obinutuzumab. The CR rate was 73% by investigator assessment versus 75% by an independent review committee. The PB and BM MRD <0·01% rate was 79%. The most common haematological adverse event (AE) was thrombocytopenia in 45 (34%) of 133 patients at grade 1−2 in Months 1−9 and in 43 (33%) of 130 patients at grade 1−2 in Months 9−15. The most common non-haematological AE were infusion-related reaction in 83 (62%) patients at grade 1−2 in Months 1−9 and gastrointestinal disorders in 62 (48%) patients at grade 1−2 in Months 9−15. A total of 49 serious AE occurred, most frequently infections (10), cardiac events (8) and haematological events (8). No treatment-related deaths occurred. After a median follow-up of 26.3 months, the 2-year PFS rate was 98% (95% CI 95−100) (Figure 1) and the 2-year OS rate was 97.5% (95% CI 96−100). The longitudinal follow-up of PB MRD in the entire cohort showed durability of a deep response, with a PB MRD <0.01% rate of 96% (n=92 evaluable patients) at Month 22 and 91% (n=85 evaluable patients) at Month 28. According to the treatment arm, in the FCGA+I arm, the PB MRD <0.01% rate was 99% at Month 22 and 93% at Month 28; by contrast, in the I arm, 77% of patients had PB MRD <0.01% at each of Months 22 and 28. The strategy achieved deep and durable molecular remission with a high level of undetectable (UD) PB MRD that was maintained over time, as shown in Figure 2. At Month 28, the rate of UD PB MRD was 83% in the FCGA+I arm versus 54% in the I arm. According to the immunoglobulin heavy gene variable (IGHV) mutational status, the PB MRD ≥0.01% rate at Month 28 was 4% for the mutated group versus 23% for the unmutated group (p=0.075, Fisher test). Conclusion These findings from the ICLL-07 trial demonstrated that, in previously untreated, medically fit patients with CLL and no 17p deletion, treatment induction with obinutuzumab and ibrutinib followed by an MRD-driven strategy yielded a high rate of CR with BM and PB MRD <0.01%, together with prolonged PFS and OS. With longer follow-up, including assessing the evolution of PB MRD, the response is maintained. This strategy could be an option in the first-line setting, although randomised trial evidence is needed. Disclosures Salles: Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Cymbalista:Sunesis: Research Funding; Roche: Research Funding; Janssen: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria. Le Garff-Tavernier:Alexion: Consultancy, Honoraria. Letestu:Alexion: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Roche: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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Minimal Residual Disease Monitoring During Maintenance In Multiple Myeloma Patients

Blood ◽

10.1182/blood.v122.21.3126.3126 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3126-3126 ◽

Cited By ~ 1

Author(s):

Alberto Rocci ◽

Manuela Gambella ◽

Paola Omedè ◽

Daniela Drandi ◽

Francesca Gay ◽

...

Keyword(s):

