Leucemia PlasmacellularePellegrino Musto
Dipartimento Onco-EmatologicoSC Ematologia Trapianto di Cellule Staminali
IRCCS - Centro di Riferimento Oncologico della BasilicataRionero In Vulture (Pz)
IRCCSCROB
Mieloma Multiplo: Una nuova eraConvegno Regionale SIE
Pescara, 22 Settembre 2009
WhatWhat isis Plasma Plasma CellCell LeukemiaLeukemia (PCL)? (PCL)?
• 2-4% of all myelomas• 20% plasma cell in peripheral blood and/or absolute number
> 2 x 109/l• Primary PCL: patients without previous evidence of MM
(60%)• Secondary PCL: leukemic transformation of a previously
diagnosed myeloma (40%, 1% of myelomas), oftenrepresenting a chemo-resistant, terminal event with a mediansurvival of only 1-2 months
• Aggressive presentation with constellation of adverse clinicaland biological prognostic factors of myeloma
Blade’ and Kyle, Hematol Oncol Clin North Am 1999Hayman and Fonseca, Curr Treat Options Oncol 2001International Myeloma Working Group, Br J Haematol 2003
Evolution of MM: the multistep processfrom MGUS to myeloma progression/PCL
Plasma Cell Leukemia
Hyperdiploidy (40%) 14q32: majority of cases
• 11q13: most common (bcl-1 locus, 30%)• 4p16 (FGFR3, MMSET, 25%)• 8q24 (c-myc, 5%)• 16q23 (c-maf, 1%)• 6p25 (IRF4, rare)17p13 deletion (p53)13 deletion (Rb): 10-20%Cytog., 50% FISHChromosome 1 gain
N-Ras, K-Ras (30%),p16 methylation (40%) Secondarytranslocations (?)
Extramedullary disease in PCL
Channels (FITC-A)0 50 100 150 200
DebrisAggregatesDip G1Dip G2An1 G1An1 G2An1 S
Diploid: 38.33 %Aneuploid 1: 61.67 %DI: 1.10
FISH for Deletion 13
Normal Deletion 13
GenesChromosomesCancer.2009Jul;48(7):624-36.
FrequentupregulationofMYCinplasmacellleukemia.ChiecchioL,DagradaGP,WhiteHE,TowsendMR,ProtheroeRK,CheungKL,StockleyDM,OrchardKH,CrossNC,HarrisonCJ,RossFM;UKMyelomaForum.
ImmunophenotypeImmunophenotype of MM and PCL of MM and PCL
100%100%CD38+
21%56%HLA-DR+
0%43%CD117+
46%78%CD9+
45%70%CD56+
50%17%CD20+
8%7%CD15+
23%31%CD13+
6%6%CD10+PCLMMAntigen
Garcia-Sanz R. et al. Blood 1999; 93; 1032
14ND22Pejing et al, 2009
52330Colovic et al, 2008
843184Total
7378Jimenez and Dominguez, 2006
22924Vela-Ojeda et al, 2002
76718Costello et al, 2001
83826Garcia-Sanz et al, 1999
123727Dimopoulos et al., 1994
7628Bernasconi et al, 1989
74725Noel and Kyle , 1987
Median Overall Survival(months)
Response rate(%)N. PatientsReference
Response rate and overall survival in larger and more recent series ofprimary PCL initially treated with “standard” chemotherapy (mainly single
alkilating agents +/- steroids or anthracyclin containing regimens)
StemStem CellCell TransplantationTransplantation and and primaryprimary PCL PCL
Induction with combination therapy followed by autologous or allogeneic stem celltransplantation is currently recommended for eligible patients with primary PCL
• Hayman and Fonseca, Curr Treat Options Oncol 2001• Gertz, Leuk Lymphoma 2007
Using transplant approaches, long term survivals have been occasionally reported
• Sajeva et al, Bone Marrow Transplant 1996• Hovenga et al, Bone Marrow Transplant 1997• Sica et al, Bone Marrow Transplant 1998• Panizo et al, Acta Haematol 1999• Nonami et al, Jpn J Clin Oncol 2007• Hosono et al, Gan To Kagaku Ryoho, 2008• Iino et al, Gan To Kagaku Ryoho, 2008
Median OS was about 36 months (range 1-106) after autologous and about 20 months (range1-84) after allogeneic stem cell transplantation in 38 evaluable patients with primary PCL
• Saccaro et al, Am J Hematol 2005
