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

Blood ◽  
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.

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 ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 694-694 ◽  
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.

scholarly journals WT1 Peptide Vaccine Is Able to Induce WT1-Specifc Immune Response with TCR Clonal Enrichment to Control Minimal Residual Disease in Patients with Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3984-3984 ◽  
Author(s):  
Hongtao Liu ◽  
Yuanyuan Zha ◽  
Gregory Malnassy ◽  
Noreen Fulton ◽  
Margaret Green ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Cd8 T Cell ◽  
Advisory Committees ◽  
Cell Responses ◽  
Qrt Pcr ◽  
Vaccine Site ◽  
Minimal Residual

Abstract Background: Immunotherapy has the potential for clinical efficacy in patients with myeloid leukemia, especially in the setting of minimal residual disease. WT-1, aberrantly expressed in both myeloid and lymphoid leukemia, is associated with adverse risk in AML. WT1 is highly antigenic and is an attractive target for immunotherapy. The optimal strategy for vaccination to induce CD8+ T cell responses against WT1 is not known. Methods: We performed a pilot randomized study of HLA-A02+ patients to receive vaccination with WT1 126-134 peptide (RMFPNAPYL) in Montanide or in poly ICLC (Hiltonol from Oncovir, a TLR3 agonist) to explore the novel immune adjuvant in patients with myeloid leukemia (NCT01842139). The vaccine was administered q 2 weeks X 6 during the induction phase followed by monthly booster vaccinations X 6 months. Enrollment: Seven patients (4 males, 3 female ages 39 to 73) were randomized. Four patients received WT1 in Montanide (3 AML, 1 CML myeloid blast phase, 2 s/p allo-SCT), and three with WT1 in poly ICLC (2 AML, one MDS RAEB2 s/p allo-SCT). Five patients were in morphologic remission (3 in CR1) and two had very low burden of residual morphologic disease at study entry. Toxicities: All patients finished the induction phase without any major toxicity except mild transient local injection reaction. One patient post allo-SCT on the Montanide arm developed transverse myelitis with evidence of bacterial meningitis following the first monthly booster vaccination. Another patient on the Montanide arm developed aseptic ulceration at the 12th vaccine site followed by inflammation at the 11th WT1 vaccine site, and persistent erythema at the 1st induction vaccine site about 4 weeks after the completion of all 12 WT1 vaccinations. The aseptic ulcers eventually healed with wound care without antibiotics. Efficacy: Three of 4 patients on the Montanide arm had decease of WT1 qRT-PCR levels after WT1 vaccination, and two of them demonstrated generation of WT1-specific cytotoxic CD8+ T cell responses with biased TCR beta chain enrichment. Three patients from who cells were available for TCR alpha and beta CDR3 sequencing had TCR clonal enrichment after WT1 vaccination. In contrast, no obvious WT1-specific immune responses were detected in 2 patients on the poly ICLC arm, nor was there clonal enrichment by TCR alpha/beta sequencing; however, these patients did have a decrease in WT1 qRT-PCR levels and remained in remission 3 years after the initiation of WT1 vaccination. Thus, WT1 peptide in poly ICLC may induce anti-leukemia immune response not detected by our current assays. The third patient on the poly ICLC arm was later found to have A0202 instead of A0201, and thus could serve as negative control. Not surprisingly, this patient did not have a decrease of WT1 qRT-PCR levels nor TCR clonal evolution during vaccination. The patient tolerated the vaccine well without injection reactions and had stable AML for 12 weeks, but the disease progressed before the first monthly WT1 vaccination. Conclusions: WT1 peptide vaccine with Montanide as an adjuvant induces WT1-specific CD8+ T cell responses with TCR clonal and specific TCR beta CDR3 enrichment, which may be capable of controlling leukemia recurrence in the setting of minimal residual disease. Future investigation to combine checkpoint inhibitors with peptide vaccination might further enhance efficacy in patients with myeloid leukemia. Disclosures Liu: Karyopharm: Research Funding; BMS: Research Funding. Salazar:Oncovir Inc: Employment. Odenike:Suneisis: 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; Spectrum: 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; Incyte: 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. Gajewski:Abbvie: Consultancy; Celldex: Consultancy, Research Funding; Jounce: Consultancy; Incyte: Consultancy, Research Funding; Evelo: Patents & Royalties: Patent application; BMS: Research Funding; Merck: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Bayer: Consultancy; Aduro: Patents & Royalties: Patent application.

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 ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2053-2053 ◽  
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.

