Linfomi IndolentiLa terapia: prima

linea, salvataggio,ruolo del

mantenimento

Corrado Tarella

S.C.U. Ematologia e Terapie Cellulari

A.O. ORDINE MAURIZIANO, Torino e

UNIVERSITA’ DEGLI STUDI DI TORINO

Follicolari

La terapia diprima linea

Incidence of various non Hodgkinlymphoma subtypes

FCLnon follicular low grade NHL

B-cell DLCLT-cell NHL

Other lymphomas

30%

6%16% 28%

20%

Div. Univ. Di Ematologia di TorinoIncidenza dei sottotipi di linfoma tra 500 pazienti

trattati negli ultimi 10 anni

Sottotipi NHL B

1%1%2% 2%3% 4%7%

10%

22%

48%

Hcl

Altri istotipi

Burkitt

Waldenstrom

MALT

MZL

MCL

CLL

FCL

DLCL

22 %

Follicular LymphomaInternational Prognostic Index

Prognostic factors:

1. Age (> 60 years)2. Ann Arbor stage3. Hb level (< 12 gr/dl)4. N° nodal areas (> 4)5. LDH level

Bcl-2/IgH mcr 9%

No evidence of Bcl2/IgH26%

PCR analysis of Bcl2/IgH in FL-NHL

at diagnosis

Bcl-2/IgH MBR 65%

represents the main improvement in therepresents the main improvement in the

management of B-cell lymphoma over themanagement of B-cell lymphoma over the

last 20 yearslast 20 years

The anti-CD20 Monoclonal AntibodyRituximab

Randomized studies in patients with follicular lymphoma using rituximab plus chemotherapy

Salles G., Hematology 2007

before deciding the therapy for patientswith indolent NHL, lymphoid tissue shouldbe tested for CD20 antigen expressionCD20 antigen expression

patients with stage I-II diseasestage I-II disease and low-tumor burden, should receive externalinvolved field radiotherapy onlyradiotherapy only [grade B]at the dose of 30-36 Gy. Adjuvantchemotherapy is not recommended inthese patients [grade D]

no indication for Rituximab aloneRituximab alone inthese clinical conditions ??

Rituximab Combined with Localized Radiotherapy as Front-Line Therapyin Limited Stage Low-Grade Lymphoma Patients

the Torino experience

since March 1999March 1999 through April 2009April 2009, 25 consecutive low-gradelymphoma patients with stage I-II presentation entered theRituximab+IF-RT treatment program

treatment included 44 weekly doses of RituximabRituximab at 375 mg/sqmfollowed by IF-RTIF-RT, with a median radiation dose of 36 Gy36 Gy (range 25-40)

the 5-yr. Overall SurvivalOverall Survival projections is 93%93%

with a 5-yr Failure-Free SurvivalFailure-Free Survival projection of 81%81%

advanced-stageadvanced-stageFollicularLymphoma

when and how towhen and how totreattreat

Criteria for starting a cytotoxic treatmentin patients with follicular lymphoma

Salles G., Hematology 2007

advanced-stageadvanced-stageFollicularLymphoma

when and how towhen and how totreattreat

Randomized studies in patients with follicular lymphoma using rituximab plus chemotherapy

Salles G., Hematology 2007

TIME TO TREATMENT FAILURE AFTER START OFTHERAPY FOR CHOP OR R-CHOP

Hiddemann et al, Blood 2005

Table 2. Outcomes associated with R-CVP vs. R-CHOP

Parameter Phase III CVP Clinical Trial Phase II CHOP Phase III CHOP

ORR 81% 100% 96%% CR 41% 87% 20%**TTP (median) 27 mos 82.3 mos NR*

Abbrviations: R-CVP, Rituximab + Cyclophosphamide + Vincristine + Prednisone; R-CHOP, Rituximab + Cyclophosphamide + Doxorubicin + Vincristine + Prednisone; ORR,overall response rate; CR, complete response; TTP, time-to-progression

* Not reached at median follow-up of 20 months (i.e., 80% of R-CHOP patients still inremission)

** Discrepancy between CR rates noted from phase II vs. phase III R-CHOP trials areaddressed later in this article and are likely secondary to differences in baseline prognosticfactors and patient entry criteria

PCR on BM and PB

Rituximab 375 mg/mRituximab 375 mg/m22 g 1 (g 8 ciclo I) g 1 (g 8 ciclo I) ‏‏Fludarabine 25 mg/mFludarabine 25 mg/m2 2 gg 2-4gg 2-4Mitoxantrone 10 mg/mMitoxantrone 10 mg/m22 g 2 g 2Dexamethasone 10 mg gg 2-4Dexamethasone 10 mg gg 2-4