However, even with these treatments, results may result unsatisfactory
• Johnson et al, Ann Diagn Pathol 2006• Masuda et al, Jpn J Clin Oncol 2007
Primary Plasma Cell Leukemia:Results of a retrospective Italian multicentric survey
Pagano L., Valentini C.G., De Stefano V., Venditti A., Visani G., Petrucci M.T., Candoni A., SpecchiaG., Visco C., Pogliani E.M., Ferrara F., Galieni P., Gozzetti A., Avvisati G., Leone G., Musto P. and
Pulsoni A for GIMEMA-ALWP
• A multicenter retrospective cohort study of 73 cases of primary PCL, carried out betweenJanuary 2000 and December 2008 in 26 Italian hematology centres
• M/F 43/30, median age 63 years (range 32-86)
• Median values of peripheral blood plasma cells at diagnosis: 2.7 x 10^9/L (range 0.4-49.9)
• Median Hb: 9.1 g/dl (range 4.8-12.9)
• Median WBC count: 13.7 x 10^9/L (range 1.3-56.7)
• Median PLT count: 116 x 10^9/L (range 8-428)
• Extramedullary disease: 10 cases (14%): testis, muscles, SNC, skin
• At least one CRAB at diagnosis: 64 pts (88%) Anemia 35 pts (48%), Hypocalcemia 20 pts (27%), Renal failure 32 pts (44%), Bone lesions 47 pts (64%)
• Uunfavourable karyotype in 17 (41%) of 41 tested patients ASH 2009,submitted
• Seventy-two pts received front-line therapy (1 died early, receiving onlysupport treatments and steroids)
• Antracycline-containing regimens: 36 pts (50%)• Single alkylating agents: 6 pts (8%, cyclofosfamide or melphalan)• Alkylating agents + bortezomib: 7 (10%)• Alkylating agents + thalidomide: 4 (6%)• Bortezomib +/-steroids: 4 (6%)• Thalidomide +/- steroids: 5 (7%)• Thalidomide + Bortezomib: 10 (13%)
• AuSCT: 17 (24%)• Tandem AuSCT-AlloSCT: 4 (6%)• Allo-SCT: 2 (3%)
• ORR: 53% (20 CR, 27% and 19 PR, 26%)
Primary Plasma Cell Leukemia:Results of a retrospective Italian multicentric survey
Pagano L., Valentini C.G., De Stefano V., Venditti A., Visani G., Petrucci M.T., Candoni A., SpecchiaG., Visco C., Pogliani E.M., Ferrara F., Galieni P., Gozzetti A., Avvisati G., Leone G., Musto P. and
Pulsoni A for GIMEMA-ALWP
ASH 2009,submitted
Overall survival
0 25 50 75 1000
50
100Legend
OS
Percent survival
Survival of Data 1:Survival proportions
0 25 50 75 1000
50
100Legend
PFS
Percent survival
Median OS: 13.1 months (range 0.5-75.8) Median PFS: 17.2 months (range 1.4-72.1)
OS and PFS in 73 patients with primary PCL
Survival of Data 1:Survival proportions
0 25 50 75 1000
50
100 TMO
NonTMO
OS
Percent survival
P<0.0001
Survival of Data 1:Survival proportions
0 25 50 75 1000
50
100RispostaNon risposta
OS
Percent survival
P<0.0001
Survival of Data 1:Survival proportions
0 25 50 75 1000
50
100alb>3alb<3
OS
Percent survival
p=0,0030
Survival of Data 1:Survival proportions
0 25 50 75 1000
50
100CD56 negCD56 pos
OS
Percent survival
p=0,0600 su 41 pz
Survival of Data 1:Survival proportions
0 25 50 75 1000
50
100TMONo TMO
0.0008
PFS
Percent survival
Survival of Data 1:Survival proportions
0 25 50 75 1000
50
100No osteolisiOsteolisi
0.0442
PFS
Percent survival
Survival of Data 1:Survival proportions
0 25 50 75 1000
50
100Alb>3Alb<3
0.0494
PFS
Percent survival
Survival of Data 1:Survival proportions
0 10 20 30 40 500
50
100CD56posCD56 neg
0.0199
PFS
Percent survival
Survival of Data 1:Survival proportions
0 25 50 75 1000
50
100autoallo
0.2190
PFS
Percent survival
Survival of Data 1:Survival proportions
0 25 50 75 1000
50
100BTZ sìBTZ no
OS
Percent survival
p=0,8420
Table 1: results of multivariate analysis for OS (tot 73 pts).
