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  • 1
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    Dynamic Changes in the Clonal Structure of MDS and AML in Response to Epigenetic Therapy
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 610-610
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 610-610
    Abstract: Hematopoietic cells from patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) contain gene mutations that are variably distributed between the founding clone and daughter subclone(s). Traditional response criteria in MDS and AML are based on bone marrow morphology and may not accurately reflect antitumor activity and clinical benefit in patients treated with hypomethylating agents. We used digital sequencing of serial bone marrow samples to monitor tumor burden and to characterize the changes in the clonal structure of MDS and AML that occur during treatment with epigenetic therapy. We hypothesized that digital sequencing may provide an alternative measure of antitumor activity and identify the persistence or emergence of resistant clones during treatment which mediate disease relapse. We conducted a phase I/II study in older adults (age ≥ 60) with advanced MDS (IPSS ≥ 1.5) or AML. Subjects received a combination of decitabine 20 mg/m2 on d1-5 with the histone deacetylase inhibitor, panobinostat 10-40 mg po 3x/week every 28 days for up to 12 cycles. Serial bone marrow samples were collected for digital sequencing at baseline, after every 2 cycles of treatment and at the time of relapse. A total of 52 patients, 14 with MDS and 38 with AML were enrolled in this study. For AML patients, 10% achieved a complete remission (CR+CRi) with an additional 18% of patients achieving a morphologic leukemia-free state (mLFS) using IWG response criteria. For patients with MDS, 14% achieved a CR and 21% achieved a marrow CR. We identified 9 MDS and 16 AML patients that had banked, paired bone marrow and skin (as a source of normal DNA) samples and a somatic mutation in at least 1 of 54 recurrently mutated MDS/ AML genes. DNA was enriched for 285 genes commonly mutated in MDS and AML (n=24 patients) or whole exome probes spiked-in with the 285 genes (enhanced exome sequencing; EES) (n=7 patients), and sequenced on a HiSeq2000 instrument with 2x101bp reads. We detected an average of 4.9 SNVs and indels per patient (range 1-15) when only the 285 gene panel was used, compared to 27.4 mutations per patient (range 9-43) using EES. Ten genes were mutated in at least 3 pre-study samples. The presence of a TP53 mutation (N=8) was associated with a trend towards achieving a response (p=0.09). We then analyzed variant allele frequencies (VAF) of mutations in serial samples. We observed five distinct patterns that were associated with different clinical responses, including i) AML patients achieving a CR+CRi (n=2): mutation VAFs were undetectable by cycle 2 using standard sequencing, ii) AML with mLFS (n=2): mutation VAFs remained detectable but decreased to 〈 10%, iii) MDS with CR/cCR+mCR (n=3): mutation VAFs decreased to 〈 10% and were intermittently below the level of detection, iv) MDS with stable disease (n=2): mutation VAFs decreased but some remained 〉 10%, and v) AML with treatment failure (n=5): mutation VAFs were essentially unchanged and remained 〉 30%. We observed responding patients can have persistent measurable clonal hematopoiesis for at least one year without disease progression. Sequencing also revealed selective AML subclone clearance in a patient with treatment failure, nominating a set of mutations that may mark super-responder clones. We observed that the blast percentage decreases prior to mutation VAFs in some patients, suggesting that the differentiation of blasts could falsely underestimate tumor burden. Finally, sequencing revealed that tumor burden can be measured even in patients achieving a CR. Using an ultra-sensitive barcode sequencing approach, we sequenced 1 MDS and 1 AML patient achieving a clinical and molecular CR (based on standard sequencing). We detected extremely rare TP53 mutations months to years prior to disease relapse (VAFs = 0.23% in MDS and 0.05% in AML during a CR - equivalent to a sensitivity of 1 in 2000 heterozygous mutant cells). While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone drives relapse or progression from MDS to secondary AML. Digital sequencing provides an alternative measure of disease response which may augment traditional clinical response criteria and should be explored in future clinical trials. Disclosures Uy: Novartis: Research Funding. Off Label Use: Panobinostat in MDS/AML. Duncavage:Cofactor Genomics: Consultancy; DI & P Consulting: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy. Abboud:Teva Phamaceutical: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.610.610
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 2
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    Patient-Reported Outcomes from a Global Phase 3 Randomized Controlled Trial of Inotuzumab Ozogamicin Versus Standard of Care Chemotherapy for Relapsed/Refractory Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 1599-1599
