Ayalew Tefferi, MD

​

Barbara Woodward Lips Professor of Medicine

Mayo Clinic, Division of Hematology

Rochester, MN

​

​

I have nothing to declare

Chronic Myelomonocytic Leukemia

2025

©2019 MFMER | slide-1

ICC classification of myeloid neoplasms with morphologic dysplasia

BM or PB blasts

10-19%

MDS/AML

CMML

WBC ≥13 x 10⁹/L or

Platelets ≥450 x 10⁹/L

MDS/MPN

MDS

MDS/MPN

CMML

AML

AML/MDS

BM or PB

Blasts/promonocytes

≥20%

AML

Yes

No

PB monocytes

≥0.5 x 10⁹/L and

PB monocyte % >10

Yes

No

Yes

No

Yes

MDS

Arber et al. Blood 2022;140:1200

No

Promonocytes

Myeloblasts

©2019 MFMER | slide-2

Chronic myelomonocytic leukemia

Mature monocytes

Promonocytes

Blasts/monoblasts

ICC diagnostic criteria:

​

1. PB AMC ≥0.5 x 10⁹/L + monocytes ≥10% of WBC
• ≥1.0 x 10⁹/L in the absence of a clonal marker
2. MDS-defining cytopenia
3. Evidence of clonality*
• Abnormal karyotype or
• Myeloid driver mutation with ≥10% VAF
4. Not classified as any other MN
• <20% blasts or promonocytes in PB or BM
• No ABL1, PDGFRA, PDGFRB, FGFR1,

JAK2, or FLT3 fusion oncogenes

CMML-MP – WBC ≥13 x 10⁹/L

CMML-MD - WBC <13 x 10⁹/L

​

CMML-1 - <5% PB and <10% BM blasts/promonocytes

CMML-2 – 5-19% PB or 10-19% BM blasts/promonocytes

Patnaik and Tefferi. AJH 2024;90:1142

Promonocytes

4

Clinical presentation:

​

• Median age 72 years

​

• Males 68%

​

• CMML-1 85%

​

• Tx-requiring 25%

​

• Median Hgb 11 g/dL

​

• Median platelets 95 x 10(9)/L

​

• Platelets <50 x 10(9)/L 21%

​

• Median WBC 12 x 10(9)/L

​

• WBC ≥13 x 10(9)/L 38%

​

• Median AMC 2.3 x 10(9)/L

​

• PB blast 2% 15%

​

• BM blasts 10% 2%

​

• Abnormal karyotype 25%

​

​

​

Patnaik and Tefferi. AJH 2024;90:1142

NGS

• TET2 48%
• ASXL1 46%
• SRSF2 42%
• NRAS 16%
• RUNX1 16%
• KRAS 9%
• U2AF1 9%
• DNMT3A 7%
• SETBP1 7%
• CBL 3%
• TP53 2%
• PHF6 <2%

Characteristic features

• Systemic inflammatory autoimmune syndromes 20-30%
• Leukemia cutis
• Lysozyme-induced nephropathy

Lysozyme immunohistochemistry of a kidney biopsy specimen demonstrating renal tubular

epithelial cells with lysozyme accumulation

5

Decitabine Versus Hydroxyurea for Advanced Proliferative Chronic Myelomonocytic Leukemia: Results of a Randomized Phase III Trial Within the EMSCO Network

Raphael Itzykson, MD, PhD JCO 2022;41: DACOTA trial

​

N=170

HU = 86

DAC = 84

⁓40% previously exposed to HU in each arm

Median f/u 17.5 months

​

Response with HU 35% (2% CR)

Response with DAC 63% (12% CR); p<0.01

​

Median duration of response with HU 17.4 months

Median duration of response with DAC 16.3 months (p=0.9)

​

Median survival on HU 18.4 months

Median survival on DAC 21.9 months (p=0.67)

​

Median EFS with HU = 10.3 months

Median EFS with DAC = 12.1 months (p=0.27)

​

2-year BT with DAC 38.4%

2-year BT with HU 60.7% (p<0.01)

