WO2017070497A1 - Procédés et compositions pour utiliser des mutations conductrices dans la llc - Google Patents

Procédés et compositions pour utiliser des mutations conductrices dans la llc Download PDF

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WO2017070497A1
WO2017070497A1 PCT/US2016/058164 US2016058164W WO2017070497A1 WO 2017070497 A1 WO2017070497 A1 WO 2017070497A1 US 2016058164 W US2016058164 W US 2016058164W WO 2017070497 A1 WO2017070497 A1 WO 2017070497A1
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del
cll
mutations
subject
cnv
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PCT/US2016/058164
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Catherine Ju-ying WU
Dan-avi LANDAU
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Dana-Farber Cancer Institute, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer

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  • the present invention provides methods for treatment and prognosis of chronic lymphocytic leukemia (CLL) using novel cancer driver mutations.
  • CLL chronic lymphocytic leukemia
  • composition of the cohort of prior WES studies has limited the ability to accurately determine the impact of drivers and clonal heterogeneity on clinical outcome since they included samples collected at variable times from subjects exposed to a variety of therapies. Understanding the genetic alterations that drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Thus, identifying novel cancer drivers is necessary to improve treatment and diagnosis of CLL.
  • Applicants analyzed WES data from 538 CLLs, including 278 pre- treatment samples collected from subjects enrolled on the phase III CLL8 study 13 .
  • This trial established the combination of fludarabine (F), cyclophosphamide (C) and rituximab (R) as the current standard-of-care first-line treatment for patients of good physical fitness, with a median of >6 years of follow-up.
  • Applicants discovered novel CLL cancer genes, performed a comprehensive genetic characterization of samples from patients prior to exposure to a uniform and contemporary treatment, and uncovered features contributing to relapse from this therapy.
  • the present invention provides for a method of treating chronic lymphocytic leukemia (CLL) in a subject in need thereof comprising identifying the presence of gene mutations and somatic copy number variations (CNV) in a genomic DNA sample obtained from the subject, wherein the mutated genes and somatic copy number variations (CNV) comprise del(13q), SF3B1, A TM, del(llq), tril2, TP53, NOTCH 1, POT1, amp(2p), del(17p), CHD2, XPOl, RPS15, BIRC3, BRAF, IGLL5, d l(8p), MGA, MYD88, del(6q21), EGR2, FBXW7, ampfSq), DDX3X, KRAS, BCOR, IKZF3, MAP2K1, ZMYM3, IRF4, SAMHD1, BAZ2A, CARD!
  • CLL chronic lymphocytic leukemia
  • the patient may have stage 0, 1, II, III, or IV CLL.
  • the method is performed before a patient has symptoms. The method may be performed before treatment, during treatment, or after treatment.
  • the method may be performed when the patient is in remission.
  • the presence of mutations in NRAS, KRAS, BRAF, and/or MAP2K1 may indicate treating with an inhibitor of the MAPK-ERK pathway.
  • the mutation in BRjiF may be a mutation that is not the canonical V600E mutation. In this instance the treatment may include a MEK inhibitor and would not indicate the use of a BRAF inhibitor.
  • the presence of mutations in RPS15 may indicate an adverse outcome and the subject is treated with an alternative treatment regimen.
  • the presence of mutations in IKZF3 may indicate an adverse outcome and the subject is treated with an alternative treatment regimen.
  • the mutation in IKZF3 may be an L162R substitution.
  • the presence of mutations in delflSq), MYD88, and/ or ( 7/7/2 may indicate decreased clinical aggressiveness.
  • the presence of mutations in TP53, SF3B1 and/or XPOl may indicate shorter progression-free survival (PFS) and overall survival (OS).
  • the genomic DNA sample may be obtained prior to treatment by any methods known in the art. Not being bound by a theory, obtaining the sample prior to treatment allows the detection of the mutations or alterations in copy number of the present invention in clonal and subclonal populations of cells present in a cancer cell fraction (CCF) before treatment. Identification of mutations or alterations in copy number can be used to predict resistence to a treatment and efficacy of a treatment.
  • the method may further comprising determining mutations in IGHV, wherein the presence of unmutated IGHV indicates increased clinical aggressiveness and the presence of mutated IGHV indicates decreased clinical aggressiveness.
