scholarly journals Sustained Residual Disease Negativity Assessed By Diffusion-Weighted Whole-Body MRI (DW-MRI) Has Strong Predictive Relevance for Survival in Newly Diagnosed Multiple Myeloma Patients on Maintenance Therapy after Autologous Stem Cell Transplantation (ASCT)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1641-1641
Author(s):  
Angelo Belotti ◽  
Rossella Ribolla ◽  
Alberta Villanacci ◽  
Marco Chiarini ◽  
Viviana Giustini ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Imaging Techniques ◽  
Response Assessment ◽  
Whole Body ◽  
Advisory Committees ◽  
Predictive Role ◽  
Imaging Response

Abstract Introduction: The role of minimal residual disease (MRD) in Multiple Myeloma (MM) as a surrogate biomarker of patients' outcome, as well as the prognostic information of functional imaging response after treatment have been established in recent years. Furthermore, the predictive relevance of sustained MRD negativity assessed by marrow and imaging techniques and its association with an excellent outcome is emerging in clinical trials. Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used in the management of MM patients, but data regarding the predictive role of sustained DW-MRI response after treatment are lacking. The Myeloma Response Assessment and Diagnosis System (MY-RADS) recommendations have established criteria for Response Assessment Category (RAC) (Messiou C et al, Radiology 2019) with a 5 point scale defining the probability of complete imaging response (i.e. RAC 1) or progressive disease after treatment (i.e. RAC 5). We implemented the RAC criteria in our clinical practice and DW-MRI at 1-year in MM patients treated with autologous stem cell transplantation (ASCT) followed by maintenance therapy. Patients and methods: We retrospectively analyzed the outcome of 57 newly diagnosed MM patients (median age 61 years) diagnosed at our institution from January 2015 to December 2019 receiving maintenance therapy after ASCT. Patients underwent DW-MRI evaluation according to MY-RADS criteria at day +100 after ASCT, before maintenance, and after 1 year with the aim of monitoring imaging residual disease. Bone marrow samples were collected for MRD assessment by 8-color FCM (sensitivity 10-5) at day +100 after ASCT, before maintenance, and after 1 year. We focused on sustained 1-year DW-MRI negativity evaluated according to RAC response, and its potential predictive role at that timepoint on progression free survival (PFS) and overall survival (OS). In patients with available 1-year MRD evaluations, concordance between 1-year MRD and DW-MRI results was calculated and the level of agreement was expressed by Cohen's kappa statistics. Results: Out of 57 patients, 23 (40%) were ISS stage 3 and 14 (25%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 42, VRD 5, Dara-VRD 6, KRD 3, KCD 1. Single ASCT with MEL200 conditioning was performed in 33 patients (58%), whereas 24 patients (42%) received double ASCT. Subsequent maintenance was performed with lenalidomide (49 patients, 86%) or daratumumab-lenalidomide (8 patients, 14%). Response rates after ASCT were PR 9%, VGPR 23%, CR 51% and sCR 17%. According to MY-RADS, a complete imaging response (RAC1) at day +100 after ASCT was observed in 34 patients (60%). Sustained 1 year complete imaging response during maintenance therapy was observed in 43 patients (75%). Some residual disease was identified at that timepoint in 14 patients (25%) [RAC 2: 6 (11%), RAC > 2: 8 (14%)]. After a median follow up of 36 months, PFS and OS were significantly longer in patients with sustained 1-year imaging negativity, compared to patients with imaging residual disease (RAC 1 vs RAC ≥2): median PFS 56 vs 24,1 months, p <0,0001, HR 0,11 (95% CI: 0,030-0,382); median OS NR vs 40,5 months, p < 0,0001, HR 0,05 (95% CI: 0,006-0,364). MRD at 1-year timepoint was available in 30 patients and was negative in 28 (93%) cases. Concordance between 1-year DW-MRI and MRD results was high (97%, kappa 0,783: 7% both positive, 90% both negative). Conclusion: Our real-life data analysis confirms the predictive value of imaging residual disease assessment with DW-MRI after ASCT and highlights the importance of achieving sustained imaging MRD negativity during maintenance therapy regardless of different treatment strategies. Moreover, given the high rates of CR seen in patients with MM with novel effective treatment combinations, the detection of residual disease with the combined evaluation of marrow and functional imaging techniques during maintenance therapy can help the physician to identify patients with increased risk of early relapse and particularly poor prognosis. Our preliminary data regarding the high concordance observed between DW-MRI and MRD results during maintenance therapy suggest that DW-MRI could represent a reliable non-invasive technique to monitor residual disease. Disclosures Belotti: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Ribolla: Janssen: Membership on an entity's Board of Directors or advisory committees. Cancelli: Amgen: Membership on an entity's Board of Directors or advisory committees. Roccaro: Amgen, Celgene, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZeneca,: Research Funding; Associazione Italiana per la Ricerca sul Cancro (AIRC): Research Funding; European Hematology Association: Research Funding; Fondazione Regionale per la Ricerca Biomedica (FRRB), Transcan-2 ERA-NET: Research Funding. Rossi: Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

