CMML
Is there anything new?
Mark Drummond
Beatson Oncology Centre
Glasgow
CMML Update
• Background
• Diagnosis
• Prognosis
• Treatment
“ A Disorder lost in Classification….”
1982
Myelodysplastic Syndrome
FAB Group1
1994
CMML-MD vs CMML-MP*
FAB Group2
2001
MDS / MPD
WHO3
2008
CMML-1 / CMML-2**
WHO4
1984 Blood, 63.
* WCC > 13 x 109/L
1Bennet
** BM Blasts <10% or 10-20%
et al, 1982; BJH, 51, 189-1999: 2Bennet et al, 1994; BJH, 87, 746-754: 3Vardiman et al, WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues 2001: : 4Vardiman et al, WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues
2008.
WHO 2008
• PB monocytosis >1.0 x 109/L (usually >10% of
leucocytes)
• Absence of BCR-ABL
• No rearrangement of PDGFRA or PDGFRB
(exclude in eosinophilia)
• <20% blasts in Blood and Marrow (includes
myeloblasts, monoblasts and promonocytes)
• Dysplasia in 1 or more myeloid lineage
Demographics
• Incidence:
WHO ≈ 4 / 100,000 (WHO 2008)
0.46 / 100,000 (Thames Cancer Registry*)
0.7 / 100,000 (www.hmrn.org)
270 – 420 cases p.a. in UK
• Age:
WHO 65 – 75 years (WHO 2008)
76 years (www.hmrn.org)
*Haematologica 2006; 91:1400-1404.
A Spectrum of Disease?
AML M4 or
M5 (30%)*
CMML – MDS
•
•
•
WCC < 13 x
60%*
Cytopaenias
Median OS 16-31 months
CMML – 1 (85%)*
•
Median OS 20 months**
109/L
FAB, 1994
CMML – MPD
•
•
•
•
•
40%*
Leucocytosis
Organomegaly
Karyotypic evolution
Median OS 11-17 months
CMML – 2 (15%)*
• Median OS 15 months**
*Such et al, 2013, Blood, Prepublished online 31.1.2013. ** Germing et al, 2007, Haematologica, 92, 974 – 977.
Diagnosis
Diagnostics
– Lots of morphological variables, therefore very
heterogeneous
– Reactive vs. clonal monocytosis: Elderly patients, comorbidities, other reasons for cytopaenias &
monocytosis.
– Monocytes difficult to assess in marrow (asp &
trephine); granulocytic hyperplasia is striking
– CMML vs. AML: overlapping morphology & flow.
Transforming CMML –mixed picture. Blasts generally
CD34 negative.
Monocyte / Monoblast Morphology
Monoblast
Promonocyte
AML (≥ 20%)
Immature
Monocyte
CMML
IWGM-MDS: Haematologica 2009; 94 (7): 994-999.
Morphology
X 100, oil Immersion
Flow Cytometry is Helpful….
Monoblast
Promonocyte
Immature
Monocyte
CMML
CD14
-
-/+
+
++
+
CD64
++
++
++
+
+ / ++
CD117
+
-
-
-
-
MPO
-
+/-
+
+
+
*Xu et al, Am J Path, 2005; 124 (5): 799-806.**Kern et al, Leuk Lymp, 2011; 52(1); 92-100
Reduced HLA-DR
Aberrant CD56
Aberrant CD2
Aberrant Markers Common
99%
83%
CD56 expressed in ≈ 80% CMML (40% AMoL)
• Nice technique for PB
• Very promiscuous antigen - caution
• May be induced in reactive states &/or G-CSF
/ GM-CSF administration
Trephine Histology
• Hypercellular
• Granulocytic Hyperplasia
• Excess monocytes; best appreciated with ICC
(e.g. CD68)
• Variable reticulin fibrosis
• May detect other causes of monocytosis or
additional pathology (e.g. SM-AHNMD)
Diagnosis: Summary
• Cytology (blood +/- marrow) crucial
• Flow useful to confirm abnormal monocytes &
maturational stage
• Trephine confirms myeloproliferative aspects
• Genetic testing: cytogenetics (non-specific,
abnormal in 30%), role of mutation analysis in
future.
Molecular Abnormalities
TET2 Mutations
Most common abnormality in
CMML
≈ 50% of cases mutated
Loss of protein function
tumour suppressor role ?
