Clinical impact of acquired alterations of DDR genes in hematologic malignancies
| Gene alteration . | Malignancy . | TTFT . | Response to treatment . | PFS and OS . |
|---|---|---|---|---|
| ATM (del/mut) | CLL | Shorter TTFT44 | Lower ORR to chemotherapy in patients with biallelic defect (P = .002).45 No impact on ORR with venetoclax-obinutuzumab treatment.46 | Reduced PFS (HR, 4.4) and OS (HR, 2.4) with chemotherapy.45 |
| TP53 (del/mut) | CLL | Shorter TTFT (HR, 1.98)23 | Lower ORR to chemotherapy (P = .001).47 No impact on ORR with targeted treatment including venetoclax-obinutuzumab,46 AVO,48 and IVO.49 | Reduced PFS (TP53 del: HR, 3.3; TP53 mut: HR, 3.8) and OS (del: HR, 2.1; mut: HR, 7.2) with chemotherapy.47,50 Reduced PFS with venetoclax-obinutuzumab (del: HR, 4.4; mut: HR, 3.1).46 Reduced PFS with IVO in patients with bialleic compared with monoalleic defect (P < .001).49 |
| MDS/AML | Shorter time to AML transformation in MDS with multihit TP53 alterations (HR, 3.0)51 | Resistance to small molecule inhibitors35 | TP53 alterations reduce OS in patients with complex karyotype29,52 or in younger patients (P < .001)53 | |
| CML BC | — | — | Reduced OS in patients with TP53 deletion or biallelic TP53 alterations (P < .001)30 | |
| MCL | — | — | Reduced PFS (HR, 3.8) and OS (HR, 4.0; P < .001)24 | |
| DLBCL | — | — | Reduced OS with TP53 alterations and high BCL2 expression (P < .001)26 | |
| MM | — | — | Reduced PFS with TP53 alterations, APOBEC signature, and HRR defect28 | |
| DYRK1A (mut) | CLL | — | — | Reduced OS (univariate HR, 4.3; multivariate HR, 2.79)23 |
| PALB2 (del) | AML | — | — | Reduced OS (2 mos vs 16.2 mos, P < .01)34 |
| SAMHD1 (expression) | AML | — | Reduced SAMHD1 expression in patients with CR after Ara-C (P < .001)54 | Reduced PFS and OS in high SAMDH1 expressors (P < .001)54 |
| Gene alteration . | Malignancy . | TTFT . | Response to treatment . | PFS and OS . |
|---|---|---|---|---|
| ATM (del/mut) | CLL | Shorter TTFT44 | Lower ORR to chemotherapy in patients with biallelic defect (P = .002).45 No impact on ORR with venetoclax-obinutuzumab treatment.46 | Reduced PFS (HR, 4.4) and OS (HR, 2.4) with chemotherapy.45 |
| TP53 (del/mut) | CLL | Shorter TTFT (HR, 1.98)23 | Lower ORR to chemotherapy (P = .001).47 No impact on ORR with targeted treatment including venetoclax-obinutuzumab,46 AVO,48 and IVO.49 | Reduced PFS (TP53 del: HR, 3.3; TP53 mut: HR, 3.8) and OS (del: HR, 2.1; mut: HR, 7.2) with chemotherapy.47,50 Reduced PFS with venetoclax-obinutuzumab (del: HR, 4.4; mut: HR, 3.1).46 Reduced PFS with IVO in patients with bialleic compared with monoalleic defect (P < .001).49 |
| MDS/AML | Shorter time to AML transformation in MDS with multihit TP53 alterations (HR, 3.0)51 | Resistance to small molecule inhibitors35 | TP53 alterations reduce OS in patients with complex karyotype29,52 or in younger patients (P < .001)53 | |
| CML BC | — | — | Reduced OS in patients with TP53 deletion or biallelic TP53 alterations (P < .001)30 | |
| MCL | — | — | Reduced PFS (HR, 3.8) and OS (HR, 4.0; P < .001)24 | |
| DLBCL | — | — | Reduced OS with TP53 alterations and high BCL2 expression (P < .001)26 | |
| MM | — | — | Reduced PFS with TP53 alterations, APOBEC signature, and HRR defect28 | |
| DYRK1A (mut) | CLL | — | — | Reduced OS (univariate HR, 4.3; multivariate HR, 2.79)23 |
| PALB2 (del) | AML | — | — | Reduced OS (2 mos vs 16.2 mos, P < .01)34 |
| SAMHD1 (expression) | AML | — | Reduced SAMHD1 expression in patients with CR after Ara-C (P < .001)54 | Reduced PFS and OS in high SAMDH1 expressors (P < .001)54 |
Ara-C, cytosine arabinoside (cytarabine); AVO, triplet therapy with acalabrutinib, venetoclax, and obinutuzumab; BC, blast crisis; BCL2. B-cell lymphoma 2; CML. chronic myeloid leukemia; CR, complete remission; del, deletion; HR, hazard ratio; IVO, triplet therapy with ibrutinib, venetoclax, and obinutuzumab; MCL, mantle cell lymphoma; MM, multiple myeloma; mut, mutation; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TTFT, time to first treatment.