scholarly journals Health-Related Quality of Life in Adults with B-Cell Precursor Acute Lymphoblastic Leukemia and Minimal Residual Disease Treated with Blinatumomab

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1377-1377 ◽  
Author(s):  
Ralf C Bargou ◽  
Gerhard Zugmaier ◽  
Massimiliano Bonifacio ◽  
Carlos Graux ◽  
Christoph Faul ◽  
...  
Keyword(s):  
Health Status ◽  
Global Health ◽  
B Cell ◽  
Social Functioning ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Global Health Status ◽  
Cell Precursor ◽  
Support Research

Abstract Background: Positive minimal residual disease (MRD) is an established prognostic marker for hematologic relapse, negative hematopoietic stem cell transplantation (HSCT) outcome, and mortality in adults with B-cell precursor acute lymphoblastic leukemia (ALL; Gökbuget N, et al. Blood. 2012;120:1868-1876). In the open-label, single-arm phase 2 BLAST study (N=116; ClinicalTrials.gov, NCT01207388), treatment with blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to residual CD19+ blast cells, led to complete MRD response in 88 of 113 (78%) patients after cycle 1 (Gökbuget N, et al. Blood. 2018;131:1522-1531). Median overall survival was 36.5 months. Among patients with Philadelphia chromosome-negative B-cell ALL in complete MRD remission, relapse-free survival was 54% at 18months. In this analysis of the BLAST study, we assessed the health-related quality of life (HRQoL) of patients during and after treatment with blinatumomab. Methods: Eligible patients (≥18 years) had B-cell precursor ALL in first or later hematologic complete remission and persistent or recurrent MRD ≥10-3 after ≥3 blocks of intensive chemotherapy. Blinatumomab 15 μg/m2/day was administered by continuous intravenous (cIV) infusion for 4 weeks, followed by a 2-week infusion-free interval, for up to 4 cycles. Patients could receive HSCT any time after cycle 1. HRQoL was assessed using the EORTC QLQ-C30 Questionnaire at baseline, on day 29 of each treatment cycle, at the safety follow-up visit (30 days after end of treatment), and at the efficacy follow-up visits (3, 6, 9, 12, 18, and 24 months after treatment start). The questionnaire included 1 global health status scale, 5 functioning scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single-symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). For global health status and functioning scales, a higher score indicates better HRQoL; for symptom scales/items, a lower score indicates better HRQoL. A 10-point change is often viewed as the minimum clinically important difference (MID) in EORTC QLQ-C30 (Zikos E, et al. EORTC, 2016). In this analysis, the mean (SD) and the mean (SD) change from baseline to end of cycle 1 of the scores for each scale/item was summarized at each scheduled assessment during and after blinatumomab treatment. Results: In total, 89 patients had a nonmissing baseline value and a nonmissing value of any scale on day 29 of cycle 1, and thus were evaluable for HRQoL. The patient-reported global health status and functioning scale scores were stable over time during and after blinatumomab treatment (Figure 1). Symptom-scale and single-symptom scores were similarly stable during and after treatment (not shown). Mean (SD) changes from baseline to end of cycle 1 in global health status and in physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning were 2.5 (18.5), 0.3 (12.5), -4.0 (30.0), 4.2 (20.5), -1.7 (16.2), and 10.4 (31.8), respectively (Figure 2). These results show that, after 1 cycle of blinatumomab, the change in HRQoL was minimal for most scales, with potential clinically meaningful improvements in social functioning. Similar minimal changes were observed for all symptom scales/items (not shown). Conclusions: In this population of patients with B-cell precursor ALL and MRD successfully treated with blinatumomab 15 μg/m2/day cIV for up to 4 cycles, HRQoL was maintained during and after blinatumomab treatment, which is an important result considering the potential HRQoL impact of standard chemotherapy. Disclosures Zugmaier: Amgen Inc.: Consultancy, Employment, Patents & Royalties: 20170327581, 9688760, 20170122947, 9486475, 20160208001, 9192665, 20150071928, 8840888, 20140227272, 20140228316, 20130323247, 20130287774, 20130287778, 20110262440, 20100112603, 7700299, 20070037228. Bonifacio:Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Topp:Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: 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, Other: Travel, Research Funding. Tran:Amgen Inc.: Employment. Zhang:Amgen Inc.: Employment, Equity Ownership. Goekbuget:Kite / Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Other: Travel support, Research Funding; Pfizer: Consultancy, Other: Travel support, Research Funding; Amgen: Consultancy, Other: Travel support, Research Funding.

