Longitudinal Assessment and Prognostic Importance of Minimal Residual Disease (MRD) By Multiparametric Flow Cytometry in Patients with Systemic Light Chain (AL) Amyloidosis

Abstract Background: Minimal residual disease (MRD) assessment can provide an index of robust disease control, particularly if MRD negativity is sustained over time. Whereas MRD status has well-established prognostic implications in multiple myeloma, its role in light chain (AL) amyloidosis-a related but biologically distinct plasma cell disorder-is presently under investigation. Aims: The aims of our study were to evaluate (1) major organ deterioration-progression-free survival (MOD-PFS) based on MRD status and (2) MRD evolution patterns during disease surveillance for patients with AL amyloidosis in hematologic complete response (hemCR) after therapy. Methods: We established MRD status using multiparametric 10-color flow cytometry of bone marrow aspirates. At least 2 x 10 6 events were measured using a Beckman Coulter Navios Flow Cytometer and analyzed by Kaluza Software (sensitivity level of ≤10 -5). Sequential MRD testing was performed (≥12 months apart) for patients returning for follow-up. We evaluated hematologic and organ responses or progression based on consensus guidelines (Palladini, 2012). MOD-PFS was defined as time from hemCR achievement to major organ deterioration (i.e., the kidney or heart), hematologic progression or death from any cause (whichever occurred first). Presence of MRD was not used to guide treatment decisions. Results: A total of 96 patients with hemCR after therapy were tested, of whom 46 (48%) were MRD negative and 50 (52%) MRD positive on first assessment. The median estimated clone size for those with MRD positivity was 3.4 x 10 -4 (range 1.4 x 10 -5 to 5.7 x 10 -3). Baseline characteristics were similar between groups, except for greater use of daratumumab and ≥2 lines of therapy to achieve hemCR in the MRD-negative group. MRD positivity correlated with a higher level of involved free light chains (iFLC) in the serum at the time of MRD assessment (23.4 mg/L vs 17.3 mg/L, P = .011). In regard to organ responses, patients with MRD negativity had a significantly higher rate of renal response (91% vs 67%, P = .017) but a similar rate of cardiac response (74% vs 68%, P = .668). After a median follow-up of 50 months from hemCR achievement, the MRD-negative group demonstrated a superior MOD-PFS (HR 0.38, 95% CI 0.16-0.88, P = .034). Progression or organ deterioration events in the MRD-negative group occurred early after hemCR achievement, while in the MRD-positive group these events continued to occur over time. A total of 8 patients had died, including 4 in each group. Sequential MRD testing (median 12 months apart, range 12-28 months) was performed for 43 patients, of whom 16/19 (84%) had sustained MRD negativity; 21/24 (88%) had persistent MRD positivity; and 6/43 (14%) had MRD conversion. No patient received therapy between MRD assessments. Among those with sustained MRD negativity, there were 2 major organ deterioration events. The 3 patients who experienced loss of MRD negativity (which occurred at 12, 107 and 114 months after last treatment) had no progression or organ deterioration events. Of those with persistent MRD positivity, 13 (62%) had durable hemCR and organ responses; moreover, 4/14 (29%) and 1/11 (9%) of these patients attained even deeper renal and cardiac responses, respectively, in the interval between sequential MRD testing. Clone progression (defined as >1-log growth in MRD clone size) was observed in 3/21 (14%) patients with persistent MRD positivity, none of whom demonstrated hematologic relapse. Conclusions: We evaluated the dynamics of MRD status in relation to clinical outcomes and found that patients with MRD negativity had longer survival free from hematologic progression, major organ deterioration or death. Longer prospective follow-up is needed to determine whether this translates into an overall survival benefit. MRD conversion occurred in a small proportion (14%) of patients, but was not linked to adverse outcomes. Understanding the role of cross-sectional MRD testing for clinical disease tracking in AL amyloidosis requires further analysis with larger sample size. Figure 1 Figure 1. Disclosures Sanchorawala: Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Pfizer: Honoraria; Karyopharm: Research Funding; Sorrento: Research Funding; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding.

