La leucemia mielomonocitica cronica

Sessione 1: Approccio terapeutico
alle sindromi mielodisplastiche e alla
leucemia mieloide cronica
La leucemia
mielomonocitica
cronica
Francesco Onida
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Università Degli Studi di Milano
2008 WHO classification of the
Myelodysplastic/Myeloproliferative
Neoplasms (MDS/MPNs)
• Chronic Myelomonocytic Leukemia (CMML)
• Atypical Chronic Myeloid Leukemia (aCML)
• Juvenile Myelomonocytic Leukemia (JMML)
• MDS/MPN, Unclassifiable (MDS/MPN-U), including
refractory anemia with ring sideroblasts and thrombocytosis
(RARS-T) as a provisional entity
Vardiman et al., Blood 2009;114:937-951
Diagnostic criteria for CMML
1. Persistent peripheral blood monocytosis >1x109/L
2. No Philadelphia chromosome or BCR-ABL1 fusion gene
3. No rearrangement of PDGFRB (cases with eosinophilia and PDGFRB
abnormalities should be classified as “myeloid neoplasm with
eosinophilia associated with PDGFRB rearrangement”)
4. Fewer than 20% blasts* in the blood and in the bone marrow
5. Dysplasia in one or more myeloid lineages.
If myelodysplasia is absent or minimal, the diagnosis of CMML may still be
made if the other requirements are met, and:
• an acquired, clonal cytogenetic or molecular genetic abnormality is present
in the haemopoietic cells, or
• the monocytosis has persisted for at least 3 months and
• all other causes of monocytosis have been excluded
*Blasts include myeloblasts, monoblasts and promonocytes.
Orazi A et al. Myelodysplastic/Myeloproliferative Neoplasms, Chapter 4, in WHO Classification of Tumours of Haematopoietic
and Lymphoid Tissues, 4° Edition, IARC Press, 2008, pp. 76-86.
CMML
• Well-defined diagnostic criteria
• Heterogeneity of clinical features
• Extreme heterogeneity of natural course
Subclassification of CMML
1994 (FAB):
− Myelodysplastic (MD)-CMML
WBC ≤13x109/L
− Myeloproliferative (MP)-CMML
WBC >13x109/L
2001-2008 (WHO):
− CMML-1
PB-blasts <5%
BM-blasts <10%
− CMML-2
PB-blasts 5-19%
or Auer rods
BM-blasts 10-19%
or Auer rods
Life expectation in CMML
(127 pts)
Onida F - Unpublished data
Management recommendations for CMML:
consensus statements from the SIE, SIES,
GITMO groups
Prognosis and risk classification
Because life expectancy in CMML is highly heterogeneous,
risk assessment is recommended for clinical decision
making in individual patients
CMML-1 and CMML-2 WHO classification is recommended
for prognostic implications but it should not be considered
sufficient on its own to discriminate between low- and highrisk patients.
Haematologica. 2013 Sep;98(9):1344-52
Management recommendations for CMML:
consensus statements from the SIE, SIES,
GITMO groups
Prognosis and risk classification
Although not included in the WHO classification, the distinction
between MD- and MP-CMML is highly recommended due to its
clinical implications
The use of CMML specific risk-oriented systems* for individual
patient risk assessment is recommended, in particular for
patients who are candidates for allogeneic HSCT or enrolled in
clinical trials
* At present, there is no universally used validated CMML-specific risk classification
system
Haematologica. 2013 Sep;98(9):1344-52
Prognostic Scoring Systems
Cytogenetic risk stratification in CMML
Abnormal karyotype: 110/414 (27%)
• Trisomy 8
• -Y
• Complex
• Monosomy 7
Low risk:
• normal or –Y (single)
High risk:
• abn chr 7, complex, +8
(n=30; 27%)
(n=18; 16%)
(n=12; 11%)
(n=6; 5%)
Overall Survival
CMML-specific
IPSS CGs
Intermediate risk:
• all others
Such et al. Haematologica 2011; 96(3): 375
CMML-specific prognostic scoring system
