US 2019/0292602 A1Published application

Therapeutic treatment of select diffuse large b cell lymphomas exhibiting distinct pathogenic mechanisms and outcomes

AssigneesDana-Farber Cancer Institute, Inc., The Broad Institute, Inc., The General Hospital Corporation

InventorsBjoern Chapuy, Margaret Shipp, Chip Stewart, Andrew Dunford, Gad Getz

Life of this patent

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Abstract

The present disclosure relates to compositions and methods for the diagnosis and treatment or prevention of DLBCL. In particular, the instant disclosure provides a DLBCL classifier that has identified at least five distinct classes of DLBCL cancer, each of which possesses distinct pathogenic mechanisms and outcomes. The instant classifier identifies preferred therapeutic options (including combination therapies) for each such class of DLBCL cancer.

Claims10

Dependent claims

A method for selecting a treatment for a subject having or at risk of developing DLBCL comprising:

(a) obtaining a sample from a subject having or at risk of DLBCL;
(b) identifying the presence or absence in the sample of five or more sequence variants or sites of copy number variation selected from the group consisting of:
1P13.1:DEL;
1P31.1:DEL;
1P36.11:DEL;
2P16.1:AMP;
3P:AMP;
3P21.31:DEL;
3Q:AMP;
4Q21.22:DEL;
4Q35.1:DEL;
5P:AMP;
9P21.3:DEL;
9Q21.13:DEL;
10Q23.31:DEL;
14Q32.31:DEL;
16Q12.1:DEL;
17P:DEL;
17Q25.1:DEL;
18P:AMP;
18Q:AMP;
19P13.2:DEL;
19Q:AMP;
19Q13.42:AMP;
21Q:AMP;
a variant or copy number variation in B2M;
a variant or copy number variation in BCL2;
a variant or copy number variation in BCL10;
a variant or copy number variation in BRAF;
a variant or copy number variation in CD58;
a variant or copy number variation in CD70;
a variant or copy number variation in CD79B;
a variant or copy number variation in CD83;
a variant or copy number variation in CREBBP;
a variant or copy number variation in ETV6;
a variant or copy number variation in EZH2;
a variant or copy number variation in FAS;
a marker that indicates genome doubling;
a variant or copy number variation in GNA13;
a variant or copy number variation in GNA12;
a variant or copy number variation in GRHPR;
a variant or copy number variation in HISTIHIB;
a variant or copy number variation in HISTIHIC;
a variant or copy number variation in HISTIHID;
a variant or copy number variation in HIST1H1E;
a variant or copy number variation in HIST1H2BC;
a variant or copy number variation in HLA-B;
a variant or copy number variation in HVCN1;
a variant or copy number variation in IRF8;
a variant or copy number variation in KLHL6;
a variant or copy number variation in KMT2D;
a variant or copy number variation in MEF2B;
MYD88:L265;
a non-L265 variant or copy number variation in MYD88;
a variant or copy number variation in NFKBIA;
a variant or copy number variation in NFKBIE;
a variant or copy number variation in NOTCH2;
a variant or copy number variation in PIM1;
a variant or copy number variation in POU2F2;
a variant or copy number variation in PTEN;
a variant or copy number variation in SGK1;
a variant or copy number variation in SPEN;
a variant or copy number variation in STAT3;
a variant or copy number variation in SV:BCL2;
a variant or copy number variation in SV:BCL6;
a variant or copy number variation in SV:CD274/PDCD1LG2;
a variant or copy number variation in SV:MYC;
a variant or copy number variation in SV:TP63;
a variant or copy number variation in TBL1XR1;
a variant or copy number variation in TMEM30A;
a variant or copy number variation in TNFAIP3;
a variant or copy number variation in TNFRSFI4;
a variant or copy number variation in TP53;
a variant or copy number variation in UBE2A;
a variant or copy number variation in ZC3H12A;
a variant or copy number variation in ZEB2;
and
a variant or copy number variation in ZFP36L1;
(c) analyzing the presence or absence of sequence variants or copy number variation of step (b) to assign the sample to a discrete class of activated B-cell DLBCL (ABC-DLBCL) or germinal center B-cell DLBCL (GCB-DLBCL);
(d) if the sample is assigned to an ABC-DLBCL class, selecting either a treatment comprising:
an agent selected from the group consisting of a NOTCH inhibitor, a BCL6 inhibitor and an activator of immune evasion, optionally an oligonucleotide inhibitor of NOTCH and/or BCL6, for administration to the subject, or
an agent selected from the group consisting of a BCR/TLR signaling inhibitor and a BCL2 inhibitor, optionally oblimersen, ABT-263, Venetoclax (ABT-199), an antibody or oligonucleotide inhibitor of BCR/TLR signaling and/or an oligonucleotide inhibitor of BCL2, for administration to the subject;
or
if the sample is assigned to a GBC-DLBCL class, selecting either a treatment comprising:
an agent selected from the group consisting of a BCL2 inhibitor, a PI3K inhibitor and an epigenetic modifier, optionally oblimersen, ABT-263, Venetoclax (ABT-199), wortmannin, LY294002, an E2H2 inhibitor (optionally 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, and/or UNC1999), a CREBBP inhibitor, an oligonucleotide inhibitor of BCL2, an oligonucleotide inhibitor of PI3K and/or an oligonucleotide inhibitor of an epigenetic modifier, for administration to the subject;
or
an agent selected from the group consisting of a JAK/STAT inhibitor and a BRAF/MEK1 inhibitor, optionally ruxolitinib, Vemurafenib, Cobimetinib, an oligonucleotide inhibitor of JAK/STAT and/or an oligonucleotide inhibitor of BRAF/MEK1, for administration to the subject;
or
if the sample is assigned to a DLBCL class that is characterized by frequent bi-allelic inactivation of TP53 by mutations and 17p copy loss, selecting a treatment comprising a CDK inhibitor,
thereby selecting a treatment for the subject having or at risk of developing DLBCL.

