die rolle der stammzell- transplantation bei b-zell ...€¦ · observation median 11.6 months...

Peter Dreger

Abteilung Innere Medizin V

Universitätsklinikum Heidelberg

Die Rolle der Stammzell-

transplantation bei B-Zell-Lymphomen

und CLL in der Rituximab-Ära

12.03.2010

The EBMT Database 2008: Transplants

by disease category

Acute leukemias Chronic leukemias Lymphomas

Multiple Myeloma Solid tumors Aplastic anemia

Inborn errors Autoinmune diseases

The EBMT Database 2008: Transplants

by disease category

Acute leukemias Chronic leukemias Lymphomas

Multiple Myeloma Solid tumors Aplastic anemia

Inborn errors Autoinmune diseases

Die 4 „Klassiker“

- Chronische lymphatische Leukämie

- Follikuläres Lymphom

- Mantelzell-Lymphom

- Diffus-großzelliges Lymphom

Die 4 „Klassiker“

- Chronische lymphatische Leukämie

- Follikuläres Lymphom

- Mantelzell-Lymphom

- Diffus-großzelliges Lymphom

Autologe SCT

= supportive Maßnahme zur

Kompensation der

hämatopoetischen Toxizität der

„single-hit“ Hochdosistherapie

Allogene SCT

= Initialzündung eines permanenten

immuntherapeutischen Prozesses!

graft-vs-tumor effect (GVT/GVL)

Autologe SCT

= supportive Maßnahme zur

Kompensation der

hämatopoetischen Toxizität der

„single-hit“ Hochdosistherapie

- autoSCT 1st-line

- autoSCT salvage

- alloSCT

Drei Gretchen-Fragen zur autoSCT

- Effektiv im Vergleich zu

Immunochemotherapie?

- Kurativ?

- Rechtfertigt der Effekt die

Toxizität?

- Kurativ?

Toxizität?

Time (months)

120 24 36 48 60 72 84 96 108

babili

1.0Outcome n 6-year OS p value

F 190 54%

F±M/C 140 59%

R-FC 300 77%

p=0.37

p<0.001

Tam CS, et al. Blood 2008;112:975–980

FC-R MDACC: FC-R und Überleben

CLL8: Update 2009(Median follow-up 37.6 months)

HR 0.664

p=0.012

“FCR improves

response rates,

progression-free,

and overall survival

in untreated patients

with CLL”

Hallek, …, Stilgenbauer.

submitted

CLL3-Studie der DCLLSG

• Phase-II-Studie zur Prüfung von

Verträglichkeit und Wirksamkeit der

primären autoSCT bei Patienten

<60J. mit Hochrisiko-CLL

• 169 auswertbare Patienten

12/1996-09/2002

• Auswertung 09/2009

CLL3: OS (n=169)

0 60 1200

Months from start of treatment

t alive

Median OS 127mo

Median f/u 99 mo (4-137)

McClanahan et al, EBMT 2010

CLL3: Non-relapse mortality (n=169)

0 60 1200

1001-y: 1.8% (0-3,9)

2-y: 3.8% (0.8-6.8)

5-y: 6.3% (2.3-10.3)

Causes of NRM

169 eligible patients

Infection Dexa-BEAM 3 (4, 4,15mo)

Infection after autoSCT 3 (9,15, 20mo)

t-MDS/AML 2 (38, 51mo)

Solid tumor 2 (34, 106mo)

Unknown 2 (90, 93mo)

Total 12

CLL3: Incidence oft-MDS/t-AML

(6 of 169)

0 60 1200

10-y incidence 8% (0-16%)

EBMT CLL autoSCT trial

• Ziel: Wirksamkeit von

Standardtherapie + autoSCT

vs Standardtherapie allein in

CR/PR 1

• 223 Patienten von 10/2001-

07/2007

• Analyse 11/2009

EBMT CLL autoSCT trial:

Ergebnisse

Michallet et al, ASH 2009

EBMT CLL autoSCT trial: Art der

Induktionstherapie

Michallet et al, ASH 2009

CHOP -> F

FCR, F + other

EBMT CLL autoSCT trial: PFS vs

FCR (CLL8)

0 1 2 3 4

FC-R arm German

CLL 8 trial

- Effektiver als Immunochemotherapie?

Eher nicht.

- Kurativ?

- Rechtfertigt der Effekt die Toxizität?