scholarly journals External Validation of Diffusion Weighted Whole Body MRI (DW-MRI) Response Assessment Category (RAC) Criteria Proposed By the Myeloma Response Assessment and Diagnosis System (MY-RADS) Imaging Recommendations: Prognostic Role of Imaging Response after Transplant in Multiple Myeloma and Comparison with MRD Evaluation By Flow Cytometry

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Angelo Belotti ◽  
Rossella Ribolla ◽  
Valeria Cancelli ◽  
Alberta Villanacci ◽  
Valentina Angelini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Functional Imaging ◽  
Residual Disease ◽  
External Validation ◽  
Response Assessment ◽  
Whole Body ◽  
Prognostic Role ◽  
Advisory Committees ◽  
Imaging Response

Introduction: The role of functional imaging in Multiple Myeloma (MM) has evolved in recent years due to the increasing availability of high platform imaging and the prognostic information of imaging response after treatment, as observed in PET/CT studies. Diffusion weighted whole body MRI (DW-MRI) is a functional imaging technique with an emerging role in the management of MM patients (pts) due to its high sensitivity, but consistent data regarding its prognostic role in the detection of residual disease after treatment in MM are lacking. The Myeloma Response Assessment and Diagnosis System (MY-RADS) imaging recommendations have been recently published (Messiou C et al, Radiology 2019) in order to promote standardization in response assessment. Criteria for Response Assessment Category (RAC) have been proposed with a 5 point scale defining the probability of complete imaging response (i.e. RAC 1) or progressive disease after treatment (i.e. RAC 5), but this score still needs to be validated in clinical practice. For this purpose, we performed an external validation of RAC criteria according to MY-RADS in newly diagnosed MM pts in order to evaluate the prognostic role of this technique after autologous stem cell transplantation (ASCT). Furthermore, we tried to correlate the results of MY-RADS with those of minimal residual disease (MRD) assessment by flow cytometry (FCM). Patients and methods: We retrospectively analyzed the outcome of 60 MM pts (median age 63 years) diagnosed between January 2016 to January 2020 who underwent DW-MRI evaluation to assess the response at day +100 after ASCT, before maintenance. After anonymization, images were reviewed according to MY-RADS by Radiologists who were blinded to the results of clinical and biological data. Post ASCT Progression free survival (PFS) was calculated from the date of last ASCT (the second one in case of double ASCT) until progression or death from any cause. The predictive role of MRI RAC response on outcome was analyzed. Bone marrow samples were collected before maintenance for MRD by 8-color FCM (sensitivity 10-5). In pts with MRD evaluations, exploratory PFS analysis was performed; concordance between MRD and DW-MRI results was calculated and the level of agreement was expressed by Cohen's kappa statistics. Results: out of 60 pts, 21 (35%) were ISS stage 3 and 13 (22%) showed high