ONCOEMATOLOGIA NUOVE CHEMIOTERAPIE - unito.it · PDF fileMIELOMA MULTIPLO tumore delle ......

ONCOEMATOLOGIAONCOEMATOLOGIAONCOEMATOLOGIA

NUOVE CHEMIOTERAPIENUOVE CHEMIOTERAPIENUOVE CHEMIOTERAPIE

DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY

MIELOMA MULTIPLOMIELOMA MULTIPLO

tumoretumore delle plasmacellule delle plasmacellule

producono immunoglobulineproducono immunoglobuline

vivono nelle ossavivono nelle ossa


Multiple myeloma• uncontrolled proliferation of Ig secreting plasma cells

– most commonly IgG (57%), IgA (21%) or light chain only (18%)

• twice as common in men as women

• and in blacks as whites

• 1% of all cancers

– 2% in african americans

• incurable

• median survival 3 years

• few therapeutic advances since the introduction of melphalan (Bergsagel, 1962)

Myeloma bone pathology

t(11;14)(q13;q32) in multiplet(11;14)(q13;q32) in multiple myeloma myeloma•• ~25% of MM (~25% of MM (cfcf ~100% of mantle cell lymphoma) ~100% of mantle cell lymphoma)

•• breakpoints spread over ~300kbbreakpoints spread over ~300kb

•• associated withassociated with ectopic ectopic expression of expression of cyclin cyclin D1 at 11q13 D1 at 11q13

•• cells morecells more lymphoplasmacytic lymphoplasmacytic

•• poor prognosispoor prognosis

t(4;14)(p16;q32) in multiplet(4;14)(p16;q32) in multiple myeloma myeloma

•• occurs in ~20-25% ofoccurs in ~20-25% of myeloma myeloma

•• breakpoints spread over 150kbbreakpoints spread over 150kb

•• associated withassociated with ectopic ectopicexpression of FGFR3 onexpression of FGFR3 on der der(4)(4)andand IgH IgH-MMSET hybrid-MMSET hybrid mRNA mRNAtranscripts ontranscripts on der der(14)(14)

Chromosome 14 paint in orange

4p16.3 cosmid in green

t(14;16)(q32;q23) in multiplet(14;16)(q32;q23) in multiple myeloma myeloma

• occurs in 15-20% ofmyeloma

• breakpoints spread over~500kb

• associated with over-expression of c-maf at16q23

Chromosome 14 paint in orange

c-maf probe in green

IL-1IL-1

OAFOAF

IL-6IL-6


hepatocytehepatocyte

CRPCRP

OSTEOCLASTOSTEOCLAST

DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA S. GIOVANNI BATTISTAAZIENDA OSPEDALIERA S. GIOVANNI BATTISTATORINO, ITALYTORINO, ITALY


malattia dell'anzianomalattia dell'anziano

5/100.000/5/100.000/pazientipazienti//annoanno

350350 pazienti pazienti//annoanno in in Piemonte Piemonte

etàetà media media alla diagnosi alla diagnosi 70 70 anni anni


Serum protein electrophoresis (SPEP)

Elevated total protein suggestshypergammaglobulinemia

Total protein= Album in + Globulins


albumin α1α1 α2α2 ββ γγ







Quantitative immunoglobulins

measures amount of IgM, IgG and IgA

in myeloma, typically see “reciprocal depression”of uninvolved Igs



γγ

κκ

λλ

Immunoeletrophoresis



γγ

κκ

λλ

Immunoeletrophoresis

γγααµµκκλλ

SP

Immunofixation



SP

Immunofixation

IgG 57%IgA 21%IgD 1%IgM or IgE almost neverLight chain only 18%



SP

Immunofixation


M-spike stands for Monoclonal, not IgM



SP

Immunofixation



IgM, IgG and IgA are all gamma-globulins



SP

Immunofixation



Light chains (Bence-Jones proteins) are notdetected in the serum , because of their lowmolecular weight, they are secreted in the urine