Clinical and molecular follow-up(12, 18, 24, 30, 36, 42 months)‏

R- FND x 4 once a month

Rituximab x 4 once a week

PCR on BM and PB

CR/PCR+/- or PR

NR OFF

RANDOM

Rituximab maintenance x 4 at months 9, 11, 13, 15

Observation

PCR on BM and PB

Studio ML17638 IIL ID: IILFL04Abs# 1278 Abs# 1278 Vitolo et al

INTERIM ANALYSIS: 80/95 pts randomized in ORRINTERIM ANALYSIS: 80/95 pts randomized in ORR

54%

37%

2%0,00%

CR PR SD

71%

13%7%

0,00%

CR PR SD/PD

CR

PR

SD/PD

Clinical response: ORR 84% after R-FND + RClinical response: ORR 84% after R-FND + R

After R-FND x 4 - Month 5-6After R-FND x 4 - Month 5-6 After Rituximab x 4 - Month 8After Rituximab x 4 - Month 8

Molecular responseMolecular response

After R-FND x 4After R-FND x 4Month 5-6Month 5-6

Bcl-2 neg 51%Bcl-2 neg 51%

After Rituximab x 4After Rituximab x 4Month 8Month 8

Bcl-2 neg 71%Bcl-2 neg 71%BaselineBaseline

Copyright © American Society of Clinical Oncology

Rummel, M. J. et al. J Clin Oncol; 23:3383-3389 2005

Bendamustine hydrochloride

Bendamustine plus Rituximab versus CHOP plus Rituximab in the First-Bendamustine plus Rituximab versus CHOP plus Rituximab in the First-

Line Treatment of Patients with Indolent and Mantle Cell Lymphoma Line Treatment of Patients with Indolent and Mantle Cell Lymphoma ––

Final Results of a Randomized Phase III Study of theFinal Results of a Randomized Phase III Study of the

StiL (Study Group indolent Lymphomas, Germany)StiL (Study Group indolent Lymphomas, Germany)

Mathias J. Rummel, N. Niederle, G. Maschmeyer, G. A. Banat, U. von Grünhagen,Mathias J. Rummel, N. Niederle, G. Maschmeyer, G. A. Banat, U. von Grünhagen,

C. Losem, G. Heil, M. Welslau, C. Balser, U. Kaiser, H. Ballo, E. Weidmann,C. Losem, G. Heil, M. Welslau, C. Balser, U. Kaiser, H. Ballo, E. Weidmann,

H. Dürk, D. Kofahl-Krause, F. Roller, J. Barth, D. Hoelzer, A. Hinke,H. Dürk, D. Kofahl-Krause, F. Roller, J. Barth, D. Hoelzer, A. Hinke,

and W. Brugger and W. Brugger ..

on behalf of the StiL on behalf of the StiL

Blood 114: 168 (abstr #405), 2009 . Blood 114: 168 (abstr #405), 2009 .

Bendamustine-Rituximab (B-R) vs CHOP-R

Bendamustine-RituximabBendamustine-Rituximab

CHOP-RituximabCHOP-Rituximab

FollicularFollicularWaldenströmsWaldenströmsMarginal zoneMarginal zoneSmall lymphocyticSmall lymphocyticMantle cellMantle cell

RR

StiL NHL 1-2003 StiL NHL 1-2003

Bendamustine 90 mg/mBendamustine 90 mg/m22 day 1+2 + R day 1, max 6 cycles, q 4 wks. day 1+2 + R day 1, max 6 cycles, q 4 wks.

CHOP-R, max 6 cycles, q 3 wks.CHOP-R, max 6 cycles, q 3 wks.