0.041.000.34 (0.12-0.98)
Stem cell transplantationNoYes
0.00081.003.33 (1.64-6.76)
Albumin≥3 g/dl< 3 g/dl
0.041.000.50 (0.25-0.97)
Hb≥m (9.2 g/dl)<m
0.031.002.62 (1.04-6.57)
Lack of initial responseNoYes
PHR (95% CI)VARIABLE
OS
0.00051.000.05 (0.0009-0.28)
Stem cell transplantationNoYes
0.0041.000.14 (0.04-0.54)
OsteolysisNoYes
0.041.004.00 (1.04-15.24)
Calcium< 11 mg/dl≥ 11 mg/dl
PHR (95% CI)VARIABLE
PFS
Results of Multivariate Analysis
New drugs for primary PCL: Thalidomide
Conflicting results• Bauduer, Br J Haematol, 2002• Tsiara et al, Acta Haematol, 2003• Johnston and Abdalla, Leuk Lymphoma 2002• Petrucci et al, Leuk Lymphoma, 2007• Ballanti et al, Nat Clin Pract Oncol 2007• Bruck et al, Int J hematol 2007• Pretz et al, Am J Hematol 2009
New drugs for primary PCL: BortezomibEfficacy of Bortezomib, as single agent or in sequence after other combinationchemotherapies, both in primary and secondary PCL
• Esparis-Ogando et al, Int J Cancer 2005• Ataergin et al, Am J Haematol 2006• Finnegan et al, Leuk Lymphoma 2006• Capalbo et al, Ann Oncol 2007• Ali et al, Leuk Lymphoma 2007• Kim et al, Jpn J Clin Oncol 2007• Al-Nawakil et al, Leuk Lymphoma 2008• Telek et al, Orv Hetil, 2008• Katroditou et al, Leuk Res 2008• Chan et al, Cases J, 2009
Efficacy of Bortezomib as induction treatment consolidated by autologous or HLA-mismatched unrelated allogeneic stem cell transplantation
• Grassinger et al, Ann Hematol 2006• Kruger et al, Onkologie, 2007
Tumor lysis syndrome may occur after Bortezomib
• Jaskiewicz et al, Pharmacother 2005
Musto P et al, Cancer 2007
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 5 10 15 20 25 Months
OS
PFS
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 5 10 15 20 25
Months
OS
PFS
Progression-free survival (PFS, blu lines) and OverallSurvival (OS, red lines) in (A) all PCL patients and (B)patients with primary PCL, treated with bortezomib assingle agent or in combination with other drugs
primary + secondary PCL primary PCL
A B
Musto P et al, Cancer 2007
TERAPIA DI PRIMA LINEA NELLALEUCEMIA PLASMACELLULARE PRIMITIVA
CON ASSOCIAZIONI CHEMIOTERAPICHECONTENENTI BORTEZOMIB: STUDIO
RETROSPETTIVO DI 29 CASI
Guariglia R, Valentini G*, Pietrantuono G, Villani O, Martorelli MC, Mansueto G,D’Auria F, Grieco V, Bianchino G, Sparano A, Zonno A, Lerose R, Musolino C*,
Giuliani N*, Visco G*, Candoni A*, Gamberi A*, Bringhen S*, Zamagni E*, OnofrilloD*, Villa MR*, Falcone A*, Rossini F*, Pitini V*, Filardi N*, Quintini G*, Musuraca G*,
Specchia G*, Semenzato G*, Di Renzo N*, Venditti A*, Mastrullo L*, Fioritoni G*,Ferrara F*, Cavo M*, Palumbo A*, Pagano L*, Musto P
S.C. Ematologia e Trapianti di Cellule Staminali, IRCCS, Centro di RiferimentoOncologico della Basilicata. Rionero in Vulture (PZ); *GIMEMA Working Parties
Mieloma Multiplo e Leucemie Acute
SCOPO DELLO STUDIO
VALUTARE IL RUOLO DI ASSOCIAZIONICHEMIOTERAPICHE CONTENENTI BORTEZOMIB NEL
TRATTAMENTO DI PRIMA LINEA DI PAZIENTI CONLEUCEMIA PLASMACELLULARE PRIMITIVA (LPP)
PAZIENTI E METODOLOGIE
STUDIO RETROSPETTIVO29 PAZIENTI AFFETTI DA LPP21 CENTRI EMATOLOGICI ITALIANI
Napoli
Roma
Palermo
Messina
VicenzaPadova
Udine
Torino
Monza
Forlì
ParmaBologna
Bari
Lecce
PescaraS. Giovanni Rotondo
Rionero in Vulture
Potenza
12 (75%)12 (75%)AnomalieAnomalie citogenetichecitogenetiche (%) (%)((valutabilivalutabili 16 16 pzpz))
5 (20%)5 (20%)LocalizzazioniLocalizzazioniextramidollari (%)extramidollari (%)
