Clinical and demographic characteristics, treatments, and responses of patients (N = 12) with IDH1/2-mutated post–MPN AML
| Characteristics . | Newly diagnosed IDH1-mutated post–MPN AML (n = 3) . | Newly diagnosed IDH2-mutated post–MPN AML (n = 4) . | IDH1-mutated R/R post–MPN AML (n = 4) . | IDH2-mutated R/R post–MPN AML (n = 1) . |
|---|---|---|---|---|
| Age, median (range), y | 64 (47-66) | 70 (65-82) | 67 (62-71) | 72 |
| ECOG performance status ≥1 | 2 | 4 | 3 | 1 |
| Hemoglobin, median (range), g/dL | 11.5 (9.3-15.5) | 8.7 (8.2-10) | 8.7 (7.9-9.5) | 7.8 |
| Platelet count, median (range), ×109/L | 38 (25-445) | 24 (15-536) | 155 (13-338) | 55 |
| WBC count, median (range), ×109/L | 5.7 (1.5-24) | 8.9 (2.3-26) | 6.0 (2.2-36) | 17 |
| IDH1/2 mutations prior to IDH1/2-inhibitor treatment | IDH1 R132C (3 patients) | IDH2 R140Q (4 patients) | IDH1 R132C (3 patients), R132H (1 patient) | IDH2 R140Q (1 patient) |
| MPN driver mutations at baseline, JAK2 V617F/MPL/CALR | 1/1/1 | 4 (JAK2 V617F only) | 4 (JAK2 V617F only) | 1 (JAK2 V617F only) |
| Other mutations*(>2 patients) | ||||
| ASXL1 | 2 | 1 | 2 | — |
| RUNX1 | 1 | 2 | 1 | 1 |
| NRAS/KRAS | — | 1/1 | 2/1 | — |
| Cytogenetic risk category | ||||
| Favorable | 2 | 1 | — | — |
| Very high-risk† | 1 | 2 | 2 | 1 |
| Unfavorable | — | 2 | 2 | — |
| IDH1/2-inhibitor monotherapy | AG-120 | — | AG-120 | AG-221 |
| FT-2102‡ | ||||
| Inv IDH1-i‡ | ||||
| IDH-305§ | ||||
| IDH1/2-inhibitor–based combinations | AG-120 + VEN | ENASIDENIB + RUX + AZA | AG-120 + VENETOCLAX‡ | |
| FT-2102 + AZA | ENASIDENIB + RUX + DAC | IVOSIDENIB + VEN + AZA‡ | ||
| AG-221 + [7+3] | IVOSIDENIB + CLIA + GO‡ | |||
| AG-221 + AZA | ||||
| Median treatment cycles, n (range) | 3 (1-7) | 4 (1-18) | 6 (2-8) | 3 |
| Overall response (CR), n¶ | 1 | 2 | — | — |
| Blast reduction ≥50% with SD|| | 1 | 1 | 3 | — |
| Transfusion independence, n | 2/2 | 1/2 | 1/4 | — |
| Outcome/cause of death | 1 alive (CR/alloSCT) | 1 alive (CR/ongoing IDH2-i Rx) | 4 patients died/AML | Patient died/AML |
| 2 patients died/AML | 3 patients died/AML (2), acute event (1) |
| Characteristics . | Newly diagnosed IDH1-mutated post–MPN AML (n = 3) . | Newly diagnosed IDH2-mutated post–MPN AML (n = 4) . | IDH1-mutated R/R post–MPN AML (n = 4) . | IDH2-mutated R/R post–MPN AML (n = 1) . |
|---|---|---|---|---|
| Age, median (range), y | 64 (47-66) | 70 (65-82) | 67 (62-71) | 72 |
| ECOG performance status ≥1 | 2 | 4 | 3 | 1 |
| Hemoglobin, median (range), g/dL | 11.5 (9.3-15.5) | 8.7 (8.2-10) | 8.7 (7.9-9.5) | 7.8 |
| Platelet count, median (range), ×109/L | 38 (25-445) | 24 (15-536) | 155 (13-338) | 55 |