87 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/358,825Filed 20 Mar 2019
Priority: 21 Mar 2018
Published: 26 Sep 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C12Q 1/6886
For diseases caused by alterations of genetic material: for cancer
C12Q 1/686
Nucleic acid amplification reactions: polymerase chain reaction [PCR]
C12Q 1/6869
Involving nucleic acids: methods for sequencing
C12Q 2600/106
Oligonucleotides characterized by their use: pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism

Family

Application62/646,214Us provisional application · filed 21 Mar 2018
US 12,571,049 B2Related patent
US 2019/0292602 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A method for selecting a treatment for a subject having or at risk of developing DLBCL comprising:

(a) obtaining a sample from a subject having or at risk of DLBCL;
(b) identifying the presence or absence in the sample of five or more sequence variants or sites of copy number variation selected from the group consisting of:
1P13.1:DEL;
1P31.1:DEL;
1P36.11:DEL;
2P16.1:AMP;
3P:AMP;
3P21.31:DEL;
3Q:AMP;
4Q21.22:DEL;
4Q35.1:DEL;
5P:AMP;
9P21.3:DEL;
9Q21.13:DEL;
10Q23.31:DEL;
14Q32.31:DEL;
16Q12.1:DEL;
17P:DEL;
17Q25.1:DEL;
18P:AMP;
18Q:AMP;
19P13.2:DEL;
19Q:AMP;
19Q13.42:AMP;
21Q:AMP;
a variant or copy number variation in B2M;
a variant or copy number variation in BCL2;
a variant or copy number variation in BCL10;
a variant or copy number variation in BRAF;
a variant or copy number variation in CD58;
a variant or copy number variation in CD70;
a variant or copy number variation in CD79B;
a variant or copy number variation in CD83;
a variant or copy number variation in CREBBP;
a variant or copy number variation in ETV6;
a variant or copy number variation in EZH2;
a variant or copy number variation in FAS;
a marker that indicates genome doubling;
a variant or copy number variation in GNA13;
a variant or copy number variation in GNA12;
a variant or copy number variation in GRHPR;
a variant or copy number variation in HISTIHIB;
a variant or copy number variation in HISTIHIC;
a variant or copy number variation in HISTIHID;
a variant or copy number variation in HIST1H1E;
a variant or copy number variation in HIST1H2BC;
a variant or copy number variation in HLA-B;
a variant or copy number variation in HVCN1;
a variant or copy number variation in IRF8;
a variant or copy number variation in KLHL6;
a variant or copy number variation in KMT2D;
a variant or copy number variation in MEF2B;
MYD88:L265;
a non-L265 variant or copy number variation in MYD88;
a variant or copy number variation in NFKBIA;
a variant or copy number variation in NFKBIE;
a variant or copy number variation in NOTCH2;
a variant or copy number variation in PIM1;
a variant or copy number variation in POU2F2;
a variant or copy number variation in PTEN;
a variant or copy number variation in SGK1;
a variant or copy number variation in SPEN;
a variant or copy number variation in STAT3;
a variant or copy number variation in SV:BCL2;
a variant or copy number variation in SV:BCL6;