  • the present invention provides for a method of determining whether a subject having chronic lymphocytic leukemia (CLL) would derive a clinical benefit of early treatment comprising determining the presence of gene mutations and somatic copy number variations (CNV) in a genomic DNA sample obtained from the subject, wherein the mutated genes and somatic copy number variations (CNV) comprise del(13q), SF3B1, ATM, del(llq), trill, TPS 3, NOTCH 1, POT1, amp(2p), del(17p), CHD2, XPOl, RPS15, BIRC3, BRAF, IGLL5, del(8p), MGA, MYD88, del(6q21), EGR2, FBXW7, amp(8q), DDX3X, KRAS, BCOIi IKZF3, MAP2K1, 7MYM3, IRF4, SAMHD!, BAZ2A, CARDIl, FUBP1, HISTIH!E,
  • BRCC3, EWSR1, FAM50A, TRAF3, ASXL1, CHEK2, GNBl, HISTIHIB, and P!Ml wherein the presence of a mutated gene and/or somatic copy number variation (CNV) indicates that the subject would derive a clinical benefit of early treatment
  • the present invention provides for a method of predicting survivability of a subject having chronic lymphocytic leukemia (CLL) comprising determining the presence of gene mutations and somatic copy number variations (CN V) in a genomic DN A sample obtained from the subject, wherein the mutated genes and somatic copy number variations (CNV) co pnsQdeI(I3q), SF3B1, ATM, del(l lq), trill, TP53, NOTCH!, POT1, amp(2p), del(17p), CIID2, XPOl, RPS15, BIRC3, BRAF, IGLL5, del(8p), MGA, MYD88, del(6q21), EGR2, FBXW7, amp(8q), DDX3X, KRAS, BCOR, IKZF3, MAP2K1, 7MYM3, IRF4, SAMHD!, BAZ2A, CARDIl, FlJBPl, HI
  • CLL chronic lympho
  • the present invention provides for a method of identifying a candidate subject for a clinical trial for a treatment protocol for chronic lymphocytic leukemia (CLL) comprising determining the presence of gene mutations and somatic copy number variations (CNV) in a genomic DNA sample obtained from the subject, wherein the mutated genes and somatic copy number variations (CNV) comprise del(13q), SF3B1, ATM, del/1 Iq), trill, TP 53, NOTCH!, POT I, amp(lp), deI(T7p), CHD2, XPOl, RPS15, B1RC3, BRAF, IGLL5, del(8p), MGA, MYD88, deMqll), EGR2, FBXW7, mpfSq), DDX3X, KRAS, BCOR, IKZF3, MAP1K1, ZMYM3, IRF4, SAMHD1, BAZ1A, CARDll, FUBPl, H1ST1H1E,
  • the present invention provides for a method of detecting chronic lymphocytic leukemia (CLL) in a subject comprising determining the presence of gene mutations and somatic copy number variations (CNV) in a genomic DNA sample obtained from the subject, wherein the mutated genes and somatic copy number variations (CNV) comprised?/ ⁇ ), SF3B1, Am, del/1 Iq), tnl2, TP 53, NOTCH 1, POT1, amp(2p), del(17p), CHD2, XPOl, RPSI5, BIRC3, BRAF, IGLL5, del(8p), MGA, MYD88, del(6q2l), EGR2, FBXW7, ⁇ , DDX3X, KRAS, BCOR, IKZF3, MAP2K1, ZMYM3, IRF4, SAMHD1, BAZ2A, CARDll, FUBPl, HISTIHIE, MED 12, NRAS, NXFI, del
  • CLL chronic lympho
  • the present invention provides for a method of identifying a subject at elevated risk of having CLL with rapid disease progression comprising: (a) analyzing genomic DNA in a sample obtained from a subject having or suspected of having chronic lymphocytic leukemia (CLL) for the presence of gene mutations and somatic copy number variations (CNV), wherein the mutated genes and somatic copy number variations (CNV) comprise£fe/ ⁇ 733 ⁇ 4), .SV- ' .?/>7, A TM, del(llq), tril2, TP53, NOTCH 1, POT I, amp(lp), del(l7p), CHDl, XPOl, RPS15, BIRC3, BRAF, IGLL5, del(8p), MGA, MYD88, deUfiqll), EGRl, FBXW7, amp(8q), DDX3X, KRAS, BCOR, IKZF3, MA 2 h i, ZMYM3, T
  • the method may further comprise treating a subject for CLL identified as a subject at elevated risk of having CLL with rapid disease progression.
  • Any of the methods may include determining mutations in more than one risk allele. Any of the methods may be repeated every month, 2 months, 3 months, 4 months, five months, 6 months 8 months, or one year or at any time where there is a change in clinical status.
  • the genomic DNA sample may be obtained from peripheral blood, bone marrow, or lymph node tissue.
  • the genomic DNA may be analyzed using whole genome sequencing (WGS), whole exome sequencing (WES), single nucleotide polymorphism (SNP) analysis, deep sequencing, targeted gene sequencing, hybridization to an array, or any combination thereof.
  • Clonal or subdorsal mutations, CNV's and/or populations of cells may be detected using whole genome sequencing (WGS), whole exome sequencing (WES), single nucleotide polymorphism (SNP) analysis, deep sequencing, targeted gene sequencing, hybridization to an array, or any combination thereof
  • WGS whole genome sequencing
  • WES whole exome sequencing
  • SNP single nucleotide polymorphism
  • the gene mutation may be a missense mutation, frameshift indel, inframe indel, splice site mutation, or nonsense mutation.
  • Figure 1 The landscape of putative driver gene mutations and recurrent somatic copy number variations in CLL. Somatic mutation information is shown across the 55 putative driver genes and recurrent sCNVs (rows) for 538 primary patient samples (from CLL8 [green], Spanish ICGC [red], DFCI/Broad [blue]) that underwent WES (columns). Blue labels- recurrent sCNVs; Bold labels- putative CLL cancer genes previously identified in Landau et al. 3 ); asterisked labels- additional cancer genes identified in this study. Samples were annotated for IGHV status (black-mutated, white-unmutated; red-unknown), and for exposure to therapy prior to sampling (black-prior therapy; white - no prior therapy; red-unknown prior treatment status).
  • Figure 2 Selected novel putative driver gene maps. Individual gene mutation maps for select putative drivers, showing mutation subtype (e.g., missense), position and evidence of mutational hotspots, based on COSMIC database information (remaining gene maps shown in Extended Data Fig. 4).
  • FIG. 3A-3B Inferred evolutionary history of CLL.
  • A. The proportion in which a recurrent driver is found as clonal or subclonal across the 538 samples is provided (top), along with the individual cancer cell fraction (CCF) values for each sample affected by a driver (tested for each driver with a Fisher's exact test, comparing to the cumulative proportions of clonal and subclonal drivers excluding the driver evaluated). Median CCF values are shown (bottom, bars represent the median and IQR for each driver),
  • B. Temporally direct edges are drawn when two drivers are found in the same sample, one in clonal and the other in subclonal frequency.
  • edges are used to infer the temporal sequences in CLL evolution, leading from early, through intermediate to late drivers. Note that only driver pairs with at least 5 connecting edges were tested for statistical significance and only drivers connected by at least one statistically significant edge are displayed (see Methods, and Supplementary Table 7).