(CPSS)
Training cohort: 558 pts (Spanish Group of Myelodysplastic Syndromes)
Validation cohort: 274 pts (Düsseldorf, Pavia)
Risk Groups:
Low = 0
Interm-1 = 1
Interm-2 = 2-3
High = 4-5
Such et al. Blood 2013; 121(15): 3005-3015
CMML-specific prognostic scoring system
(CPSS)
Training cohort
Validation cohort
An alternative CPSS with Hb instead of RBC transfusion dependency offered identical
prognostic capacity
Such et al. Blood 2013; 121(15): 3005-3015
Prognostic score including gene
mutations in CMML (GFM)
Training cohort: 312 pts (GFM)
Validation cohort: 165 pts (Munich Leukemia Laboratory cohort)
Itzykson R et al. J Clin Oncol. 2013 Jul 1;31(19):2428-36
Prognostic score including gene
mutations in CMML (GFM)
• Age > 65 yrs
= 2 points
• Anemia (M < 10 g/dL, F < 11 d/dL)
= 2 points
• WBC > 15 x 109/L
= 3 points
• Platelet < 100 x 109/L
= 2 points
• ASXL1 status
= 2 points
Risk Groups:
Low = 0-4
Interm = 5-7
High ≥ 8
Itzykson R et al. J Clin Oncol. 2013 Jul 1;31(19):2428-36
Prognostic score including gene
mutations in CMML (GFM)
Training cohort
Validation cohort
Itzykson R et al. J Clin Oncol. 2013 Jul 1;31(19):2428-36
International CMML Consortium
International CMML Consortium
International CMML Consortium
International CMML Consortium
Baseline characteristics
Padron E et al. ASH 2014
International CMML Consortium
Baseline characteristics - BM
Padron E et al. ASH 2014
International CMML Consortium
Baseline characteristics - blood
Padron E et al. ASH 2014
International CMML Consortium
Padron E et al. ASH 2014
International CMML Consortium
Padron E et al. ASH 2014
International CMML Consortium
Padron E et al. ASH 2014
Molecular analysis in CMML
(42 pts)
Onida F - Unpublished data
SRSF2
TET2
100%
100%
P = 0.0418
80%
80%
87%
60%
40%
60%
53%
47%
Patients with gene20%mutations
33%
20%
40%
38%
8%
100%
0%
MD
0%
P = 0.4134
MP
80%
mut TET2
2 mut TET2
60%
85%
1 mut TET2
MD
MP
73%
40%
ASXL1
20%
Proliferation-associated genes
100%
100%
0%
P = 0.0123
P = 0.0296
80%
MD
60%
80%
MP
60%
60%
40%
45%
20%
40%
20%
9%
9%
0%
0%
MD
MP
MD
MP
Onida F - Unpublished data
Prognostic impact of gene mutation
Onida F - Unpublished data
Prognostic impact of gene mutation
Onida F - Unpublished data
Management recommendations for CMML:
SIE, SIES, GITMO consensus statements
Determinants of therapeutic intervention
Therapy should be started when the disease is
symptomatic or progressive, and, in particular, when one
of these events occurs:
• a) severe anemia (Hb less than 10 g/dL);
• b) percentage of blasts in peripheral blood >5%
(including myeloblasts, monoblasts and promonocytes;)
•
•
•
•
•
c) platelet count ≤ 50x109/L;
d) WBC count ≥ 30x109/L;
e) immature granulocytes ≥ 10% in peripheral blood;
f) extramedullary manifestations of the disease
g) symptomatic splenomegaly
Haematologica. 2013 Sep;98(9):1344-52
Response rate: 60% vs 36%
Median Survival: 20 vs 9 months
Blood 1996, 88;7: 2480-2487
Intensive CT in CMML
Topotecan 1.25 mg/m2 c.i. x 5 d + Ara-C 1 g/m2 x 5 d
Response rate:
CR 12/27 (44%)
Response duration: median 33 wks
Beran M at al. JCO 1999, 17: 2819-2830.
Further intensification of treatment increases toxicity and mortality
and does not appear to significantly benefit response and survival.
Beran et al. Blood 2001, 98:624a
FTIs in CMML
CRs:
CMML-1 (1 of 8; 12.5%)
CMML-2 (2 of 9; 22.2%)
Median survival: 14.5 months
Leukemia 2008;22:1707–1711;
Blood 2007;109:4158-4163
In CMML, tipifarnib and lonafarnib as single agents were associated with low
and short-lasting response rates independent of RAS mutational status and
inhibition of farnesyltransferase.