IgM, IgG and IgA are all gamma-globulins

Myeloma - clinical features

bone pain - often with loss of height

constitutional - weakness, fatigue and weight loss

anemia - responds to erythropoeitin

renal disease -renal tubular dysfunction

susceptibility to infections - neutropenia, hypogammaglobulinemia)

hypercalcemia - myeloma cells secrete osteoclast activating factors

hyperviscosity - 2 % with myeloma, 50 % with macroglobulinemia

neurologic dysfunction - spinal cord or nerve root compression

Myeloma stagingsystem cells x 10 /m

12 2

MedianSurvival(months)

Stage I No anemia >60 <0.6No hypercalcemiano more than one bony lesionlow M protein

Stage II in between I and III 41 0.6-1.2

Stage III Anemia 23 >1.2hypercalcemiaadvanced lytic bone diseasehigh M protein

Principles of treatment• no evidence that early treatment prolongs survival

• wait for symptoms, or evidence of disease progressionto start treatment

• supportive measures are critically important– drink 3l of fluids daily

– treat infections promptly

– prophylactic bisphosphonates reduce skeletal cmplications

– anemia responds to erythropoeitin

Causes of death in multiple myeloma

• Progressive myeloma 45%

• Sepsis 25%

• Renal failure 10%

• Other (old age) 20%

Treatmentcourse

Asymptomatic

MGUSStable MM

Years Months Days

Treatmentcourse

Asymptomatic

MGUSStable MM

Symptomatic

Years Months Days

Treatments

M protein

Treatmentcourse

Asymptomatic

MGUSStable MM

Symptomatic Acute

PancytopeniaPlasma cell leukemia

Years Months Days

Treatments

M protein


trattatotrattato con con blande chemioterapie blande chemioterapie

parzialmente chemiosensibileparzialmente chemiosensibile

il tumore si riduceil tumore si riduce ma ma dopo breve dopo breve intervallo riprendeintervallo riprende a a crescere crescere



chemioterapiachemioterapia

Melphalan e Prednisone (MP)Melphalan e Prednisone (MP)

((AlexanianAlexanian, 1969), 1969)



100100

5050

3636 mesi mesi

sopravvivenzasopravvivenza


A PROSPECTIVE, RANDOMIZED TRIAL OF A PROSPECTIVE, RANDOMIZED TRIAL OF AUTOLOGOUS BONE MARROW AUTOLOGOUS BONE MARROW

TRANSPLANTATION AND CHEMOTHERAPY TRANSPLANTATION AND CHEMOTHERAPY IN MULTIPLE MYELOMAIN MULTIPLE MYELOMA

SopravvivenzaSopravvivenza a 5 a 5 anni anni 52%52% trapianto trapianto12%12% convenzionale convenzionale

AttalAttal, et al., NEJM, 1996, et al., NEJM, 1996


relazionerelazione dosedose-rispostarisposta

ALTA-DOSE =ALTA-DOSE = ++ risposte risposte complete complete

++ lunga sopravvivenza lunga sopravvivenza



età dietà di 613 613 pazienti sottoposti pazienti sottoposti ad autotrapianto ad autotrapianto

BarlogieBarlogie et al. et al.231231 pazienti pazientietà medianaetà mediana 50 50 anni anni

FermandFermand et al. et al.9393 pazienti pazientietà medianaetà mediana 44 44 anni anni

AttalAttal et al. et al.100100 pazienti pazientietà medianaetà mediana 57 57 anni anni(no ABMT 42%(no ABMT 42% fra fra 60 60 e 65e 65 anni anni))

GahrtonGahrton et. al et. al189189 pazienti pazientietà medianaetà mediana 49 49 anni anni