scholarly journals Switching Towards Monocytic Lineage and Discordancy between Flow Cytometric and PCR Minimal Residual Disease Results Is a Hallmark Feature of DUX4 Rearranged B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2825-2825
Author(s):  
Michaela Novakova ◽  
Barbora Vakrmanova ◽  
Lucie Slamova ◽  
Alena Musilova ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
B Cell ◽  
Treatment Response ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Response To Treatment ◽  
Cell Precursor ◽  
Treatment Protocols ◽  
Monocytic Lineage ◽  
Minimal Residual

Abstract Introduction: Recently we described a subgroup of pediatric patients with B cell precursor acute lymphoblastic leukemia (BCP ALL) with switching from B to monocytic lineage in early phase of the therapy (Slamova et al., 2014). In a limited cohort of patients with switching ALL (swALL), we observed inferior response to treatment with discrepancy of minimal residual disease level (MRD) assessed by flow cytometry (FC) and quantitative polymerase chain reaction (qPCR) of Immunoglobulin-T cell receptor (Ig-TCR) rearrangements. In current Berlin-Frankfurt-Münster (BFM) treatment protocols, FC MRD value at day 15 (d15) and PCR MRD value at day 33 (d33) and week 12 (w12) are used for stratification. Using an extended cohort of patients with available RNA sequencing data (cohort mainly focused on B other cases or swALLs) we aimed to answer following questions:What is the genetic background of swALL? What is the frequency among swALLs of the recently described DUX4 rearranged subgroup?How do B cell oriented FC and PCR MRD correlate in standard protocol timepoints, i.e. day 8 (d8) (peripheral blood, PB) d15, d33 and w12 (bone marrow, BM) of treatment?What is the characteristic MRD response to treatment in swALL? Results:We performed RNA sequencing in 177 patients (median age 6.1 years, range 0-18) treated by several treatment protocols (ALL BFM 95 n=5, ALL IC BFM 2002 n=14, ALL AIEOP BFM 2000 n=17, ALL AIEOP BFM 2009 n=135, Interfant n=3, ALL IC/Interfant n=2, EsPhALL n=1). In 68 patients we observed switching phenomenon by appearance of B/monocytoid population coexpressing B lineage (CD19, CD34) and monocytic lineage (CD33, CD14) markers (median 0.98%, range 0.032-38%). In non swALLs median of this population was 0.059% (range 0.0025-1.1%) and the cells did not form a clear cluster. According to RNAseq data, majority of swALL patients (n=42/68) belong to DUX4 subgroup (chi square p< 0.00001). The distribution into other molecular genetic subtypes is summarized in table 1.Correlation coefficient (Spearman) of all included samples with both available values (n=552) was 0.82 (p<0.0001), Concordance in categorization of positivity and negativity with cut-off 1e-4 was 85%. We observed worse correlation between FC and PCR MRD in patients with swALL (d8 R=0.58, d15 R=0.6, d33 R=0.36, w12 n.s.) compared to non swALL (d8 R=0.83, d15 R=0.91, d33 R=0.69, w12 R=0.37). However, concordance in swALL in categorization of positivity and negativity with cut-off 1e-4 was still ≥80% in each analyzed timepoint apart from d33 with concordance only 44% showing significant discrepancy of both methods (Figure 1a). On the contrary, concordance in non swALL was ≥87% for each analyzed timepoint (d33 with concordance 87% shown in Figure 1b). Poor correlation between B-cell oriented FC MRD and PCR MRD at d33 was also obvious when analyzed DUX4 subgroup separately (R=0.31 (p=0.04), concordance 45%).We observed significantly higher MRD in swALLs compared to non swALLs at all analyzed timepoints: d8 (p=0.0021), d15 (p=0.0088, d33 (p<0.0001) and w12 (p=0.008). Higher MRD levels were also found in DUX4 patients when compared to non DUX4 (all timepoints p<0.05). Interestingly, when compared swALL and non swALLs pts in DUX4 subgroup only, the DUX4 swALLs are those with poorer treatment response (all timepoints p<0.05). With respect to protocolar cut-off values, FC MRD at d15 was above 10% in 18/67 swALL patients (in 13/52 DUX4 patients), d33 PCR MRD was above 0.1% in 33/57 swALLs (24/44 DUX4 pts) and at w12 PCR MRD was above 0.01% in 12/55 swALLs (10/44 DUX4 pts). Conclusions: DUX4 subgroup is the most prevalent genetic subtype among swALLs. SwALLs and/or DUX4 subgroup have poorer treatment response at d15, d33 and w12. However, it remains to be elucidated whether poor initial treatment response is eventually reflected in treatment outcome. In majority of swALL patients B cell phenotype of blasts is preserved at day 15 enabling correct classification. Prominent discrepancy between FC and PCR MRD is present especially at d33 and development of different FC MRD strategies focused on monocytic compartment is needed. Supported by Ministry of Health of the Czech Republic, grant nr. 15-28525A and NV18-03-00343; Czech Science Foundation nr. P302/12/G101, UNCE204012 Disclosures Brüggemann: Affimed: Research Funding; Regeneron: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau; Incyte: Consultancy; PRMA: Consultancy. Ritgen:abbvie: Research Funding; Roche: Honoraria, Research Funding.