Bone Marrow ◽

Maintenance Therapy ◽

Research Funding ◽

Plasma Cells ◽

Residual Disease ◽

Clinical Relapse ◽

Advisory Committees ◽

Minimal Residual

Abstract Background The quality of response and the residual disease after treatment are important prognostic factors in several hematological diseases including multiple myeloma (MM). Several papers demonstrated that the deeper the response after treatment, the longer the survival. However few data are available on the monitoring of minimal residual disease (MRD) during the maintenance therapy in transplant eligible MM patients. Aims to evaluate the role of maintenance therapy in reducing MRD and the role of monitoring the response to predict clinical relapse. Patients and Methods newly diagnosed MM patients enrolled in the RV-MM-EMN-441 trial (NCT01091831) and achieving at least a very good partial response (VGPR) after consolidation were included in the study. Patients received 4 Lenalidomide-Dexamethasone (RD) courses as induction, Cyclophosphamide to mobilize bone marrow stem cells (BMSC) and then were randomized to receive 6 cycles of Cyclophosphamide-Lenalidomide-Dexamethasone (CRD) or Autologous Stem Cell Transplantation (ASCT) with Melphalan 200 mg/m2. All patients received maintenance therapy with Lenalidomide (R) or Lenalidomide-Dexamethasone (RD) until relapse. MRD analysis was performed in a single laboratory (University of Turin, Italy) using flow cytometry according to European Myeloma Network guideline (Rawstron AC, Haematologica 2008). Samples of bone marrow (BM) were collected at diagnosis, after consolidation, after 3 and 6 courses of maintenance and then every 6 months until clinical relapse. The samples were considered MRD +ve if ≥ 0.01% of PC were detected. Immunophenotypic (IF) relapse was defined as an increase of ≥ 25% in the amount of malignant plasma cells in BM compared to the previous determination. Results Fifty patients (27 female/23 male) with a median age of 57 yrs (40-65) entered the study. According to ISS, 27 patients were stage I, 15 stage II and 8 stage III. Fish risk profile was standard in 31 patients, high in 11 and not available in 8. Twenty-five patients received CRD as consolidation and 25 underwent ASCT. The median follow-up was 28.6 months. After consolidation 16 (32%) patients achieve a complete response (CR) and 34 (68%) a VGPR. MRD was negative in 19/48 (40%) patients, of which 12 received ASCT (out of 23, 52%) and 7 received CRD (out of 25, 28%). Patients receiving ASCT showed a lower value of residual cells (median 0.08%, range 0 – 1.00) compared to patients receiving CRD (median 0.5%, range 0 – 2.9%, p=0.0134). The lower MRD value was achieved after consolidation in 31 patients (62%), after 3 courses of maintenance in 6 patients (12%) and after 6 or more courses of maintenance in 13 patients (26%). The increase in quality of response was observed primarily in patients receiving CRD: the average amount of residual plasma cells in bone marrow was 71/uL after induction, lowering to 51/uL after 6 and 12 courses of maintenance therapy. Nine patients clinically relapsed after an average time of 25.6 months from the beginning of the therapy and in all patients this was anticipated by immunophenotypic relapse. Conclusion 1) consolidation therapy with ASCT determines a deeper response compared to CRD; 2) maintenance therapy can improve the quality of response, in particular in patients not receiving ASCT; 3) Immunophenotypic relapse anticipate the clinical relapse. These results suggest the possible role of MRD monitoring to better assess the response to therapy also during maintenance and as marker of early relapse. Disclosures: Ladetto: Celgene: Research Funding, Speakers Bureau; Janssen Cilag: Research Funding, Speakers Bureau; Mundipharma: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

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Clinical Relevance of Minimal Residual Disease Monitoring in NPM1 Mutated AML: A Study of the AML Study Group (AMLSG)

Blood ◽

10.1182/blood.v126.23.227.227 ◽

2015 ◽

Vol 126 (23) ◽

pp. 227-227

Author(s):

Silke Kapp-Schwoerer ◽

Andrea Corbacioglu ◽

Verena I. Gaidzik ◽

Peter Paschka ◽

Daniela Weber ◽

...

Keyword(s):