MJRMJR

Inclusion criteria : B-R vs CHOP-RInclusion criteria : B-R vs CHOP-R

Patients with one of the following CD20 positive lymphoma entitiesPatients with one of the following CD20 positive lymphoma entities - follicular lymphoma, grade 1 and 2- follicular lymphoma, grade 1 and 2 - lymphoplasmacytic lymphoma / Immunocytoma (Waldenström) - lymphoplasmacytic lymphoma / Immunocytoma (Waldenström) - small lymphocytic lymphoma (CLL without leukemic phase) - small lymphocytic lymphoma (CLL without leukemic phase) - nodular and generalized (nodal und extranodal) marginal zone lymphoma - nodular and generalized (nodal und extranodal) marginal zone lymphoma - mantle cell lymphoma - mantle cell lymphoma

No pretreatment with chemotherapeutics, Interferon or RituximabNo pretreatment with chemotherapeutics, Interferon or Rituximab

Defined indication for treatment, except in mantle cell lymphomaDefined indication for treatment, except in mantle cell lymphoma

Histology not older than 6 monthsHistology not older than 6 months

Stage III or IVStage III or IV

Age at least 18 years, no upper age limit, WHO 0-2Age at least 18 years, no upper age limit, WHO 0-2

Written informed consent of the patientWritten informed consent of the patient

MJRMJR

Defined Indications for treatmentDefined Indications for treatment

B-symptomsB-symptoms

Hematopoietic failureHematopoietic failure(Hb < 11 g/dl, granulocytes < 1.500 /µl, thrombocytes < 100.000 /µl)(Hb < 11 g/dl, granulocytes < 1.500 /µl, thrombocytes < 100.000 /µl)

Large tumor burdenLarge tumor burden(3 areas > 5 cm or 1 area > 7.5 cm)(3 areas > 5 cm or 1 area > 7.5 cm)

Rapid progressionRapid progression(increase of tumor mass > 50% within 6 months)(increase of tumor mass > 50% within 6 months)

Complications due to diseaseComplications due to disease(pain, infarction of spleen, hyperviscosity syndrome, etc.)(pain, infarction of spleen, hyperviscosity syndrome, etc.)

MJRMJR

549 patients randomized. 513 patients evaluable for response and toxicity549 patients randomized. 513 patients evaluable for response and toxicity

B-R CHOP-R Age B-R CHOP-R Age

Total nTotal n 260260 253253 64 64

FollicularFollicular 54 % 54 % 139139 140140 6060

Mantle cellMantle cell 18 %18 % 4545 4848 7070

Marginal zoneMarginal zone 13 %13 % 3737 3030 6666

WaldenströmsWaldenströms 8 %8 % 2222 1919 6464

SLLSLL 4 %4 % 1010 1111 6868

UnclassifiableUnclassifiable 2 %2 % 77 55 6969

EntitiesEntities

MJRMJR

B-R CHOP-R B-R CHOP-R (n=260) (n=253)(n=260) (n=253)

Age (median)Age (median) 64 yrs64 yrs 63 yrs63 yrs

> 70 yrs. > 70 yrs. 23 %23 % 23 %23 %

Stage IVStage IV 77 %77 % 77 %77 %

Bone marrowBone marrow 68 %68 % 67 %67 %

B-Symptoms B-Symptoms 38 %38 % 29 %29 %

LDH > 240 U/lLDH > 240 U/l 38 %38 % 34 %34 %

Bulky diseaseBulky disease 27 %27 % 29 %29 %

IPI > 2 IPI > 2 37 %37 % 34 %34 %

FLIPI 0-1 FLIPI 0-1 12 %12 % 19 %19 %FLIPI 2 FLIPI 2 42 %42 % 33 % 33 % FLIPI FLIPI >> 3 3 46 %46 % 48 %48 %

Patient characteristicsPatient characteristics

n = 279n = 279

Progression free survivalProgression free survival

B-RB-R

CHOP-RCHOP-R

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

Pro

babi

lity

Pro

babi

lity

00 1212 2424 3636 4848 6060 72 months72 months

B-R: 54,9 vs CHOP-R: 34,8 months (median)B-R: 54,9 vs CHOP-R: 34,8 months (median)

HR = 0.57 (95% CI: 0.43 - 0.76) HR = 0.57 (95% CI: 0.43 - 0.76)

p = 0.00012p = 0.00012

Median observation period 34 months Median observation period 34 months Rummel et al.: Rummel et al.: Blood 114: 168 (abstr #405), 2009Blood 114: 168 (abstr #405), 2009

Progression free survival follicular lymphomaProgression free survival follicular lymphoma

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

Pro

babi

lity

Pro

babi

lity

00 1212 2424 3636 4848 6060 72 months72 months

B-RB-R

CHOP-RCHOP-R

B-R: not reached vs CHOP-R: 46,7 months (median)B-R: not reached vs CHOP-R: 46,7 months (median)

HR = 0.63 (95% CI: 0.42 - 0.95) HR = 0.63 (95% CI: 0.42 - 0.95)

p = 0.0281p = 0.0281

Rummel et al.: Rummel et al.: Blood 114: 168 (abstr #405), 2009Blood 114: 168 (abstr #405), 2009