scholarly journals Monitoring of the Clonal Architecture of B-Cell Precursor ALL during Induction Chemoimmunotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1555-1555
Author(s):  
Michaela Kotrova ◽  
Monika Szczepanowski ◽  
Henrik Knecht ◽  
Christoph Faul ◽  
Mustafa Kondakci ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Response To Treatment ◽  
Induction Treatment ◽  
Cell Precursor ◽  
Clonal Architecture ◽  
Kinetics Of ◽  
Support Research

Abstract Background: High throughput sequencing of immunoglobuline heavy chain gene rearrangements (IGH) recently demonstrated that B-cell precursor ALL (BCP-ALL) is a highly oligoclonal disease in children (Theunissen, Hematologica, 2017), however, little is known about the degree of oligoclonality in adults with BCP-ALL. Furthermore, no data exist on potential changes of the subclonal composition during therapy. Therefore, we aimed to monitor the clonal architecture of the leukemic blasts before and after Rituximab containing induction treatment in the context of the current German Multicentric Acute Lymphoblastic Leukemia (GMALL) 08/2013 trial. Materials & Methods: We identified and studied complete and incomplete immunoglobulin (IG) heavy chain rearrangements in 100ng of bone marrow (BM) DNA at diagnosis (dx) and 500ng BM DNA after Rituximab-containing induction I in 19 patients with BCP-ALL. We employed IGH-VJ FR1 and IGH-DJ NGS assays developed within the EuroClonality-NGS Consortium (www.euroclonalityngs.org), performing next generation sequencing on Illumina MiSeq. We analysed data with the ARResT/Interrogate bioinformatics platform (Bystry, Bioinformatics, 2017), which is also able to isolate and use the DN-J stem of V/DJ junctions to link clonally related rearrangements. Clones with abundance ≥5 %, and all subclones carrying the same DN-J stem as the dominant clones were considered as leukemia-associated and studied further. Employing the sequence of the DN-J stem, we could also link related complete and incomplete rearrangements, even though those are amplified in two separate PCRs. Results: At dx, 18/19 patients carried at least 1 IGH rearrangement with abundance ≥ 5%, 10 patients carried 2 or more. In all 18 patients with dominant markers detected at dx, subclones with abundance <5% carrying the same DN-J stem as the dominant clone were present, indicating oligoclonality and clonal evolution. On average, 53.1 (range 0-295) (sub)clones per DN-J stem were detected at dx, and 32.7 (range 0-238) after treatment. Next, we compared the kinetics of all (sub)clones with abundance ≥1% in at least one of the time-points. Of the 18 patients, 6 only had subclones with abundance <1%, and we did not investigate the kinetics of such subclones. In another 11 patients (Fig. 1, Pt. 1-11), all sub(clones) had the same kinetics, with no clone gaining predominance over time. In 1 patient (Fig. 1, Pt. 12), 3 (sub)clones which were present at dx disappeared and a new subclone appeared after treatment. This patient had a pro-B immunophenotype, where oligoclonality and clonal instability are well known phenomena (Szczepanski, Leukemia, 2001). Conclusions: It has recently been shown that ALL is a highly oligoclonal disease in children (Theunissen, Hematologica, 2017), and our study extends this finding to adults with BCP-ALL. We furthermore demonstrate that the subclonal composition remains stable in the majority of patient during induction chemoimmunotherapy. The fact that the response to treatment is generally consistent among different (sub)clones has important implications for MRD quantification as it reassures the usage of the dominant clonal IG gene rearrangement for MRD monitoring in ALL. However, also significant changes of the clonal composition may occur in BCP-ALL as exemplified in one patient of our cohort. Further investigations are necessary to elucidate factors that influence subclonal heterogeneity in response to treatment. Disclosures Viardot: Pfizer: Consultancy, Honoraria; Gilead Kite: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy; BMS: Consultancy, Honoraria. Kneba:AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Goekbuget:Pfizer: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Kite / Gilead: Consultancy; Amgen: Consultancy, Other: Travel support, Research Funding; Celgene: Consultancy. Brüggemann:Incyte: Consultancy; PRMA: Consultancy; Regeneron: Research Funding; Affimed: Research Funding; Pfizer: Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Roche: Speakers Bureau.

