allogeneic stem cell transplant for hodgkins lymphoma

16
2015/8/28 B.S. Andersson Timing of Allogeneic sCT for Hodgkin’s Lymphoma Borje S. Andersson, MD, Ph.D. Molecular Pharmacology and Translat. Drug Development Program, Department of Stem Cell Transplantation UT MD Anderson Cancer Center August 28, 2015.

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Page 1: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

2015/8/28 B.S. Andersson

Timing of Allogeneic sCT for

Hodgkin’s Lymphoma

Borje S. Andersson, MD, Ph.D.

Molecular Pharmacology and Translat.

Drug Development Program,

Department of Stem Cell Transplantation

UT MD Anderson Cancer Center

August 28, 2015.

Page 2: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Gemcitibine+Busulfan+MelphalanImprove Survival in Refractory

Hodgkin’s Lymphoma

Carmustine (BiCNU)EtoposideCytarabine (Ara-C)Melphalan

Page 3: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

-3 -2 -1-4-6 -5 +14 +21 +100 >1800

Graft

RIC ?

Conditioning

Supportive Care

GVHD prophylaxis and therapy

Patient

(age, gender, CMV,

comorbidities…)

1

2

35

6

4

Malignant

Disease

Features

Optimize Therapy to Improve outcome?

Page 4: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Myeloablative allo-SCT in HL

0

10

20

30

40

50

60

70

Early TRM (%) Total TRM (%) PFS (%) OS (%) PD (%)

IBMTR

JHOC

FHCRC

Page 5: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Hodgkin Lymphoma: current issues in allogeneic stem cell

transplantation (allo-SCT)

• Reduced-intensity conditioning (RIC) now widely

used. No consensus on “optimal” regimen.

• Transplant-related mortality (TRM) low but disease

progression (PD) major problem. Patient outcome

negatively affected.

• Recognition of prognostic value of complete

response (CR) pretransplant.

• Availability of brentuximab vedotin and optimization

of its use.

Page 6: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

G-FM140: treatment schema

G8: Gemcitabine 800 mg/m2; ADM: Hospital admission;

F= Fludarabine 33 mg/m2; M = Melphalan 70 mg/m2;

T= Thymoglobulin 2 mg/kg (MUDs/MM);

SCT: stem cell transplant; GVHD prophylaxis: tacrolimus – miniMTX.

DAYS

-7 -1 -6 -5 -4 -3 -2 0

F F F F

M M SCTRest

TT

ADMG

Page 7: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Patient CharacteristicsTotal

N=27

Age a 31 (20-46)

Gender 15 M / 12 F

Prior chemotherapy regimensa 4 (2-10)

Prior autologous SCTb, n (%) 19 (70%)

Donor type

Matched related

Matched unrelated

16 (60%)

11 (40%)

Response status at allo-SCT, n (%)

CR/CRu 17 (63%)

PR 9 (33%)

Other 1 (4%)

TTP after autologous SCT (mo) 5 (1-68)

a Median (range). SCT: stem cell transplant; TTP: time to progression. CR/CRu:

complete response/undetermined. PR: partial response.

Page 8: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Brentuximab Vedotin (BV)

• SGN-35 antibody-drug conjugate

– CD30-targeted antibody (cAC10) conjugated to an auristatin (MMAE), an anti-tubulin agent

• Selectively induces apoptosis in

HL and ALCL cells:

– Binds to CD30

– Becomes internalized

– Releases MMAE

SGN-35 Antibody-Drug

Conjugate

SGN-35

binds

CD30

Endocytosis

ADC traffics to

lysosome

Enzymatic

linker cleavage

releases MMAE

from ADC

MMAE binds

tubulin

G2/M cell

cycle arrest

& apoptosis

CD30

SGN-35 Antibody-Drug

Conjugate

SGN-35

binds

CD30

Endocytosis

ADC traffics to

lysosome

Enzymatic

linker cleavage

releases MMAE

from ADC

MMAE binds

tubulin

G2/M cell

cycle arrest

& apoptosis

CD30

BV was granted accelerated approval by the FDA in Aug 2011 Courtesy of Dr. A. Younes

Page 9: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

PFS by Best Response (by PET/CT) - HL

Time (months)

% P

atie

nts

Fre

e of

PD

or

Dea

th

Page 10: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Brentuximab (BV)-treated vs BV-

näive: Complete Response (CR) rates

• The seven patients who received BV as last line of tx prior to allo-SCT are a/w in

CR/CRu

BV-treated

n=14

n (%)

BV-näive

n=13

n (%)

Total

N=27

p value

CR rate pre-allo SCT 11/14 (79%) 6/13 (46%) 0.12 (Fisher’s)

CR-rate post-allo SCT 12/14 (85%) 11/13 (85%) ns

Page 11: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Patient outcomes

• Six deaths, three early ones (< day 100).

• Causes of death: PD n=2, graft rejection n=1,

pneumonia n=2, respiratory failure n=1.

• 21 patients alive.

• TRM (day 100/overall): 15%.

• Acute GVHD (grade II-IV): 19% (95% CI 9-42).

• Chronic GVHD: 39% (95% CI 24-65).

• Median follow up: 18 months (4-55).

PD: progressive disease. TRM: Transplant-related mortality

Page 12: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Overall survival (OS)

and progression-free survival (PFS)

0 10 20 30 40 50 60

Months Post Transplant

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

OS

PFS

69%

55%

N= 27

Page 13: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Disease progression (PD)

Median time to PD: 13 months (2-22)

0 3 6 9 12 15 18 21 24

Months Post Transplant

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ula

tive In

cid

ence o

f Dis

ease P

rogre

ssio

n

30% (95% CI 15-61)

Page 14: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

FM140 vs G-FM140 comparison

a Haematologica 2008; 93:257

b Study group included patients (n=28) with < PR

Variable

FM140a

n=58

n (%)

G-FM140

n=27

n (%)

Age (yrs) 32 (19-59) 31 (20-46)

Brentuximab vedotin pre-SCT (Y/N) 0 / 58 14 / 13

CR/CRu pretransplant 24%b 63%

TRM (day 100/overall) 7% / 15% 15% / 15%

OS (2-year) 64% 78%

PFS (2-year) 32% 55%

PD (2-year) 55% 30%

Time to PD after allo-SCT (mo) 4.5 (1-35) 13 (2-22)

Page 15: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Progression-Free Survival after RIC Matched Sib SCT

Hodgkins lymphoma, N. America

- by disease status -

CR

ResistantPR

n = 87

Page 16: Allogeneic Stem Cell Transplant for Hodgkins Lymphoma

Summary

• Even in the face of refractory relapse or relapse after

a previous auto-SCT, allo-SCT may yield long-term

disease control in Hodgkin’s Lymphoma.

• The outcomes with RIC-conditioning is becoming

the preferred choice.

• The relatively high TRM-risk suggests that auto-SCT

should still be the preferred initial choice for most

patients with recurrent HL