Azacitidine in CMML
Azacitidine in CMML
Pleyer L et al. Leukemia Research (2014) 38, 475-483
Azacitidine in CMML: A UK multi-centre phase 2
prospective controlled study
Drummond MW et al. Leukemia (2014) 28, 1570–1572
Decitabine in CMML
European trial: 66 high-risk MDS patients. 45 mg/m2/d for 3 dq 6 wks
9 CMML pts 1 CR, 1 PR, 2 HI (overall RR of 44%)
Wijermans P et al. J Clin Oncol 2000, 18:956–962
MDACC trial: Number of patients
19 CMML/95 MDS
13 (68%)
WBC >12 x 109/L
Schedule
20 mg/m2 i.v. x 5 d q28
20 mg/m2 s.c. x 5 d q28
10 mg/m2 i.v. x 10 d q28
16
1
2
Median number of courses
9 (range 1-18)
Complete response
Hematologic improvement
11 (58%)
2 (11%)
Aribi A et al. Cancer 2007. 109;13:713-717
Decitabine in CMML – GFM Trial
39 patients (Nov 2008 – Jun 2009) – 32/39 MP-CMML
• Inclusion criteria:
- CMML dx according to WHO 2008, except BM blasts up to 29%
- Poor prognosis (Int-2/High in MD, additional criteria in MP)
• Treatment schedule: 20 mg/m2 i.v. x 5 d q28
Braun T et al. Blood 2011 118 (14) : 3824-3831
Decitabine in CMML – GFM Trial
• Median number of cycles = 10 (range 1-24)
• ORR 38% (15 pts)
• 10% CR (4 pts)
• 20% marrow CR (8 pts)
• 8% HI (3 pts)
RBC-transfusion independence in 36% (8/22)
• 46% SD (18 pts)
• 15% progression to AML (6 pts)
Braun T et al. Blood 2011 118 (14) : 3824-3831
Decitabine in CMML – Italian Trial
Titolo dello studio
Studio clinico di fase II, aperto, multicentico che
valuta l’efficacia di decitabina nel trattamento della
leucemia mielomonocitica cronica nell’adulto
Tipo di studio
Studio aperto multicentrico
Dose
6 cicli di decitabina 20 mg/m2 ev in infusione continua per
5 gg ogni 28 gg
Obiettivo principale
Efficacia di decitabina : percentuale di risposta secondo
IWG 2000/2006
Obiettivi secondari
Durata di risposta, sopravvivenza , Qualità di vita, studio
biologico (midollo e s. periferico) della metilazione e
espressione genica
Arruolamento
12 mesi , 43 pazienti
Durata dello studio
2 anni
By courtesy of V. Santini
Italian Trial - Criteri di inclusione
1. Età > 18 anni
2. Diagnosi di LMMC secondo criteri WHO 2008
3. Se leucociti ≤ 12 000/mm3: IPSS alto o INT-2
Se leucociti > 12 000/mm3: almeno 2 dei criteri seguenti:
- Blasti midollari > 5 %
- Tutte le anomalie citogenetiche clonali, esclusa t(5;12) (q33; p13)
- Anemia < 10 g/dL
- Piastrinopenia < 100 x 109/L
- Splenomegalia > 5 cm sotto il margine costale
- Localizzazione extra midollare dimostrata
Decitabine in CMML – Risultati preliminari
• N ° pazienti arruolati = 44 (variante proliferativa > 80%)
• Età mediana = 72 anni (range 46-84)
• Mediana cicli somministrati = 14 (range 1-34)
• 2 pazienti ancora in trattamento (08/2014)
• Risposta completa = 36% (16/44).
• Buona tolleranza globale. Tossicità prevalentemente ematologica.
• Metiloma alla diagnosi predittivo di risposta
V. Santini, comunicazione personale
Lenalidomide//Melphalan in CMML
Lenalidomide
Buckstein R et al. Leukemia Research (2014) 38, 756-763
Lenalidomide//Melphalan in CMML
Lenalidomide
CMML pts number = 12 (9 MP-CMML). Median age 73 (range 52-87)
Lenalidomide 10 mg + Melphalan 2 mg x 21 days (q28) up to 12 cycles
3 responses, all in MP-CMML: 1 CR (68 d), 1 HI-PLT (63 d), 1 HI-E (147 d)
Buckstein R et al. Leukemia Research (2014) 38, 756-763
Management recommendations for CMML:
SIE, SIES, GITMO consensus statements
First-line therapy - 1
The treatment strategy should be decided first according to the
disease hematologic phenotype (MD vs MP) and to the number
of blasts
Patients with MD-CMML and less than 10% blasts in BM
should be managed with supportive therapy aimed at
correcting cytopenias. Patients with severe anemia and with
serum EPO ≤ 500 mU/dL) should be treated with ESA.