Eher nicht.

AutoSCT bei CLL: Stand 2010

- autoSCT 1st-line

- autoSCT salvage

- alloSCT

- Kurativ?

- Indikation?

AlloSCT bei CLL: Stand 2010

Allo-SCT in CLL: Effect of del 17p-

CLL8 (EFS)

Stilgenbauer et al, submittedDreger et al, GLLSG 2010

Allo-SCT in CLL: Effect of del 17p-

0 12 24 36 48 60 720

4-y EFS 45% (17, 73)

* ** * *

Months from SCT

CLL8 (EFS)CLL3X (EFS; n=13)

* MRD-negative by MRD flow

Stilgenbauer et al, submittedDreger et al, GCLLSG 2010

Time to treatment failure

Median: 5.6 mo. Overall survival

Median: 19.1 mo

Time (months)

0 6 12 18 24 30 36 42 48

Time (months)

0 6 12 18 24 30 36 42 48 54

CLL: Outcome of patients refractory to

purine analoguesAlemtuzumab therapy (GCLLSG CLL2H trial); n=103

Stilgenbauer et al, JCO 27:3394 (2009)

CLL: Survival of patients refractory to

purine analoguesAlemtuzumab therapy (GCLLSG CLL2H trial); n=103

Stilgenbauer et al, JCO 27:3394 (2009)

Allo salvage

No allo salvage

- Kurativ?

- Indikation?

CLL alloSCT (EBMT) : OS by donor(n = 370)

2010 Tandem meeting

CLL3X: Clinical impact of MRD

negativity at +12mo (of 38 patients with MRD monitoring and event-free at mo +12)

Relapse EFS

Dreger, Böttcher et al, GCLLSG 2009

12 24 36 48 60 72 84 960

100+12 MRD- (27)

+12 MRD+ (11)

HR 0.09 (0.02-0.49); p 0.0052

Months from SCT

12 24 36 48 60 72 84 960

HR 0.13 (0.03-0.65); p 0.013

+12 MRD pos

+12 MRD neg

Months from SCT

t even

03.02.2010

- Kurativ?

- Indikation?

EBMT CLL transplant consensus

allo-SCT is a reasonable treatment

option in poor-risk CLL:– .Relapse <24 mo after intensive treatment

(purine analogue combinations or auto-SCT)

– .p53 mutation with treatment indication

– .Non-response or early relapse (<12 mo) after

purine analogue-based therapy

(= fludarabine resistance)

Dreger, Montserrat et al: Leukemia 21:12-17 (2007)

Still valid in 2010!

EBMT risk score

• 56,505 patients allografted

1980-2005

• Used for validation of the

“Gratwohl” score (age, stage, time

dx_SCT, donor type, donor-recipient sex)

Gratwohl et al, Cancer 115:4715 (2009)

CLL (n=370): OS by EBMT score

2010 Tandem meeting

- Kurativ?

- Indikation?

Consensus-Kriterien; Gratwohl-Score

berücksichtigen!

- autoSCT 1st-line

- autoSCT salvage

- alloSCT

- Kurativ?

Toxizität?

Stil: B-R vs CHOP-R bei FL: PFS

babili

0 12 24 36 48 60 72 months

CHOP-R

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

p = 0.028

Rummel et al, ASH 2009

Long-term follow-up of autoSCT in FL

PBSCT vs IFN(Remission duration;

per-protocol,n=635)

Update 05/2009; courtesy of M Dreyling GLSG

GLSG 5-yearGOELA

MS9-year GELA 7-year GITMO 4-year

auto control auto control auto control R-auto R

n 153 154 86 80 192 209 68 66

PFS 65% 33% 56% 39% 38% 28% 61% 28%

OS n.a. n.a. 76% 80% 76% 71% 81% 80%

1st-line autoSCT in FL: Randomized trials

Lenz Blood 2004; Gyan JCO 2009; Sebban Blood 2006; Ladetto Blood 2008

Long-term follow-up of autoSCT in FLGLSG PBSCT vs IFN (effect of R-CHOP, n=575)

Hiddemann et al.; DGHO 2009; V798

Remission

duration

R-CHOP/

autoSCT

Is autoSCT + rituximab better

than rituximab?

