The Evolving Role of Transplantation in Lymphoma Stephen Mackinnon Royal Free Hospital / University College London

The Evolving Role of

Transplantation in Lymphoma

Stephen Mackinnon

Royal Free Hospital / University College London

Theoretical Advantages for Allogeneic Transplantation

• Tumour free graft

• Undamaged Stem Cells

• Avoidance of MDS/secondary AML

• Graft versus lymphoma effect

Disadvantages of Allogeneic Transplantation in Lymphoma

• Lack of suitable donors

• High Treatment Related Mortality

– Regimen related toxicity

– Infection

– GVHD

Allogeneic transplant in NHL

• No randomised trials available

• Relapse lower than auto transplant

• Possibly a graft versus lymphoma effect

• Can be used in poor mobilisers

• Higher TRM than autologous transplant

Allogeneic Transplantation

Myeloablative or Reduced Intensity?

Peneket el al, Bone Marrow Transplant 31:667, 2003

Auto vs Ablative Allo Transplant

TRM

Graft Versus Lymphoma effect or effect of tumour free graft?

Low Grade Histology

Bierman et al. J Clin Oncol 21:3711, 2003

RelapseProgression Free Survival

GVL Effects of DLI / GVHD

� Proven to be good

• CML

� DLI shown to be limited or poor

• AML / ALL / MDS / Hodgkin’s

� DLI probably good

• CLL / Follicular NHL / Myeloma

� Unknown

• DLBCL

9

Long-term follow-up of reduced-intensitytransplantation with an alemtuzumab-containing regimen:

Aggressive NHL

J Clin Oncol. 2009;27:426-32

10

High-grade NHL: Patients (I)

• n=48• Median age 46 years (range 23–64)• Median lines therapy 5 (range 2–7)• Prior autograft 34 (71%)• No autograft 14 (29%)

– 8 progression through salvage chemo within 3 months of primary treatment, 3 failed mobilization, 3 MDS/lymphoma/lung fibrosis

• Median follow-up 52 months (range 18–89)

• Status at transplant– CR 9– PR 31– Refractory 8

J Clin Oncol. 2009;27:426-32

11

High-grade NHL: Patients (II)

• High-grade HNL (n=48)– 18 HG transformation follicular NHL– 30 primary DLBCL

• Donor– 30 HLA-matched sibling– 18 unrelated

• 12 HLA-matched

• 8 HLA-mismatched (4 x 1 locus, 3 x 2 loci, 1 x 3 loci)

J Clin Oncol. 2009;27:426-32

Conditioning regimen

Alemtuzumab 20 mg/d

Fludarabine 30 mg/m2/d

Melphalan 140 mg/m2

Unmanipulated PBSC / Marrow

–8 –7 –6 –5 –4 –3 –2 –1 0Day:

Cyclosporin A as GVHD prophylaxis from Day –1

Thomson et al. J Clin Oncol 2008 (in press)

13

Aggressive NHL: Treatment-related mortality (n=48)

0.25

0.50

0.75

1.00

Cu

mu

lati

ve I

nci

den

ce

32%

Time (years)2 4 6 8

J Clin Oncol. 2009;27:426-32

14

Aggressive NHL: Relapse (n=48)

0.25

0.50

0.75

1.00

Cu

mu

lati

ve I

nci

den

ce

33%

Time (years)

2 4 6 8

J Clin Oncol. 2009;27:426-32

15

Aggressive NHL:Overall survival (n=48)

0.25

0.50

0.75

1.0

Su

rviv

al

47%

Time (years)

2 4 6 8

J Clin Oncol. 2009;27:426-32

16

High-grade NHL: DLI for relapse

• 15 patients relapsed / progressed• Median time to relapse 6 months (2–56)• 12 patients given dose-escalated DLI

– 5 primary high-grade

• 4 DLI alone, 3 grade 3/4 aGVHD, all had progression

• 1 surgery + XRT + Ritux then DLI, in CR at 76 months

– 7 transformed low-grade

• 3 no GVHD, no response

• 3 CR ongoing at 7, 27, 37 months – no GVHD in 2/3

• 1 surgery then DLI in CR at 76 months

• Summary 5 / 15 relapses back in remission

DLI, donor lymphocyte infusionaGVHD/cGVHD, acute/chronic graft-versus-host disease

17

Current PFS (n=48)

PFS, progression-free survival

0.25

0.50

0.75

1.00

Su

rviv

al

48%

Time (years)