​

2-year death without progression 27.5% vs. 17.4% (p<0.01)

6

DACOTA phase-3 trial continued…

HU arm

HU arm

7

Venetoclax in combination with hypomethylating agents

in chronic myelomonocytic leukemia: a propensity score

matched multicenter cohort study

Tremblay et al. Leukemia 2024; DOI: 10.1038/s41375-024-02466-6

Multicenter retrospective study

51 patients with CMML

CMML-MP 55%

CMML-MD 45%

CMML-2 65%

CPSS low.int-1 12%

CPSS int-2/high 88%

​

CR 22%

Optimal marrow response ??? 50%

Partial marrow response ??? 6%

Clinical benefit ??? 12%

​

Overall survival

Blast transformation-free survival

CR =

BM blast/promonocytes <5%

WBC <10

Hgb >11

Plt >100

ANC >1

AMC<1

PB blast 0%

vs. 13% with PSM-HMA alone vs. 12% DACOTA

8

Randomized Phase II Study of Azacitidine Alone or in

Combination With Lenalidomide or With Vorinostat in

Higher-Risk Myelodysplastic Syndromes and Chronic

Myelomonocytic Leukemia: North American Intergroup

Study SWOG S1117

Sekeres et al. JCO 2017;35https://doi.org/10.1200/JCO.2015.66.2510

​

277 patients with CMML (N=53) or HR-MDS (N=224)

AZA - ORR/CR 38%/24%

AZA + LEN – ORR/CR 49%/24%

AZA + VOR – 27%/17%

​

CMML

AZA - ORR 28%

AZA + LEN – ORR 68%

AZA + VOR – ORR 12%

​

IWG-2006 criteria

CR

BM blasts <5%

Hgb ≥11

ANC ≥1

Plt ≥100

Blasts 0%

​

PR

Hgb ≥11

ANC ≥1

Plt ≥100

Blasts 0%

BM blasts ↓>50%

​

HI

Hgb increase ≥1.5 g/dL

Plt <20 to >20 + 100% increase

Plt >20 need increase by 30+

ANC 100% increase + 0.5 minimum

ORR= CR + PR + HI + marrow CR

0.68

0.22

0.35

Transplant-censored survival data among 457 Mayo Clinic patients with chronic myelomonocytic leukemia

No treatment

N=155

Median 29 months

Hydroxyurea

N=102

Median 23 months

Hypomethylating agent

N=78

Median 35 months

Other cytotoxic drug

N=27

Median 18 months

Other non-cytotoxic drug

N=95

Median 25 months

Overall P value = 0.2

HU vs. HMA (P=0.28)

HU vs. no treatment (p=0.25)

HMA vs. no treatment (p=0.87)

Muhammad Y. et al. Manuscript in preparation

10

Eltrombopag in chronic myelomonocytic leukemia with severe thrombocytopenia.

A Groupe Francophone des Myélodysplasies (GFM) study

Rabian et al. Leukemia 2024;38:2510

​

Multicenter phase-2 study of CMML patients with platelets <50 x 10(9)/L and BM blasts <5%

Eltrombopag 50-100 mg/day (escalated up to 300 mg/day)

30 patients enrolled one withdrew (CMML-MP 31%)

41% platelet transfusion-dependent

​

• Platelet response at 12 weeks (IWG-2006 criteria) = 48%
• Platelet response at any time = 72%
• Resolution of platelet transfusion dependency = 50%
• Median time to response 14 days
• Median response duration 2.6 months
• No impact on leukocytosis or anemia
• No difference between CMML-MP and CMML-MD

​

​

HI

Hgb increase ≥1.5 g/dL

Plt <20 to >20 + 100% increase

Plt >20 need increase by 30+

ANC 100% increase + 0.5 minimum

11

Response to erythropoietic-stimulating agents in patients with chronic myelomonocytic leukemia

Xicoy et al. EJH 2016;97:33

N=94; MD 57%; MP 43%; CMML-1 83%; CMML-2 17%;