Ghielmini et al, Blood 2004; update ASCO, 2009

202 FL (diag/rel)

Rituximab 375 mg/m2 x4

CR/PR/SD

Rituximab Observation

375 mg/m2/2mo x4

Years since start of treatment

bility

/ / / // / // //// / /// /

1 2 3 4 5 6 7 8 9 10

Event-free survival in randomized follicular lymphoma patients

ProlongedStandard

p= 0.0007, median FU: 9.4 yrs

Rituximab monotherapy:

Long-term follow-up (SAKK)

Courtesy of S Montoto

Unklar.

- Kurativ?

Es spricht vieles dafür.

Sicher nicht immer.

1st-line autoSCT bei FL

Anwendung nur in Studien!

- autoSCT 1st-line

- autoSCT salvage

- alloSCT

- Kurativ?

Toxizität?

Rituximab maintenance therapy after R-CHOP as

well as CHOP significantly prolongs progression-

free survival (PFS)

Subgroups according to induction treatment

PFS after CHOP (n=145)

Overall log-rank test: p<0.0001

HR=0.30

0 1 2 3 4 5

Overall log-rank test: p=0.004

HR=0.54

PFS after R-CHOP (n=189)

0 1 2 3 4 5

Rituximab maintenance

Median 42.2 months

Observation

Median 11.6 months

Observation

Median 23.0 months

Rituximab maintenance

Median 51.8 months

van Oers MHJ, et al. Blood 2006;108:3295–301

Schouten et al, JCO 2003

AutoSCT vs chemo for relapsed FL(Prospective randomized multicenter study CUP; n=140)

PFS OS

but: - only 89 were randomized (70+19)

- 33%/21-44% other mobilization/high dose regimens

- imbalance of study arms (e.g. follicular small cell: 43% vs. 21-25%)

- overall survival in only 1 of 4 comparisons significantly different

ASCT +/- Rituximab in patients with

relapsed follicular lymphoma

Retrospective analysis of 2 randomized GLSG trials

DGHO * Mannheim, 3. Oktober 2009

O. Weigert, A. Uysal, B. Metzner, M. Pfreundschuh,

N. Schmitz, H. Wandt, C. Peschl, E. Hoster,

M. Unterhalt, W. Hiddemann, and M. Dreyling

Design

• Zwei prospektiv randomisierte Phase III Studien:

• GLSG 03/96: MCP vs. CHOP nachfolgend ASCT vs. IFN

• GLSG 04/00: CHOP vs. R-CHOP nachfolgend ASCT vs. IFN

Salvage therapy for FL relapse

Rituximab 2nd line

No Rituxi Rituxi total

SCT 2nd

no SCT 45(28%)

53(33%)

98(60%)

autoSCT 28(17%)

34(21%)

62(38%)

Allo 2(1%)

total 75(46%)

88(54%)

163(100%)

Progression-free and overall survival

adjusted p<0.001

median 86 mo

median NR

median 19 mo

median 67 mo

adjusted p<0.001

autoSCT 2nd line (n=62) vs.

no autoSCT 2nd line (n=98)

median 17 mo

median 39 mo

adjusted p=0.267

median NR

adjusted p=0.494

Rituximab 2nd line (n=87) vs.

no Rituximab 2nd line (n=73)

Progression-free and overall survival (total)

median 35 mo

median NR

p=0.075

median NR

p=0.828

Progression-free and overall survival

(AutoSCT in CR/PR)

AutoSCT ohne Rituximab (n=24)

AutoSCT mit Rituximab (n=22)

GLSG GOE LAMS GELA

salvage auto rituximab auto rituximab auto rituximab

n 62 87 42 101 98 69

PFS benefit + - ++ ++ + +

OS benefit + - ++ ++ + +

OS with auto

+ rituximab80% (5-year) 92% (3-year) 93% (5-year)

Salvage autoSCT in FL in the rituximab era

Weigert DGHO 2009; Le Gouill ASH 2008; Sebban JCO 2008

Salvage autoSCT in FL (GOELAMS): OS

3-year OS:

auto 63% vs

no auto 92%

Le Gouill ASH 2008

Salvage autoSCT in FL (GELA): OS

Coiffier ASH 2007

- Kurativ?

Toxizität?