  • FIG. 4A-4B Associations of CLL drivers with cli ical outcome.
  • A Kaplan- Meier analysis (with logrank values) for putative drivers with associated impact on progression free survival (PFS) or overall survival (OS) in the cohort of 278 patients that were treated as part of the CLLS trial.
  • PFS progression free survival
  • OS overall survival
  • B Presence of a subclonal driver is associated with shorter PFS, in both the FC and FCR arms, and a trend towards shorter OS.
  • FIG. 5A-5C Matched pre-treatment and relapse samples reveal patterns of clo al evolution in relation to therapy, A. The number and proportion of the patterns of clonal evolution of CLLs studied at pre-treatment and at relapse.
  • B Selected plots of 2D clustering of pre-treatment and relapse cancer cell fraction (CCF) demonstrating clonal stability of tri(12) (CLL case: GCLL115), concordant increase in CCFs of TP53 and del(ll ⁇ ) (GCLL27), clonal shifts in ATM sSNVs in a sample with clonally stable monoallelic deletion of A TM (GCLL307).
  • CCF cancer cell fraction
  • Extended Data Figure I Candidate CLL cancer genes discovered in the combined cohort of 538 primary CLL samples. Significantly mutated genes identified in 538 primary CLL. Top panel: the rate of coding mutations (mutations per megabase) per sample. Center panel: Detection of individual gene found to be mutated (sSNVs or sINDELs) in each of the 538 patient samples (columns), color-coded by type of mutation. Only one mutation per gene is shown if multiple mutations from the same gene were found in a sample. Right panel: Q- values (red: Q ⁇ 0.1; purple dashed: Q ⁇ 0.05) and Hugo Symbol gene identification.
  • New candidate CLL genes are marked with asterisks (*)
  • Left panel The percentages of samples affected with mutations (sSNVs and sINDELs) in each gene.
  • Bottom panel plots showing allelic fractions and the spectrum of mutations (sSNVs and sINDELs) for each sample.
  • Extended Data Figure 2 Cellular networks and processes affected by putative CLL drivers.
  • Putative CLL cancer genes cluster in pathways that are central to CLL biology such as Notch signaling, inflammatory response and B cell receptor signaling.
  • proteins that participate in central cellular processes such as DNA damage repair, chromatin modification and mRNA processing, export and translation are also recurrently affected. Boxed in yellow— new CLL subpathways highlighted by the current driver discovery effort. Red circles- putative driver genes previously identified 3 , purple circles- newly identified in the current study,
  • Extended Data Figure 3A-3B RNAseq expression data for candidate CLL genes and targeted candidate driver validation.
  • Applicants subsequently counted the number of instances in which a mutation was detected ⁇ 'detected') and compared it to the number of instances in which mutation detection had >90% power based on the allelic fraction in the WES and the read depth in the RNAseq data powered'). Overall, Applicants detected 78.1% of putative CLL gene mutations at sites that had >90% power for detection in RNAseq data B.
  • Targeted orthogonal validation accession Analysis, Fluidigm
  • Extended Data Figure 4A-4V Gene mutation maps for candidate CLL genes. Individual gene mutation maps are shown for all newly identified candidate CLL cancer genes not included in Fig. 2, The plots show mutation subtype (e.g., missense, nonsense etc) and position along the gene.
  • Extended Data Figure 5 CLL copy number profiles. Copy number profile across 538 CLLs detected from WES data from primary samples (see Methods).
  • Extended Data Figure 6A-6D Annotation of drivers based on clinical characteristics and co-occurrence patterns.
  • B Putative drivers affecting greater than 10 patients were assessed for enrichment in samples that received therapy prior to sampling (Fisher's exact test). Putative drivers affecting greater than 10 patients were tested for co-occurrence. Significantly high (C) or low (D) co-occurrences are shown (Q ⁇ 0. ⁇ , Fisher's exact test with BH FDR, after accounting for pri or therapy and IGHV mutation status, see Methods).
  • Extended Data Figure 7 Mutation spectrum analysis, clonal vs. subclonal sSNVs, The spectrum of mutation is shown for the clonal and subclonal subsets of coding somatic sSNVs across WES of 538 samples. The rate is calculated by dividing the number of trinucleotides with the specified sSNVs by the covered territory containing the specified trinucleotide. Both clonal and subclonal sSNVs were similarly dominated by C>T transitions at C*pG sites.
  • this mutational process that was previously associated with aging 39 , not only predates oncogenic transformation (since clonal mutations will be highly enriched in mutations that precede the malignant transformation 40 ), but also is the dominant mechanism of malignant diversification after transformation in CLL.
  • Extended Data Figure 8 The CLL driver landscape in the CLL8 cohort. Somatic mutation information shown across the 55 candidate CLL cancer genes and recurrent sCNVs (rows) for 278 CLL samples collected from patients enrolled on the CLLS clinical trial primary that underwent WES (columns). Recurrent sCNA labels are listed in blue, and candidate CLL cancer genes are listed in bold if previously identified in Landau et & ⁇ . and with an asterisk (*) if newly identified in the current study.
  • Extended Data Figure 9 CLLS patient cohort clinical outcome (from 278 patients) information by CLL cancer gene. Kaplan-Meier analysis (with logrank P values) for putative drivers not associated with significant impact on progression free survival (PFS) or overall survival (OS) in the cohort of 278 patients that were treated as part of the CLLS trial . For candidate CLL genes tested here for the first time regarding impact on outcome, a Bonferroni P value is also shown.
  • Extended Data Figure 10 Comparison of pre-treatment and relapse cancer cell fraction (CCF) for non-silent mutations in candidate CLL genes across 59 CLLs.
  • CCF cancer cell fraction
  • CCF increases (red), decreases (blue) or stable (grey) over time are shown (in addition to CLL genes shown in Figure 6).