Overall SurvivalOverall Survival

00 1212 2424 3636 4848 6060 7272 84 months84 months

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

Pro

babi

lity

Pro

babi

lity

Bendamustine-R vs CHOP-RBendamustine-R vs CHOP-R

ConclusionConclusion

Bendamustine plus Rituximab has the potentialBendamustine plus Rituximab has the potential

to become a treatment of 1to become a treatment of 1stst-choice in these-choice in these

disease entitiesdisease entities

The issue of “response assessment” is ofparticular relevance whenever CR achievementis the ultimate treatment goal, i.e. whenever CR

is required for a curative outcomecurative outcome

aggressive lymphoma (DLCL, BL)Hodgkin’s Lymphoma Follicular Lymphoma

since the availability of new treatment armaments, namely thehumanized MoAbs, CR achievement is a major end-point

in the management of most lymphoma patients

……..the value of Molecular Remission achievement in FL..the value of Molecular Remission achievement in FL

Minimal residual disease monitoring afterCHOP followed by rituximab forpreviously untreated indolent NHL

100

90

80

70

60

50

40

30

20

10

0–24 Baseline 12 28 44 weeks

RituximabCHOP

PCR

-pos

itive

pat

ient

s (%

) BM

PB

n=77

n=76

n=73

n=72

Rambaldi A, et al. Blood 2002; 99:856–62

Molecular monitoring of MRD inFL-NHL

after HDT and autologoustransplantation

Turin-group experiencewith the i-HDS scheme

Corradini P et al, Blood 1997 Jan 15;89:724-31Tarella C et al, Leukemia 2000 Apr 14:740-7

a “high-dose” approach, aimed toobtain maximal tumor cytoreductionand to exploit the in vivo-purgingin vivo-purgingeffect operated by chemotherapy

MOLECULAR RESULTS IN LOW GRADELYMPHOMAS

F L(CD10+ CD5-)

HARVESTS FOLLOW-UP

59%41% 62%38%

MCL + SLL(CD10- CD5+)

17%

83%

6%

94%

PCR POSITIVE

PCR NEGATIVE

1st multicenter, prospective GITMO trial

► between December 1996 and February 1999

► 92 FCL patients were enrolled and treated with i-HDS(Rituximab-free) by 20 GITMO Centers

► previously untreated FCL patients were eligible ifpresenting with one or more of the following signs: - bulky disease (greater than 5 cm) - high serum LDH - systemic or disease-related compression symptoms - ECOG performance status ≥ 2 - BM invasion greater than 20%

► preliminary results: Blood 2002

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120

% s

urvi

vng

months

PCR neg

PCR pos

1st multicenter, prospective GITMO trial – 1996PROGRESSION FREE SURVIVALPROGRESSION FREE SURVIVAL

ACCORDING TO FOLLOW-UP STATUSACCORDING TO FOLLOW-UP STATUS

RITUXIMAB-supplemented HDS

versus

RITUXIMAB-supplemented CHOP

Randomized Trial in Poor-risk (aaIPI 2-3) FL at DiseaseOnset, Comparing

Multicenter, Prospective GITMO/IIL trial

Closing date 31.05.2005

Ladetto M et al.: Blood First Edition Paper, prepublished online January 31, 2008

MOLECULAR REMISSION ACHIEVEMENT(at least two PCR-negative samples in a CR patient)

Persistent PCR-positive patients

CHOP-RCHOP-R

44%44%

11/25R-HDSR-HDS

80%80%

28/35

Ladetto M et al.: Blood First Edition Paper, prepublished online January 31, 2008

R-HDS vs CHOP-R RANDOMIZED TRIALEVALUABLE PATIENTS: 60

p<0.001

PCR neg

PCR pos

75% at 4 yrs.75% at 4 yrs.

21% at 4 yrs.21% at 4 yrs.