2 4 6 8

18

Current PFS by donor type

0.25

0.50

0.75

1.00

Su

rviv

al

50%

43%

Time (years)

p=0.65

2 4 6 8

Sibling

Unrelated

19

Current PFS by chemo-responsiveness

0.25

0.50

0.75

1.00

Su

rviv

al

55%

12%

0 2 4 6 8

Time (years)

p=0.006

Chemorefractory

Chemosensitive

J Clin Oncol. 2009;27:426-32

20

Conclusions – Aggressive NHL

• Reduced intensity approaches show:

– significant TRM in aggressive lymphoma

– surprising low relapse rate• T cell depletion

• Non ablative regimen

– long-term remissions – cure probable

• DLI only benefit a minority

• Chemosensitivity is a predictor for outcome

– we no longer transplant refractory aggressive NHL

• Is there a role for mini allo in preference to auto transplant in patients who remain PET+ following salvage chemo?

Follicular Lymphoma

Seattle Regimen 2 Gy TBI ± Flu

Transformed follicular

Follicular

J Clin Oncol 26:211,2008

Chronic extensive GVHD in 45%

Related TransplantsIndolent Disease

Overall Survival

Progression Free Survival

Flu / Cy / Rituximab

• Patients– Related 45– Unrelated 2

• Median age 53yrs (33 – 68)• Prior therapy

– ≤ 2 regimens 23– 3 – 5 regimens 24– auto transplant 9

• Disease status at transplant– CR 18– PR 29– Refractory 0

• GVHD prophylaxis Tacro + MTX

Khouri et al. Blood 2008, 111: 5530



Survival

Progression Free Survival



Acute GVHD Chronic GVHD

Chronic

Chronic Extensive

II - IV

III - IV

26

Follicular NHL: Patients (I)

• n=78• Median age 45 years (range 26–65)• Median lines therapy 3 (range 1–8)• Prior autograft 28%• Median follow-up 40 months (range 4–103)

Thomson et al. ASH 2007; abstr 1661

27

Alemtuzumab

• Advantages– Engraftment

– Low GVHD• Unrelated

– Low TRM

• Disadvantages– CMV infection

– Mixed chimerism

– Lack of GVL

28

Flu/Mel conditioning & GVHD prophylaxis:CSA/alemtuzumab vs CSA/MTX

Alemtuzumab MTX

Acute GVHD II–IV 9% 43%

Chronic GVHD 5% 67%

CMV infection 85% 24%

TRM 10% 20%

Pérez-Simón et al. Blood 2002;100: 3121–7

29

Follicular NHL: Patients (II)

• Donor– 39 HLA-matched sibling– 39 unrelated

• 29 HLA-matched• 10 HLA-mismatched (7 x 1 locus, 3 x 2 loci)

• Chemosensitive– Yes 69– No 8 – Untested 1


30

Follicular NHL: Non-relapse mortalityby donor type

9% Sibling

22% Unrelated0.25

0.5

0.75

1.0

1000 2000 3000

Cum

ulat

ive

Inci

denc

e

Days


31

Follicular NHL: Overall survival (n=78) GVHD and donor type

0.25

0.5

0.75

1.0

1.8 3.6 5.4 7.2 9

0.25

0.5

0.75

1.0

1.8 3.6 5.4 7.2 9

76%

Impact of GVHD

Sibling 90%

Unrelated 61%

Years

p<0.005

Years


32

Follicular NHL: Overall survival by prior autograft and chemosensitivity

0.25

0.5

0.75

1.0

0.25

0.5

0.75

1.0

1.8 3.6 5.4 7.2 9 1.8 3.6 5.4 7.2 9

Prior Autologous Transplant

No 85%

Yes 52%

p<0.002

Chemosensitive

Yes 79%

No 50%

p<0.04


Years Years

33

- Donor

- Recipient

- Post-Transplant +60 Days

- Post-transplant +90 Days

- Post DLI + 73 Days

(Post Transplant + 6 Months)

34

0 1 2 3 4 5 6 7 8 9 10 11

0.25

0.50

0.75

1.00

Time (years)

Relapse and Chimerism

Full Donor

Mixed Chimerism

p < 0.01

13%

40%

35

Follicular NHL: Relapse (n=78)

0.25

0.5

0.75

1.0

1000 2000 3000

0.25

0.5

0.75

1.0

1000 2000 3000

All patientsImpact of GVHD

acute II–IV or chronic

No GVHD 35%

GVHD 14%


36

Follicular NHL: DLI for relapse

• 16 patients relapsed / progressed• Median time to relapse 8 months (2–43)• 10 patients given dose escalated DLI

– 3 non-responders• no GVHD

– 7 CRs, 3 with rituximab• 3 with GVHD, 4 no GVHD

• 1 progressed after 6 months

• 6 CRs ongoing at a median of 41 months (21–60)


37

Follicular NHL: cPFS (n=78) by donor type

0.25

0.5

0.75

1.0

1 2 3 4 5 6 7 8 9 10

0.25

0.5

0.75

1.0

1 2 3 4 5 6 7 8 9 10

74%

All patients

Siblings 87%

Unrelated 62%

p<0.02


Years Years

RIC Sibling Allo preferred over Auto

• Failure to mobilise autologous PBSC

• Bone involvement at end of chemotherapy

• Relapse post autograft

• Younger patients ?