  • a significant change in CCF over time (red or blue) was determined if the 95%CI of the CCF in the pre-treatment and relapse samples did not overlap.
  • the term "therapeutic effect” refers to some extent of relief of one or more of the symptoms of a disorder (e.g., a neoplasia or tumor) or its associated pathology.
  • “Therapeutically effective amount” as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the cell or subject, in prolonging the survivability of the patient with such a disorder, reducing one or more signs or symptoms of the disorder, preventing or delaying, and the like beyond that expected in the absence of such treatment.
  • “Therapeutically effective amount” is intended to qualify the amount required to achieve a therapeutic effect.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the "therapeutically effective amount" (e.g., ED50) of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in a pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • clinical aggressiveness refers to the average aggressiveness of a cancer. Increased clinical aggressiveness refers to a cancer that is more aggressive as compared to the average.
  • a "CLL driver” is any mutation, chromosomal abnormality, or altered gene expression, that contributes to the etiology, progression, severity, aggressiveness, or prognosis of CLL.
  • a CLL driver is a mutation that provides a selectable fitness advantage to a CLL cell and facilitates its clonal expansion in the population.
  • CLL driver may be used interchangeably with CLL driver event and CLL driver mutation.
  • CLL driver mutations occur in genes, genetic loci, or chromosomal regions which may be referred to herein interchangeably as CLL risk alleles, CLL alleles, CLL risk genes, CLL genes, CLL-associated genes and the like.
  • staging of chronic lymphocytic leukemia is used to determine treatment of a subject in need thereof.
  • Any CLL staging system may be used.
  • the Rai staging system and the Binet classification are exemplary systems that may be used in the present invention (Rai KR, et al.: Clinical staging of chronic lymphocytic leukemia. Blood 46 (2): 219-34, 1975; Binet JL, et al. : A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48 (1): 198-206, 1981).
  • NCI National Cancer institute
  • the Binet classification integrates the number of nodal groups involved with the disease with bone marrow failure. Its major benefit derives from the recognition of a predominantly splenic form of the disease, which may have a better prognosis than in the Rai staging, and from recognition that the presence of anemia or thrombocytopenia has a similar prognosis and does not merit a separate stage. Neither system separates immune from nonimmune causes of cytopenia. Patients with thrombocytopenia or anemia or both, which is caused by extensive marrow infiltration and impaired production (Rai i ii/iV. Binet C) have a poorer prognosis than patients with immune cytopenias.
  • Treatments or therapeutic agents contemplated by the present disclosure include but are not limited to immunotherapy, chemotherapy, bone marrow and stem cell transplantation, and others known in the art.
  • the treatment described herein is based upon current treatments and clinical trials of treatments used to treat a patient in need thereof suffering from CLL. Doses and administration of treatments may be any regimen used. The treatment may be based on age, health, weight, sex, or ethnicity. The standard of care for the most common cancers can be found on the website of National Cancer Institute (www.cancer.gov/cancertopics). Alternative treatments of leukemia can be found at www.cancer.gov/types/leukemia/hp.
  • Standard of care is the current treatment that is accepted by medical experts as a proper treatment for a certain type of disease and that is widely used by healthcare professionals. Standard or care is also called best practice, standard medical care, and standard therapy. Standards of Care for cancer generally include surgery, lymph node removal, radiation, chemotherapy, targeted therapies, antibodies targeting the tumor, and immunotherapy. Immunotherapy can include checkpoint blockers (CBP), chimeric antigen receptors (CARs), and adoptive T-cell therapy.
  • CBP checkpoint blockers
  • CARs chimeric antigen receptors
  • patients diagnosed with stage 0, I, II, III, and IV Chronic Lymphocytic Leukemia are treated with the current standard-of-care first-line treatment.
  • This treatment may be a combination of fludarabine (F), cyclophosphamide (C) and rituximab (R).
  • alternative treatment options tested in clinical trials are used.
  • an alternative treatment of stage 0 CLL is any treatment described herein, not limited to standard treatments for stage 0 CLL.
  • the present invention provides for novel stratification of patients suffering from CLL and the stratification may indicate early treatment or observation. Early treatment may be before the appearance of symptoms.
  • the present invention may provide for delaying treatment of patients determined to have CLL. Not being bound by a theory, the absence of cancer drivers may indicate a less aggressive CLL.
  • the methods of the present invention indicate a subject is treated with a specific treatment.
  • the treatment may be different than current treatments.
  • the treatments may be the same as current treatments, but administered to a specific population identified with the methods of the present invention.
  • patients having different mutations or alterations may have a different response to a specific treatment.
  • the identification of novel cancer drivers or alterations allows a more informed treatment choice.
  • incorporation of the methods of the present invention allows for delaying treatment or providing earlier treatment as compared to the previous standard of care.
  • the identification of a novel cancer driver or alteration may indicate increased aggressiveness of a cancer.
  • the subject may have stage 0 CLL or have no symptoms, but have a mutation or alteration of the present invention, such that treatment is indicated. Early treatment of the cancer may lead to longer progression free survival and overall survival.
  • the treatment may be any treatment regimen approved or in clinical trials.
  • CLL chronic lymphocytic leukemia
  • the driver mutations of the present invention are used to determine if a patient should be treated. Not being bound by a theory, monitoring of driver mutation presence can predict spontaneous regressions.
  • the methods of the present invention allow an alternative treatment to the current standard of care for Stage 0 CLL.
  • treatment for patients grouped as Stage 0 is no treatment.
  • the French Cooperative Group on CLL randomly assigned 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for immediate treatment with chlorambucil. (Dighiero G, et al., N Engl J Med 338 (21): 1506-14, 1998).
  • a meta-analysis of six trials of immediate versus deferred therapy with chlorambucil showed no difference in overall survival at 10 years. (CLL Trialists' Collaborative Group.