PFS ACCORDING TO PCR-STATUS

p <0.001

recent update on the long-term outcome of the FLrecent update on the long-term outcome of the FLpatients treated with the HDS schedule in the threepatients treated with the HDS schedule in the threetrials performed over the last 18 yearstrials performed over the last 18 years

single-Center (Torino)phase II study for indolentNHL (1991-1998)

26 patients(advanced-stage +adverse prognostic

factors)

GITMO multicenter phase IIstudy for FL (1996-1999)

92 patients(advanced-stage +adverse prognostic

factors)

GITMO multicenter phase IIIstudy with R+ (2001-2005)

67 F L(aaIPI 2-3aaIPI 2-3)

Total 185 FL185 FL

updated

2626

7979

6565

170 (92%)170 (92%)

at present 120120 patients (70%)(70%) are alivealive

main causes of death were:

77 early (peri-transplant) deaths

25 25 lymphoma progressions

11 11 secondary neoplasms

77 other causes

170 advanced-stage FL patientsOVERALL SURVIVAL

median f.u.: 10 yrs.

69 %81 %

61 %

median survival: not yet reachednot yet reached

2015105years

at present 8282 patients (48% of the whole(48% of the wholeseries)series) are alive in their first Continuousalive in their first ContinuousComplete RemissionComplete Remission (CCR) (CCR)

4747 of them (28%)(28%) are in their first CCRat 8 to 15 yrs.8 to 15 yrs. since HDS

the latest relapselatest relapse has been recorded at 8 yrs.8 yrs.following HDS

among patients in CCR:

3434 are in Molecular RemissionMolecular Remission

2 2 have a ““mixedmixed”” PCR PCR

33 have a PCR +vePCR +ve

170 advanced-stage FL patientsDISEASE FREE SURVIVAL

(events: recurrence and both early and late toxic deaths)

48 %

61 %

48 %

2015105years

PREDICTIVE FACTORSOF THE LONG-TERM OUTCOME

None of the pre-treatment parameters considered hadpredictive value on the long-term outcome, including:

sex - age (borderline) - histology (grade 1-2 vs. 3a)– symptoms – ECOG P.S. – splenomegaly – high LDH –extranodal disease Rituximab addition to HDS

two factors only were highly predictive for aprolonged progression-free survival, i.e. :

CR achievement and Molecular Remission achievement

the Italian experience with intensified programs withautograft in follicular lymphoma

what we have learnt:

the value of Molecular RemissionMolecular Remission (MR) achievementfollowing either conventional and intensifiedchemotherapy, with and w/o Rituximab

the chances of long-term survival, in continuousclinical and molecular remission: FollicularFollicularLymphomaLymphoma a curable diseasea curable disease ?

the need to achieve maximal tumor reductionmaximal tumor reduction whilereducing treatment toxicityreducing treatment toxicity in the primary treatmentof Follicular Lymphoma

Gitmo-IIL study: 61% at 16 yrs.

the steps forward in the treatmentstrategy for Follicular Lymphoma:

to try to achieve CR alongto try to achieve CR alongwith MR,with MR,

by combining Rituximab withby combining Rituximab withconventional chemotherapyconventional chemotherapy

exploiting HDT and autograft for theexploiting HDT and autograft for therescue of refractory/relapsed patients,rescue of refractory/relapsed patients,including those unable to achieveincluding those unable to achieveclinical and molecular remissionclinical and molecular remission

FINAL CONSIDERATIONS

• …however, CHOP-R is not yet an optimal strategy, atleast for high-risk FL

• at present, the favored strategy for FL may be the use ofR-CHOP as induction, even in high-risk patients

early inclusion of additional therapy, includingeither Rituximab-maintenance or intensive

chemo-immunotherapy with autograft in case ofsigns of treatment failure ?

….or even the allogeneic optionallogeneic option, at least foryounger patients with highly unfavourable

clinical presentation ?

ACKNOWLEDGEMENTS

Div. of Hematology -University of TorinoDir. Prof. M. BoccadoroLymphoma Team:Daniele CaraccioloLuciana BerguiPaolo GavarottiFederica De MarcoAngela GueliMarco Ruella

Alessandro PileriPaolo CorradiniMarco Ladetto

Statistical work byRoberto Passera

Tandem Autologous – AllogeneicNonmyeloablative Sibling Transplant inRelapsed Follicular Lymphoma Leads to

Impressive Progression Free Survival withMinimal Toxicity

Sandra Cohen, Lambert Busque, Thomas Kiss, GuySauvageau ,Thomas Kiss, Silvy Lachance, Denis-

Claude Roy, Jean Roy.Maisonneuve Rosemont Hospital

University of MontrealMontreal, Canada

Treatment planStem cell mobilization:

Cyclophosphamide (Cy) 1.5g/m2 + G-CSF 5µg/kg BID

Autologous transplant:BEAM or BEAC

Nonmyeloablative allogeneic transplant:Fludarabine 30mg/m2/d + Cy 300mg/m2/d x 5d