• PET+ pretransplant ?

• Regimen with TRM < 10% ?

• Patient choice ?

Conclusions – Follicular Lymphoma

• Allogeneic conditioning regimens:

– higher TRM with myeloablative conditioning

• Some reduced intensity regimens may also have a high TRM

– low relapse rate for chemosensitive patients• Lymphoma free stem cells?

• GVL?

– long-term remissions – cure probable

• Chronic GVHD still a problem especially in MUD recipients

• DLI are effective in the majority of patients

• Chemosensitivity is a predictor for outcome

• Role for mini allo in preference to auto transplant?

Prognostic Role of PET

before and after Allogeneic

Stem Cell Transplantation

PET and Lymphoma

� PET predictive of outcome of chemotherapy or pre AUTO transplant

� Predictive role pre ALLO transplant unknown

� Role post ALLO transplant unknown

42

Prognostic value of PET status pre-auto-transplant for aggressive lymphoma: PFS

40

60

80

100

Time (days)

Cum

ulat

ive

perc

ent

surv

ivin

g

0

20

0

Spaepen et al. Blood 2003;102:53–59

PET –PET +

Copyright ©2003 American Society of Hematology.

500 1000 1500 2000 2500

Trial Aims

1. Is pre-transplant PET predictive of outcome ?

2. Is post-transplant PET clinically useful ?

Methods

� Prospective trial

� 80 consecutive lymphoma patients

� PET and CT pretransplant

• chemosensitivity assessed by CT

� Post transplant scans at 3, 6, 9, 15, 24 and 36 months

Post Transplant Interventions

� Patients with evidence of relapse given DLI

• clinical, CT or PET

� Patients with stable abnormal CT and PET negative were not given DLI

Patient Characteristics

Subtype PET negative (n=38) PET positive (n=42)CT positive

(n=17)CT

negative(n=21)

CT positive(n=34)

CT negative

(n=8)

Follicular lymphoma 8 6 12 4

Hodgkin lymphoma 4 4 11 3

Mantle cell lymphoma 1 4 6 0

Diffuse large B-cell lymphoma 2 4 1 0

Transformed follicular 1 2 2 1

Peripheral T-cell lymphoma 1 1 2 0

47

Relapse

0 20 40 60 80 1000

20

40

60

80

100

Time (months)

p=0.52

Per

cen

t

Overall survival

0 20 40 60 80 1000

20

40

60

80

100p=0.91

Time (months)

Per

cen

t

Disease-free survival

0 20 40 60 80 1000

20

40

60

80

100p=0.78

Time (months)

Per

cen

t

Current DFS

0 20 40 60 80 1000

20

40

60

80

100p=0.87

Time (months)

Pe

rce

nt

48

Follicular Lymphoma cPFS by PET Status

Pretransplant

Months

PET negative

PET positive

49

subsequent coursefirst 6 monthspre-RIT subsequent coursefirst 6 monthspre-RITPre Tx 1st 6 months Subsequent follow up

PET +ve(n = 38)

PET +ve(n = 13)

PET +ve(n = 21)

NRM(n = 5)

50


PET +ve(n = 38)

PET +ve(n = 13)

PET +ve(n = 21)

PET -ve(n = 15)

NRM(n = 4)

51


PET +ve(n = 38)

PET +ve(n = 13)

No DLI(n = 5)

Rel(n = 4)

No DLI(n = 1)

PET +ve(n = 21)

PET -ve(n = 15)

NRM(n = 4)

NRM(n = 2)

DLI(n = 3)

DLI(n = 8)

52


PET +ve(n = 38)

PET +ve(n = 13)

No DLI(n = 5)

PR(n = 2)

Rel(n = 4)

No DLI(n = 1)

PET +ve(n = 1)

PET +ve(n = 21)

PET -ve(n = 6)

PET -ve(n = 3)

PET -ve(n = 15)

PET -ve(n = 2)

NRM(n = 4)

NRM(n = 2)

DLI(n = 3)

DLI(n = 8)

53


PET +ve(n = 38)

PET +ve(n = 13)

No DLI(n = 5)

PR(n = 2)

2nd Rel(n = 3)

No DLI(n = 1)

Rel(n = 4)