risk cytogenetics. Pts were treated with the following induction regimens: VTD 51, VRD 4, Dara-VRD 3, VCD 1, KRD 1. Single ASCT with MEL200 conditioning was performed in 41 pts (68%), %), whereas 19 patients (32%) received double ASCT. Response rates were VGPR 18,3%, CR 51,6% and sCR 13,3%. MRD before maintenance was available for 44 pts and was positive in 20 (45,5%). According to MY-RADS, a complete imaging response after transplant was observed in 36 (RAC 1: 60%). Some residual MM was identified in 24 (40%) [RAC2: 20 (33%), RAC3: 3 (5%), RAC4: 1 (2%), respectively]. After a median of 28 months, post ASCT PFS was significantly longer in pts with RAC 1 vs RAC ≥2: median NR vs 26,5 months, p 0,017, HR 0,29 (95% CI: 0,10-0,80). Concordance between WB-MRI and MRD results was low (52%, kappa 0,017: 16% both positive, 36% both negative). PFS according to DW-MRI response and MRD was significantly better for pts DW-MRI RAC1 and MRD negative before maintenance, compared to pts with RAC ≥2 and MRD positive results (PFS NR vs 10,6monts; p 0.012, HR 0,11 - 95%CI: 0,02-0,62). Intermediate PFS was observed for pts with either imaging or MRD positive results (PFS NR), with a significantly different outcome of the three subgroups (p 0,021) Figure 1. In 30 pts achieving CR or sCR, residual disease was identified in 14 (47%); in 4 of them by FCM only, in 8 by DW-MRI only, including two pts in sCR, and in two by both techniques. Conclusion: given the high rates of CR seen in pts with MM with new treatment approaches, DW-MRI is a powerful tool to better evaluate the prognosis of pts treated with novel combinations and ASCT. Our external validation of RAC criteria highlights the ability of DW-MRI to stratify pts with different outcome and promotes the standardization in reporting functional imaging response after treatment. The low concordance between DW-MRI response and MRD results suggests that these two techniques may be complementary for the definition of response: their combined use could help clinicians to better refine the prognosis of MM pts achieving CR Figure 1 Disclosures Belotti: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees. Rossi:Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2455-2455
Author(s):  
Carlos Bachier ◽  
Henning Schade ◽  
Behyar Zoghi ◽  
Aravind Ramakrishnan ◽  
Nirav N. Shah
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Residual Disease ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Extranodal Disease

Abstract Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse <12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

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.

Continuous Clinical Remisssion with High MRD Negativity and High PB and BM MRD Concordance during Venetoclax Monotherapy in R/R CLL Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Maria Dimou ◽  
Ioannis Anagnostopoulos ◽  
Sotiria Kalyva ◽  
Vasileios Pardalis ◽  
Athanasios Markopoulos ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Positive Sample ◽  
Hematological Toxicity ◽  
Clinical Relapse ◽  
Single Center ◽  
Advisory Committees