PBSCT vs IFN(Remission duration;

per-protocol,n=635)

Update 05/2009; courtesy of M Dreyling GLSG

Long-term follow-up of autoSCT in FLTBI/CY + purged

2nd-line autoBMT(Remission duration,

n=121)

Rohatiner et al, JCO 2007

n=121)

Rohatiner et al, JCO 2007 Kornacker et al, Ann Oncol 2009

1st or 2nd-line unpurged

autoPBSCT (PFS, n=241)

0 60 120 1800

10-y PFS 0.37 (95%CI .27, .48)

1st-line (155)

2nd-line (86)

* bcl2-IgH RQ-PCR

Months from SCT

n=121)

Rohatiner et al, JCO 2007 Kornacker et al, Ann Oncol 2009

1st or 2nd-line unpurged

autoPBSCT (PFS, n=241)

0 60 120 1800

10-y PFS 0.37 (95%CI .27, .48)

1st-line (155)

2nd-line (86)

** ***

***** ** **** ** *

MRD-negative*

MRD-positive*

* bcl2-IgH RQ-PCR

Months from SCT

VariableBoston/

LondonEBMT HD/KI/HH GOELAMS GLSG

n 121 693 241 86 284

Follow-up

(years)13.5 10.3 8 9 n.r.

Line Salvage 1/salvage 1/salvage 1 1

Plateau ++ - ++ ++ ++

Rohatiner JCO 2007; Montoto Leukemia 2007; Kornacker Ann Oncol 2009;

Gyan Blood 2009; Hiddemann DGHO 2009

Wahrscheinlich.

- Kurativ?

Es spricht vieles dafür.

ja, wenn <70, gogo, (Frührezidiv?).

Salvage autoSCT bei FL

- autoSCT 1st-line

- autoSCT salvage

- alloSCT

FL-Rezidiv nach autoSCT:

Die Indikation zur alloSCT?

Allo-SCT bei FL

- existieren GVL-Effekte?

- Indikation?

0 12 24 36 48 60 72 840

Months from SCT

FL (Heidelberg, n=10)

RIC salvage for autoSCT failure

0 12 24 36 48 60 72 840

Months from SCT

0 12 24 36 48 60 72 840

Months from SCT

0 12 24 36 48 60 72 840

Months from SCT

CLL (GCLLSG, n=23)

Allo-SCT bei FL

- existieren GVL-Effekte?

- Indikation?

Heidelberg-Hamburg study on FL relapse

after autoSCT: OS from relapse

0 24 48 72 96 120 1440

Months from relapse

median OS 8.3 years

Kornacker et al, Ann Oncol 2009

FL relapse after autoSCT: OS from relapse

by time to relapse (salvage autoSCT only)

0 24 48 72 96 120 1440

Tx_REL <= 12mo (14/16)

Tx_REL > 12mo (9/31)

HR 4.72 (2.89, 20.1); p < 0.0001

Months from relapse

Kornacker et al, Ann Oncol 2009

Adverse factors for PFS in alloSCT for FL

Variable CIBMTR EBMT

n 208 sib 131 MUD

Age n.i. ++

Poor PS ++ ++

Refr. at SCT ++ ++

MAC (vs RIC) - ++

Hary BBMT 2008; Avivi BJH 2009

MDACC (n=47; 0% refr.)Seattle (n=62; 37% refr.)

RIC allo for advanced FL:

PFS (Seattle and MDACC)

Rezvani et al, JCO 2008 Khouri et al, Blood 2008

1. REL:

-> autoSCT +/- R Erhaltung

2. REL – früh nach autoSCT oder R-haltiger

Kominationstherapie und „gogo“ Patient:

-> alloSCT

2. REL – spät:

-> Erneut R-basierte Salvage-Chemo,

Zevalin, experimentell (GA 101 etc)

SCT beim rezidivierten FL -Heidelberger Therapie-Algorithmus

- autoSCT 1st-line

- autoSCT salvage

- alloSCT

- Kurativ?

Toxizität?

