leucémies à plasmocytes · biologie • phénotype (différences / mm) : ≈ d38 d138 ↓ d56 ↓...
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Leucémies à plasmocytes
Dr Bruno Royer
Hématologie clinique et thérapie cellulaire
sPCL : secondaire à un MM évolutif, 40 à 50% des PCL
pPCL : 2-4% des MM de novo
Plus jeunes, plus forte masse tumorale, plus d’atteinte extramedullaire plus
de BJ et d’insuffisance rénale => vont plus mal que les MM
Biologie
• Cytogénétique
Série IFM 70 patients (Leukemia 2011)
t(4;14) 21% (vs 15%)
t(11;14) 25% (vs 20%)
t(14;16) 17% (vs 3%)
del17p 20% (vs 7%)
t @ ch14
t @ ch14 ≈ 2/3
Usmani et al. Leukemia 2012
27 pPCL / 1474 MM (TT& TT2 TT3) = 1,8%
Biologie
• Phénotype (différences / MM) :
≈ CD38 CD138
↓ CD56
↓ CD19 CD117 HLADR
↑ CD20 CD27 CD28
Intérêt au diagnostic (+ sensible que la cytologie)
Pas de données MRD
Leucémie à plasmocytes
Plasmocytose réactionnelle
Plasmocytes (CD38+++ CD138+++) de profil anormal : CD19- CD56+ monotypie kappa
Plasmocytes (CD38+++ CD138+++) de profil normal : CD19+ CD56- polytypique (ckappa/ clambda = 1,1)
Biologie
• SNP array
Anomalies très fréquemment retrouvées (CN ou LOH)
amp 1q21
del 1p21, 13q, 16q, 2q, 6q, 8p …
CCND1, FGFR3/MMSET, MAF
MYC amp
CDKN2C del
TP53 del
Mosca et al. AMJ2012
Biologie
• GEP
Groupe haut risque :
44% (70-gene model) et 31% (80-gene model) vs 16% et 7%
Sous groupe moléculaire: CD-1 et MF
203 genes pPCL / non pPCL :
Métabolisme des lipides
CD14, TNF receptor-associated factor2, chemokine C-C ligand
Usmani et al. Leukemia 2012
Critères de réponse
Pronostic / Traitements
TT classiques : OS < 12m
Traitements intensifs :
Série rétrospective (n=38)1
• Auto-HCT OS 36m [1-106]
• Allo-HCT OS 20m [1-84]
Registre CIBMTR (n=147)2 :
• OS à 3 ans : • Allo = 64 %
• Auto = 39%
1 Saccaro et al. Am J Hem 2005 2 Mahindra et al.Leukemia 2012
Pronostic / Traitements
Usmani et al. Leukemia 2012
OS PFS
CRD
Total Therapy
Pronostic / Traitements
Bortezomib Qq case reports Série rétrospective grecque
42 pts: pPCL (n=25), sPCL (n=17) 6/25 pPCL => auto-HCT Median OS = 18m / pPCL
Katodritou
et al. Am J Hem 2013
Pronostic / Traitements
Lenalidomide
Qq case reports
Une étude prospective
23 pts, pPCL
Rev-Dex x 4 mois
• Si réponse et éligible/Auto => high dose MLP + auto
9/15 ont eu auto (4 single, 4 double) + 1 auto/RIC-allo
• Si réponse et non éligible => RD x 4 puis maintenance Rev
Median PFS = 14m, OS = 28m
Musto et al. Leukemia 2013
Pronostic / Traitements
Musto et al. Leukemia 2013
Reco / Traitements
First large prospective study for patients with primary plasma cell
leukemia: bortezomib-doxorubicin-dexamethasone /
bortezomib-cyclophosphamide-dexamethasone regimens as
induction before stem cell transplantation followed by
consolidation with lenalidomide-bortezomib-dex or allograft.
(A study of the IFM group)
B Royer, F Magrangeas, B Lioure, JP Fermand, C Hulin, L Karlin, S Cailleres, C Dauriac, M Macro, M Wetterwald, L Garderet, X Leleu, P Moreau, F Guilhot, JG Fuzibet, M Tiab, J Fontan, C Chaleteix, D Caillot, P Casassus, R Delarue, K Beladj, JP Marolleau, M Roussel and H Avet-Loiseau.