Introduction Venetoclax, a novel BCL2 inhibitor, used either as monotherapy or in combinations, induces rapid disease control , with durable clinical remissions, especially in patients with deep responses. In the Venetoclax era, minimal residual disease(MRD) is a new endpoint in CLL studies. MRD negativity is associated with better clinical outcomes (Jain N, et al. ASH 2019, abstract 186, Tam CS, et al. ASH 2019, abstract 642). Aim We present our single-center MRD data from a cohort of patients with relapsed/refractory(RR) CLL, treated with venetoclax monotherapy. Patients and Methods We collected data from 24 R/R CLL patients who have been treated with venetoclax monotherapy until progression, in the context of VENICE-1 study (NCT02756611) in our department between 11/2016 and 1/2018. MRD was locally evaluated with 10-colour flow cytometry(FC) according to ERIC guidelines, with the cut off of <10-4 (<0.01%) as negative, >10-4-<10-2 (>0.01%-<1%) as low-positive and >10-2 (>1%) cut off as high-positive. Peripheral blood(PB) MRD was assessed every 3-6 months. At week48 (1 year), CT scans were performed for response assessment. Bone marrow (BM) biopsy and BM MRD at week48 were also performed in pts with CT confirmed CR. Results Between 11/2016 and 1/2018, 24 patients started treatment with venetoclax monotherapy. Our patients' baseline characteristics are shown in table 1. Disease responses and patients' treatment status as of end-July 2020 are shown in table 2. Progression free survival(PFS) and overall survival at 34 months is estimated 91.6% and 87.5% respectively. Four patients (16.7%) had to reduce their daily Venetoclax dose due to hematological toxicity: 2 to 300mg due to neutropenia and 2 to 200 and 100mg due to thrombocytopenia. MRD results at week 48 are shown in table 3. Sixteen patients have paired PB and BM MRD results (15 at week 48 and 1 at week 24) with 87.5% concordance (14 patients). In seven MRD negative patients MRD conversion (2 consecutive samples) was observed, after a median time of 16 m(6-28): six patients to low-positive and one to high-positive. The high-positive MRD-converted patient presented clinical relapse at the 2nd high-MRD positive sample, according to iwCLL criteria. One of 6 low-positive MRD-converted patients, became MRD negative again at a later time-point. Conclusion Our single-center data from 24 CLL patients enrolled in the Venice-1 study reveal high concordance of PB and BM MRD at week48. Higher PB MRD negativity rate at week 48 is observed (79.2%) in comparison to Venice trial (Kater A, et al. EHA 2020, S156) due to differences in MRD methodology/number of evaluable patients. Our FC MRD data show that MRD conversion from negative to low-positive may be observed during continuous Venetoclax treatment, without clinical disease progression. This observation, along with high PFS at 34 months (91.5%) confirms the importance of continuing Venetoclax therapy in RR CLL patients when given as monotherapy. Disclosures Kyrtsonis: Genesis pharma SA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Panayiotidis:Genesis: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Gilead: Honoraria; Takeda: Honoraria; Phizer: Honoraria; ASH: Honoraria.

A Phase 1b Dose Escalation Safety Analysis of Lenalidomide and Azacitidine Maintenance Therapy for Poor Risk AML,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3625-3625
Author(s):  
Andrew H Wei ◽  
Peter T. Tan ◽  
Patricia A. Walker ◽  
Sharon Avery ◽  
Sushrut S. Patil ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Residual Disease ◽  
Maximum Tolerated Dose ◽  
Intensive Chemotherapy ◽  
Advisory Committees ◽  
Dose Escalation Study