  • a therapeutic effect may be achieved using the present invention to stratify patients in the clinical trial based upon the presence of cancer drivers.
  • the invention provided herein is useful in determining whether and when to start treatment.
  • treatments used to treat Stage I, II, III, and IV CLL are used to treat patients based on identification of the mutations or alterations of the present invention.
  • EFS event-free survival
  • PFS progression-free survival
  • the standard therapy begins when patients develop profound cytopenias, which are consistently indicative of advanced-stage disease, or when they become symptomatic enough that quality of life is substantially impacted, such as with enlarging bulky lymphadenopathy or debilitating symptoms.
  • the methods of the present invention allow prediction and early treatment of patients before having advanced-stage disease,
  • a patient is treated with a maximal cytoreduction strategy.
  • an alternative treatment of a CLL indicated as having an adverse outcome is treated with this strategy.
  • This strategy involves using a combination regimen to achieve a durable complete remission.
  • FCR is a popular choice for induction therapy (Haliek M, et al. : Lancet 376 (9747): 1164-74, 2010).
  • BR bovine rituxirnab
  • R-CHOP rituxirnab + cyclophosphamide + doxorubicin + vincristine plus prednisone
  • R-CVP eliminating doxorubicin from R-CHOP
  • a patient is treated with an avoidance of alkylators and purine analogues strategy.
  • the goal of this strategy is to minimize the possibility that subclones with deleterious mutations, which are subsequently resistant to further therapy, will emerge.
  • the presence of subclones having any of the driver mutations of the present invention are treated with this alternative strategy.
  • This strategy also avoids prolonged cytopenias and the recurrent, long-lasting, sometimes fatal, infections seen after therapy with these agents.
  • Initial therapy with a monoclonal antibody, such as rituxirnab (in high doses or more frequent scheduling) with or without maintenance rituxirnab, is consistent with this strategy.
  • a patient is treated with a risk-adapted therapy.
  • prognostic factors such as the mutational immunoglobulin variable region heavy chain (IgVH), 17p ⁇ , or HQ-status, were used to help inform the choice of therapy.
  • Patients with a better prognosis might receive more gentle therapy with fewer short-term and long-term side effects. This approach might also be applicable for older patients with multiple comorbidities.
  • Patients with a worse prognosis might receive combination regimens that are used for maximal cytoreduction.
  • the methods of the present invention may be used to further determine a prognosis,
  • Standard options for CLL treatment are roughly ordered by level of toxic effects, starting with the least toxic options.
  • the present invention provides for treating a patient in need thereof based on identification of cancer drivers that indicate an adverse outcome.
  • treatment is with a more toxic option.
  • the standard options include the following:
  • CLL chronic lymphocytic leukemia
  • Rituximab is a murine anti-CD20 monoclonal antibody (Mavromatis B, et ai. : J Clin Oncol 21 (9): 1874-81, 2003; O'Brien SM, et al. : J Clin Oncol 19 (8): 2165-70, 2001; Byrd JC, et al. : J Clin Oncol 19 (8): 2153-64, 2001.; Hainsworth ID, et al.: J Clin Oncol 21 (9): 1746-51 , 2003; and Castro JE, et al. : Leukemia 22 (11): 2048-53, 2008), When used alone, higher doses of rituximab or increased frequency or duration of therapy is required for comparable responses to those seen for other indolent lymphomas,
  • Ofatumomab is a human anti-CD20 monoclonal antibody (Wierda WG, et al. : J Clin Oncol 28 (10): 1749-55, 2010).
  • Obinutuzumab is a human anti-CD20 monoclonal antibody.
  • NCT01010061 781 previously untreated patients with coexisting medical problems were randomly assigned to chlorambucil and obinutuzumab versus chlorambucil and rituximab versus chlorambucil alone (Goede V, et al. : N Engl J Med 370 (12): 1101-10, 2014).
  • the median PFS was best for the obinutuzumab arm (26.7 months) versus the rituximab arm (16.3 months) versus chlorambucil alone (1 1.1 months ) (hazard ratio [HR], 0.18; 95% confidence interval [CI], 0, 13-0.24; P ⁇ .001) for obinutuzumab and chlorambucil versus chlorambucil alone; for rituximab and chlorambucil versus chlorambucil alone [HR, 0,44; 95% CI, 0.34-0.57; P ⁇ .001 ].
  • Idelalisib is an oral inhibitor of the delta isoform of the phosphatidylinositol 3- kinase, which is located in the B-cell receptor-signaling cascade.
  • NCT01539512 In a randomized, double-blind, prospective trial (NCT01539512), 220 patients treated mainly with fludarabine-based regimens and who had coexisting medical problems, such as renal dysfunction, received rituximab and idelalisib versus rituximab and placebo (Furman RR, et al: N Engl J Med 370 (11): 997-1007, 2014).
  • Ibrutinib is a selective irreversible inhibitor of Bruton tyrosine kinase, a signaling molecule located upstream in the B-eell receptor-signaling cascade. Trials of previously untreated patients and of patients with relapsed or refractory CLL showed durable responses to the oral agent in phase I and II studies (Advani RH, et al.
  • Bendamustine is a cytotoxic agent with bifunctional properties of an alkylator and a purine analog (Leoni LM, et al. : Clin Cancer Res 14 (1): 309-17, 2008). In previously treated and untreated patients, bendamustine with rituximab has shown response rates around 70% to 90% (Fischer K, et al. : J Clin Oncol 29 (26): 3559-66, 2011; and lannitto E, et al: Br J Haematol 153 (3): 351-7, 201 1).
  • bendamustine showed a better response rate (68% vs. 31%, P ⁇ .0001) and PFS (21 .6 months vs. 8 months) with a median follow-up of 35 months (Knauf WU, et al. : J Clin Oncol 27 (26): 4378- 84, 2009).