CPSS low/intermediate-1 65%; CPSS intermediate-2/high 35%

Tx-dependent 29%

Median Epo level 39.4 (6.3-1940)

Epo<500 93%

​

Erythroid response = 64% (74% lower risk 42% higher risk)

RBC Tx independence 31%

ER duration median 7 months

CPSS and Epo level correlated with response

​

HI

Hgb increase ≥1.5 g/dL

Plt <20 to >20 + 100% increase

Plt >20 need increase by 30+

ANC 100% increase + 0.5 minimum

Ruxolitinib in chronic myelomonocytic leukemia

Hunter et al. Clinical Cancer Research 2021;27:6095

A phase-2 multicenter study ruxolitinib 20 mg BID

Splenomegaly or MF-like symptoms

Platelets ≥35 x 10(9)/L

N=50

Lower-risk 66%

CMML-0 56%

CMML-MP 68%

​

​

Clinical ORR 38% by MDS/MPN IWG criteria

CR – 2%

1 of 8 Tx-dep patients sustained Tx-independence for 8 weeks or more

Clinical benefit 66%

Spleen response 44%

Median response duration 7.7 months

​

CR = complete remission

PR = partial remission

MR = Major response

CB = Clinical benefit

Robin et al. Blood Volume 140, Issue 12, 22 September 2022, Pages 1408-1418

5-year

post-transplant

survival

29%

29%

44%

54%

Post-transplant survival data in 138 Mayo Clinic patients with

CMML who received allogeneic stem cell transplantation,

stratified by pre-transplant history of blast transformation (BT)

Transplanted prior to experiencing blast transformation (N=104); median 95 months

Transplanted after experiencing blast transformation (N=44); median 16 months

10-year

post-transplant

survival

Experienced BT before transplant (N=29)

Alsugair, A.K.A. et al. Manuscript in preparation

BM blasts <5%

N=76

Median 171 months

BM blasts 10-19% (N=4)

Median 18 months

Stratified by BM blast % at time of transplant

Pre-transplant bridging chemotherapy

Chronic phase

Blast phase

Time of

transplantation

P=0.01

HR 1.9, 1.2-3.2

BM blasts 5-9%

N=15

Median 81 months

BM blasts <5%

N=26

Median 50 months

No history of BT before transplant (N=95)

P=0.33

BM blasts 5-19% (N=3)

Median 13-25 months

P=0.14

P<0.01

P=0.13

Intensive (N=12)

Median 29 months

HMA (N=12)

Median 16 months

Intensive (N=7)

Median not reached

HMA (N=64)

Median 46 months

P=0.33

P=0.48

Chronic phase (N=101)

HMA-naïve

N=35

Median 207 months

HMA-exposed

N=66

Median 46 months

P=0.02

HMA-naïve

N=20

Median 29 months

P=0.54

Pre-transplant HMA exposure history

HMA-exposed (N=12)

Median 16 months

Blast phase (N=32)

7

7

24

65

Median 60 months to unreached

P=0.9

Stratified by donor type (N=103)

Stratified by conditioning regimen (N=100)

16

15

13

52

4

Stratified by post-transplant

cyclophosphamide use (N=98)

PTCy not used

N=66

Median 107 months

PTCy used

N=32

Median 22 months

Stratified by mutations, karyotype or

clinical risk factors at initial diagnosis

and survival calculated from time of initial diagnosis

TET2

​

P=0.47

ASXL1

​

P=0.29

Karyotype

​

P=0.39

CMML-MP (N=37)

Median not reached

CMML-MD (N=60)

Median 65 months

P=0.12

CMML-1 (N=80)

Median 111 months

CMML-2 (N=17)

Median 52 months

P=0.45

Tx-dep (N=18)

Median not reached

Not Tx-dep (N=73)

Median 111 months

P=0.85

Alsugair, A.K.A. et al. Manuscript in preparation

Post-

transplant

survival

in

CMML-CP

Circulating Blast, Leukocytosis, and Anemia based Scoring Tool (BLAST model)

for Survival in Chronic Myelomonocytic Leukemia (N=457)

Risk Variables: i) circulating blasts ≥2% (1 point); ii) leukocyte count ≥13 x 10⁹/L (1 point);

iii) severe* (2 points) or moderate* (1 point) anemia.

