Baseline characteristics for the assessable cohort of patients on the clinical trial
| Patient . | Age at diagnosis, y . | Sex . | Baseline Hb, gm/dL . | Baseline PLTs, ×109 per liter . | Baseline ANC, ×109 per liter . | Baseline AMC, ×109 per liter . | Baseline monocyte % . | AA deficiency at baseline . | No. of somatic MTs at time of enrollment . | TET2 MT and VAF, % . | Somatic co-MTs . | Bone marrow karyotype at enrollment . | Bone marrow atypia at enrollment . | Bone marrow cellularity at enrollment . | Clinical outcomes . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 73.8 | M | 12.5 | 81 | 1.2 | 0.4 | 14.7% | N | 2 | Q1555V (36%) | SRSF2 P95L (42%) | 46, XY [20] | Slight | Hypercellularity (60%) | Week 20: ANC improvement from CTACE grade 2 to grade 1. Duration of improvement: 18 d |
| 2 | 69.1 | F | 13.5 | 134 | 0.7 | 0.6 | 25.7% | N | 1 | Y163L (31%) | — | 46, XX [20] | None | Normal cellularity | Stable disease at week 20 and week 52, and ANC showed a durable improvement from week 52 onward |
| 3 | 77.4 | M | 12.1 | 117 | 0.8 | 0.2 | 12% | N | 3 | N275I (60%) | ZRSR2 K98Nfs∗10 (27%) | 46, XY [20] | None | Hypercellularity (40%) | Week 20: ANC improvement from CTACE grade 3 to grade 2. Duration of improvement: 119 d. |
| 4 | 64.7 | M | 13.1 | 32 | 0.8 | 0.4 | 17.5% | Y | 2 | R1808∗ (15%) | SRSF2 P95L (43%) | 46, XY,del(20)(q11.2q13.3)[1]/46,XY[16] | Slight | Hypercellularity (—) | Week 20: Met fourth edition WHO criteria for CMML-1 |
| 5 | 73.7 | M | 13.6 | 72 | 1.0 | 0.2 | 11.8% | N | 3 | N1743I (51%) R1214W (16%) | SRSF2 P95R (40%) | 46, XY [20] | Moderate | Normal cellularity | Withdrew from the study due to PICC line thrombosis |
| 6 | 67.4 | M | 7.8 | 409 | 4.9 | 0.4 | 4.5% | N | 2 | L1447R (45%) | SRSF2 P95H (49.9%) | 46, XY [20] | Slight | Hypercellularity (—) | Stable disease at week 20 and week 52 |
| 8 | 77.3 | M | 12.8 | 172 | 0.3 | 0.5 | 25.5% | N | 3 | R250∗ (39%) | ASXL1 L732Yfs∗12 (39%); ZRSR2 Y347Tfs∗? (73%) | 46, XY [20] | Slight | Hypercellularity (60%) | Week 20: Progression to MDS-EB-1 |
| 9 | 79.0 | F | 14.8 | 39 | 1.9 | 0.8 | 22.9% | Y | 2 | C1378Lfs∗70 (39%) | SRSF2 P95H (28%) | 46, XX [20] | None | Hypercellularity (35%) | Stable disease at week 20 and week 52 |
| 10 | 64.9 | M | 12.1 | 100 | 0.3 | 0.7 | 38.9% | N | 3 | G259∗ c.3955-1G>A (39%) | ZRSR2 E49∗ (74%) | 45, X, –Y [20] | Slight | Hypercellularity (—) | Stable disease at week 20, with progression to MDS-EB-1 at week 52 |
| Patient . | Age at diagnosis, y . | Sex . | Baseline Hb, gm/dL . | Baseline PLTs, ×109 per liter . | Baseline ANC, ×109 per liter . | Baseline AMC, ×109 per liter . | Baseline monocyte % . | AA deficiency at baseline . | No. of somatic MTs at time of enrollment . | TET2 MT and VAF, % . | Somatic co-MTs . | Bone marrow karyotype at enrollment . | Bone marrow atypia at enrollment . | Bone marrow cellularity at enrollment . | Clinical outcomes . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 73.8 | M | 12.5 | 81 | 1.2 | 0.4 | 14.7% | N | 2 | Q1555V (36%) | SRSF2 P95L (42%) | 46, XY [20] | Slight | Hypercellularity (60%) | Week 20: ANC improvement from CTACE grade 2 to grade 1. Duration of improvement: 18 d |