| WBC count, median (range), ×109/L | 5.7 (1.5-24) | 8.9 (2.3-26) | 6.0 (2.2-36) | 17 |
| IDH1/2 mutations prior to IDH1/2-inhibitor treatment | IDH1 R132C (3 patients) | IDH2 R140Q (4 patients) | IDH1 R132C (3 patients), R132H (1 patient) | IDH2 R140Q (1 patient) |
| MPN driver mutations at baseline, JAK2 V617F/MPL/CALR | 1/1/1 | 4 (JAK2 V617F only) | 4 (JAK2 V617F only) | 1 (JAK2 V617F only) |
| Other mutations*(>2 patients) | ||||
| ASXL1 | 2 | 1 | 2 | — |
| RUNX1 | 1 | 2 | 1 | 1 |
| NRAS/KRAS | — | 1/1 | 2/1 | — |
| Cytogenetic risk category | ||||
| Favorable | 2 | 1 | — | — |
| Very high-risk† | 1 | 2 | 2 | 1 |
| Unfavorable | — | 2 | 2 | — |
| IDH1/2-inhibitor monotherapy | AG-120 | — | AG-120 | AG-221 |
| FT-2102‡ | ||||
| Inv IDH1-i‡ | ||||
| IDH-305§ | ||||
| IDH1/2-inhibitor–based combinations | AG-120 + VEN | ENASIDENIB + RUX + AZA | AG-120 + VENETOCLAX‡ | |
| FT-2102 + AZA | ENASIDENIB + RUX + DAC | IVOSIDENIB + VEN + AZA‡ | ||
| AG-221 + [7+3] | IVOSIDENIB + CLIA + GO‡ | |||
| AG-221 + AZA | ||||
| Median treatment cycles, n (range) | 3 (1-7) | 4 (1-18) | 6 (2-8) | 3 |
| Overall response (CR), n¶ | 1 | 2 | — | — |
| Blast reduction ≥50% with SD|| | 1 | 1 | 3 | — |
| Transfusion independence, n | 2/2 | 1/2 | 1/4 | — |
| Outcome/cause of death | 1 alive (CR/alloSCT) | 1 alive (CR/ongoing IDH2-i Rx) | 4 patients died/AML | Patient died/AML |
| 2 patients died/AML | 3 patients died/AML (2), acute event (1) |
AZA, azacitidine; CLIA, combination chemotherapy with cladribine, high-dose cytarabine, and idarubicin; CR, complete remission; DAC, decitabine; ECOG, Eastern Cooperative Oncology Group; GO, gemtuzumab ozogamicin (Mylotarg); Inv IDH1-i, investigational IDH1 inhibitor; RUX, ruxolitinib; SD, stable disease; VEN, venetoclax; WBC, white blood cell; [7+3], 7-day continuous infusion of cytarabine on days 1 to 7 and idarubicin on days 1 to 3.
The most frequent co-occurring mutations were ASXL1 and RUNX1. Other non-driver mutations were also detected at baseline in the subgroups as follows: newly diagnosed IDH1-mutated AML (EZH2, NF1, SRSF2, U2AF1); newly diagnosed IDH2-mutated AML (DNMT3A, EZH2, FLT3-ITD, PTPN11, SRSF2); and R/R IDH1-mutated AML (DNMT3A, SRSF2, SETBP1, TET2, WT1).
Very high-risk cytogenetics, for example, −7, i(17q), inv(3)/3q21, 11q−/11q23, 12p−/12p11.2.27
Patients 8 and 12 were treated with 3 and 2 different IDH1-inhibitor–based regimens, respectively (Figure 1B).
Clinical development of IDH-305 has been halted.17
Only complete remissions with full count recoveries were included in the overall responses according to the 2017 ELN criteria.15
SD is defined according to the 2017 ELN criteria.15