11 (44%)11 (44%)IR (%)IR (%)37 % (15-88)37 % (15-88)% % PlPl circ. mediana ( circ. mediana (rangerange))
61 anni (47-82)61 anni (47-82)Età media (Età media (rangerange))1:21:2M:FM:F2525N. N. PazientiPazienti valutabilivalutabili
2929N. N. PazientiPazienti raccoltiraccolti
CARATTERISTICHE DEI PAZIENTI
11VMPTVMPTBortezomib-Melphalan-Prednisone-TalidomideBortezomib-Melphalan-Prednisone-Talidomide
11BCDBCDBortezomib-Ciclofosfamide-DesametasoneBortezomib-Ciclofosfamide-Desametasone
22VMPVMPBortezomib-Melphalan-PrednisoneBortezomib-Melphalan-Prednisone
22PAD-VPAD-VBortezomib-Doxorubicina-Desametasone-VincristinaBortezomib-Doxorubicina-Desametasone-Vincristina
44PADPADBortezomib-Doxorubicina-DesametasoneBortezomib-Doxorubicina-Desametasone
66BDBDBortezomib-DesametasoneBortezomib-Desametasone
99VTDVTDBortezomib-Talidomide-DesametasoneBortezomib-Talidomide-Desametasone
SCHEMI DI TERAPIA CONTENTENTIBORTEZOMIB
BortezomibBortezomib 1,3 mg/ 1,3 mg/mqmq (g. 1, 4, 8, 11) (g. 1, 4, 8, 11)92 92 ciclicicli totalitotali
(media 3.7 (media 3.7 –– range 1-9) range 1-9)
11AlloSCTAlloSCT
33AuSCTAuSCT + + AlloSCTAlloSCT
33DoppioDoppio AuSCTAuSCT
22AuSCTAuSCT
TRAPIANTO DI CELLULE STAMINALI
1 Paziente ha fallito la raccolta di cellule staminali
80%80%ORRORR
10 (40%)10 (40%)PRPR
2 (8%)2 (8%)VGVGPRPR
8 (32%)8 (32%)CRCR
RISPOSTE (IMWG)
10/1110/11miglioramentomiglioramento o o risoluzionerisoluzione
delldell’’insufficienzainsufficienza renalerenale
TOSSICITA’ (gr. 3-4)
1 (4%)1 (4%) InfezioniInfezioni
4 (16%)4 (16%) RenaleRenale
5 (20%)5 (20%) NeurologicaNeurologica
3 (12%)3 (12%) EmatologicaEmatologica
997 (77%)7 (77%)
16166 (37%)6 (37%)
PzPz. . TrapiantatiTrapiantatiViviVivi
PzPz. Non . Non trapiantatitrapiantatiViviVivi
13 (52%) 13 (52%) 1111 2 2 (16, 31 mesi)(16, 31 mesi)
PazientiPazienti vivivivi (%) (%) in in remissioneremissione
in in recidivarecidiva
17 17 mesimesiFollow-up Follow-up medianomediano (25 (25 pzpz))
OUTCOME CLINICO
CONCLUSIONI
♦ Le combinazioni di chemioterapia contenentiBortezomib sono fattibili ed efficaci neltrattamento di 1° linea per pazienti con LPP
♦ Tossicità accettabili e generalmente gestibili
♦ Miglioramento o risoluzione della IR
♦ Migliori risultati nei pazienti inseriti inprogrammi trapiantologici
New drugs for primary PCL: Lenalidomide
Promising but temporary benefits, it needsto be further investigated
• Benson et al, Leuk Lymphoma 2007• Musto et al, Leuk Res 2008• Olivieri et al, Leuk Res 2009• Pretz et, al Am J Hematol 2009
PROTOCOL No. CROB0108/1 -- RV-PCL-PI-350
(Final 1.0 – May 5, 2008)
EudraCT No. 2008-003246-28
A Pilot Study of Lenalidomide and Dexamethasone in Patients withPrimary Plasma Cell Leukemia
Sponsor: IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture
Principal Investigator: Dr. Pellegrino Musto
ObjectivesPrimary: To explore the anti-tumor activity of the lenalidomide/dexamethasone
combination as first line therapy in patients with primary PCL
Secondary: To evaluate the safety of the lenalidomide/dexamethasone combination in
patients with untreated, primary PCL, in terms of Adverse Events andSerious Adverse Events frequency
To evaluate the role of the lenalidomide/dexamethasone combination inprimary PCL eligible to Stem Cell Transplantation
To evaluate the efficacy of the lenalidomide/dexamethasone combination inpatients with primary PCL, in terms of TTP, PFS and OS.