  • the German CLL Study Group compared bendamustine plus rituximab versus FCR as first-line therapy in patients with CLL who require therapy (Fischer K, et al. : J Clin Oncol 29 (26): 3559-66, 201 1).
  • Lenalidomide is an oral immunomodulatory agent with response rates over 50%, with or without rituximab, for patients with previously treated and untreated disease. Prolonged, lower-dose approaches and attention to prevention of tumor lysis syndrome are suggested with this agent (Chen CI, et al. : J Clin Oncol 29 (9): 1175-81, 201 1 ; Chanan-Khan A, et al.: J Clin Oncol 24 (34): 5343-9, 2006, Ferrajoli A, et al : Blood 111 (11): 5291-7, 2008; Strati P, et al.
  • o CVP cyclophosphamide plus vincristine plus prednisone
  • o CHOP cyclophosphamide plus doxorubicin plus vincristine plus prednisone
  • Involved-field radiation therapy Relatively low doses of radiation therapy will affect an excellent response for months or years. Sometimes radiation therapy to one nodal area or the spleen will result in abscopal effect (i.e., the shrinkage of lymph node tumors in untreated sites).
  • Alemtuzumab the monoclonal antibody directed at CD52, shows activity in the setting of chemotherapy-resistant disease or high-risk untreated patients with 17p deletion or p53 mutation (Moreton P, et al. : J Clin Oncol 23 (13): 2971 -9, 2005; Parikh SA, et al.: Blood 118 (8): 2062-8, 2011; Pettitt AR, et al. : J Clin Oncol 30 (14): 1647-55, 2012).
  • patients are treated if a cancer driver of the present invention is identified.
  • the subcutaneous route of delivery for alemtuzumab is preferred to the intravenous route in patients because of the similar efficacy and decreased adverse effects, including less acute allergic reactions that were shown in some nonrandomized reports (Pettitt AR, et al. : J Clin Oncol 30 (14): 1647-55, 2012; Stilgenbauer S, et al. : J Clin Oncol 27 (24): 3994-4001 , 2009; Cortelezzi A, et al. : Leukemia 23 (11): 2027-33, 2009; Osterborg A, et al.: Leukemia 23 (11): 1980-8, 2009, and Gritti G, et al.: Leuk Lymphoma 53 (3): 424-9, 2012).
  • Bone marrow and peripheral stem cell transplantations are alternative treatment options (Doney KC, et al.: Bone Marrow Transplant 29 (10): 817-23, 2002; Schetelig J, et al .: J Clin Oncol 21 (14): 2747- 53, 2003; Ritgen M, et al. : Blood 104 (8): 2600-2, 2004; Moreno C, et al.: J Clin Oncol 23 (15): 3433-8, 2005; houri IF, et al.
  • Autologous T-cells directed at specific antigen targets were modified by a ientiviral vector to incorporate antigen receptor specificity for the B-cell antigen CD19 and then infused into a previously treated patient (Porter DL, et al. : N Engl J Med 365 (8): 725-33, 2011). A dramatic response lasting 6 months has prompted larger trials of this concept. Ongoing clinical trials are testing the concept of T-cells directed at specific antigen targets with engineered chimeric-antigen receptors (termed CARs (Maus MV, et al. : Blood 123 (17): 2625-35, 2014).
  • the present invention provides for treatment with a MEK inhibitor.
  • a MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2. They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers.
  • the present invention provides for identification of CLL driver mutations indicating that treatment with MEK inhibitors should be performed.
  • MEK inhibitors may be Trametinib (GSK1 120212), Selumetinib (Janne, Pasi A, et al. (2013).
  • the present invention provides for novel targets for therapeutic intervention.
  • Cancer drivers may be targeted with any agent that modulates the activity or expression of the target.
  • the agent may be an antibody, a soluble polypeptide, a polypeptide agent, a peptide agent, a nucleic acid agent, a nucleic acid ligand, or a small molecule agent.
  • the agent may target any of the genes or CNV's described herein.
  • the nucleic acid agent may encode for RNAi, a Zinc finger nuclease (ZFN), a Transcription Activator-Like Effector Nuclease (TALEN), or a CRISPR/Cas system.
  • the present invention advantageously utilized large sequencing datasets of clinically informative samples to enable the discovery of novel cancer drivers and the network of relationships between the driver events and their impact on disease relapse and clinical outcome.
  • the present advantageously allows improved clinical outcomes for patients suffering with
  • the CLL8 cohort with two previously reported and non-overlapping WES cohorts 1 '', thereby increasing the size of the cohort to 538 CLLs.
  • This cohort size is expected to saturate candidate CLL gene discovery for genes mutated in 5% of patients, and provides 94% and 61% power to detect genes mutated in 3% and 2% of patients, respectively 5 .
  • Applicants detected 44 putative CLL. driver genes including 18 CLL mutated drivers that Applicants previously identified 3 , as well as 26 additional putative CLL genes ⁇ Fig. 1-2, Extended Data Fig. 1-2). In total, 33.5% of CLLs harbored mutation in at least one of these 26 additional genes.
  • Targeted DNA sequencing as well as variant allele expression by RNAseq demonstrated high rates of orthogonal validation (Extended Data Fig. 3),
  • CLL 19 In addition to highlighting novel cellular processes and pathways affected in CLL, many of the 26 additional CLL genes more densely annotated pathways or functional categories previously identified in CLL 19 , including R A processing and export (FUBPI, XP04, ESWR1, NXFI), DNA damage (CHEK2, BRCC3, ELF4 20 and DYRK1A 21 ), chromatin modification (ASXLI, HIST1H IB, BAZ2B, FKZF3) and B cell activity related pathways (TRAF2, TRAF3, CARD11).