scholarly journals Cost-Effectiveness of Blinatumomab Versus Standard of Care in Adult Patients with Philadelphia-Chromosome-Negative B-Precursor Acute Lymphoblastic Leukemia in First Hematological Complete Remission (CR) with Minimal Residual Disease (MRD) from a US Payer Perspective

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4746-4746
Author(s):  
Thomas Delea ◽  
Nicholas Despiegel ◽  
Diana Boyko ◽  
Jordan Amdahl ◽  
Ze Cong ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
B Cell ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cost Effective ◽  
Sensitivity Analyses ◽  
Cell Precursor ◽  
Payer Perspective ◽  
Life Years

Abstract INTRODUCTION: Blinatumomab is a bispecific CD19 directed CD3 T cell engager indicated for the treatment of adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%. In BLAST (NCT01207388), an open-label, multicenter, single-arm, phase 2 study of blinatumomab in patients with MRD positive B-precursor ALL in hematological CR, blinatumomab resulted in complete MRD response in cycle 1 in 78% of patients. Overall survival (OS) was significantly better in those with MRD vs those without MRD. The objective of this study is to evaluate the cost-effectiveness of blinatumomab vs. standard of care (SOC) therapy in patients with Ph- B-cell precursor ALL in first hematological CR with MRD based on the BLAST study from a US healthcare payer perspective. METHODS: A partitioned survival model was used to estimate the incremental cost-effectiveness ratio (ICER) of blinatumomab vs. SOC maintenance. A 50-year lifetime horizon and US payer perspective were employed. Costs and outcomes were discounted at 3% annually. Probabilities of complete MRD response, relapse-free survival (RFS), OS, numbers of cycles of blinatumomab and SOC, and transplant rates were estimated from BLAST and a historical cohort comparator study using propensity score analyses. RFS and OS were based on parametric survival distributions fit to individual patient failure-time data. Utility values were based from a generalized linear model/generalized estimating equation (GLM/GEE) model fitted to EQ-5D data collected in BLAST applying US tariffs. Inpatient and outpatient healthcare use by MRD status was from an observational study which evaluated treatment patterns and healthcare resource utilization in adult B-cell precursor ALL in first hematological CR with and without MRD. Deterministic and probabilistic sensitivity analyses were conducted to assess the effects of changes in model assumptions and uncertainty around key parameters. RESULTS: The unrestricted Gompertz distribution for RFS and lognormal mixture cure model distribution for OS were selected. In the base case, blinatumomab was projected to yield 3.52 additional life years and 2.93 additional quality-adjusted life years (QALYs) compared with SOC. Blinatumomab is associated with higher drug and administration costs and transplant costs, which were partially offset by lower post-relapse costs. The ICER for blinatumomab vs. SOC maintenance therapy was estimated to be $81,807/QALY gained (table). The main cost drivers were the drug acquisition costs and the additional hematopoietic stem cell transplant costs with blinatumomab. Cost-effectiveness was mostly sensitive to the uncertainty around the cure fraction (proportion of patients whose survival pattern is similar to the general cancer-free population) and transplant rates. Assumptions that most affected cost-effectiveness were the duration of benefit of blinatumomab and the long-term mortality estimation. The cost-effectiveness remained below the willingness-to-pay threshold value of $150,000/QALY gained in all scenarios tested. In the probabilistic sensitivity analyses, the estimated probability that blinatumomab is cost-effective was 87% at a willingness-to-pay threshold of $150,000/QALY. CONCLUSIONS: Blinatumomab is a cost effective treatment option vs. SOC for adults with Ph - B-precursor ALL in first hematological CR with MRD from the US healthcare perspective with an ICER well below the threshold of $150,000 per QALY gained. The value of blinatumomab is derived from its high complete MRD response rate, prolonged RFS, and OS. Disclosures Delea: Seattle Genetics: Research Funding; Takeda: Research Funding; Sanofi: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Policy Analysis Inc.: Employment. Despiegel:Amgen, Inc.: Employment, Equity Ownership. Boyko:Amgen: Research Funding. Amdahl:Amgen: Research Funding. Cong:Amgen, Inc.: Employment, Equity Ownership.