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2325-2325 ◽  
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.

scholarly journals 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 ◽  
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.

scholarly journals Minimal Residual Disease in Patients with Follicular Lymphoma Treated with Obinutuzumab or Rituximab As First-Line Induction Immunochemotherapy and Maintenance in the Phase 3 GALLIUM Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 613-613 ◽  
Author(s):  
Christiane Pott ◽  
Eva Hoster ◽  
Britta Kehden ◽  
Michael Unterhalt ◽  
Michael Herold ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Value ◽  
Residual Disease ◽  
First Line ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Minimal Residual

Abstract Background: Minimal residual disease (MRD) status reflects treatment efficacy and may predict prognosis after first-line therapy in patients (pts) with follicular lymphoma (FL). GALLIUM (NCT01332968) is an ongoing, randomized global Phase 3 study evaluating the efficacy and safety of obinutuzumab (GA101; GAZYVA/GAZYVARO; G) vs rituximab (R) as induction (with chemotherapy [chemo]; bendamustine, CHOP or CVP) and maintenance (in responders) in previously untreated pts with indolent non-Hodgkin lymphoma. In GALLIUM, the primary endpoint of investigator-assessed PFS in pts with FL was significantly improved with G- vs R-based treatment. We report the results of MRD assessment at mid induction (MI) and end of induction (EOI) in FL pts in GALLIUM. Methods: Diagnostic peripheral blood (PB) and bone marrow (BM) samples from FL pts were screened by consensus PCR to detect a t(14;18) translocation and/or clonal Ig variable domain rearrangement suitable for MRD assessment. In pts with a detectable clonal marker, allele- or translocation-specific real-time quantitative (RQ)-PCR assays were designed with a sensitivity ≤10-4. RQ-PCR data were evaluated by European Study Group criteria for MRD detection (van der Velden, Leukemia 2007). MRD status was assessed at MI in PB, and at EOI in PB and BM, and defined as negative (MRD response) if RQ-PCR and subsequent nested PCR were negative in all samples analyzed at the respective time point. Results: Of the 1202 FL pts enrolled in GALLIUM, 1138 provided consent for MRD analyses. Baseline PB or BM samples were available for 1101 pts; a clonal marker was detected in 968 (88%) of these pts and 815 (74%) had an RQ-PCR assay fulfilling sensitivity criteria. Pts with a detectable clonal marker had baseline characteristics comparable to pts without a marker, with the exception of higher-stage disease (61% vs 34% Ann Arbor stage IV), reflecting increased BM involvement. Among 696 pts with an available PB or BM sample at EOI, MRD response was significantly higher in the G-chemo arm than the R-chemo arm (92% vs 85%; p=0.0041; Table 1). BM clearance of residual tumor cells at EOI was higher in the G-chemo vs R-chemo arm (93% [199/214] vs 83% [165/200]; p=0.0014), whereas PB clearance at EOI was similarly high in both arms (96% [323/336] vs 94% [320/341]; p=0.22). MRD clearance occurred early during treatment: at MI, 94% of pts in the G-chemo arm achieved MRD-negative status in PB compared with 89% in the R-chemo arm (p=0.013; Table 2). The anti-lymphoma activity of G-chemo induction was confirmed by analyzing quantitative MRD data in PB at MI: all 20 (100%) pts who remained MRD-positive at MI in the G-chemo arm had low-level MRD (below the limit of quantification) compared with 24/38 (63%) pts in the R-chemo arm. The chemo backbone in the R-chemo arm affected MRD status in PB at EOI giving an MRD response rate of 96% (201/209) after R-bendamustine (B), 93% (100/108) after R-CHOP, and 79% (19/24) after R-CVP. No such effect was seen in the G-chemo arm, where MRD response rates in PB at EOI were high and similar with all three chemo regimens: 96% (187/194), 96% (105/109), and 94% (31/33), respectively. Similarly, in BM, chemo had a large influence on MRD-negative status at EOI in the R-chemo arm (87% [100/115] after R-B, 74% [55/74] after R-CHOP), but negligible impact in the G-chemo arm (93% [109/117] after G-B, 93% [76/82] after G-CHOP). Achievement of MRD negativity at EOI in PB/BM for pts with CR/PR at EOI was associated with longer subsequent PFS, with a hazard ratio of 0.35 (95% CI, 0.22, 0.56; p<0.0001; Figure 1), and comparable effects in both treatment arms. Conclusions: Data from this exploratory analysis support the potential prognostic value of MRD assessment after EOI in FL pts treated with immunochemotherapy. The higher proportion of pts achieving MRD-negative status at MI and EOI, and of pts with low-level MRD among MRD-positives at MI, in the G-chemo arm suggests that G-based induction induces rapid and more effective tumor cell clearance than R-containing therapy. G was more effective than R at enhancing the depth of response to induction therapy in PB and BM, potentially leading to a compensation of differential chemo activity. Future analyses of MRD kinetics during maintenance/follow-up will investigate the pattern and prognostic value of changes in MRD status before relapse, and further evaluate the impact of different chemo regimens. Figure 1. PFS from date of EOI sample by MRD status in PB and/or BM Figure 1. PFS from date of EOI sample by MRD status in PB and/or BM Disclosures Herold: Roche: Honoraria, Other: Grants; Genentech: Other: Grants; Celgene: Honoraria; Gilead: Other: Personal fees from member advisory board. Kneba:AbbVie: Consultancy, Honoraria, Other: Travel grants; Gilead: Consultancy, Honoraria, Other: Travel grants, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: Travel grants; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Amgen: Research Funding; Glaxo-SmithKline: Other: Travel grants. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Danesi:F. Hoffmann-La Roche Ltd: Employment. Fingerle-Rowson:Roche: Employment, Equity Ownership. Harbron:Roche: Employment, Equity Ownership; AstraZeneca: Equity Ownership. Mundt:Roche: Employment. Marcus:Takeda: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Hiddemann:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding.