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Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-134237 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-14

Author(s):

Alexander Coltoff ◽

Joseph G. Jurcic ◽

Peter Campbell ◽

Daniel J. Lee ◽

Mark L Heaney ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Median Overall Survival ◽

Residual Disease ◽

Institutional Research ◽

Negative Group ◽

Advisory Committees ◽

Research Grants

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

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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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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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Serial Minimal Residual Disease Evaluation in Patients with Chronic Lymphocytic Leukemia Under Long-Term Venetoclax Treatment

Blood ◽

10.1182/blood-2018-99-114048 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1876-1876

Author(s):

Thomas Lew ◽

Mary Ann Anderson ◽

Constantine S. Tam ◽

Sasanka Handunnetti ◽

Dennis Carney ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Residual Disease ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Minimal Residual

Abstract Background The selective BCL2 inhibitor venetoclax (Ven) achieves an overall response rate of approximately 75-80% as a single agent in relapsed and refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL)1. At one year ~75% of patients (pts) are progression-free at the approved monotherapy dose of 400 mg/day1,2 and Ven is the only novel agent with a significant rate of minimal residual disease (MRD) negativity (MRD-neg)3. The temporal pattern of MRD levels and systematic long term follow up of pts stratified by their MRD status on Ven have not been reported. We report the long term outcomes according to MRD status for 59 pts with RR-CLL/SLL who attained objective disease response to Ven, and the temporal patterns of change in MRD. Methods We reviewed the clinical outcomes to July 2018 of 67 pts with RR-CLL/SLL enrolled since June 2011 on early phase clinical studies of Ven at our two hospitals. Analysis was restricted to the 59 pts who achieved a partial response or complete response by iwCLL criteria. Pts initially received 150-1200mg Ven/day (45 ≥400mg/day) on one of three ongoing trials: Phase 1 Ven monotherapy (NCT01328626) (n=36), Phase 1b Ven plus rituximab (NCT01682616) (n=14), or Phase 2 Ven monotherapy in del(17p) CLL/SLL (NCT01889186) (n=9). For this analysis MRD-negativity was defined as <1 cell in 10-4 leukocytes by ERIC criteria, or no cells with a CLL phenotype when <400,000 cells were analyzed in an assay with a minimum sensitivity of 0.1%. Of those pts reported as MRD-neg this was confirmed at a level of 10-4 in 71%4. Unless otherwise specified, MRD-neg refers to status in the bone marrow (BM) and pts who were not tested were considered to be MRD-pos (n=2 pts). Landmark analyses of time to progression (TTP) by MRD status used the median time to achievement of MRD-neg. Fisher exact test was used to assess the association of clinical, biological and treatment variables with achievement of MRD-neg. TTP and time to MRD-neg were estimated using the method of Kaplan-Meier, and comparisons among groups used the