a variant or copy number variation in SV:CD274/PDCD1LG2;
a variant or copy number variation in SV:MYC;
a variant or copy number variation in SV:TP63;
a variant or copy number variation in TBL1XR1;
a variant or copy number variation in TMEM30A;
a variant or copy number variation in TNFAIP3;
a variant or copy number variation in TNFRSFI4;
a variant or copy number variation in TP53;
a variant or copy number variation in UBE2A;
a variant or copy number variation in ZC3H12A;
a variant or copy number variation in ZEB2;
and
a variant or copy number variation in ZFP36L1;
(c) analyzing the presence or absence of sequence variants or copy number variation of step (b) to assign the sample to a discrete class of activated B-cell DLBCL (ABC-DLBCL) or germinal center B-cell DLBCL (GCB-DLBCL);
(d) if the sample is assigned to an ABC-DLBCL class, selecting either a treatment comprising:
an agent selected from the group consisting of a NOTCH inhibitor, a BCL6 inhibitor and an activator of immune evasion, optionally an oligonucleotide inhibitor of NOTCH and/or BCL6, for administration to the subject, or
an agent selected from the group consisting of a BCR/TLR signaling inhibitor and a BCL2 inhibitor, optionally oblimersen, ABT-263, Venetoclax (ABT-199), an antibody or oligonucleotide inhibitor of BCR/TLR signaling and/or an oligonucleotide inhibitor of BCL2, for administration to the subject;
or
if the sample is assigned to a GBC-DLBCL class, selecting either a treatment comprising:
an agent selected from the group consisting of a BCL2 inhibitor, a PI3K inhibitor and an epigenetic modifier, optionally oblimersen, ABT-263, Venetoclax (ABT-199), wortmannin, LY294002, an E2H2 inhibitor (optionally 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, and/or UNC1999), a CREBBP inhibitor, an oligonucleotide inhibitor of BCL2, an oligonucleotide inhibitor of PI3K and/or an oligonucleotide inhibitor of an epigenetic modifier, for administration to the subject;
or
an agent selected from the group consisting of a JAK/STAT inhibitor and a BRAF/MEK1 inhibitor, optionally ruxolitinib, Vemurafenib, Cobimetinib, an oligonucleotide inhibitor of JAK/STAT and/or an oligonucleotide inhibitor of BRAF/MEK1, for administration to the subject;
or
if the sample is assigned to a DLBCL class that is characterized by frequent bi-allelic inactivation of TP53 by mutations and 17p copy loss, selecting a treatment comprising a CDK inhibitor,
thereby selecting a treatment for the subject having or at risk of developing DLBCL.

87 more elements

Facts

Application

16/358,825Filed 20 Mar 2019

Priority

21 Mar 2018

Published

26 Sep 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C12Q 1/6886
For diseases caused by alterations of genetic material: for cancer
C12Q 1/686
Nucleic acid amplification reactions: polymerase chain reaction [PCR]
C12Q 1/6869
Involving nucleic acids: methods for sequencing
C12Q 2600/106
Oligonucleotides characterized by their use: pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism