•Treatment-naive and relapsed/refractory MDS patients receiving venetoclax and HMAs have an ORR of 59% with 63% of responders proceeding to transplant.•Allogeneic stem cell transplantation after ...treatment with venetoclax in combination with HMA is associated with prolonged survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Patients with secondary acute myeloid leukemia (sAML) have poor outcomes compared to those with de novo AML. In 2017, liposomal daunorubicin and cytarabine (CPX-351) was FDA approved for ...the treatment of adults with newly diagnosed AML with myelodysplasia-related change (AML-MRC) or therapy-related AML (t-AML). In its landmark trial, CPX-351 has displayed significant improvement in overall survival (OS) compared to conventional 7+3 in patients 60-75 years of age with sAML. Gaps remain in the literature regarding the clinical use of CPX-351 in context of the FDA approved label. Here we evaluate real-world outcomes with disease response and molecular monitoring in patients treated with CPX-351.
Methods
Adults who received CPX-351 between September 2017 and December 2019 were identified. The primary endpoint was overall response rate (ORR), defined by complete remission (CR) and CR with incomplete hematologic recovery (CRi) according to the Revised IWG criteria. Additional outcomes of interest included molecular minimal residual disease (MRD) status post induction as measured by next-generation sequencing (NGS), ORR in patients with baseline TP53, and progression-free survival (PFS) in patients with CR/CRi, with and without MRD after induction. Mutations associated with clonal hematopoiesis (TET2, ASXL1, DNMT3A) were excluded from analysis of molecular MRD.
Results
Fifty-four patients were identified with baseline characteristics as shown in Table 1. Overall, the study population was elderly with the median age of 64 IQR: 60-68, and 13 patients were younger than 60 years old. Six patients developed AML in the setting of a pre-existing myeloproliferative neoplasm (MPN). The most common indication for treatment with CPX-351 was antecedent MDS (42.6%), followed by de novo AML with MDS karyotype (24.1%), therapy-related AML (13%), and antecedent MPN (11.1%). NGS was performed prior to treatment with CPX-351 in all but one patient, and 88.7% had at least one molecular marker that is not identified as one of the mutations associated with clonal hematopoiesis. Most commonly identified molecular markers were TP53 (16/53, 30.2%), RUNX1 (10/53, 18.9%), SRSF2 (8/53, 15.1%), NRAS (7/53, 13.2%), and IDH2 and JAK2 (6/53, 11.3%, each).
Most patients were hospitalized until hematologic recovery. However, 5 patients received induction in the outpatient setting, and an additional 6 patients were discharged early before hematologic recovery. Among the patients who were discharged early or underwent outpatient induction, 81.8% (9/11) were admitted for a complication. There were no deaths associated with outpatient induction. Overall, 46 patients (85.2%) experienced febrile neutropenia and 17 patients (31.5%) had bacteremia. Thirty-day and 60-day mortality were 9.3% and 14.8%, respectively.
The ORR was 54%, and the response rates observed in patients who were younger vs older than 60 years were similar (41.7% vs. 57.9%, p=0.508). In patients who achieved a remission after induction, 56% (14/25) were MRD positive by NGS. Among those who had TP53 mutation at baseline, 14 were available for response assessment after induction. The ORR in this subgroup was 57% (8/14) and all but 3 (63%) were MRD negative by NGS. Consolidation with allogeneic transplant was performed in 18 patients (33%).
Median OS was 10.4 mos. Median OS was similar for patients older or younger than 60 years (p=0.76). For patients achieving a CR/CRi, median OS had not been reached at the time of analysis but was significantly improved compared to those with refractory disease (6.1 mos, p=0.0007). Median OS or PFS did not differ significantly (p=0.68) based on MRD negativity (Figure 1).
Conclusion
This analysis demonstrates comparable response rates to the landmark trial (54% in our analysis vs. 47.7%). Outpatient induction and/or early discharge was safe and feasible in appropriately selected patients. While this analysis is limited by the small sample size, CPX-351 appeared effective in populations that were not included in the published randomized studies, such as patients below the age of 60 years old and those with antecedent MPN. Remission rates and MRD clearance was high among TP53 mutants. A considerable number of patients who achieved a remission remained MRD positive by NGS, but this did not impact PFS. Future studies should evaluate the impact of molecular MRD and allele frequency to further guide treatment.