log-rank (Mantel-Cox) test. Results Of the 59 pts who achieved an objective response to Ven, 21 (36%) achieved MRD-neg in the BM and 26 (44%) in the PB. Of the 38 pts who did not achieve BM MRD-neg, 36 (95%) had at least one BM assessment on treatment; the two remaining pts did not clear MRD in the PB. The strongest positive predictor for the achievement of BM MRD-neg was treatment with Ven plus rituximab (9 of 14 [64%]) achieved vs 13 of 45 [27%] on Ven monotherapy (p=0.02)). Complex karyotype was a negative predictor in pts receiving ≥400mg/day. TP53 aberrant state (mutation and/or del(17p)), bulky adenopathy >5cm and fludarabine-refractoriness were not significantly associated with achievement of MRD-neg, irrespective of dose (table 1). The median time to MRD-neg was 8.2 (range 2 - 46) mths for BM (fig 1A) and 5 (range <1 - 50) mths for PB, with 22/26 (85%) pts who achieved PB MRD-neg doing so within 12 mths of starting Ven. 25/26 had a contemporaneous or subsequent BM aspirate and 20 (80%) achieved BM MRD-neg after a median of 3 (<1 - 17) further mths. After a median follow up of 25 (range 2 - 55) mths since attainment of BM MRD-neg, 8/21 (38%) pts have developed confirmed re-emergence of BM MRD, and a further 2 pts have re-developed PB MRD-pos. Median time to reemergence of BM MRD has not been reached (59% BM MRD relapse free at 2 years post attainment). In a landmark analysis from median time to BM MRD-neg (8.2 mths), TTP by iwCLL criteria was significantly longer among BM MRD-neg pts (n = 21; median TTP 65 mths [95% CI 47 - undefined]) than BM MRD-pos pts (n = 31; median 22 mths [95% CI 14 - 39]; Hazard Ratio (HR) 0.11; p<0.0001) (figure 1B). Similar patterns held for the equivalent landmark analysis according to PB MRD (HR 0.21; p = 0.0002). Conclusions Venetoclax frequently induces BM MRD-neg, and pts achieving BM MRD-neg have very durable responses. Combined Ven plus rituximab increases the rate of BM MRD-neg. With Ven therapy, PB MRD status appears to be a reasonable surrogate for BM MRD status, but further validation is required. Achievement of BM MRD-neg should be the aim of therapy with Ven and Ven-based combination approaches may be the most effective way to achieve this.Roberts; N Engl J Med; 2016;374:311-22.Stilgenbauer; Lancet Oncol; 2016;17:768-78.Seymour; Lancet Oncol; 2017;18:230-40.Rawstron; Leukemia; 2016;30:929-36. Disclosures Lew: Walter and Eliza Hall: Employment, Patents & Royalties. Anderson:Genentech: Research Funding; AbbVie, Inc: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties. Tam:Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria, Other: Travel funding; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria, Travel funding; Gilead: Honoraria; Pharmacyclics: Honoraria; Roche: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria; Roche: Honoraria. Roberts:AbbVie: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; Genentech: Research Funding; Janssen: Research Funding. Seymour:Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, 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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Venetoclax and Azacitidine for Older Newly Diagnosed Patients with Acute Myeloid Leukemia: A Single-Institution Pilot Study Using Measurable Residual Disease to Guide Therapy