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1599-1599
    Abstract: Background: Inotuzumab Ozogamicin (InO), an anti-CD22 antibody-calicheamicin conjugate, has demonstrated superior clinical activity versus standard of care (SOC; intensive chemotherapy) for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in the phase 3 INO-VATE trial (Kantarjian. N Engl J Med. June 12, 2016 [E-pub]). A previous intent-to-treat (ITT) analysis of patient-reported outcomes (PROs) in 279 randomized patients demonstrated that InO is associated with generally better quality of life (QoL), functioning, and symptoms versus SOC (Kantarjian. J Clin Oncol 34, 2016 [abstract 7027] ; data cutoff date, October 2, 2014). Herein, updated PROs results from 326 randomized patients are presented (data cutoff date, March 8, 2016; median follow-up, 6.6 [range, 0.03-39.75] months; long-term safety follow-up is ongoing). Methods: Patients were randomized to InO (max 1.8 mg/m2/cycle [≤6 cycles]) or SOC (fludarabine/cytarabine [ara-C] /granulocyte colony-stimulating factor, ara-C + mitoxantrone, or high-dose ara-C [≤4 cycles]) and completed the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) and the EuroQoL 5 Dimensions questionnaire (EQ-5D) Index and EQ visual analogue scale (EQ-VAS) at baseline, day 1 of each cycle, and end of treatment. Treatment differences in PRO measures over time were assessed in the ITT populationusing longitudinal mixed-effects models with random intercepts and slopes with treatment, time, treatment-by-time interaction, and baseline scores as covariates. Analyses were supportive and no multiplicity adjustments were made. Results: EORTC QLQ-C30 completion rates in patients receiving InO and SOC who completed ≥1 question were 85% and 65%, respectively; EQ-5D completion rates were similar. Baseline PRO scores were in general comparable for InO (n=164) and SOC (n=162) arms (eg, mean [SE] EORTC QLQ-C30 Global Health Status/QoL, 56.51 [2.06] vs 55.24 [2.18]; Physical, 73.69 [1.78] vs 73.48 [2.08], Role, 57.17 [2.67] vs 62.36 [2.97], Social functioning, 62.03 [2.52] vs 55.16 [3.17]; Appetite loss, 20.97 [2.31] vs 21.84 [2.62]; Dyspnea, 20.53 [2.34] vs 22.13 [2.55]; Fatigue, 40.84 [2.08] vs 40.23 [2.46]; EQ-5D Index, 0.77 [0.01] vs 0.76 [0.02]; EQ-VAS, 59.79 [2.12] vs 62.27 [2.03]). Compared with SOC, patients receiving InO reported numerically better QoL, functioning, and symptom scores (except for Constipation and Emotional functioning). After adjusting for baseline scores, as well as treatment, time, and treatment-by-time interaction, least squares mean [95% CI] differences in Physical, Role, Social functioning, and Appetite loss were statistically significant (6.9 [1.4-12.3], 11.4 [3.2-19.5] , 8.4 [0.7-16.1], -8.7 [-16.0, -1.4] , respectively; P 〈 0.05); and exceeded 5 (generally considered the minimally important difference [MID] to be clinically meaningful) (Figure). Mean treatment differences in favor of InO inEQ-VAS and Global Health Status/QoL, dyspnea, and fatigue reached or were close to the MID of 5, although without statistical significance. There was no dimension that was clinically significantly worse in patients receiving InO compared with those receiving SOC. Conclusion: This updated analysis of PROs from the phase 3 INO-VATE trial with the full ITT population (n=326) adds to earlier findings based on a smaller ITT population that the superior clinical activity of InO versus SOC in patients with relapsed/refractory ALL is accompanied by generally better patient-reported QoL, functioning, and symptoms. Patients receiving InO were observed to have significantly better appetite, are significantly more ambulatory, and experience significantly less impact on family and social life. They were also observed to be significantly more able to perform strenuous activities, basic living needs, work, other daily activities, hobbies, and other leisure activities. These data support the favorable qualitative benefit risk ratio of InO for R/R ALL treatment, with superior clinical efficacy that does not compromise patients' QoL. Figure Figure. Disclosures Su: Pfizer: Employment, Equity Ownership; Bristol Myers Squibb: Equity Ownership. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Bhattacharyya:Pfizer Inc: Employment, Equity Ownership. Yan:Pfizer Inc: Employment, Equity Ownership. Shapiro:Pfizer Inc: Employment, Equity Ownership. Cappelleri:Pfizer Inc: Employment, Equity Ownership. Marks:Pfizer Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.1599.1599
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 3
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    Signaling Gene Mutations Are Characterized By Diverse Patterns of Expansion and Contraction during Progression from MDS to Secondary AML
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 2-3
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 2-3