5555 6060 6565 7070

MULTIPLE MYELOMAMULTIPLE MYELOMAMULTIPLE MYELOMA


AGEAGE

AGE AT DIAGNOSISAGE AT DIAGNOSIS



età alla diagnosietà alla diagnosi

pazientipazienti con con meno di meno di 60 60 anni anni

7070 anni anni

20%20%



Age of 613 patients who received an autographAge of 613 patients who received an autographAge of 613 patients who received an autograph

Barlogie et al.231 patientsmedian age 50

BarlogieBarlogie et al. et al.231 patients231 patientsmedian age 50 median age 50

Fermand et al.93 patientsmedian age 44

FermandFermand et al. et al.93 patients93 patientsmedian age 44median age 44

Attal et al.100 patientsmedian age 5742% no ABMTbetween 60 and 65

AttalAttal et al. et al.100 patients100 patientsmedian age 57median age 5742% no ABMT42% no ABMTbetween 60 and 65between 60 and 65

Gahrton et. Al189 patientsmedian age 49

GahrtonGahrton et. Al et. Al189 patients189 patientsmedian age 49median age 49



5555 6060 6565 7070



AGEAGE

AGE AT DIAGNOSISAGE AT DIAGNOSIS

HIGHHIGH--DOSEDOSE CONVENTIONALCONVENTIONAL


Obiettivi delloObiettivi dello studio: studio:

intensificazione della terapiaintensificazione della terapia

riduzione della tossicitàriduzione della tossicità

trattamento dei pazienti anzianitrattamento dei pazienti anziani((finofino a 70 a 70 anni anni))


INTENSIFIED CHEMOTHERAPYWITH PBPC SUPPORT

FOR PATIENTS AGE 55-70

INTENSIFIED CHEMOTHERAPYINTENSIFIED CHEMOTHERAPYWITH WITH PBPC PBPC SUPPORTSUPPORT

FOR PATIENTS AGE 55-70FOR PATIENTS AGE 55-70



MELPHALAN 100 mg/mMELPHALAN 100 mg/mMELPHALAN 100 mg/m 222

IN A TIGHTLY REPEATED FASHIONIN A TIGHTLY REPEATED FASHIONIN A TIGHTLY REPEATED FASHION

MEL100 mg/mMEL100 mg/mMEL100 mg/m222

10 11 1210 11 1210 11 12

PBPCCollections

PBPCPBPCCollectionsCollections

100mg/m100mg/m100mg/m 100mg/m100mg/m100mg/m

CTX4 g/mCTXCTX

4 g/m4 g/m222 G-CSF10 µg

G-CSFG-CSF10 µg10 µg

000 3-93-93-9 303030 909090 150150150

222 222 MEL MEL MEL MEL MEL MEL MEL MEL MEL

daydayday

100mg/m100mg/m100mg/m222DAVDAVDAV DAVDAVDAV

FOR PATIENTS NOT IN CR

FOR PATIENTS NOT IN CR



EVENT FREE SURVIVAL

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50 60 70 80

Months

EFS

P<0.001

MP

MEL100 (81 pz)

JANUARY 2000JANUARY 2000DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY

DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY

OVERALL SURVIVAL

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50 60 70 80

Months

V

V

SUR

I

AL

p<0.01MEL100 (81 pz)

MP

JANUARY 2000JANUARY 2000DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY


RIDUZIONE DELLA TOSSICITA'RIDUZIONE DELLA TOSSICITA'DELLE TERAPIE AD ALTE DOSIDELLE TERAPIE AD ALTE DOSI

FATTORI DI CRESCITAFATTORI DI CRESCITA

CELLULE STAMINALI PERIFERICHECELLULE STAMINALI PERIFERICHE

tossicità comparabile alla terapia tossicità comparabile alla terapia convenzionaleconvenzionale