Found in CD34+ cells and Tcells
Prognostic impact controversial
Molecular Heterogeneity in CMML
Epigenetic
Regulation
Signalling
Pathways
TET2 ≈ 50%
? outcome
ASXL1 ≈ 40%
MPD phenotype, poor
outcome
EZH2 ≈ 10%
Poor outcome
JAK2 V617F ≈ 10%
MPD phenotype
CBL ≈ 20%
KRAS / NRAS ≈ 30%
mRNA Splicing
MPD phenotype, disease
progression
SRSF2 ≈ 50%
Transcription
RUNX1 ≈ 20%
Metabolism
IDH2 ≈ 10%
93% of CMML has
one or more
mutations in these
genes
Prognosis
“ A Disorder lost in Prognostication….”
1Aul
1992
Düsseldorf Score
Dusseldorf Registry1
1997
IPSS
WCC >12 x 109 excluded2
2002
MD Anderson Score
213 CMML pts3
2011
Cytogenetic Risk Score
Spanish MDS Registry4
2012
IPSS-R
WCC >12 x 109 excluded5
2013
CPSS
Spanish MDS Registry6
et al, Leukaemia 1992, 6, 52-59; 2Greenberg et al, Blood, 1997, 89 (6) 2079;3Onida et al, Blood 2002, 90 (3), 840; 4Such et al,
Haematologica 2011, 96 (3), 375; 5Greenberg et al, Blood 2012, 120 (12), 2454; 6Such et al, Blood 2013 epub ahead of print
Cytogenetic Risk Classification in CMML
• 414 pts from Spanish registry (1980-2008)
– 110 (27%) had abnormal karyotype
• 3 Cytogenetic Risk categories identified:
– LOW RISK (78%): Normal, or isolated loss of Y
– NORMAL RISK (9%): All other
– HIGH RISK (12%): Trisomy 8, abnormalities of
chr7, or complex
Such et al, Haematologica 2011, 96 (3)
5yr OS
35%
26%
4%
CMML-Specific Prognostic Scoring
System (CPSS)
Such et al, Blood 2013 epub ahead of print
CMML-Specific Prognostic Scoring System
(CPSS)
Median OS
Low (41%): 72 Months
Int-1 (29%): 31 Months
Int-2 (26%): 13 months
High (4%): 5 months
Such et al, Blood 2013 epub ahead of print
Treatment
Patient / Doctor Treatment Goals in CMML
Watch & wait
Palliation
Disease Modification
Supportive Care
? Demethylating Agents
Hydroxycarbamide
LD Ara C
? Experimental therapies
Steroids
HD chemo for sAML
Cure
Allo SCT (+/- HD
chemo pretransplant)
MS 20 months. p<0.0001
AML – 27%, ns
MS 9 months, p<0.001
AML – 38%, ns
Wattel et al, Blood 1996; 2480 - 2487
Palliation / LD Chemo / HD Chemo
• LD ARA-C
– No studies specific to CMML, some reponses reported
– Cytoreductive: use in extramedullary disease, pts with
poor response to hydroxy
• Prednisilone
– Symptomatic control; skin and pleural effusions.
• HD Chemo
– No role in isolation
– Pre allo SCT (1 or 2 cycles)
– ‘intensive’ palliation?
Patient / Doctor Treatment Goals in CMML
Palliation
Transfusion support
Hydroxycarbamide
LD Ara C
Steroids
Disease Modification
? Demethylating Agents
? Experimental therapies
Cure
Allo SCT (+/- HD chemo
pre-transplant)
Male Cases
Female Cases
Male Rate
Female Rate
100
12
≈ 85-90% of patients are >65
90
10
80
70
rate per 100,000 population
estimated cases UK
8
60
50
6
40
4
30
20
2
10
0
0
0-4
5-9
www.hmrn.org
10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79
age at diagnosis (years)
80+
Treatment Patterns
Spanish Registry (414 pts, 1980 – 2008)1
•
•
•
•
•
•
Supportive care (100%)
ESA (42%)
HC (16%)
AML-type Intensive Chemo (6%)
Allo SCT (<1%)
No Demethylating agents used
French Transplant Registry2
• 73 allos done 1992 – 2009
• approx 1.5 % of all cases of CMML transplanted based on incidence of
0.47 / 100,000 p.a.3
1Such
et al, Haematologica 2011, 96 (3); 2Park et al, EJH 2013; 3Drummond 2013, Back of an envelope, based on incidence
Transplant Outcome: 1992-2009
73 pts 1992 – 2009
Median age 53
43 RIC / 30 MA; 41 sibling / 32 VUD
Multivariate analysis
Splenomegaly at transplant (HR 0.48)
Transplant pre 2004 (HR 0.42)
?cytogenetic risk groups
1/3rd: Cured
1/3rd: TRM
1/3rd: Relapse
Park et al, 2013, EJH; epub ahead of print.