    Abstract: Background: Previous studies indicate that mutations in signaling (e.g., receptor tyrosine kinases and RAS pathway members) and transcription factor genes are more common in secondary acute myeloid leukemia (sAML) than myelodysplastic syndrome (MDS), suggesting a role in disease progression. However, our understanding of the timing and order of mutation acquisition in these genes remains incomplete without analyzing paired MDS and sAML samples from the same patient. Defining the role of signaling gene mutations during progression should provide biologic insight into clonal evolution and help define prognostic markers for MDS progression. Methods: We banked paired MDS and sAML (and matched skin) samples from 44 patients (median time to progression: 306 days, range 21-3568). We sequenced 44 sAML (+ skin) samples for 285 recurrently mutated genes (RMGs) and 12 samples were selected for enhanced whole genome sequencing (eWGS, genome with deep exome coverage) of MDS and sAML samples (+ skin) to determine clonal hierarchy. Somatic mutations in these 12 samples were validated with high coverage error-corrected sequencing, and clonality was defined in MDS and sAML samples using mutation variant allele frequencies (VAFs). Additionally, error-corrected sequencing for all sAML RMG mutations, plus 40 additional genes, was performed on 43 of the MDS samples. Single cell DNA sequencing (scDNAseq, Mission Bio) was performed on 6 samples. Results: We identified 32 signaling gene mutations in 15 of the 44 sAML samples, with only 11 of 32 mutations (34%) detected in the initial, paired MDS sample (limit of detection; & lt;0.1% VAF). This was significantly less than the percentage of sAML transcription factor gene mutations present at MDS (17 of 23, 74%, p=0.006). We used eWGS data to define clonal hierarchies for 12 patients, and found that both signaling and transcription factor gene mutations were in subclones (9 of 9, and 7 of 8 clones, respectively), with signaling gene mutations occurring as terminal events during clonal evolution. Finally, 8 of 9 subclones with signaling gene mutations expanded at progression. Together, the data confirm that both signaling and transcription factor mutations occur in subclones, but with a preferred order of mutation acquisition. We next asked if low-level ( & lt;1% VAF) signaling gene mutations were present in MDS samples. Using error-corrected sequencing, we identified 22 signaling gene mutations that were present at MDS and absent at sAML (avg VAF: 0.8%; range 0.05%-11.7%). Combined with sAML-defined signaling genes, 33 total signaling gene mutations were detected at MDS in 19 patients, but only 11 (33%) were present after progression. We observed 5 distinct patterns of clonal evolution for signaling genes: 1) MDS mutations persist and expand at sAML (n=6), 2) ≥2 mutations are present at MDS, at least one mutation persists (and expands) and another contracts at sAML (n=4), 3) MDS mutations contract and a new mutation emerges at sAML (n=2), 4) MDS mutations collapse at sAML (n=7), and 5) no MDS mutations, but ≥1 mutation emerges at sAML (n=5). These diverse patterns of clonal evolution suggest that MDS cells undergo strong selective pressure to acquire a signaling gene mutation, but only mutations in the correct context contribute to progression. Finally, we observed that several MDS (n=6) and sAML (n=10) samples had multiple signaling gene mutations, and it was not always clear whether they occurred in the same subclone. We performed scDNAseq of 6 sAML samples with multiple signaling gene mutations (2-4/case). In 5 of 6 cases the signaling gene mutations did not occur in the same subclone. One sample contained 2 subclones with a NRAS and a PTPN11 mutation, with a separate subclone harboring an additional NRAS mutation. In sum, the co-occurrence of two signaling gene mutations in the same subclone is rare, indicating that the presence of multiple signaling gene mutations may be functionally redundant or detrimental to leukemia cells. Conclusions: Rare cells containing signaling gene mutations are present in nearly half of MDS patients who progress to sAML. The high frequency of signaling gene mutations and diverse patterns of clonal evolution (including the loss of one mutation and acquisition of another), suggest that signaling genes are a major driver of progression to sAML. The paucity of subclones with multiple signaling gene mutations suggests a therapeutic vulnerability for mutant cells. Disclosures DiPersio: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Jacoby:AbbVie: Research Funding; Jazz Pharmaceuticals: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-140394
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 4
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    The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism
    American Society of Hematology ; 2016
    In:  Blood Vol. 127, No. 25 ( 2016-06-23), p. 3215-3224
    Details
    In: Blood, American Society of Hematology, Vol. 127, No. 25 ( 2016-06-23), p. 3215-3224