| 2 | 69.1 | F | 13.5 | 134 | 0.7 | 0.6 | 25.7% | N | 1 | Y163L (31%) | — | 46, XX [20] | None | Normal cellularity | Stable disease at week 20 and week 52, and ANC showed a durable improvement from week 52 onward |
| 3 | 77.4 | M | 12.1 | 117 | 0.8 | 0.2 | 12% | N | 3 | N275I (60%) | ZRSR2 K98Nfs∗10 (27%) | 46, XY [20] | None | Hypercellularity (40%) | Week 20: ANC improvement from CTACE grade 3 to grade 2. Duration of improvement: 119 d. |
| 4 | 64.7 | M | 13.1 | 32 | 0.8 | 0.4 | 17.5% | Y | 2 | R1808∗ (15%) | SRSF2 P95L (43%) | 46, XY,del(20)(q11.2q13.3)[1]/46,XY[16] | Slight | Hypercellularity (—) | Week 20: Met fourth edition WHO criteria for CMML-1 |
| 5 | 73.7 | M | 13.6 | 72 | 1.0 | 0.2 | 11.8% | N | 3 | N1743I (51%) R1214W (16%) | SRSF2 P95R (40%) | 46, XY [20] | Moderate | Normal cellularity | Withdrew from the study due to PICC line thrombosis |
| 6 | 67.4 | M | 7.8 | 409 | 4.9 | 0.4 | 4.5% | N | 2 | L1447R (45%) | SRSF2 P95H (49.9%) | 46, XY [20] | Slight | Hypercellularity (—) | Stable disease at week 20 and week 52 |
| 8 | 77.3 | M | 12.8 | 172 | 0.3 | 0.5 | 25.5% | N | 3 | R250∗ (39%) | ASXL1 L732Yfs∗12 (39%); ZRSR2 Y347Tfs∗? (73%) | 46, XY [20] | Slight | Hypercellularity (60%) | Week 20: Progression to MDS-EB-1 |
| 9 | 79.0 | F | 14.8 | 39 | 1.9 | 0.8 | 22.9% | Y | 2 | C1378Lfs∗70 (39%) | SRSF2 P95H (28%) | 46, XX [20] | None | Hypercellularity (35%) | Stable disease at week 20 and week 52 |
| 10 | 64.9 | M | 12.1 | 100 | 0.3 | 0.7 | 38.9% | N | 3 | G259∗ c.3955-1G>A (39%) | ZRSR2 E49∗ (74%) | 45, X, –Y [20] | Slight | Hypercellularity (—) | Stable disease at week 20, with progression to MDS-EB-1 at week 52 |
(−) indicates the percentage of cellularity was not reported.
Both patients 4 and 9 had baseline AA levels of 0.2 mg/dL.
Although patients 2, 9, and 10 had AMC >0.5 × 109 per liter and <1.0 × 109 per liter, they did not meet CMML diagnostic criteria per the revised fourth edition of the WHO criteria (2016), which we used for inclusion criteria in this study. These criteria were revised in 2022 by the ICC and WHO, lowering the AMC threshold for CMML to ≥0.5 ×109 per liter. The high number of patients with monocytosis is likely due to the well-established mechanism(s) by which TET2 MTs, especially biallelic TET2 MTs or TET2/SRSF2 co-MTs, result in epigenetic dysregulation, clonal hematopoietic stem cell dominance, and monocytic lineage skewing (granulocyte-monocyte progenitor–biased hematopoiesis).16 Although patient 7 exhibited relative and absolute monocytosis, with WBC 13.7 × 109 per liter and TET2, SRSF2, and KRAS MTs, on bone marrow biopsy review, no bone marrow dysplasia/atypia was found, and this patient had a classical monocyte fraction (M01) <94% by monocyte repartitioning flow cytometry.17,18 The final diagnosis by the pathologist was TET2, SRSF2, and KRAS mutant CCUS; however, we excluded this patient from our analyses.
∗10 indicates that the frameshift leads to a premature stop codon 10 amino acids downstream from the mutation, causing the protein to be truncated early.
∗∗? indicates uncertainty about where the stop codon occurs after the frameshift.
AMC, absolute monocyte count; F, female; ICC, International Consensus Classification; M, male; N, no; WBC, white blood cell; WHO, World Health Organization; Y, yes.