Patient / Doctor Treatment Goals in CMML
Palliation
Transfusion support
Hydroxycarbamide
LD Ara C
Steroids
Disease Modification
? Demethylating Agents
? Experimental therapies
Cure
Allo SCT (+/- HD chemo
pre-transplant)
AZA 001 Study. Fenaux et al 2009. The Lancet Oncology, 10;3:223-232
24.5 months V 15.0 months. Median FU 21.1 months
SMC Advice Sept 2011
Azacitidine is recommended as a treatment option for adults who are not
eligible for HSC and have:
1.
2.
3.
Int-2 or HR MDS according to IPSS
CMML with 10-29% marrow blasts and without myeloproliferative
disorder*
AML with 20-30% marrow blasts and multi-lineage dysplasia,
according to the WHO classification.
• CMML in AZA001 study had WCC <13 x 109/l*
• Identical to EMEA licensed indications
• (approved by NICE 2010 on back of pt access scheme. Approved by FDA in
2004; EMEA 2009).
Azacytidine in CMML: does it work?
• Europe: Registration Study (2009)
– AZA001 trial
– 11 pts with CMML; not separately reported
• USA: Registration Studies (2004)
– 3 studies (CALGB 9221, 8921, 8421)
– Total of 19 patients with CMML
– ORR (CR + PR, MDS criteria): 15.8%
Summary of Studies of Demethylating Agents in CMML
Year
Drug
Number of
subjects
Single Centre?
Response
2011
Azacitidine
38
Yes,
Retrospective
39% ORR
11% CR
25% HI
2012
Azacitidine
10
Yes,
Retrospective
60% ORR
40% CR
2007
Decitabine
19
Yes
69% ORR
58% CR
11% HI
2008
Decitabine
31
No
ORR 25%
CR 14%
PR 11%
HI 11%
2011
Decitabine
39
No
ORR 38%
CR 10%
Marrow resp
21%
In order: 2011 Costa et al, Cancer 117, 2690-2696; 2012 Thorpe et al, Leuk Res, 36, 1071-1073; 2007 Aribi et al, Cancer 109, 713717; 2008 Wijermans et al, Leuk Res 32, 587-591; 2011 Braun et al, Blood 118, 3824-3830.
• A phase 2 study of azacitidine in chronic
myelomonocytic leukaemia (CMML)
• Supported by the NCRI Haematological Oncology
MDS Subgroup
• Sponsored by Leeds Teaching Hospitals NHS Trust
• EudraCT Number: 2008-006349-23
Recruitment & Treatment
32 patients recruited (11 centres) Jan
2010 - August 2010
 Median age 70 (57 – 85); 67% male
 2 pts received <1 cycle
 14 pts < intended 6 cycles (most
progressed)
 16 pts ≥ 6 cycles

Drummond et al, abstract 0869, EHA 2012
Results
Drummond et al, abstract 0869, EHA 2012
Results
• 20 patients transfusion dependent at
diagnosis; 6 became transfusion
independent
• 5/7 pts on Hydroxycarbamide were able to
stop this drug
• Only 1/5 patients with skin lesions at outset
demonstrated resolution
• Median duration of responses 7.5 months
Drummond et al, abstract 0869, EHA 2012
Drummond et al, abstract 0869, EHA 2012
Conclusions…
“ Clinically meaningful responses (including
CR, GR, and PR) were limited (10-17%
depending on response criteria).” 3 patients
continue on drug (>cycle 18).
Support for Phase 3 trial: await oral aza?
Implications for MDS Guidelines.
Drummond et al, abstract 0869, EHA 2012
BCSH MDS Guidelines (Draft): Management of
CMML
Recommendations:
• Supportive care +/- hydroxycarbamide as required is recommended for most
patients (Grade 1B).
• Azacitidine is licensed for non-proliferative CMML-2 and can reasonably be
recommended. Hypomethylating agents are unlicensed for proliferative disease
(WCC ≥ 13 x 109/L) and as such their routine use is not recommended (Grade
2C).
• Allo-SCT with or without preceding AML-type chemotherapy should be
considered for selected patients (Grade 2B).
• Patients requiring treatment should be considered for any appropriate clinical
trial.
Drummond & Bowen 2012
Summary
•
•
•
•
Diagnosis may be challenging
New molecular markers
New CMML-specific prognostic score
Transplant curative in ≈ 30% but applicable to
very few patients
• Efficacy of azacitidine modest; not a universal
treatment.
Acknowledgements
Leeds CRU and Cellgene UK for CMML201 Support
David Bowen & Alex Szubert (statistician) Leeds
Participating Centres in CMML201 and MDS NCRN Trials Subgroup
Allyson Doig (Flow Cytometry)