  • R A processing and export FUBPI, XP04, ESWR1, NXFI
  • DNA damage CHEK2, BRCC3, ELF4 20 and DYRK1A 21
  • ASXLI chromatin modification
  • HIST1H IB HIST1H IB
  • BAZ2B BAZ2B
  • FKZF3 B cell activity related pathways
  • This component of the S40 ribosomal sub unit has not been extensively studied in cancer, although rare mutations have been identified in Diamond- Blackfan anemia 22 .
  • CCF cancer-cell fraction
  • driver events recurrent sCNVs and candidate CLL gene non-silent mutations
  • classifying the driver events based on the relative enrichment of out-degrees vs. in- degrees as early (O ⁇ 0.2 and number of out-degrees > in-degrees). late ⁇ Q ⁇ Q,2 and number of out-degrees ⁇ in-degrees) and intermediate or not powered (£>>0.2. Inter./not powered).
  • Out- degrees are defined as instances in which the driver event is clonal and found in the same CLL with another driver event that is subclonal.
  • in-degrees are defined as instances in which the driver event is subclonal and found in the same CLL with another driver event that is clonal.
  • These tables includes all pairs of driver events (dl, d2) that had at least 5 cases in which the two drivers were detected in the same CLL sample, but one of the drivers is clonal and the other is subclonal.
  • a two-tailed binomial test is performed to test whether the pairings are found to be in one order more frequently than the other (i.e., dl c!2 > d2 dl ).
  • a multi-hypothesis correction is then applied and the table lists all hypotheses tested.
  • An important benefit of the larger cohort size is the enhanced ability to explore relationships between driver lesions based on patterns of their co-occurrence. Focusing on temporal patterns of driver acquisition - based on the distinction between clonal versus subclonal alterations in a cross-sectional analysis - Applicants derived a temporal map for the evolutionary history of CLL. In the context of relapse after first-line fludarabine based therapy, Applicants note highly frequent clonal evolution, and that the future evolutionary trajectories were already anticipated in the pre-treatment sample in one third of cases with WES.
  • Immuno-magnetic tumor cell enrichment via CD 19 was performed on all baseline pretreatment samples (Midi MACS, Miltenyi Biotec, Bergisch Gladbach, Germany) achieving a separation of PBMCs into a CD19- positive tumor sample and a CD19-negative normal sample with a purity of >95% by flow cytometry.
  • the source of matched normal tissue was PBMC collected following chemoimmunotherapy when the samples were evaluated by flow cytometry as minimal residual disease-negative (Kiel Laboratory, Germany). Samples were used fresh or cryopreserved (with FBS with 10% DMSO) and stored in vapor-phase liquid nitrogen until the time of analysis.
  • DNA quality control Applicants used standard Broad Institute protocols as previously described 5,6 . Tumor and normal DNA concentration were measured using PicoGreen® dsDNA Quantitation Reagent (Invitrogen, Carlsbad, CA). A minimum DNA concentration of 5 ng/ ⁇ was required for sequencing. All Illumina sequencing libraries were created with the native DNA. The identities of ail tumor and normal DNA samples were confirmed by mass spectrometric fingerprint genotyping of 95 common SNPs by Fluidigm Genotyping (Fluidigm, San Francisco, CA).
  • Standard quality control metrics including error rates, percentage-passing filter reads, and total Gb produced, were used to characterize process performance before downstream analysis. Note that due to a change in the Agilent capture bait set, the NOTCH 1 hotspot was not covered in samples GCLL-199 through GCLL-313, which included 10 samples with NOTCH! c.7544_7545delCT deletions by Sanger sequencing 8 . CLL samples found to harbor NOTCH! mutations by Sanger sequencing were subsequently submitted to targeted sequencing with Illumina TruSeq Custom Amplicon library, and sequenced on an Illumina MiSeq with a mean coverage depth of 1332X.
  • samples with NOTCH 1 mutations by Sanger sequencing were also submitted to targeted sequencing.
  • samples from patients included in the CLL8 clinical trial Applicants have analyzed 157 WES samples from the cohort Applicants have previously published 5 '. The sequencing reads were realigned to hgl9 and all downstream analysis was done using the same methods as with the sequencing data for the CLL8 cohort.
  • Somatic single nucleotide variations were detected using MuTect (Firehose version vl3112); somatic small insertions and deletions were detected using an improved version (manuscript in preparation, Cibulskis et al.,) of Indelocator J .
  • the primary improvement is implementation of local reassembly, which results in more accurate allele fraction estimation.
  • Applicants filter sSNVs and sINDELs by removing events seen in sequencing data of a large panel of normal samples. Overall, this filtering removed -35% of all candidate somatic mutations, mostly ones with very low allelic fraction.
  • MutSig2CV16 to detect candidate cancer genes using three signals of positive selection: (i) increased mutation burden as compared to a background model; (ii) clustering of mutations along the gene; and (iii) enrichment of mutations at likely functional sites.
  • Genome-wide copy number analysis Genome-wide copy number profiles of the CLL samples and their patient-matched germline DNA were estimated directly from the WES data, based on the ratio of CLL sample read-depth to the average read-depth observed in normal samples for that region. Applicants observed a high level of agreement between sCNV detection by exome and standard FISH cytogenetics, with the exception of smaller deletions in the region of chromosome 13ql 4, where 14.5% of cases were missed by WES ⁇ Supplementary Table 5). Allelic copy number analysis was then performed by examination of alternate and reference read counts at heterozygous SNP positions (as determined by analysis of the matched normal sample).
  • RNA sequencing and data analysis RNA sequencing (RNAseq) was performed as previously described 24 .
  • previously published RNAseq data for additional CLL RNA samples were downloaded with permission from the European Genome-Phenome Archive 25 , and processed in an identical fashion to the in-house produced libraries.