Blood ◽

10.1182/blood-2019-122120 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2638-2638 ◽

Cited By ~ 1

Author(s):

Amanda Winters ◽

Jonathan A Gutman ◽

Enkhtsetseg Purev ◽

Brett M. Stevens ◽

Shanshan Pei ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Refractory Disease ◽

Advisory Committees ◽

Ras Pathway ◽

Measurable Residual Disease ◽

Count Recovery

Background: Venetoclax (ven) was approved for older untreated acute myeloid leukemia (AML) patients due to high response rates and durable remissions. As a participating site in the dose escalation study, we observed deeper/more durable responses in some who received >400mg ven. We also noted 16/33 discontinued azacitidine (aza) after achieving a response; 9 relapsed and 7 remained in long term remission on ven only. Based on these observations, we designed a study that hypothesized: A)Higher initial doses of ven would allow deeper/more durable responses, and B)Multi modality high sensitivity measurable residual disease (MRD) testing could identify patients able to discontinue aza and remain on maintenance ven. Methods: This is an ongoing phase 2 study (NCT03466294) of 42 untreated AML patients ≥60 who decline/are ineligible for induction. Patients have adequate organ function and white blood cell counts <25x109/L (hydrea permitted). In cycle 1, patients receive aza 75mg/m2 on days (d) 1-7 and ven, escalated from 100 to 200 to 400 to 600mg on d 1-4. Ven continues at 600mg d 5-28 and bone marrow biopsies (BMBXs) are performed on d 8 and 28. Patients who achieve morphologic remission without count recovery have up to 14 days off therapy before subsequent cycles, with growth factor support; "upgraded" responses are recorded if count recovery occurs. Non responders discontinue or receive up to two additional cycles of aza and ven 600mg. Responders who remain MRD+ by multiparameter flow cytometry (MPFC, Hematologics) and/or digital droplet PCR (ddPCR) for as many identifiable diagnostic genes as possible also receive up to 2 additional cycles of aza and ven 600mg. MRD+ responders after 3 cycles continue aza and ven 400mg until toxicity/progression. Patients who experience MRD- responses at any time stop aza and continue ven 400mg daily (Fig 1). Results: 30 patients enrolled between May 2018 and July 2019; median age is 71 (60-88), 10% evolved from MDS and 10% and 73% had intermediate and unfavorable risk disease by ELN, respectively (Table 1). 732 adverse events (AEs) occurred; 46 (6%) were serious, the most common were neutropenic fever (37%) and pneumonia (13%). The most common >grade 2 related AEs were leukopenia (53%), thrombocytopenia (44%) and neutropenia (35%); there were no related grade 5 AEs. The overall response rate was 70% (21/30; CR=19, MLFS=2). Median number of cycles to achieve best response was 1. Significant blast reductions were seen on day 8; of the 28 with interpretable day 8 BMBXs, 10 achieved MLFS on day 8. 4 completed ≥1 cycle and were refractory. An additional 4 did not complete cycle 1: 1 died of disease and 3 elected to come off therapy (all subsequently died of disease). Four (19%) responders relapsed, after a median 180 days (27-279). With median follow up of 214 days, median response duration has not been reached. 10 patients died, after a median 65 days (29-256); 1/30 died within 30 days. Median overall survival has not been reached. Of the 26 who completed ≥1 cycle, 19 were MRD- by MPFC, including 18/19 who achieved CR. Of these 26, 3 were not monitored by ddPCR: for 2 patients this was due to the absence of detectable baseline mutations and for 1 patient it was due to refractory disease. The remaining 23 had ddPCR monitoring; 3 became MRD- by this modality (Fig 2). All 3 were also MRD- by MPFC and per protocol discontinued aza and initiated ven maintenance (Fig 1). MRD negativity by both parameters occurred after cycles 1, 2 and 3, respectively. One MRD- patient relapsed after 216 days; two remain in remission after 301 and 124 days. An additional 4 who achieved MRD+ responses discontinued aza at their insistence (and in violation of the protocol); 1 relapsed after 279 days, and 3 remain in ongoing remission. Univariate predictors of refractory disease were FAB M0/M1 (OR 0.070, p=0.02) and RAS pathway mutations (OR 14.25, p=0.02). Conclusions: Higher initial doses of ven are tolerated in this population. Blast reduction occurs quickly in many patients (day 8), for this low intensity regimen. Response rates are consistent with lower doses of ven. Very deep responses, as measured by highly sensitive MRD methods (MPFC and ddPCR are capable of sensitivity up to 0.02%), are attainable. Longer follow up time will determine if higher ven doses and MRD-driven decisions related to continuation of aza result in more durable responses. Increased maturation of blasts and RAS pathway mutations are predictors for refractory disease. Disclosures Lyle: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo Incyte: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pollyea:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: 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; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Improving the Definition of Response Assessment: Prognostic Value of Minimal Residual Disease Combined with PET/CT at Day 100 Post Autologous Stem Cell Transplantation in Multiple Myeloma

Blood ◽

10.1182/blood-2020-142845 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-34

Author(s):

Miguel Gonzalez-Velez ◽

Mariano Arribas ◽

Heidi E. Kosiorek ◽

Richard Butterfield ◽

Carlo Guerrero ◽

...

Keyword(s):

