Immunophenotypic alterations of BM myeloid cells in Multiple

Immunophenotypic alterations of BM myeloid cells in Multiple Myeloma predict for MDS‐associated cytogenetic alterations
Cytometry Service, Department of Medicine Centro de Investigación del Cáncer (IBMCC, CSIC‐USAL) and Instituto de Investigación Biomédica de Salamanca (IBSAL)
University of Salamanca, SPAIN
Sergio Matarraz
The Hague, May 2014
MM therapy overtime  1960s. MELFALAN: anti‐MM effect.  1980s. HDM‐ASCT in younger MM patients: improved response rates and progression‐free survival.  Last decade. Thalidomide, bortezomib, lenalidomide: improved response rates, progression‐free survival and overall survival.
Cumulative incidence risk of second primary cancers in MM McCarthy et al, N Engl J Med. 2012 May 10;366(19):1770-81
Risk of hematologic and nonhematologic malignancies
Hematologic
MM (n=8740)
MGUS (n=5652)
Non‐hematologic
Mailankody S et al. Blood 2011;118:4086-4092
Risk of hematologic malignancies
Hematologic
MM (n=8740)
SIR: 11.5
MGUS (n=5652)
SIR: 8.1
SIR: 12.8 (IgM)
Median time to AML/MDS diagnosis: 45.3 months………………………….14.4 months
Mailankody S et al. Blood 2011;118:4086-4092
Immunophenotypic alterations in myeloid BM cells from symptomatic and smoldering MM
Diagnosis
Matarraz S et al. Haematologica 2012; 97:1608-11
Immunophenotypic alterations in myeloid BM cells from symptomatic and smoldering MM
Diagnosis
After Induction
Matarraz S et al. Haematologica 2012; 97:1608-11
Objectives
 To investigate the presence of bone marrow MDS‐associated phenotypic
alterations in newly diagnosed patients with PLASMA CELL DISORDERS.
 To investigate the presence of additional MDS‐associated features.
Myeloid
clonality
Patients and Methods
n= 250 consecutive BM samples from PLASMA CELL NEOPLASIAS
n= 33 (13%) depicted MYELOID phenotypic alterations:
MGUS (n=8)
MM (n=25)
 Neutrophil
 Monocytic
 PC
‐ Neutrophil hypogranulation
‐ Normal neutrophil granulation
Aberrant CD56 monocytic expression
Matarraz S et al. Leukemia 2014 [Epub ahead of print]
Objectives
 To investigate the presence of additional CLONAL MYELOID FEATURES in MGUS/MM patients with Phenotypic abnormalitites. n= 33/250
 Additional Immunophenotyping
 FACS‐sorting: FISH/HUMARA
 Conventional morphologic assessment
Additional flow cytometry studies: n= 33
 EuroFlow AML/MDS panel
 FACS-sorting (purity ≥97%): o CD34+ HPC
 iFISH
o Neutrophil
 HUMARA
o Monocytic o Erythroid Matarraz S et al. Leukemia 2014 [Epub ahead of print]
 EuroFlow AML/MDS panel: n= 33
Cases with phenotypic alterations
Matarraz S et al. Leukemia 2014 [Epub ahead of print]
 EuroFlow AML/MDS panel: n= 33
Matarraz S et al. Leukemia 2014 [Epub ahead of print]
Neutrophil alterations in a MM patient with further confirmation
of del5q-
 Normal reference Neutrophil maturation (n=47 normal BM samples)
Plasma cells
Percentage of events
Differences vs. Normalized Maturation
Neutrophil stages (n=20)
Monocytic alterations in a MM patient with further confirmation of
del5q-
 Normal reference Monocytic maturation (n=47 normal BM samples)
Percentage of events
Differences in Normalized Maturation
 Myeloid Genetic alterations in MGUS and MM
N. of altered cases
Matarraz S et al. Leukemia 2014 [Epub ahead of print]
 Morphologic alterations in MGUS and MM
 Megakaryocytic Lineage: disperse nuclei, monolobated nucleus
 Myeloid cells: degranulation, internuclear and intercytoplasmic bridges, nuclei
hyposegmentation, clumping chromatin
 Erythroblasts: karyorrhexis, excentric nucleus, basophilic stipling, internuclear
bridges, inclusions.
Matarraz S et al. Leukemia 2014 [Epub ahead of print]
 Myeloid morfologic alterations in MGUS and
MM (n= 19)
Megakaryocytic dysplasia
 Myeloid morfologic alterations in MGUS and
MM (n= 19)
DISPLASIA MULTILÍNEA Y CÉLULAS PLASMÁTICAS
1
3
2
MGUS and MM with MDS-PA: Outcome
 MGUS (n=5)
‐ 3/5 cases were finally diagnosed as having also MDS
‐ 1/5 depicted deep worsening of thrombocytopenia
 MM (n=15)
‐ 2/15 cases were finally diagnosed as having also MDS
‐ 1/15 developed clinical MDS one year after diagnosis of MM
‐ 42% of remaining cases died during the first year
Matarraz S et al. Leukemia 2014 [Epub ahead of print]
Conclusions
 Clonality outside the PC compartment was fully demonstrated in >5% of patients with PC disorders.
 A significant proportion of MM and MGUS patients with either isolated or
multiple/marked phenotypic alterations also display genetic and/or
morphologic evidences of myeloid clonality.
 Immunophenotyping of BM precursors and myeloid cells at diagnosis may
help to discard underlying MDS. More careful follow‐up.
 The high rate of deaths point to the need of further evaluation (in large
patient series) of the adverse clinical impact of these MDS‐like features in clinical trials.
Acknowledgements
Funding
•
Fundación Científica Asociación Española Contra el Cáncer (AECC)
•
Fundación Solórzano (Universidad de Salamanca, Spain)
•
Gerencia Regional de Salud de Castilla y León, Spain
Thanks to:
•
Prof. Alberto Orfao and cols. (n~50). CIC, Salamanca, Spain.
•
Dr. Bruno Paiva, Prof. Jesús F. San Miguel. Clínica Universidad de Navarra (Pamplona).
•
Dr. María Díez-Campelo, Prof. MC del Cañizo. University Hospital of Salamanca.
•
Dr. MJ Berruezo, Dr. MP Garrastazul. Punta Europa H. (Algeciras, Spain)
•
Dr. JM Durán. La Linea H. (Cádiz, Spain)
•
Dr. Carlos Cerveró. Virgen de la Luz H. (Cuenca, Spain)
•
Dr. JA García-Erce. San Jorge H. (Huesca, Spain)
•
Dr. Lourdes Florensa. H. del Mar (Barcelona, Spain)
•
Dr. Guy D. Méndez. Jerez H. (Cádiz, Spain)
•
Dr. Oliver Gutierrez. Rio Hortega H (Valladolid, Spain)

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