possibilità di trattare pazienti anzianipossibilità di trattare pazienti anziani

alte percentuali di risposte completealte percentuali di risposte complete


High-doseHigh-dose

ConventionalConventional

RICOVERO E CADUTA DEIGLOBULI BIANCHI

RICOVERO E CADUTA DEIRICOVERO E CADUTA DEIGLOBULI BIANCHIGLOBULI BIANCHI

ALTE DOSIALTE DOSIALTE DOSIricoveroricoveroricovero

000 555 101010 151515 202020

WBCWBCWBC



giornigiorni

EXTRA-HEMATOLOGIC TOXICITYMEL100

EXTRA-HEMATOLOGIC TOXICITYEXTRA-HEMATOLOGIC TOXICITYMEL100MEL100

MUCOSITISMUCOSITISMUCOSITIS

FEVER > 38°CFEVER > 38°CFEVER > 38°C

HOSPITAL STAYHOSPITAL STAYHOSPITAL STAY

1 CYCLE1 CYCLE1 CYCLE

PATIENTS (%)PATIENTS (%)PATIENTS (%)2 CYCLE2 CYCLE2 CYCLE

PATIENTS (%)PATIENTS (%)PATIENTS (%)3 CYCLE3 CYCLE3 CYCLE

PATIENTS (%)PATIENTS (%)PATIENTS (%)

171717 1010 171717

272727 181818 141414

252525 242424 232323



survivalsurvival%%

yearsyears

100100


MALATTIA INCURABILEMALATTIA INCURABILE

Brief reportBrief report, , Blood JuneBlood June, 2000, 2000

Results ofResults of high-dose high-dose therapy for therapy for 1000 1000 patients with patients with multiple multiplemyeloma:myeloma:durabledurable complete complete remissions and superior survival remissions and superior survivalinin the absence of chromosome the absence of chromosome 13 13 abnormalities abnormalities

Raman Desikan, Bart Barlogie, Jeffrey Sawyer, et al

survivalsurvival%%

yearsyears

100100


towardtoward cure cure

MALATTIA CURABILEMALATTIA CURABILE

THALIDOMIDE + DEXAMETHASONE

LOW-DOSE THALIDOMIDE+DEX IS EFFECTIVE INREFRACTORY PATIENTS ?

Thalidomide1 co/die

(100 mg)

steroid

+Dex 40 mg/dieper os 4 days monthly


THALIDOMIDE + DEXAMETHASONE PATIENTS CHARACTERISTICS

No of Patients: 77

65Median age

b2-m >3 mg/dl 43

Stage II 34

Stage III 43

•relapse•primary resistant•resistant relapse•previuous ABMT

52214

37


TALIDOMIDE + DESAMETASONE:RISPOSTE

No of Patients

%

77

18Response 75%-100%

Response 50%-75% 23

Response 25%-50% 25

NO Response* 34

* Response <25%, stable disease or progression DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY

THALIDOMIDE + DEXAMETHASONE:

TOXICITY

- Tingling and numbness

- Fatigue

- Costipation

17

12

8

% PAZIENTI

- Sedation

- discontinuation

6

10

- other toxicity 23DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 2 4 6 8 10 12 14 16 18

MONTHS

PR

OG

RE

SSIO

N-F

RE

E S

UR

VIV

AL

THALIDOMIDE + DEXAMETHASONE: PROGRESSION-FREE SURVIVAL


CONCLUSIONS

r Good response in refractory patients

r Low toxicity

r Short follow-up


Waldenström’s macroglobulinemia• uncontrolled proliferation of lymphoplasmacytes producing IgM

• associated with t(9;14) and pax-5 dysregulation• median age 63

• presents with weakness, fatigue,epistaxis, blurred vision

• bone pain and lytic bone lesions are uncommon (<5%)

• 25% have hepatomegaly, splenomegaly and lymphadenopathy• hyperviscosity common

Hyperviscosity syndrome

• bleeding (nasal and gums)• blurred vision• dizziness, headaches, ataxia• congestive heart failure• retinal vein engorgement, and papilledema• rarely occurs with serum viscosity <4 centipoises (cp)

(normal 1.8 cp)

IgM pentamer

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