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Koprivnikar:Alexion: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau. McCloskey:Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Hypomethylating agents (HMAs) are the current standard of care therapy in high-risk MDS. However, only ~50% of patients with MDS respond to HMAs and most responding patients eventually ...progress. Outcomes after HMA failure in patients with high-risk MDS are especially poor, with median survival of 4 to 6 months. Venetoclax in combination with HMAs led to deep and durable remissions in elderly patients with newly diagnosed AML with CR+CRi rate of 67% and median survival of 17.5 months.Here, we performed a multicenter retrospective analysis to determine outcomes in patients with MDS receiving HMA + venetoclax (off-label) and identified risk factors associated with response and survival.
Methods
After obtaining institutional review board approval(s), we retrospectively reviewed charts of patients receiving HMA and venetoclax between January 1, 2018 to July 15, 2019. Criteria for inclusion were a pathologically confirmed diagnosis of MDS and treatment with either decitabine or azacitidine in combination with venetoclax. Patients with progression to AML prior to treatment with HMA+ venetoclax were excluded. Bone marrow response assessments were evaluated per WHO 2006 criteria. For subjects who required a delay in study treatment for blood count recovery after bone marrow evaluation, hematology values for up to 2 weeks were used to determine response. When available, cytogenetics, next generation sequencing, and flow cytometry data were included for analysis. HMA failure was defined as progression to a higher IPSS-R risk MDS while on HMA or lack of response after 4 cycles of HMA treatment. On univariate analysis, Fisher's exact test and Student t tests were used for overall response and Kaplan-Meier estimates were used to summarize OS and RFS.
Results
42 patients met criteria for inclusion. The patient population was predominantly male, elderly, R-IPSS very poor cytogenetics, R-IPSS very high risk, MDS-EB2, and with HMA failure prior to initiation of HMA + venetoclax (Table 1.) Median blast count was 13% (range 2-18%). MDS was classified as therapy-related (t-MN) in 13 (31%) patients. TP53 mutations with complex karyotype occurred in 9 out of 34 (26%) patients (Figure 2). Azacitidine was the most common HMA used in combination with venetoclax (63%). Median follow up from the start of the combination was 5.4 months. Out of 40 patients evaluable for response, the ORR and marrow CR rate was 55%, median RFS and OS were not reached. Patients who achieved a marrow CR had a significantly prolonged OS in comparison to non-responders (median OS not reached vs. 5.64 months, p= 0.002). Among HMA naïve patients, the marrow CR rate was 73%. Furthermore, the marrow CR rate was 47% for patients with HMA failure and there was no significant difference in response or survival based on HMA exposure (Table 2). Median time to initial response was 1.6 months. On univariate analysis, therapy related disease and very poor risk cytogenetics were significantly associated with decreased response and a delay in starting cycle 2 or 3 was associated with increased response. Female gender, t-MN, very poor risk cytogenetics and a TP53 mutation were significantly associated with inferior OS. Very poor risk cytogenetics, a TP53 mutation, and the decitabine combination was significantly associated with decreased RFS (Table 3). Of note, neither a dose delay of venetoclax > 7 days or <21 day cycle of venetoclax were associated with decreased median OS or RFS. Out of 22 responders, 13 (59%) received allogeneic stem cell transplantation (allo-SCT). Allo-SCT was associated with increased median OS (not reached vs. 6.07 months, p=0.02, Figure 3.) and RFS (not reached vs. 3.51 months, p<0.01).