Board Of Directors ◽

Prognostic Value ◽

Residual Disease ◽

High Sensitivity ◽

Response Assessment ◽

Advisory Committees ◽

Pet Ct ◽

Definition Of ◽

Minimal Residual

Introduction: Response assessment at day 100 post Autologous Stem Cell Transplant (ASCT) is associated with long-term relapsed free survival (RFS) and overall survival (OS) in multiple myeloma (MM). The International Myeloma Working Group (IMWG) are the preferred criteria to define best response to treatment and define relapse. In the last years, response assessment has incorporated minimal residual disease (MRD) status -associated with improved RFS and OS (Munshi et al); and PET/CT combined with clinical characteristics -also associated with favorable outcomes (Zamagni et al. NCT01910987; MMY3033). The 2016 IMWG MRD criteria, combined imaging (PET/CT) plus next-generation sequencing (NGS) MRD-negative to define complete response (CR). To our knowledge, there is limited data examining the correlation and prognostic value of MRD and FDG-PET/CT at day 100 post ASCT in MM. IN this study, we aimed to determine the prognostic valued of MRD by NGS combined with PET/CT in RFS and OS status after high dose chemotherapy and ASCT in MM. Methods: Patients who underwent ASCT for MM at Mayo Clinic Arizona and had MRD and PET/CT data were included in the study. Clinical data was obtained via retrospective chart review. Cytogenetic risk (CyR) was classified using the mSMART criteria . Disease and ASCT related characteristics were compared by MRD status. MRD was measured by NGS on bone marrow aspirates using the previosly validated clonoSEQ ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) tracking the IgH, IgK and IgL rearrangements at a minimum sensitivity level of 10-5. MRD was defined by residual clonal cells per million nucleated cells as: negative= 0, borderline= 1-5, positive >5. PET/CT scans were performed locally at baseline and at day 100. Comparisons were performed using the chi-square test for categorical variables, Wilcoxon rank-sum test for continuos variables, McNemar's test and Cohens's Kappa for agreement measures. Results: A total of 103 patients had matched MRD and PET/CT assessment around day 100 (+/-9 days) and were included in the analysis. Median age at diagnosis was 62 years (range, 54-66 years), 71 patients (68.9%) were men. CyR was standard risk in 49 (47.6%), high-risk in 39 (37.9%) and unknown in 15 (14.6%) patients. Most 75 (72.8%) patients were MRD positive, 16 (15.5%) were MRD negative, and 12 (11.7%) borderline. The median main MRD clone detected was 64 (range 0-91,874). 70 patients (68%) and 33 (32%) had a negative and positive PET/CT respectively. The median follow-up time was 18 months (range, 13-31 months). At the time of data analysis, 10 patients (9.7%) had relapsed and only 4 (3.9%) had died. There was a high-correlation between MRD status and PET/CT, 31 patients (93.9%) with positive PET/CT were also MRD positive (p=0.0027). There were no statistical differences between PET/CT and CyR (p=0.95). We analyzed the correlation using the FREQ procedure (McNemars's test); there was a strong association between positive PET/CT and positive MRD in 31/33 patients (93.9%, high sensitivity), and low association for negative PET/CT the negative/borderline MRD in 26/70 (37.1%, low specificity; p<0.001). The agreement measure between the PET/CT and MRD using negative/borderline combined had a kappa of 0.23 (95% CI 0.11, 0.35) indicating a fair agreement beyond chance (Figure 1). PET/CT-CT was a statistically significant predictor of worse RFS (HR 3.53, 95%CI: 1.02-12.24, p<0.0337) and OS (HR 11.38, 95%CI: 1.18-109.56, p<0.0078) (Figure 2-3, respectively). MRD was not predictive of neither RFS (HR 1.72, 95%CI: 0.36-8.14, p<0.49) or OS (p<0.16). Conclusions: In conclusion, we demonstrate that the combination of MRD by NGS (clonoSEQ ®) and PET/CT at day 100 are complementary and have a high sensitivity (true positive rate) and fair correlation of agreement but low specificity (true negative rate). PET/CT was the best most sensitive technique to prognosticate RFS and OS. We did not find prognostic correlation of MRD with RFS and OS. However, our findings might be confounded by the low risk of relapse and death, a longer follow-up may demonstrate clinically important differences. Our results add evidence that MRD plus PET/CT improve the definition of CR in MM patients post ASCT. Prospective studies are needed to elucidate the optimal timing and role of combined MRD, PET/CT with other prognostic markers of clinical outcomes. Disclosures Larsen: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fonseca:Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy.

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LONG-TERM RESULTS of the GIMEMA VTD Consolidation TRIAL In Autografted MULTIPLE Myeloma PATIENTS (VEL-03-096): IMPACT of Minimal RESIDUAL DISEASE Detection by REAL Time Quantitative PCR On LATE Recurrences and Overall SURVIVAL

Blood ◽

10.1182/blood.v118.21.827.827 ◽

2011 ◽

Vol 118 (21) ◽

pp. 827-827 ◽

Cited By ~ 5

Author(s):

Marco Ladetto ◽

Simone Ferrero ◽

Daniela Drandi ◽

Federica Cavallo ◽

Luigia Monitillo ◽

...