G-CSF may be considered in febrile neutropenia.
In MD-CMML with high number of blasts (≥10% in BM, ≥5%
in the blood), supportive therapy should be integrated with
the use of hypomethylating agents.
Haematologica. 2013 Sep;98(9):1344-52
Management recommendations for CMML:
SIE, SIES, GITMO consensus statements
First-line therapy - 2
In selected patients with MD-CMML, allo-SCT may be offered
within clinical trials
Patients with MP-CMML with a low number of blasts should
be treated with cytoreductive therapy. HU is the drug of
choice to control proliferative myelomonocytic cells and to
reduce organomegaly.
Patients with MP-CMML and a high number of blasts should
receive blastolytic therapy with polychemotherapy followed,
when possible, by allo-SCT (within clinical trial).
Haematologica. 2013 Sep;98(9):1344-52
Allo--SCT in CMML
Allo
FHCRC (1990-2004)
Pts number = 43. Median age 48 yrs (range 1-66)
MD-CMML 16 (37%) / MP-CMML 27 (63%)
WHO CMML-1: 32 /CMML-2: 11
Related donors in 21/ 22 UD
Various conditioning regimens
(mostly Bu-Cy or Bu-Cy-TBI)
RFS 41% at 4 yrs, Cum. relapse 21%, NRM 35%
Kerbauy et al. Biol BMT 11:713-720 (2005)
EBMT (1988-2000)
Pts number = 50. Median age 44 yrs (range 19-61)
Related donors in 43 / 7 MUD
Various conditioning regimens
RFS 18% at 5 yrs, Cum. relapse 49%, NRM 52%
Graft versus CMML effect?
Kröger et al. Br J Haematol 2002, 118:67–73.
Allo--SCT in CMML
Allo
Pts number = 85 Median age 52 yrs (range 1-69)
CMML: de novo in 84%, secondary in 16%
Donors: related in 38 (45%); unrelated in 47 (55%)
Major causes of death: relapse and infections ± GvHD
Outcomes at 10 yrs:
• Progression-free Survival 38%
• Cumulative relapse 27% (correlated with MDAPS)
• Mortality associated with: lower Hct, HR CGs, High C.I., Older age
• Outcome not affected by WHO classification
Eissa H et al. BBMT 2010
Allo--SCT in CMML (SFGM
Allo
(SFGM--TC)
Pts number = 73 (1992-2009).
Median age 53 yrs (range 27-66)
MD-CMML 57 (78%) / MP-CMML 16 (22%)
WHO CMML-1: 24 /CMML-2: 26
Related donors in 41/ 32 UD
MAC 41%, RIC 59%
OS 42 % at 2 yrs, 32% at 3 yrs
RFS 29% at 3 yrs,
Cum. relapse 35% at 3 yrs,
NRM 36% at 3 yrs
Park et al. Eur J Haematol. 2013 May;90(5):355-64
Open questions
Criteri diagnostici:
Definizione di monocitosi. Relativa o assoluta?
• AMC >1000/mcL, >10%?
• WBC? Stable vs unstable count?
• IMC?
Eterogeneità clinica sottoclassificazioni:
• MD- vs MP-CMML (what should be really considered MP?)
• CMML-1 vs CMML-2
• Different molecular aberrations/signature (pathways)
A proposal for a possible solution to the
MD vs MP classification dilemma
A new MDS subcategory:
• RCUD/RCMD with monocytosis
(monocyte >10%, WBC <10.000/mcL, IMC 0%, no splenomegaly)
Within the MDS/MPN:
• CMML with WBC 10.000 to 20.000/mcL (monocyte >10%)
• CMML with WBC <10.000/mcL (monocyte >10%) if IMC >0% and/or
splenomegaly and or organ infiltration (e.g. skin)
A new Ph-negative MPN subcategory:
• MP-CMML with WBC >20.000/mcL (monocyte >10%), or requiring
cytoreductive treatment to maintain WBC <20.000/mcL
Myeloid Disorders
RCUD/RCMD with monocytosis
MDS
MDS/MPN
CMML
MPN
MP-CMML
AML