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.