Tacrolimus D -8 to +50 (10-15 nmol/L) → tapered by D +100Mycophenolate mofetil 1g BID D+2 to +50

3 months

N=27

Median Follow-up 37 months

1 patient has died from GVHD at +11 months1 patient has died from GVHD at +11 months

to date, there has been no disease progression to date, there has been no disease progression

18 (67%) pts developed extensive chronic GVHD 18 (67%) pts developed extensive chronic GVHD

Adding Rituximab to chemotherapy significantlyExtends Survival Without Increasing Toxicity in

Patients With Follicular LymphomaFollicular Lymphoma

Time to treatment failure

67 43 29 14 13 9 1 0 0159 100 87

114 95 73 50 37 20 8 3 0162 140 123

CVP

R-CVP

Patients at risk

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33

Study month

Even

t-fre

e pr

obab

ility

R- CVP: median 26 months

CVP: median 7 monthsp<0.0001

18 months follow-up Marcus et al, Blood 2005, 105: 1417

the the possible use of possible use of rituximab monotherapyrituximab monotherapyin patients with advanced stage FL,in patients with advanced stage FL,potentially manageable with a watchfulpotentially manageable with a watchfulwaiting approachwaiting approach

[486] Single Treatment with Rituximab Monotherapy for Low-Tumor[486] Single Treatment with Rituximab Monotherapy for Low-TumorBurden Follicular Lymphoma (FL): Survival Analyses with ExtendedBurden Follicular Lymphoma (FL): Survival Analyses with ExtendedFollow-Up (F/Up) of 7 Years. Session Type: Oral SessionFollow-Up (F/Up) of 7 Years. Session Type: Oral Session

Philippe Colombat, Nicole Brousse, Franck Morschhauser, Patricia Franchi-Rezgui,Philippe Colombat, Nicole Brousse, Franck Morschhauser, Patricia Franchi-Rezgui,Pierre Soubeyran, Vincent Delwail, Eric Deconinck, Corinne Haioun, CharlesPierre Soubeyran, Vincent Delwail, Eric Deconinck, Corinne Haioun, CharlesFoussard, Catherine Sebban, Herve Tilly, Noel-Jean Milpied, Francois Boue, Jean-Foussard, Catherine Sebban, Herve Tilly, Noel-Jean Milpied, Francois Boue, Jean-Michel Karsenti, Pierre Lederlin, Albert Najman, Catherine Thieblemont, DelphineMichel Karsenti, Pierre Lederlin, Albert Najman, Catherine Thieblemont, DelphineMoreau, Loic Bergougnoux, Gilles Andre Salles, Philippe Solal-CelignyMoreau, Loic Bergougnoux, Gilles Andre Salles, Philippe Solal-Celigny

Patients with stage III-IVdisease and not candidate to awatch and wait strategy shouldbe treated with frontlinechemotherapy [grade BB]

PFS IN PCR + and PCR -ACCORDING TO TREATMENT ARM

%

surv

ivin

g

%

surv

ivin

g

p = N S p = N S

Ladetto M et al.: Blood First Edition Paper, prepublished online January 31, 2008

the extremely good outcome of patients achievingMR is unrelated to treatment arm

Time To Next TreatmentTime To Next Treatment

00 1212 2424 3636 4848 6060 7272 84 months84 months

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

Pro

babi

lity

Pro

babi

lity

B-RB-R

CHOP-RCHOP-R

B-R: not reached vs CHOP-R: 37,5 months (median)B-R: not reached vs CHOP-R: 37,5 months (median)

HR = 0.52 (95% CI: 0.38 - 0.70) HR = 0.52 (95% CI: 0.38 - 0.70)

p = 0.00002p = 0.00002

Rummel et al.: Rummel et al.: Blood 114: 168 (abstr #405), 2009Blood 114: 168 (abstr #405), 2009

Front-line therapy with rituximab added to thecombination of cyclophosphamide, doxorubicin,vincristine and prednisone (CHOP) significantly improvesthe outcome of patients with advanced stage follicularlymphomas as compared to CHOP alone - results of aprospective randomized study of the german low gradelymphoma study group (GLSG)

Hiddemann W, Kneba M, Dreyling M et alBloodBlood 2005 Dec 1; 106(12): 3725-32

L’importanza della accurata Valutazione

della risposta al trattamento

L’impiego sempre più esteso della P E TP E T

La valutazione in PCRPCR della MalattiaMinima Residua (M R DM R D) nei casi BM+