scholarly journals Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy Provides Very Good Outcome in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: First Results from the EWALL-INO Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 511-511
Author(s):  
Patrice Chevallier ◽  
Thibault Leguay ◽  
Michael Doubek ◽  
Francoise Huguet ◽  
Cyril Salek ◽  
...  
Keyword(s):  
B Cell ◽  
Older Patients ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Newly Diagnosed ◽  
Cell Precursor ◽  
Inotuzumab Ozogamicin ◽  
Low Intensity

Abstract On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group. Introduction. Treatment of older patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains an unmet medical need. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, is approved for the treatment of relapsed/refractory BCP-ALL in adults, sinusoidal obstruction syndrome (SOS) being the major adverse event associated with INO. A previous first line study conducted by the MDACC in pts 60 years or older successfully used INO in combination with a lower intensity version of the hyper-CVAD (mini-hyper-CVD). Due to the occurrence of SOS, the total doses were fixed at 1.3 mg/m² for cycle 1 followed by 3 cycles at 1 mg/m² (Kantarjian H et al. Lancet Oncol, 2018). Here, we aimed to assess the activity and safety of fractionated INO at a reduced dosage in combination with low-intensity chemotherapy as frontline therapy for older pts with CD22+ Philadelphia chromosome-negative (Ph-neg) BCP-ALL. Methods. EWALL-INO is a single arm prospective phase 2 multicentric study conducted in European centers belonging to the EWALL group. Eligibility criteria were pts aged 55y or older, performance status ≤2, and newly diagnosed CD22+ (20% or more of positive blast cells) Ph-neg BCP-ALL without central nervous system involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and a single intrathecal injection (IT), the induction regimen was begun and split in 2 parts. Induction part I (Induc1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70y) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Induc2) was offered to pts in CR or CRp (CR with platelets &lt; 100 G/l) after Induc1 or as salvage therapy. Induc2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Pts in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4; Methotrexate (MTX) 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5; CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allograft was allowed after at least 3 blocks of consolidation at the discretion of the investigators. The evaluable population was pts who received at least 1 dose of INO. Analyses were by modified intention to treat and performed JUN 28, 2021. All pts gave informed consent. The study is registered at ClinicalTrials.gov under the NCT number: NCT03249870. Results. Between DEC 29, 2017 and JUN 22, 2021, 115 pts (out of 130 planned pts) were enrolled including 6 pts with screen failure. The first 90 eligible pts (up to MAR 1, 2021) were considered for this analysis to obtain a minimum of 4 months follow-up. Median age was 69y (range 55-84) and median follow-up for alive pts was 1.18 years (range 0.3-3.5). At time of analysis, 90 and 88 pts had started induc1 and induc2, respectively. Treatment related mortality was 2.2% (2/90) and CR/CRp rate was 85.5% (77/90, 6 CRp) after induc1. Three cases relapsed between induc1 and induc2 and 5 pts were salvaged by induc2 allowing to a CR/CRp rate of 87.7% (79/90, 8 CRp) after induc2. One pts died from refractory disease during induc2. One, 2, 3 4 and 5 injections of INO were administered to 2 (2.2%), 2(2.2%), 11 (12.2%), 2 (2.2%) and 73 pts (81.1%) respectively. Only 6 pts were allografted. One-year OS was estimated to be 78.5% (95%CI 68-85.9) and median OS was not reached. One-year relapse free survival was 74.5% (95CI 63.5-82.6) (Figure 1). Grade 3-4 liver toxicity was observed in 8 pts (8.8%) during the study including 3 pts (3.3%) developing SOS, 2 related to INO during induc1 and one occurred after transplant. Twenty-nine pts died during the follow-up, 16 from relapses (overall incidence 18%) and 13 from adverse events (overall incidence 14.4%), including one COVID19 fatal infection during consolidation. Conclusion. Fractionated inotuzumab ozogamicin at reduced doses (0.8/0.5/0.5/0.5 mg/m²) combined with low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL. Figure 1 Figure 1. Disclosures Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Raffoux: ABBVIE: Consultancy; PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy. Boissel: CELGENE: Honoraria; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; SANOFI: Honoraria. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia

scholarly journals Bispecific T-cell engaging antibodies in B-cell precursor acute lymphoblastic leukemias: focus on blinatumomab