Keyword(s):

Clin Oncol ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Tumor Burden ◽

Long Term Results ◽

Clinical Relapse ◽

Advisory Committees ◽

Tumor Load

Abstract Abstract 827 Background and aims: We have recently shown that a consolidation therapy with bortezomib/thalidomide/dexamethasone (VTD) in multiple myeloma (MM) patients responding to autologous transplantation (ASCT) induces major tumor shrinking assessed by real time-quantitative (RQ)-PCR. Moreover we found that low levels of minimal residual disease (MRD) associated to a better progression-free survival (PFS) [GIMEMA VEL-03-096 trial, EudraCT Number 2004-000531-28: Ladetto et al, J Clin Oncol 2010]. We here present the updated results of this study at a median follow-up of 65 months. In the present analysis the following additional issues have been addressed: a) impact of MRD on PFS over time, with special interest to the role of MRD kinetics on outcome; b) impact of MRD on overall survival (OS). Patients and methods: Inclusion criteria and treatment schedule for this study have been already reported [Ladetto et al., J Clin Oncol 2010] and included: 1) a documented complete or very good partial remission following ASCT delivered as first line treatment; 2) no previous therapy with thalidomide or bortezomib; 3) presence of a molecular marker based on the immunoglobulin heavy chain rearrangement (IGH). MRD was assessed on bone marrow samples at diagnosis, study entry, after two VTD courses, at the end of treatment and then at six months intervals, up to clinical relapse. Patients underwent MRD detection using either qualitative nested PCR and RQ-PCR, employing IGH-derived patient specific primers as already described [Voena et al., Leukemia 1997; Ladetto et al., Biol Bone Marrow Transpl 2000]. For outcome analysis patients were grouped according to following definitions: a) MRD negativity on two consecutive samples by the most sensitive PCR method (nested PCR): full molecular remission (FMR); b) MRD negativity on two consecutive samples by RQ-PCR (less sensitive but currently better standardized, according to European Study Group on MRD detection guidelines [van der Vendel et al., Leukemia 2007]): standard molecular remission (SMR); c) post-treatment tumor load above the median by RQ-PCR: high tumor burden (HTB); d) post-treatment tumor load below the median by RQ-PCR: low tumor burden (LTB); e) recurrence of detectable MRD after FMR/SMR: molecular relapse (M-rel); f) increase of MRD levels of at least one log: active disease (AD). Results: Feasibility, toxicity and clinical outcome of the trial have been already reported [Ladetto et al., J Clin Oncol 2010]. Thirty-nine patients were enrolled and median clinical follow-up from start of first line treatment is 65 months. 270 of the planned samples for MRD monitoring (86%) were actually received by the centralized lab. So far 17 relapses and six deaths have been reported. Following VTD consolidation, 7/38 evaluable patients achieved FMR (18%) and 15/38 achieved SMR (39%). Three M-rel were observed, two of them followed by clinical relapse within six months. Achievement of SMR proved highly predictive for PFS (5-years (y) PFS 82% vs 44%, p=0.009, figure 1A), as well as the presence of HTB and AD (5-y PFS 35% vs 87%, p<0.001, figure 2). Interestingly, patients with LTB and no evidence of M-rel or AD had an excellent outcome with a 5-y PFS of 87%, (even considering that molecular follow-up was incomplete due to lack of samples in the two events observed in the low risk group, figure 2). Most notably, none of the patients achieving FMR or SMR has so far died and both SMR and AD proved to be significant predictors for OS (respectively, 5y-OS 100% vs 74%, p=0.012, figure 1B, and 5y-OS 86% vs 100%, p=0.037, data not shown). Conclusions: Our long-term results indicate that: 1) the achievement of SMR following VTD consolidation in MM patients is associated with a better outcome in terms of PFS and OS; 2) a dynamic increase in molecular tumor burden (AD), detectable by RQ-PCR, predicts late disease relapses several months before clinical recurrence. Taken together these results suggest the importance of developing tailored treatment for patients with high residual burden or showing increasing levels of MRD during follow-up, as already pursued for example in mantle cell lymphoma [Andersen et al., J Clin Oncol 2009]. Disclosures: Ladetto: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Bayer: Honoraria; Mundipharma: Honoraria; Janssen-Cilag: Research Funding; Italfarmaco: Research Funding. Cavallo:celgene: Honoraria. Guglielmelli:celgene: Honoraria; Janssen-Cilag: Honoraria. 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:Merck: Honoraria; 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; Amgen: 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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Potential Impact of Consolidation Radiation Therapy for Advanced Hodgkin Lymphoma: A Secondary Modeling of SWOG S0816 with Receiver Operating Characteristic Analysis

Blood ◽

10.1182/blood-2018-99-113133 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2927-2927 ◽

Cited By ~ 1

Author(s):

Chul S. Ha ◽

Hongli Li ◽

Heiko Schoder ◽

Chelsea C Pinnix ◽

Elizabeth Brem ◽

...