  • matching WES and RNAseq data were available for 156 samples including 103 samples collected at the DFCI and 53 samples collected by the ICGC.
  • RNAseq BAMs were aligned to the hg!9 genome using the TopHat suite. Each somatic base substitution detected by WES was compared to reads at the same location in RNAseq.
  • CN T is the local copy number in the tumor cell and CN N is the local copy number in the normal cells (2 in the autosome, and 1 or 2 on the X chromosome depending on gender).
  • the allele fraction probability density in the tumor is estimated from the binomial probability density "binopdf over the range of reference allele counts in the tumor "t ref between 0 and t_ref_count:
  • AF T is the full range of allele fractions from 0 to 1 and Z is set such that p(AFY) is normalized to 1.
  • ⁇ ( ⁇ 1 7 ⁇ ) no longer contains the normal cell component, which simplifies the remaining steps to estimate the mutation cancer cell fraction (CCF).
  • CCF mutation cancer cell fraction
  • the CCF estimate is integrated over all possible mutation multiplicities "m", the number of mutations per tumor cell.
  • the multiplicity m can range from 1 to q hat I or q hat2 (the local somatic absolute copy numbers of each homologous allele in the tumor). Applicants assume that the mutation occurred before or after any local copy number change and each possible multiplicity is given equal weight w m such that the w's are normalized to 1.
  • Clustering analysis of sSNVs and sINDELs ie 59 CLL sample pairs Applicants performed WES on matched samples collected at the time of first progression following therapy from 59 of 278 CLL8 subjects (Supplementary Table 9). The median time to progression was 35.1 months (range 5.9-75.5), with relapse samples collected at a median of 7.6 months following documented progression, ail before receipt of subsequent therapy. The two time point CCF clustering procedure was performed as previously described 9 . Clonal evolution between pretreatment and relapse samples was defined based on the presence of mutations with a P ⁇ CCF > 0.1)>0.5. Branched evolution was classified when a dominant clone in the pre-treatment sample was replaced by sibling dominant clone.
  • Targeted deep sequencing was performed using microfluidic PGR (Access Array System, Fluidigm). Six unmatched saliva samples were included in this analysis to assist with the quantification of background sequencing error noise. Target-specific primers were designed to flank sites of interest and produce amplicons of 200 bp ⁇ 20 bp. Per well, molecularly barcoded, lilumina-compatible specific oligonucleotides containing sequences complementary to the primer tails were added to the Fluidigm Access Array chip together with genomic DNA samples (20-50 ng of input) such that all amplicons for a given DNA sample shared the same index, and PGR was performed according to the manufacturer's instructions.
  • Time to event data were estimated by the Kaplan-Meier method, and differences between groups were assessed using two-sided non- stratified log-rank tests. Additionally, hazard ratios (HR) and 95% confidence intervals (CI) were calculated using unadjusted and adjusted Cox regression modeling. Independent factors for PFS and OS were identified by multivariable analysis using Cox proportional hazards regression models.
  • Trisomy 19 Seilmann, L. et al. Trisomy 19 is associated with trisomy 12 and mutated IGHV genes in B-chronic lymphocytic leukaemia. Br J Haematol 138, 217-220, doi :BJH6636 [pii] 10.11 1 1/j .1365-2141.2007.06636.x (2007).

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Abstract

Les demandeurs ont identifié (44) gènes à mutation récurrente et (11) variations du nombre de copies (VNC) somatiques récurrentes par le séquençage de l'exome entier de 538 leucémies lymphoïdes chroniques (LLC) et des échantillons d'ADN de lignée germinale correspondantes, dont 278 ont été collectés dans un essai clinique prospectif. Ils comprennent des conducteurs de cancer précédemment inconnus (RPS15, IKZF3) et identifient collectivement le traitement et l'exportation d'ARN, l'activité MYC et la signalisation MAPK comme des voies centrales impliquées dans la LLC. L'analyse de clonalité de ce grand ensemble de données a ensuite permis la reconstruction des relations temporelles entre les événements conducteurs. Une comparaison directe entre des échantillons de prétraitement et de rechute correspondants prélevés sur 59 patients a démontré une évolution clonale très fréquente. La découverte de nouveaux gènes du cancer et du réseau de relations entre les événements conducteurs et leur impact sur la rechute et l'issue clinique de la maladie permet d'ouvrir de nouvelles options de traitement.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10741270B2 (en) 2012-03-08 2020-08-11 The Chinese University Of Hong Kong Size-based analysis of cell-free tumor DNA for classifying level of cancer
US11031100B2 (en) 2012-03-08 2021-06-08 The Chinese University Of Hong Kong Size-based sequencing analysis of cell-free tumor DNA for classifying level of cancer
US10364467B2 (en) 2015-01-13 2019-07-30 The Chinese University Of Hong Kong Using size and number aberrations in plasma DNA for detecting cancer
CN108570503A (zh) * 2018-05-29 2018-09-25 成都中创清科医学检验所有限公司 一种用于检测慢性淋巴细胞性白血病基因多态性位点的引物及其检测方法
WO2020006431A1 (fr) * 2018-06-29 2020-01-02 Rady Children's Hospital Research Center Procédé et système d'assurance d'identité d'échantillon
DE102020102143B3 (de) * 2020-01-29 2021-03-04 Cellphenomics GmbH Verfahren zur Bestimmung, ob eine Behandlung einer Krebserkrankung begonnen oder fortgesetzt werden soll, ein Biomarker, der mindestens einem Markergen entspricht, und eine Verwendung des Biomarkers in dem erfindungsgemäßen Verfahren
WO2021178595A3 (fr) * 2020-03-04 2021-10-21 Foundation Medicine, Inc. Remaniements de bcor et leurs utilisations

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