Abstract Abstract 3625 Background: Despite achieving remission after intensive chemotherapy for AML, the majority of patients will relapse. Maintenance therapy is an attractive option, with the goal of eradicating residual disease and prolonging disease remission. The hypomethylating agent azacitidine and the immunomodulatory drug lenalidomide have been shown to be active in high risk MDS, especially in combination (Sekeres et al, Journal of Clinical Oncology 2010; 2253). Azacitidine maintenance therapy has been examined after intensive induction chemotherapy for high risk MDS and MDS progressing to AML (Grövdal et al, British Journ of Haem 2010; 293). In this study, an azacitidine dose of 75 mg/m2 resulted in excessive neutropenic toxicity. An amended dose of azacitidine 60 mg/m2 for 5 days each cycle was found to be deliverable, with acceptable hematopoietic toxicity. The goal of this study was to determine the optimal maintenance dosing schedule of azacitidine in combination with lenalidomide after intensive chemotherapy for AML in complete remission (CR) and a high risk of relapse. Methods: A phase Ib/II open label dose escalation study enrolled patients with high risk AML in CR/CRi and high risk features (age > 60, adverse risk karyotype, FLT3-ITD+ or CR2). Patients were treated with azacitidine subcutaneously on days 1–5 of each 28-day cycle combined with lenalidomide orally on days 5–25 for a maximum of 12 cycles. A 3×3 dose escalation schema to identify the maximum tolerated dose was conducted. Cohort A (Table 1) assessed the safety of azacitidine 50 mg/m2 alone. Cohorts B-H planned to investigate azacitidine 50–75 mg/m2 in combination with lenalidomide 5–25mg. Results: We report herein the analysis of the first 16 patients (M 8, F 8), median age 65 years (43–73) recruited to the study. Patients were at high-risk for relapse, based on age >60 years (n=11), CR2 (n=3), adverse risk karyotype (n=1) or FLT3-ITD+ (n=1). Neutrophil (Figure 1) and platelet (Figure 2) toxicity was modest during cycle 1. A summary of outcomes is shown in table 1. After a median follow-up of 301 days, 6/16 patients have relapsed with a median relapse-free survival (RFS) of 219 days (17–546) and median overall survival (OS) of 443 days (86–546). Dose-escalation is ongoing. Conclusion: The combination of azacitidine with lenalidomide as maintenance therapy after intensive chemotherapy for high-risk AML is well tolerated. The clinical efficacy of this regimen and the maximum tolerated dose remains to be determined. Disclosures: Wei: Celgene: Honoraria, Research Funding. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Hospira: Membership on an entity's Board of Directors or advisory committees. Harrison:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:Celgene: Honoraria.

NCRN CLL207 Study of Alemtuzumab Consolidation In CLL: Final Response Assessment and Early Follow-up (on Behalf of the NCRI CLL Trials Sub-Group)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 60-60 ◽  
Author(s):  
Abraham M Varghese ◽  
Dena Cohen ◽  
Christopher F.E. Pocock ◽  
Andy Rawstron ◽  
Walter M Gregory ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Response Assessment ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Close Monitoring ◽  
Advisory Committees ◽  
End Of Treatment ◽  
Time Point