scholarly journals Efficacy of Venetoclax Plus Hypomethylating Agent in Blast Phase Myeloproliferative Neoplasm

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-21
Author(s):  
Erika Morsia ◽  
Naseema Gangat ◽  
James M. Foran ◽  
Jeanne M. Palmer ◽  
Michelle A Elliott ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Myeloproliferative Neoplasm ◽  
Intensive Chemotherapy ◽  
Blast Phase ◽  
Advisory Committees ◽  
Best Response ◽  
Minimal Residual

Introduction: Myeloproliferative neoplasms (MPN), including primary myelofibrosis (PMF), essential thrombocythemia (ET) and polycythemia vera (PV), have a propensity to evolve into blast phase myeloproliferative neoplasm (BP-MPN) with a 20-year incidence rate of 9.3 %, 3.9% and 2.6%, respectively. (Szuber et al., 2019)Treatment options for BP-MPN are limited and the prognosis of these patients is dismal with a median survival of only 3.6 months and 5-year survival rate of &lt;5%.(Tefferi et al., 2018) Considering the recent reported data on the efficacy of venetoclax when combined with hypomethylating agents (HMA) in acute myeloid leukemia (AML) in both relapsed/refractory and newly diagnosed unfit patients, we have extended such combination therapy for patients with BP-MPN. Methods: We retrospectively analyzed 14 consecutive BP-MPN patients who received venetoclax plus HMA therapy between August 2018 and June 2020. We collected data regarding clinical characteristics of chronic phase MPN and BP-MPN, cytogenetic and leukemia mutation profile, efficacy and outcome. Oral venetoclax was administered in combination with azacitidine 75 mg/m2 days 1-7 (5 patients) or decitabine 20 mg/m2 days 1-5 (9 patients). Venetoclax dose was adjusted based on drug interactions particularly with azole antifungal prophylaxis. Diagnostic, risk and response assignments were according to the 2017 European LeukemiaNet (ELN) criteria.(Döhner et al., 2017) Minimal residual disease (MRD) assessment by flow cytometry, karyotype or next-generation sequencing (NGS) was performed in a subset of patients. Results: Patient characteristics at time of leukemic transformation, treatment details, response rates and overall outcome are shown in Table 1. Median age of patients was 67 years (range 48-81) with poor-risk cytogenetics in 69% of patients. JAK2 was mutated in 10 patients (71%) and CALR in 2 (14%); other mutations included TP53 in 5 patients (36%), TET2 in 4 (29%), KRAS in 3 (21%), IDH1/2 in 3 (21%), ASXL1 in 2 (14%) and U2AF1 in 2 (14%). Eight patients (57%) received venetoclax and HMA combination therapy upfront for their BP-MPN, 2 patients (14%) had failed HMA therapy previously and one patient had prior allogeneic hematopoietic stem cell transplant (AHSCT). Two patients (14%) presented with myeloid sarcoma; one of these two patients documented partial resolution of the extramedullary tumor by imaging studies, after treatment with venetoclax plus HMA. Among the remaining 12 patients, overall response rate (ORR) was 42% (n=5) and included complete remission (CR) in 3 patients (25%) and partial remission (PR) in another 2 (17%). The best response to therapy was seen after a median of 1 month (range, 1-2). Among 3 CR responders, 2 (66.6%) had minimal residual disease negative by NGS and not evidence of preceding MPN, then they successfully transitioned to AHSCT, while the third CR patient at the time of best response showed persistence of the TP53 mutation. Additionally, one PR patient subsequently relapsed and received salvage chemotherapy followed by AHSCT. (Table 2) Although data is limited by the small cohort and short follow up when the outcome of patients treated with venetoclax in combination with HMA were compared to Mayo Clinic's historical control of patients with BP-MPN treated with HMA alone (n=26) or intensive chemotherapy (n=69), there was higher CR rate in patients treated with venetoclax and HMA (25%) compared to those receiving HMA alone (4%; p=0.048) but not to those receiving intensive chemotherapy (35%; p&lt;0.0001). Moreover, the intensive chemotherapy cohort showed 24% of CR with incomplete hematologic recovery (CRi) not seen in patients receiving HMA alone or HMA with venetoclax (Figure1). Conclusions: The relatively high rate of complete response observed in our patients with BP-MPN were similar to those reported in a pivotal study of elderly unfit AML patients treated upfront with venetoclax + HMA with overall response rates of 68%.(DiNardo et al., 2019) Furthermore, responders included patients with adverse molecular risk factors who usually respond poorly to conventional chemotherapy (i.e. TP53 mutated patients). Our observations provide preliminary evidence for the potential efficacy of venetoclax and HMA combination therapy in BP-MPN with the goal of achieving CR/CRi followed by consolidative AHSCT wherever possible to provide durable remission and meaningful survival benefit. Disclosures Foran: Agios: Honoraria, Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy; Xencor: Research Funding; H3Biosciences: Research Funding.