    Abstract: Venetoclax potently induces rapid onset apoptosis of CLL cells in vitro and in vivo, independently of TP53 function. Objective responses in patients with del(17p) and/or TP53-mutated CLL are as deep as patients with no perturbation of TP53.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2016-01-688796
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 5
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    Dynamic Changes in MDS Clonal Architecture Following Allogeneic Stem Cell Transplant
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 5506-5506
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5506-5506
    Abstract: Background: MDS is a genetically complex, oligoclonal disease consisting of a founding clone and typically one or more subclones derived from the founding clone. Previously we have shown that in MDS patients treated with chemotherapy, a minor subclone present at diagnosis can expand during disease progression from MDS to secondary AML, highlighting the clinical implications of clonal heterogeneity. Whether a similar pattern of clonal evolution occurs in MDS patients that relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) is not known. Methods: We identified 9 MDS patients who progressed after receiving either a myeloablative (n=3) or reduced-intensity (n=6) alloHSCT (median time to progression 309 days, range 98-881). We performed enhanced exome sequencing (EES) to define the clonal architecture of 23 tumor samples at the following clinical landmarks (with matched skin as a source of normal DNA): diagnosis, 〈 2 months pre-alloHSCT (where available), and relapse post-alloHSCT. Somatic mutations were validated in the 23 discovery samples and genotyped in 35 additional serial banked samples at various time-points post-alloHSCT, including day 30 and 100, using capture probes targeting all putative single-nucleotide variants (SNV) and short insertions and deletions (INDELs) identified by EES. The variant allele fraction (VAF) of all validated somatic mutations was determined. Ultra-deep, error-corrected sequencing (i.e., barcoded sequencing) was performed on 49 tumor samples to provide increased sensitivity to detect low-level mutations post-alloHSCT. Copy number alterations were identified using exome and SNP array data. Results: Averaged sequencing coverage depth was 246x for tumors subjected to EES; 537x for validation sequencing, and 24,150x total and 5,180x unique for the ultra-deep sequencing. In all cases, we observed that mutations found in the diagnostic founding clone were always detected at relapse. However, using SNVs, INDELs, and copy number analysis, we show that the dominant clone at relapse was often derived from a population that was subclonal at presentation. We observed the following, non-mutually exclusive patterns of clonal evolution at relapse: i) A subclone expanded or emerged and became the dominant clone at relapse as compared to presentation (n=6). In 2 of these cases, the subclone contained mutations that were not detected at presentation even via ultra-deep sequencing. ii) A subclone was cleared with alloHSCT (defined as VAF 〈 1% by EES, n=4), confirmed by ultra-deep sequencing when available (n=2). iii) The founding/dominant clone at diagnosis was also the dominant clone at relapse (n=3). However, in 2 of these 3 cases, changes in clonal architecture were observed with evidence of rising or contracting subclones. Although our sample size is relatively small, the intensity of the alloHSCT conditioning regimen did not impact the relapse pattern. No acquired abnormalities were detected in the MHC locus, and no mutations in a particular gene family or cellular pathway were consistently observed in rising or contracting subclones. Finally, we used ultra-deep sequencing to determine if mutations (i.e., tumor cells) could be detected at day 30 post-alloHSCT in 7 of the 8 patients with no evidence of disease, who had available data. Mutations were detected in 6 of 7 patients. The average detectable mutation VAF per patient was 0.37% (ranged from 0.04% to 0.93%)(i.e., 1 mutant cell in 135). Conclusion: Complex clonal dynamics and clonal evolution are observed at relapse post-alloHSCT for MDS. Although minor subclones rise and may become the dominant clone at relapse, mutations present in the dominant (i.e., founding) clone of the diagnostic MDS sample pre-alloHSCT are always detected at relapse. This is similar to the pattern of clonal evolution previously observed for MDS progression to secondary AML following chemotherapy. These observations have implications for targeted therapy and tumor burden monitoring. Ultra-deep sequencing can detect persistent or emerging mutations at early time-points post-alloHSCT that are associated with subsequent relapse. The predictive value of detecting persistent mutations early after post-alloHSCT merits testing in future studies. Disclosures Jacoby: Quintiles: Consultancy; Sunesis: Research Funding; Celgene: Speakers Bureau. DiPersio:Incyte Corporation: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.5506.5506
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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