Low-risk

(0 points)

N=167

Median 63 months

Intermediate-risk

(1 point)

N=120

Median 28 months

HR 2.2, 95% CI 1.6-3.0

High-risk

(2-4 points)

N=170

Median 13 months

HR 5.4, 95% CI 4.1-7.3

167

120

170

56

20

8

14

2

1

4

Low

Intermediate

High

At risk

AUC 0.85 (at 5 years)

AUC 0.77 (at 3 years)

AIC 211 (at 5 years)

AIC 373 (at 3 years)

P<0.01

P<0.01

*Severe anemia: transfusion-requiring or hemoglobin <8 g/dL for women or <9 g/dL for men

*Moderate anemia: hemoglobin 8 to <10 g/dL in women and 9 to <11 g/dL for men

Risk

N

43

160

81

61

71

36

Median

51 mos.

42 mos.

28 mos.

18 mos.

14 mos.

10 mos.

Stratified by IPSS-M (N=452): AUC 0.74 at 5 years and 0.73 at 3 years

Stratified CPSS-mol (N=451): AUC 0.75 at 5 years and 0.73 at 3 years

Median

65 mos.

38 mos.

21 mos.

14 mos.

N

75

109

167

100

Risk

Modified from Tefferi et al. ASH 2024

Survival Impact of Molecular Risk Stratification within Each BLAST Clinical Risk Category in Chronic Myelomonocytic Leukemia

Unfavorable genetic markers included DNMT3A^MUT, U2AF1^MUT, BCOR^MUT, SETBP1^MUT, PTPN11^MUT, NRAS^MUT, RUNX1^MUT, ASXL1^MUT, TP53^MUT

and cytogenetic abnormalities other than sole abnormalities of loss of Y chromosome or trisomy 8

BLAST-clinical low-risk

N=165

Blast-clinical high-risk

N=166

N=48

Median 74 months

N=87

Median 63 months

N=30

Median 31 months

N=57

Median 18 months

N=15

Median 17 months

BLAST-clinical intermediate-risk

N=117

P=0.036

N=94

Median 10 months

N=14

Median 99 months

N=48

Median 24 months

N=55

Median 22 months

P<0.01

Favorable mutations

Included TET2 and PHF6

LMR: low molecular risk

IMR: intermediate molecular risk

HMR: high molecular risk

LMR

HMR

IMR

Figure 3a

Figure 3b

Figure 3c

P<0.01

Modified from Tefferi et al. ASH 2024

18

Progression to leukemia was analyzed as cumulative incidence rates,

in which the outcome of death without leukemia

was considered a competing risk

Risk factors:

Absence of PHF6^MUT (3 points)

DNMT3A^MUT (2 points)

bone marrow blasts ≥10% (2 points)

circulating blasts ≥2% (1 point)

ASXL1^MUT (1 point)

Leukocyte count ≥13 x 10⁹/L (1 point)

Very high risk

High risk

Intermediate risk

Low risk

Very low risk

Modified from Tefferi et al. ASH 2024

19

2025 proposed treatment strategy in chronic myelomonocytic leukemia

Allogeneic stem cell transplantation

Higher risk disease

WBC ≥50 x 10(9)/L

Lower risk disease

High symptom burden

Consider hydroxyurea, especially

in the presence of evidence for renal insufficiency

Symptomatic

therapy

Severe

thrombocytopenia

Proliferative symptoms

Leukocytosis

Splenomegaly

Severe

anemia

Eltrombopag

HMA

ESA

HMA

Lenalidomide

HMA

HMA + Ven

Lenalidomide

Ruxolitinib

Hydroxyurea

Lower risk disease

Low symptom burden

Observation

alone

WBC <50 x 10(9)/L