Conclusion
In summary, venetoclax in combination with HMAs led to high rates of marrow remission (55%) and hematologic improvement (38%) in a very high risk and heavily treated MDS population. The response rate was higher in HMA naïve patients but not significantly decreased among patients with HMA failure. Achievement of marrow CR led to significantly prolonged OS. HMA + venetoclax also led to allo-SCT in 59% of all responders and 56% of responders with HMA failure. Complex karyotypes and TP53 mutations were associated with worse response and survival. These results suggest that adding venetoclax may salvage patients failing to respond optimally to HMA, thus allowing more patients to proceed to allo- SCT, and likely warrant testing prospectively.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approaches ...of current practice. A second workshop followed a quality control exercise in which 21 laboratories analyzed diagnostic cases of purified plasma cells for recurrent abnormalities. The summary report was discussed at the EHA Myeloma Scientific Working Group Meeting 2010. During the quality control exercise, there was acceptable agreement on more than 1,000 tests. The conclusions from the exercise were that the primary clinical applications for FISH analysis were for newly diagnosed cases of MM or frank relapse cases. A range of technical recommendations included: 1) material should be part of the first draw of the aspirate; 2) samples should be sent at suitable times to allow for the lengthy processing procedure; 3) most importantly, PCs must be purified or specifically identified; 4) positive cut-off levels should be relatively conservative: 10% for fusion or break-apart probes, 20% for numerical abnormalities; 5) informative probes should be combined to best effect; 6) in specialist laboratories, a single experienced analyst is considered adequate; 7) at least 100 PC should be scored; 8) essential abnormalities to test for are t(4;14), t(14;16) and 17p13 deletions; 9) suitable commercial probes should be available for clinically relevant abnormalities; 10) the clinical report should be expressed clearly and must state the percentage of PC involved and the method used for identification; 11) a retrospective European based FISH data bank linked to clinical data should be generated; and 12) prospective analysis should be centralized for upcoming trials based on the recommendations made. The European Myeloma Network aims to build on these recommendations to establish standards for a common European data base to define subgroups with prognostic significance.
This review article explores the potential of blockchain technology (BCT) as a key enabler for fostering transparency, trust, and citizen engagement in smart governance within smart cities. By ...examining the benefits of BCT in various aspects of smart city systems, such as data security and privacy, the paper highlights the advantages of implementing consortium blockchain architecture and the Proof of Authority (PoA) consensus algorithm and discusses the challenges of scalability and security concerns. Based on the literature showed in this article, we believe that the use of BCT in smart governance could significantly enhance citizen participation and help manage and deliver public services, paving the way for more effective decision-making processes and improved quality of life for citizens.
This review article explores the potential of blockchain technology (BCT) as a key enabler for fostering transparency, trust, and citizen engagement in smart governance within smart cities. By ...examining the benefits of BCT in various aspects of smart city systems, such as data security and privacy, the paper highlights the advantages of implementing consortium blockchain architecture and the Proof of Authority (PoA) consensus algorithm and discusses the challenges of scalability and security concerns. Based on the literature showed in this article, we believe that the use of BCT in smart governance could significantly enhance citizen participation and help manage and deliver public services, paving the way for more effective decision-making processes and improved quality of life for citizens.
This review article explores the potential of blockchain technology (BCT) as a key enabler for fostering transparency, trust, and citizen engagement in smart governance within smart cities. By ...examining the benefits of BCT in various aspects of smart city systems, such as data security and privacy, the paper highlights the advantages of implementing consortium blockchain architecture and the Proof of Authority (PoA) consensus algorithm and discusses the challenges of scalability and security concerns. Based on the literature showed in this article, we believe that the use of BCT in smart governance could significantly enhance citizen participation and help manage and deliver public services, paving the way for more effective decision-making processes and improved quality of life for citizens.
The gold standard for typing at the allele level of the highly polymorphic Human Leucocyte Antigen (HLA) gene system is sequence based typing. Since sequencing strategies have mainly focused on ...identification of the peptide binding groove, full-length sequence information is lacking for >90% of the HLA alleles. One of the goals of the 17th IHIWS workshop is to establish full-length sequences for as many HLA alleles as possible. In our component “Extension of HLA sequences by full-length HLA allele-specific hemizygous Sanger sequencing” we have used full-length hemizygous Sanger Sequence Based Typing to achieve this goal. We selected samples of which full length sequences were not available in the IPD-IMGT/HLA database. In total we have generated the full-length sequences of 48 HLA-A, 45 -B and 31 -C alleles. For HLA-A extended alleles, 39/48 showed no intron differences compared to the first allele of the corresponding allele group, for HLA-B this was 26/45 and for HLA-C 20/31. Comparing the intron sequences to other alleles of the same allele group revealed that in 5/48 HLA-A, 16/45 HLA-B and 8/31 HLA-C alleles the intron sequence was identical to another allele of the same allele group. In the remaining 10 cases, the sequence either showed polymorphism at a conserved nucleotide or was the result of a gene conversion event. Elucidation of the full-length sequence gives insight in the polymorphic content of the alleles and facilitates the identification of its evolutionary origin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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