Board Of Directors ◽

Clinical Relevance ◽

Research Funding ◽

Residual Disease ◽

Advisory Committees ◽

Time Points ◽

Check Points ◽

The Impact ◽

Kinetics Of ◽

Minimal Residual

Abstract Background: Nucleophosmin (NPM1mut) mutations represent one of the most common gene mutations in acute myeloid leukaemia (AML) and can be used for monitoring minimal residual disease (MRD). In a former study, we could define clinical relevant check-points and a cut-off value to identify patients (pts) at high risk of relapse. Aims: To confirm our previous results on the clinical relevance of NPM1mut transcript levels (TL) in an extended cohort of younger AML pts (18 to 60 years) harbouring NPM1mut type A, B, C, D, JT, 4, QM, NM or KM, and to assess the impact of concurrent FLT3 internal tandem duplications (ITD) and DNMT3A (DNMT3Amut) mutations on NPM1mut TL kinetics. Methods: All pts were enrolled in one of four AMLSG [AMLHD98A (n=46; NCT00146120); AMLSG 07-04 (n=199; NCT00151242); AMLSG 09-09 (n=179; NCT00893399); AMLSG 16-10 (n=75; NCT01477606)] treatment trials. Treatment comprised double induction therapy (DI) with ICE (idarubicin, cytarabine, etoposide) with or without ATRA or gemtuzumab ozogamicin, or 1 cycle of daunorubicin and cytarabine followed by 1 to 4 cycles of high-dose cytarabine (n=292), autologous (n=19) or allogeneic stem cell transplantation (n=141). NPM1mut TL (ratio of NPM1mut/ABL1 transcripts x 104) were determined by RQ-PCR using TaqMan technology; the sensitivity of the assays was 10-5 to 10-6. DNMT3A and FLT3 -ITD (FLT3 -ITDmut) mutation status was assessed by standard PCR-based methods. Results: A total of 2835 samples from 499 NPM1mut pts were analysed at diagnosis (n=439), after each treatment cycle (n=1394) and during follow-up (FU) (n=1002). Peripheral blood (PB) samples were only included in the advanced FU period (defined as at least 12 months after completion of therapy). NPM1mut TL at diagnosis varied between 7.03 x103 and 2.38 x 107 (median 5.37 x 105). Pretreatment NPM1mut TL were not associated with clinical characteristics (e.g., age, WBC, BM blasts, FLT3 -ITDmut, DNMT3Amut) with the exception of LDH level (p=0.006) and did not impact event-free survival (EFS), relapse-free (RFS) and overall survival (OS). NPM1mut TL as log 10 transformed continuous variable at different time points during therapy were significantly associated with shorter remission duration (RD) and shorter OS. After DI therapy, the cumulative incidence of relapse (CIR) at 4 years was 10% for RQ-PCR-negative pts (n=41) versus 45% for RQ-PCR-positive pts (n=226) (p<0.0001); the lower CIR translated into a significant better OS (92% versus 60%, respectively; p=0.001). After completion of therapy, CIR at 4 years was 13% for RQ-PCR-negative pts (n=126) and thus significantly lower compared with 56% in RQ-PCR-positive pts (n=139; p<0.00001). Again, the lower CIR translated into a significantly better OS (81% versus 55%, respectively; p<0.00001). Multivariable analysis performed at both time points showed that NPM1mut TL were significantly associated with a shorter RD (HR, 1.86; 2.30, respectively) and shorter OS (HR, 1.58; 1.72, respectively). During FU, 1002 bone marrow (BM) and PB samples from 280 pts were analysed. The relapse rate at 2 years for pts exceeding the previously defined cut-off value of >200 NPM1mut copies was 90% with a median time to relapse of 1.38 months. In contrast, only 6/104 pts with sustaining RQ-PCR negativity relapsed. Finally, we evaluated the impact of concurrent FLT3 -ITDmut and DNMT3Amut on kinetics of NPM1mut TL. Following the first induction cycle, the median NPM1mut TL was significantly lower in pts with the NPM1mut/FLT3 -ITDwildtype/DNMT3Awildtype genotype compared to pts with the genotype NPM1mut/FLT3 -ITDmut/DNMT3Amut. This effect could be observed throughout subsequent treatment cycles. Conclusions: The results of our analysis on an extended cohort of younger AML pts with NPM1mut highly confirmed the two clinically relevant MRD check-points, after DI and after completion of therapy; during the FU period, exceeding a cut-off value of >200 TL was highly predictive for relapse. Finally, we found a significant impact of concurrent FLT3 -ITDmut/DNMT3Amut on the kinetics of NPM1mut TL. Disclosures Fielder: Amgen: Other: Congress Participation; Teva: Other: Congress Participation; Kolltan: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Astellas: Other: Congress Participation. Horst:Boehringer Ingleheim: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Gilead: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Götze:Celgene Corp.: Honoraria; Novartis: Honoraria. Schlenk:Pfizer: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Arog: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees.

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