Stil: B-R vs CHOP-R bei MCL: PFS

0 12 24 36 48 60 720.0

Follicular

p = 0,0281Mantle cell

p = 0.015

Marginal zone

p = 0.6210

Waldenström

B-RB-R

CHOP-R

p = 0.0024

Rummel et al, ASH 2009

GLSG: CHOP vs CHOP-R bei MCL: PFS

Hoster et al, ASH 2008

Dreyling et al, ASH 2008

GLSG: auto vs IFN bei MCL: PFS

Peritransplant rituximab vs standard TBI/CY

in 1st MCL: PFS (n = 34)

0 60 120 1800

100R-TBI/CY (n=34)

TBI/CY (n=34)

Months from SCT

HR 0.36 (0.18; 0.9); p 0.027

Dreger et al, Haematologica 2007; Dreger and Laport, BBMT 2008

Nordic MCL Project: MCL1 + 2

Protocol MCL1

Week 0 3 6 9 12 15 18 21

Rituximab 375mg/m2

Eligible: MCL, stage II-IV, <66 years

harvest

infusion

Protocol MCL2

Week 0 3 6 9 12 15 18 21

harvest

infusion

Maxi-CHOP

HD ara-C

Geisler et al, Blood 2008

Nordic MCL Project: Outcome of

MCL1 vs MLC2

MDACC MCL 1st-line transplants: PFS

Tam et al. Blood 2009

Rituxi yes (21)

Rituxi no (29)

Autologous stem cell transplantation

and addition of Rituximab

independently prolong response duration

in advanced stage mantle cell lymphoma

E. Hoster, B. Metzner, R. Forstpointner, M. Pfreundschuh, L. Trümper,

M. Hallek, B. Wörmann, U. Dührsen, C. Gisselbrecht, J.C. Kluin-Nelemans,

A. Van Hoof, M. Unterhalt, W. Hiddemann, M. Dreyling

on behalf of the

German Low Grade Lymphoma

Study Group (GLSG)

and the European MCL Network

ASCT and Rituximab in MCL

• explorative analysis of 3 studies:- GLSG 1996

- GLSG 2000

- European MCL high dose study

• univariate analysis:- +/- ASCT (all randomized)

- +/- Rituximab (partially randomized)

• multivariate analysis including:- +/- ASCT

- +/- Rituximab

- CR vs. PR

- MIPI score

Multivariate analysis (n= 180)

Response duration

Variable

Hazard

Ratio RD 95% CI p

R 0.61 0.42 0.89 0.0096

autoSCT 0.53 0.36 0.76 0.0006

CR 0.78 0.52 1.17 0.22

score 1.16 0.85 1.59 0.34

Multivariate analysis (n = 180)

Overall survival

Variable

Hazard

Ratio OS 95% CI P

R 0.74 0.46 1.21 0.23

autoSCT 0.67 0.43 1.05 0.084

CR 0.80 0.48 1.32 0.37

score 1.60 1.12 2.29 0.0107

Univariate analysis: Pooled ASCT vs. IFN

Overall survival

- Kurativ?

Es spricht manches dafür.

1st-line autoSCT bei MCL

Standard bei „gogo“ Patienten!

- autoSCT 1st-line

- autoSCT salvage

- alloSCT

Mature results of MDACC MCL transplants: PFS

auto1 auto2

Rituxi yes (21)

Rituxi no (29)

Rituxi yes (19)

Rituxi no (17)

The European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow Transplantation

MCL salvage auto: +/- rituximab

Canals et al, 2009, unpublished

n = 59

Kein Effektivitätszuwachs in der R-Ära.

- Kurativ?

Salvage autoSCT bei MCL

alloSCT bei „gogo“ Patienten?

Allogeneic SCT in relapsed MCL:

Relapse-free survival (Seattle)

Maris et al, Blood 2004

MCL: AlloSCT for autoSCT failureHD/KI/HH 1994-2008 (46 REL after 116 autotransplants)

Overall survival

Dietrich et al, EBMT 2010

Months from relapse

p = 0.049

auto2 (36)

allo (35)

- Kurativ?

Wahrscheinlich ja.

- Indikation?

Salvage bei „gogo“ Patienten.

Salvage alloSCT bei MCL

in Studien!

- CLL:

Auto: Keine! Allo: Salvage HR-CLL.

Auto: Salvage. Allo: Rez. nach auto.

- MCL:

Auto: Primär! Allo: Salvage.