ASH 2013
IFM study
• French, multicenter and prospective phase II trial *
• Inclusion criteria: pPCL not previously treated
18 y ≤ age ≤ 70 y
• Primary end-point: Progression free survival (PFS)
• Secondary end-points: Response rate, overall survival (OS), toxicity Cytogenetic analysis: FISH, SNP array Minimal residual disease (MRD) evaluation
Of note, severe renal insufficiency or dialysis were not an exclusion criteria
* N° EUDRACT 2009-016607-33
Primary Plasma Cell Leukemia No prior therapy
Induction: PAD / VCD
alternance of 4 cycles (D1=D22)
Response ≥ SD and blood PC < 1% => Cyclophosphamide + G-CSF
=> PSC collection
Melphalan 200mg/m2 + ASCT
If response ≥ VGPR, age < 66y and donor
Melphalan 200mg/m2 + ASCT n°2
Consolidation/maintenance for 12 months VRD / 3months
Len: 15mg D1-D21/ every other months Reduced Intensity Conditioning-allograft
If age > 66y or no donor
PAD: Bor1.3mg/m2 +Dex 40mg ) D1 D4 D8 D11 + Doxo 30mg/m2 D4 VCD: Bor1.3mg/m2 + Dex 40mg ) D1 D4 D8 D11 + Cyclophosphamide 300mg/m2 D1 D8 VRD: Bor1.3mg/m2 + Dex 40mg ) D1 D4 D8 D11 + Len 15mg D1-D14 RIC-allo: Fludarabin-Busulfan-Antilymphocyte serum
Design
Cytogenetic
MRD
MRD
MRD
MRD
Results
From April 2010 to July 2013:
40 patients were included
Patients (M / F), n 40 (14 / 26 )
Age , y 57 (27 - 71)
Circulating plasma cell (109/l) 5.8 (0.9 - 66.2)
Hemoglobin (g/dl) 9.4 (7.4 – 13.6)
Platelets (109/l) 110 (15 - 453)
Creatinin clearance (ml/mn) Cr Cl < 50 Cr Cl < 30
66.2 (5.5 – 162) 27% 10%
Albumin (g/l) 37.5 (14.5 - 61)
LDH (x normal value) 1.3 (0.7 - 10.7)
Β2 microglobulin (mg/l) 5.1 (1.2 - 73)
ISS 2 / ISS 3 43% / 43%
M component (n) Ig G Ig A Ig D Ig M Light chain only No component ND
15 5 2 1 13 3 1
Cytogenetic
*no data, n=8
Results at analysis (Nov 2013)
• Median follow-up was 15.0 months (CI 95% = [11.3; 25.4])
• 1 pt died before any treatment and was excluded from analysis
• 39 pts are evaluable after induction phase:
27 (69%) responded (IMWG criteria AND circulating PC <1%)
CR 16%
VGPR 32%
PR 44%
SD 8%
12 (31%) did not respond or died
They did not continue the program, as per protocole
48%
Results
• On 27 responding patients:
24 underwent stem cell transplant n°1 ( 23 Auto, 1 Allo) and were evaluable at 3 months:
sCR 4%
CR 33%
VGPR 29%
PR 22%
SD 4%
PD 8%
Second ASCT = 6 pts
Consolidation/maintenance (ongoing) = 7
RIC-Allo = 15 pts
66%
Results
In intent to treat analysis:
Median PFS = 15.1 months (CI 95% = [8.44; -])
Median OS = 36.3 months (CI 95% = [25.6; -])
Results
For the 24 pts who underwent the first transplant (auto n = 23, allo = 1):
Median OS = 36.3 m [25.6 ; -]
For the 12 pts who did not respond to induction:
Median OS = 10.5 m [8.5 ; -]
Allo-HSCT
17 patients :
Syngenic (1), Ric-Allo (1*), tandem (15)
J100 :
≥ VGPR 76%, PR 12%
TRM 12%
Immuno-modulation (n=3):
PR => RC (n=1)
VGPR => VGPR (n=2)
aGvHD 35%, cGvHD 30%
Follow-up 22m [7-41] / Diag
Follow-up 14m [1-32] / Allo
Rechute 35% ; Décès 25%
A 1 an/diag : OS 87% PFS 86%
A 1 an/Allo : OS 68%, PFS 65%
* Réfractaire à l’induction et au Rev Abstract EHA 2014 : ABSSUB-3564.
Toxicity
• Major toxicities were hematological and manageable
• No grade III/IV neuropathy
• 12 patients died:
• 1 before any treatment: sepsis
• 2 during induction: sepsis
• 2 post RIC-Allo: EBV+ relapse (1), EBV + toxoplasmosis (1)
• 7 from disease progression
• Of note, 2 patients had neuromeningeal relapse (post ASCT n=1 and post RIC-Allo n=1)
Conclusion
First large prospective phase II trial for pPCL patients.
Alternating PAD/VCD as induction before HDM/ASCT
Is feasible
Induces high response rates
Prolongs PFS (median 15.1 m) and OS (median 36.3 m)
Allograft or second HDM/ASCT plus consolidation/maintenance are ongoing
Correlation with cytogenetic and MDR are currently under investigation
Novel therapeutic approches and prospective trials are needed for pPCL patients