scholarly journals 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 ◽  
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.

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

Blood ◽  
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.

PET-CT Defined Focal Lesions at Baseline and Day 7 Predict Outcome in GEP 70 Defined High Risk Multiple Myeloma Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3407-3407
Author(s):  
Yogesh Jethava ◽  
Rachel Hunter-Merrill ◽  
Gareth J Morgan ◽  
Rashid Z Khan ◽  
Aasiya Matin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Focal Lesions ◽  
Advisory Committees ◽  
Early Therapy ◽  
Time Points ◽  
The Impact

Abstract Introduction: Fluoro-deoxy-glucose (FDG) positron emission tomography (PET) scanning is an important state-of-the-art imaging tool in the initial workup of patients with multiple myeloma (MM). We evaluate the impact of PET focal lesions (FL) at baseline (BL), 7 days after starting induction therapy (D7) and prior to first autologous transplant (pre-ACST) in gene expression profiling (GEP 70) defined high risk (HR) multiple myeloma (MM) patients. Patients and methods: 48 GEP 70 HR MM patients were treated uniformly on IRB approved protocol consisting of tandem transplants with dose reduced Mel-80-VRD-PACE (melphalan, velcade, revlimid, dexamethasone, cisplatin, adreamycin, cyclophosphamide and etoposide) and interspersed Mel-20-VTD-PACE (melphalan, velcade, thalidomide, dexamethasone, cisplatin, adreamycin, cyclophosphamide and etoposide) consolidation and VRD (velcade, revlimid, dexamethasone) maintenance. PET examinations were performed at (BL), D7 and pre-ASCT, enumerating FDG-avid FL, their SUV max and extra-medullary disease (EMD).Of the 48 GEP 70 HR patients, 39 had BL, 28 had D7 and 42 had pre-ASCT PET examinations. 20 patients had examinations at all 3 time points. At BL, there were 24 (50%) patients with B2M >5.5mg/L and 26 (54%) with albumin <3.5g/dL. Metaphase cytogenetic abnormalities were documented in 36 (75%) patients, including deletion 13/hypodiploidy in 30 (63%). EMD was present in 3 (8%) patients, 28 (58%) had diffuse SUV <= 2 (median 2.4; range 1.4 to 9.5) and 14 (29%) had FL max SUV >3.9 (median 4.6; range 1.6 to 14.4). Results: From BL, the 3-yr PFS estimate was 46% for the group with no FL and 29% for those with FL (Figure 1a). The corresponding PFS data for the D7 was 53% for no FL at D7 as opposed to 11% for those with FL (Figure 1b), and for pre-ASCT it was 34% for no FL and 33% for those with FL (Figure 1c). Joint consideration of BL and D7 landmark revealed 3-yr PFS of 54% for those with no FL at BL, compared to 40% for those with resolution of BL FL by D7 and 18% for those whose FL did not resolve (log rank p-value=0.09), confirming the significance of FL resolution. Cox regression of PFS revealed that those with FL at BL had 2.34 times the risk of progression or death compared to those with no FL at BL (p=0.075), while those with FL at D7 had 3.27 times the risk (p=0.033). Diffuse SUV and SUV max had no impact on PFS at the three time points. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Fig 1a- PFS from baseline PET Fig 1b- PFS from D7 PET Fig 1c- PFS from pre-ASCT PET Conclusion: The prognosis of GEP 70 HR MM is dominantly affected by BL indicators of MM metabolism, as revealed by FDG uptake in FL. Our analysis in HR GEP70 MM patients confirms that early suppression of FL by D7 was key to improved PFS. MM patients who had absence of FL resolution from BL to D7 had poorer PFS and are candidates for early therapy change. Disclosures Morgan: Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. van Rhee:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.

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