2020 ◽  
Vol 11 ◽  
pp. 204062072091963
Author(s):  
Jose-Maria Ribera ◽  
Eulalia Genescà ◽  
Jordi Ribera
Keyword(s):  
T Cell ◽  
B Cell ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Development Program ◽  
Cell Transplant ◽  
Cell Precursor ◽  
Hematopoietic Stem ◽  
Clinical Development Program

Bispecific T-cell engaging antibodies are constructs engineered to bind to two different antigens, one to a tumor-specific target and the other to CD3-positive T cells or natural killer (NK) cells. Blinatumomab engages CD19 and CD3, performing effective serial lysis. The clinical development program in acute lymphoblastic leukemia (ALL) includes clinical trials in relapsed or refractory (R/R) patients and in B-cell precursor (BCP) ALL patients with measurable residual disease. Several trials are currently being conducted in de novo BCP-ALL, either in induction, consolidation, or before or after hematopoietic stem cell transplant. Combination with other targeted therapies or with other immunotherapeutic approaches are also underway. Several strategies are aimed to optimize the use of blinatumomab either by overcoming the mechanisms of resistance (e.g. inhibition of PD-1/PD-L1) or by improvements in the route of application, among others.

scholarly journals Curative outcomes following blinatumomab in adults with minimal residual disease B-cell precursor acute lymphoblastic leukemia

2020 ◽  
Vol 61 (11) ◽  
pp. 2665-2673 ◽  
Author(s):  
Nicola Gökbuget ◽  
Gerhard Zugmaier ◽  
Hervé Dombret ◽  
Anthony Stein ◽  
Massimiliano Bonifacio ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Minimal Residual

scholarly journals The hematopoietic stem cell marker VNN2 is associated with chemoresistance in pediatric B-cell precursor ALL

2020 ◽  
Vol 4 (17) ◽  
pp. 4052-4064
Author(s):  
Beat Bornhauser ◽  
Gunnar Cario ◽  
Anna Rinaldi ◽  
Thomas Risch ◽  
Virginia Rodriguez Martinez ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Surface ◽  
B Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Surface Protein ◽  
Stem Cell Marker ◽  
Cell Precursor ◽  
Hematopoietic Stem

Abstract Most relapses of acute lymphoblastic leukemia (ALL) occur in patients with a medium risk (MR) for relapse on the Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL protocol, based on persistence of minimal residual disease (MRD). New insights into biological features that are associated with MRD are needed. Here, we identify the glycosylphosphatidylinositol-anchored cell surface protein vanin-2 (VNN2; GPI-80) by charting the cell surface proteome of MRD very high-risk (HR) B-cell precursor (BCP) ALL using a chemoproteomics strategy. The correlation between VNN2 transcript and surface protein expression enabled a retrospective analysis (ALL-BFM 2000; N = 770 cases) using quantitative polymerase chain reaction to confirm the association of VNN2 with MRD and independent prediction of worse outcome. Using flow cytometry, we detected VNN2 expression in 2 waves, in human adult bone marrow stem and progenitor cells and in the mature myeloid compartment, in line with proposed roles for fetal hematopoietic stem cells and inflammation. Prospective validation by flow cytometry in the ongoing clinical trial (AIEOP-BFM 2009) identified 10% (103/1069) of VNN2+ BCP ALL patients at first diagnosis, primarily in the MRD MR (48/103, 47%) and HR (37/103, 36%) groups, across various cytogenetic subtypes. We also detected frequent mutations in epigenetic regulators in VNN2+ ALLs, including histone H3 methyltransferases MLL2, SETD2, and EZH2 and demethylase KDM6A. Inactivation of the VNN2 gene did not impair leukemia repopulation capacity in xenografts. Taken together, VNN2 marks a cellular state of increased resistance to chemotherapy that warrants further investigations. Therefore, this marker should be included in diagnostic flow cytometry panels.

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