Keyword(s):

Radiation Therapy ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Residual Disease ◽

Entire Group ◽

Advisory Committees ◽

Potential Impact ◽

Receiver Operating

Abstract Background:The role of radiation therapy (XRT) for advanced stage Hodgkin lymphoma (HL) is controversial. In the HD15 trial, the German Hodgkin Study Group (GHSG) administered XRT for PET-positive residual disease ≥2.5 cm at least 2 weeks after completion of chemotherapy and showed 91.5 % in-field control rate with a median follow-up of 102 months (Engert, A; personal communication). However, there is no comparison arm where patients with PET-positive residual disease ≥2.5 cm did not receive XRT. SWOG S0816 was a US intergroup trial utilizing ABVD-based therapy with response adaptation based on interim PET imaging; XRT was not allowed per protocol, and counted as an event. In this analysis, we identified patients in S0816 who would have met HD15 criteria for XRT, but did not receive XRT per design. We then modeled the potential impact of XRT on disease control. Patients and Methods:Of 336 eligible and evaluable HIV-negative patients enrolled in S0816, 49 had an end-of-treatment PET (termed "PET3," to be done 6-8 weeks after completion of chemotherapy) that was positive (i.e. Deauville 4-5) upon central review. We simulated the progression free survival (PFS) if XRT had been delivered per HD15 criteria (PET positive disease and ≥2.5 cm), evaluating by assumptions of 50, 80 and 90% control of the disease within the XRT fields. Receiver operating characteristics (ROC) analyses were performed with additional size cut-off points of 2.0 and 1.5 cm. Results:The median follow-up for the 49 PET3 positive patients was 71 months (range 9.7-92.6). For these 49 patients, the observed landmark PFS at 2 years after the date of PET3 was 30.6%. Twenty-four (49%), 33(67%), and 40 (82%) of the 49 patients had at least one site of disease that met the HD15 criteria for XRT with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm size cut-offs respectively. Sixteen, 19, and 25 patients had disease progression respectively from each group at median of 1.4-1.5 months. Twelve, 12, and 15 patients had relapses limited to the sites that would have been radiated following HD15 criteria with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm respectively. Estimated landmark PFS at 2 years for the 49 PET3 positive patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are summarized in columns A, B, and C of the table respectively. For the entire group of 336 patients, the observed PFS at 2 years was 79%. Estimated 2-year PFS for the entire group of 336 patients assuming 50, 80, and 90 % control of the disease within the radiated sites following HD15 guideline with ≥2.5 cm, ≥2.0 cm, and ≥1.5 cm cut-off are in columns D, E, and F of the table respectively. Conclusion: Among the PET3 positive patients, consolidation XRT per HD15 criteria with cut-off points of 2.5, 2.0, and 1.5 cm could have raised the 2-year PFS by 12-28 % assuming 50-90% local control within radiated sites. However, the improvement in PFS is more moderate at 1.6-3.9 % if we consider the entire cohort of 336 patients. Although there may be some gain in PFS as the cut-off point is lowered by our ROC analysis, one needs to consider the trade-off against potentially increasing normal tissue toxicity as more sites are irradiated. Table. Table. Disclosures Brem: Pharamcyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees. Bartlett:Merck & Co: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Janssen: Research Funding; KITE: 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Millennium: Research Funding; Genentech: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Janssen: Consultancy; Tesaro: Research Funding; Bayer: Consultancy; Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Rimsza:NanoString: Other: Inventor on the patent for the Lymph2Cx assay. Leonard:Novartis: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; Biotest: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Bayer: Consultancy. Kahl:Seattle Genetics: Consultancy; Genentech: Consultancy; Acerta: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; ADC Therapeutics: Consultancy; CTI: Consultancy; Gilead: Consultancy; Juno: Consultancy; Celgene: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Friedberg:Bayer: Honoraria.

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