Rolle der SCT in der “R”-Ära

Heidelberg/

Hamburg/ Kiel

consortium

M Rieger

M Nickelsen

N Schmitz

M Kneba

M Witzens

S Dietrich

B Tielesch

Nordic LG

C Geisler

E Kimby

M Dreyling

W Hiddemann

A Sureda

O Hermine

S Dietrich

C Canals

MCL Network

M Dreyling

C Pott

M Sorror

R Storb

CLL sc

P Corradini

M Hallek

E Kimby

M Sohb

D Milligan

W Wiktor

E Montserrat

R Brand

M Michallet

DCLLSG

M Ritgen

S Stilgenbauer

S Cohen

J Schubert

M Hensel

N Schmitz

M Hallek

S Böttcher

M Kneba

H Döhner

What about 1st-line allo in MCL?

auto1 (50)

allo (35)

• MCL

• > 18 years at SCT

• SCT 1990-2007

• 1st SCT (Auto or Allo)

• 1st-line SCT

• MedB with rituximab info available

Retrospective analysis on

1st-line transplants: Selection criteria

Variable auto allo

Rituximab prior /

peri / post SCT190 16

No rituximab 158 26

Total 348 42

Retrospective analysis on

1st-line transplants: Eligible patients

1st-line transplants: PFS allo vs auto (all)

p<0.001

1st-line transplants: PFS allo vs auto (no rituximab)

1st-line transplants: PFS allo vs auto (rituximab)

Is there a place for 1st-line alloSCT in

No! - unless we identify a

high-risk subset which does

poorly under modern

autoSCT strategies.

The MCL International Prognostic

Index (MIPI)

Hoster et al, Blood 2008

Factors relevant for

MIPI score

established with

455 patients

including 80 auto!

Nordic MCL Project: Outcome of

MCL1 vs MLC2

Geisler et al, EHA 2009

MCL2 Trial: OS according to MIPI

p=0.382

p=0.012 (log rank) p=0.004 (log rank)

< 12 mo. (n=55), 12–35 mo. (n=73), > 36 mo. (n=35)

Time to salvage treatment survival

Prognostic factors for PFS in autoSCT for FL

VariableBoston/

LondonEBMT Omaha HD/KI/HH

n 121 693 248 241

Age n.i. ++ - -

Pretreatment lines - - ++ ++

FLIPI high n.i. n.i. ++ -

Time from dx - n.i. - n.i.

CR vs PR at SCT - n.i. n.i. -

Refr. at SCT n.i. ++ - n.i.

Rohatiner JCO 2007; Montoto Leukemia 2007; Vose BBMT 2008;

Kornacker Ann Oncol 2009

Ljungman et al, BMT 2009

Current EBMT indications for allo-SCT:

Lymphoma

Entity 1st-line Relapse Refractory

Aggressive B - (+) D

FL - (+) (+)

MCL (+) (+) D

CLL p53 (+) +

TCL (+) (+) D

Hodgkin - (+) D

Study GCLLSG Seattle Boston Houston GCTSG

n 90 82 46 39 30

PFS 40% (3y) 39% (5y) 34% (2y) 44% (4y) 58% (4y)

OS 70% (3y) 50% (5y) 54% (2y) 48% (4y) 69% (4y)

NRM 21% (3y) 23% (5y) 17% (2y) n.a. 15% (4y)

Ext. chronic

55% 49-53% 38% 58% 21%

F/U y 37 (7-92) 60 20 27 (4-80) 44

Mortalität nach RIC-alloSCT bei CLL

Adaptiert nach Delgado, Milligan & Dreger,

Blood 114:2581-88 (2009)

die rolle der stammzell- transplantation bei b-zell ...€¦ · observation median 11.6 months...

Documents

the prognostic factors and treatment outcome of squamous...

healthcare sector update · 2017. 11. 27. · healthcare...

neuroendocrine tumors of the appendix in adolescents and...

long-term survival advantage for recurrent ovarian cancer...

braftovi (encorafenib) capsules, for oral use...median time...

conventional linear versus purse-string skin closure after...

udia wa property market statistics june 2018 · march, 2018...

dshs grand roundsapr 02, 2014 · • age of onset...

activating the...disease control rate (dcr) 90% 83% cr, pr &...

re/max · honolulu, hi +1.4% sold june 2018 median sales...

court-based child welfare reforms final · in wayne county,...

the median-median line

jefferies global healthcare conference...retrospective...

invented name: keytruda international non …...median pfs...

colorectal cancer: new drugs on the horizon · primary...

clinical outcomes of bosniak category iif complex renal...

nktr sitc ir event 11.9.2018 final slides - nektar.com ·...

database construction n=1,715 median os=40.0 months, age:...

indicazioni alla terapia adiuvante...ialt advances m...

nccnhr 2009 assisted living carlson-edelman-polzer...