Abstract Abstract 60 Background: The length of remission in patients with chronic lymphocytic leukemia (CLL) is dependent on the level of minimal residual disease (MRD) at the end of therapy, regardless of the therapy received. The conversion of remissions from MRD positive to negative should prolong remissions and survival. Several small studies have used alemtuzumab as consolidation therapy following conventional chemotherapy but with concerns over toxicity; primarily due to immune suppression and infections. The dose and timing (i.e. interval between prior chemotherapy and alemtuzumab) seem to be critical. Trial Design: The Phase II NCRN CLL207 Trial assessed alemtuzumab consolidation post-chemotherapy. Between 6 and 24 months from completing treatment (1 to 3 prior therapies) blood was screened for MRD using multi-parameter flow cytometry with a sensitivity of less than a single CLL cell in 10,000 leucocytes (0.01%). The marrow of MRD positive patients was assessed to quantify the CLL before treatment with alemtuzumab at a dose of 30mg given subcutaneously 3 times a week for 6 weeks, at which time the marrow was repeated. MRD negative patients and non-responders stopped therapy; MRD positive patients with at least one log reduction in MRD continued therapy for a further 6 weeks. All patients received prophylaxis with co-trimoxazole and aciclovir as well as weekly cytomegalovirus (CMV) monitoring by PCR. It was pre-determined that at least 14 of up to 54 (26%) patients would need to be converted from MRD positivity to negativity to justify further studies of this treatment strategy. Results: 47 patients received alemtuzumab in NCRN CLL207 with median age of 58 yrs (40-77) and 35 (74.5%) males. There was a median of 2 prior therapies (range 1 to 4) with 46 pts receiving fludarabine combinations as the latest therapy and 9 receiving rituximab-containing combinations. There were a total of 21 SAE's in 17 (36.2%) pts with 2 (4.3%) treatment related deaths (EBV-LPD and a parainfluenza infection). Alemtuzumab was stopped in 6 patients before week 6 mainly due to toxicity, 32 patients received 6–8 weeks of treatment and 9 patients received a 12-week course. G-CSF was given when the neutrophil count fell below 1 × 10^9/l and 14 (30%) patients required G-CSF during alemtuzumab with an additional 13 (28%) receiving G-CSF after completion of alemtuzumab. Positive CMV PCRs were detected in 21 (45%) patients, all of whom were successfully treated with pre-emptive antiviral therapy. Prior to alemtuzumab 24 patients were in complete remission (CR) and 23 were in partial remission (PR). Three months after alemtuzumab 13/23 (56%) PR converted to CR. 39/47 (83%) patients had MRD negative marrows at the end of alemtuzumab, 7 (15%) remained MRD positive and 1 (2%) was not evaluable. Blood MRD assessment 6 months after completing alemtuzumab showed that 15/31 (48%) MRD negative patients became MRD positive, although all except 2 had low CLL levels (below 0.1×10^9/l) at this time-point. Therefore overall 16/39 (41%) patients were MRD negative 6 months after completing alemtuzumab and of these 8/9 (89%) remained MRD negative in the blood at 12 months. Therefore MRD negativity in the blood at 6 months seems to better predict for persistent MRD negativity than the marrow at the end of therapy and appears to be the most appropriate assessment for the outcome of consolidation. Patients who are MRD negative at this time-point usually have durable remissions. 6 of the 9 patients receiving 12 weeks of alemtuzumab were MRD negative at the end of treatment but only 1 (11%) remained MRD negative in the blood at 6 months. In contrast 33/38 patients receiving up to 8 weeks of alemtuzumab were MRD negative at the end of treatment and 15 (39%) remained MRD negative at 6 months suggesting that the patients who benefit most from alemtuzumab consolidation are those who are MRD negative at 6 weeks. Conclusion: Alemtuzumab consolidation results in the eradication of detectable MRD in 83% of patients and 41% remain MRD negative 6 months later. Consolidation with alemtuzumab is associated with mainly infective toxicities, which are largely manageable with prophylaxis and close monitoring. These results justify the continued investigation of this approach in CLL within a clinical trial setting and with appropriate monitoring of patients. To this end we are now commencing a randomized Phase III trial of consolidation with alemtuzumab compared to observation (the CLARET study). Disclosures: Pocock: F.Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rawstron:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BD Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Genzyme: Honoraria. Dearden:Roche Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hillmen:Genzyme: Honoraria, Research Funding, Speakers Bureau; Roche Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Glaxo Smith Kline: Honoraria, Research Funding.

scholarly journals Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1956-1956
Author(s):  
Amy Wang ◽  
Justin Kline ◽  
Wendy Stock ◽  
Satyajit Kosuri ◽  
Andrew S. Artz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Stem Cell ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Checkpoint Inhibitors ◽  
Advisory Committees ◽  
Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