Trial design and characteristics
• Open label, multicenter, exploratory, single arm study• Two-stage design, according to Simon model
• Sample size: 22 patients accrued, 10 during stage 1 and 12during stage 2 (performed only if at least 2 responses occurduring stage 1)
• Patients with diagnosis of previously untreated, primary PCL• No profit, spontaneous study• Single Institution insurance covering• Pregnancy prevention program• Lenalidomide provided by Celgene
Inclusion criteria
• Patients fulfilling the IMWG diagnostic criteriaof primary PCL at diagnosis
• Voluntary written informed consent• Patients > 18 years of age• ECOG Performance Status of 0,1 or 2*• Patients with a life expectancy of at least 12
weeks
* See exclusion criteria for Performance Status 3
Lenalidomide + Low dose Dex x 4 cycles (Rd)
sCR/CR/VGPR/PR< PR, progression
Not eligible for transplant:
Rd up to 4 additional cycles,
Eligible for autologous orallogeneic transplant:
To proceed according to singleCentre transplant policy
Response evaluation (IMWG criteria)
Maintenance therapy:
Lenalidomide 10 mg/d, days 1-21 q28,until disease progression, unacceptabletoxicity, patient’s decision
Off-study
4.2.2 Treatment Schedule
For the responsive patients not eligible for SCT,, if clinically appropriate, a maintenance dose oflenalidomide equal to 10 mg/die days 1-21 q28 and a suspension of dexamethasone, after 8cycles of full dose of lenalidomide/dexamethasone regimen will be considered.
Dex = 40 mg PO
Biological studies
• Immune-phenotype (Locally performed, according to EuropeanMyeloma Network criteria, Rawstrom et al, Haematologica, 2008)
• Cytogenetics/FISH (Centralized, Dr. P. Omede’, Torino)
• Gene profiling (Centralized, Dr. A. Neri, Milano)
• Free light chains (Centralized, Dr. F. D’Auria, Rionero in Vulture)
A Pilot Study of Lenalidomide and Dexamethasone asFirst Line Therapy in Patients with Primary Plasma
Cell Leukemia
Pellegrino Musto 1, Maria Teresa Petrucci2*, Fortunato Morabito2*,Francesco Nobile2*, Fiorella D'Auria1*, Rosa Lerose1*, Anna Sparano1*,
Antonia Zonno1*, Vincenzo Callea2*, Anna Levi2*, Carla Mazzone2*,Giuseppe Pietrantuono1*, Maria Carmen Martorelli1*, Antonino Neri2*,
Paola Omedè2*, Sara Bringhen2*, Michele Cavo2*, Mario Boccadoro2* andAntonio Palumbo2*
1 Hematology and Stem Cell Transplantation Unit, IRCCS, CentroRiferimento Oncologico Basilicata, Rionero in Vulture, Italy;
2 Italian Multiple Myeloma Network, GIMEMA
ASH 2009, submitted
• Four enrolled patients (1 male, 3 female, mean age 65years, range 58-69) are currently evaluable for earlyresponse
• All had unfavourable cytogenetics, including del13,t(4;14), t (14;16), or a complex karyotype
• Circulating plasma cells ranged from 4.4 to 9.2 x10e9/l
• One patient had at baseline a moderate degree of renalfailure
Rd in primary PCL
• After at least 2 Rd cycles (range 2-4), two PR and twoVGPR were achieved (overall response rate 100%), withdisappearance or near complete reduction of circulatingplasma cells in all cases.
• Grade 3 neutropenia and pneumonia occurred in onepatient and was resolved by appropriate lenalidomide dosereduction, introduction of G-CSF and antibiotic therapy.
• One patient died in PR, due to causes unrelated to PPCLor treatment.
Rd in primary PCL
PCL: the present and the future• PCL remains an aggressive variant of MM, with some
peculiar clinical and biological characteristics and,generally, a poor prognosis.
• Available data suggest that the inclusion of Bortezomibas initial therapy for primary PCL improves the responserate and, possibly, survival of treated patients.
• However, early relapse may occur; so, the best resultsare observed in patients who consolidate response afterbortezomib treatment with transplant procedures.
• The role of lenalidomide in PCL is currently under clinicalinvestigation.