scholarly journals Results of a Phase I Study of Pnk-007, Allogeneic, Off the Shelf NK Cell, Post Autologous Transplant in Multiple Myeloma (NCT02955550)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4451-4451
Author(s):  
Sarah A. Holstein ◽  
Sarah Cooley ◽  
Parameswaran Hari ◽  
Sundar Jagannath ◽  
Catherine R Balint ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
Nk Cell ◽  
Single Infusion ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Background: PNK-007 is an allogeneic, off the shelf cell therapy product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. PNK-007 cells exhibit cytotoxicity against various cancer cell types, including multiple myeloma (MM), and secrete cytokines during co-culture with cancer cells. This is a Phase I study of single infusion PNK-007 after autologous stem cell transplant (ASCT) in MM. Methods: Placental CD34+ cells were cultivated in the presence of cytokines for 35 days to generate PNK-007 under cGMP standards followed by release testing. HLA matching and KIR mismatching were not used. Four treatment arms were evaluated on patients (pts) following ASCT: 10 million (M) cells/kg Day (D) 14 with or without recombinant human IL-2 (rhIL-2), 30M cells/kg D14 with rhIL-2, or 30M cells/kg D7 with rhIL-2. rhIL-2 was administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 expansion. Pts received variable pre-ASCT induction therapy. Maintenance therapy was permitted after the Day 90-100 visit (D90). Subjects were followed for up to 1-year. Results: 15 pts who received PNK-007 (12 of whom received rhIL-2) were followed on this study. Pts aged 44-69 yrs included 12 newly diagnosed (ND)MM and 3 relapsed/refractory (RR)MM. The 3 RRMM pts had received 1, 2 or 5 prior lines of therapy, with 2 pts having previous ASCT. All pts had been exposed to immunomodulatory drug (IMiDs) and proteasome inhibitors (PIs). No serious adverse events (AEs) were attributable to PNK-007 and no dose-limiting toxicity, GvHD, graft failure or graft rejection were observed. 12/15 pts started maintenance therapy following the transplant while participating in this study, at the physician's discretion. Based on physician assessed responses by International Myeloma Working Group pre-ASCT, of the NDMM pts 10/12 achieved VGPR or better (1 CR and 9 VGPR), 1/12 achieved PR and 1/12 was not assessed during pre-ASCT induction. By D90 10/12 pts achieved VGPR or better (5 CR or sCR and 5 VGPR), 1/12 maintained PR and 1/12 stable disease. At 1-year 9/11 achieved VGPR or better (4 CR or sCR and 5 VGPR), 2/11 were not assessed and 1 was removed from the study prior to 1 year due to failure to respond to ASCT. Of the RRMM pts 2/3 achieved PR and 1/3 was not assessed during pre-ASCT induction, by D90 2/3 achieved VGPR and the pt that had not been assessed pre-ASCT achieved PR. At 1-year, 1 pt maintained VGPR, 1 pt was not assessed and 1 pt did not continue to the 1-year visit. Using a validated Euro-flow minimal residual disease (MRD) assay of bone marrow aspirate (BMA) samples, of the NDMM pts 4/12 were MRD negative (MRD-) pre-ASCT; by D90 9/12 were MRD-. At 1-year 6/12 were MRD-, 2/12 had insufficient BMA to perform testing, 2/12 refused BMA procedure, 1/12 did not convert to MRD-, and 1 was removed from the study prior to 1-year due to failure to respond to ASCT. Of the RRMM pts 0/3 were MRD- pre-ASCT with 1/3 having insufficient BMA to perform testing; by D90 1/3 were MRD-. At 1-year 1/3 was MRD-, 1/3 did not convert to MRD- and 1 pt did not continue to the 1-year visit. PNK-007 infusion did not interfere with immune reconstitution kinetics. Platelet, neutrophil, and absolute lymphocyte counts recovered by day 28 post-ASCT in 12/15 patients. All pts' sera tested negative for the presence of anti-HLA antibodies at all timepoints indicating the absence of humoral immunity and alloantibodies to PNK-007. Conclusion: PNK-007 is the first fully allogeneic, off the shelf CD34+ derived NK cell product in MM clinical trials. A single infusion of PNK-007 up to 30M cells/kg with and without rhIL-2 was well tolerated in the post-ASCT setting. We established the feasibility of infusing PNK-007 as early as 7 days post-ASCT without negative impact on blood count recovery or successful engraftment. BMA MRD- status was observed in 7/9 MRD evaluable pts at 1-year post ASCT. These clinical data are encouraging and warrant further evaluation. Disclosures Holstein: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees. Cooley:Fate Therapeutics, Inc: Employment, Equity Ownership. Hari:Cell Vault: Equity Ownership; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Jagannath:BMS: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau. Balint:Celgene: Equity Ownership; Celularity, Inc: Employment. Van Der Touw:Celularity, Inc: Employment. Zhang:Celularity Inc: Employment. Hariri:Celularity Inc: Employment. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding.

scholarly journals 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 ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2638-2638 ◽  
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.

scholarly journals Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽  
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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