No DLI(n = 1)

PET +ve(n = 1)

PET +ve(n = 21)

PET -ve(n = 6)

PET -ve(n = 3)

PET -ve(n = 2)

PET -ve(n = 15)

PET -ve(n = 2)

NRM(n = 4)

NRM(n = 2)

DLI(n = 3)

DLI(n = 8)

DLI(n = 2)

Diagnosis of Relapse

� 34 episodes of relapse in 28 patients

• 4 clinically detected

• 13 PET + / CT +

• 17 PET + / CT –

• 16 / 17 at site positive pretransplant

� 19 patients were CT + / PET –

• 13 remained in CR

• 6 relapsed, 4 at site of prior CT abnormality

Indication for DLI

Indication CR / Episode

Clinical progression alone 1 / 3

PET + and relapse/progression on CT 6 / 9

PET + and normal/unchanged CT 13 / 14

PET + Infection / Inflammation

� 11 / 475 scans

� 5 lesions biopsed

• 2 infections

• 1 sarcoidosis

• 1 non-specific

• 1 bone remodelling

� 6 cervical uptake with respiratory infection

Potential Problems

� Relatively small numbers of each lymphoma subtype

• e.g. only 7 patients with de novo DLBCL

� Few PET + lesions biopsied – false positives ?

• majority of abnormalities at site of previous disease

• All patients either had resolution with DLI or had overt clinical relapse

Conclusions

� A positive pre transplant PET does not preclude a successful outcome

� Post transplant PET picks up relapse earlier and allows optimal efficacy of DLI

59

The Future

• Challenges

– Relapse e.g. Hodgkin lymphoma

• Increase antitumour activity of conditioning regimen

– Without excess regimen-related mortality

• Solution?

– Targeted radiotherapy

– Anti CD25

– Anti CD66

60

Why radioimmunotherapy?

• Specific, targeted therapy

• No grade III/IV non-haematologic toxicity

• Outpatient-based

• No effect on future therapies

61

Principles of Radioimmunotherapy

External-beam radiation Radioimmunotherapy

62

Principles of radioimmunotherapy

63

Principles of Radioimmunotherapy

Naked antibody Radio-labelled antibody

64

CHT25 program

• Challenge of relapsed/refractory lymphomas • CD25 expressed in a range of lymphomas• Hypothesis: RIT may be beneficial • Chimeric antibody CHT25

– Labelled with Iodine-131 (Amlot P, et al)

65

Objectives

• Primary endpoints

– Toxicity

– Pharmacokinetics and dosimetry

• Secondary endpoints

– Preliminary evidence of response

– ImmunogenicityRoyal Free Hospital

66

Study Information

• CD25 positive Hodgkin or T-cell lymphomas

• Standard inclusion and exclusion criteria ≥

• ≤ 25% bone marrow involved

• No human anti-CHT25 antibody

• 50% lymphoma cells to express CD25

Eligibility

67

Study details

• Therapy 10 mg CHT25 escalating 131Iodine activity 14 patients had 26 treatments (range 1-3)

131I activity

MBq/m2 370 740 1200 1480 2220 2960

No

patients

3 6 3 6 3 1

68

Patients

• 14 patients (8 M, 6 F)

• Median age 38 (28-70)

• 11 Hodgkin; 3 T-cell lymphoma• Median number of prior treatments 4 (range 2-8)

• 9 had an ASCT

• Stable dose steroids allowed

69

Toxicity: Non-haematological

• Infusional reactions• Grade 1 elevation liver enzymes - transient • Tunneled line infections and chest infection• 1 patient with renal failure• 1 patient hypothyroid

70

Toxicity - haematological

• 1 death – Reported as PCP when neutropenic • 6 patients had platelet support – at doses ≥ 1200 MBq/m2

Administered

Activity

MBq/m2

370 740 1200 1480 ≥ 2220

Platelets:

Grade 3 (%)/

duration (days)

nil nil 60%

3-42

83%

27-78

100%

32-176

Neutrophils:

Grade 4 (%)/

duration (days)

nil nil nil 50%

2-30+

25%

36

71

Response Data -modified Cheson criteria

2007

• 1 of 3 responses in T cell patients• 2 went on to transplant with successful engraftment

Injected single dose level

PET / CT combined

%

< 1200 MBq/m2 1/8 CR 12.5%

≥ 1200 MBq/m2 6/9 ORR-3/6 PR

-3/6 CR

66.7%

72

73

74

Conclusions CHT25

• Demonstrable activity with a chimeric antibody• Well tolerated at a non-myeloablative dose• MTD defined as 1200 MBq/m2

• Transplantation possible post-treatment• Future directions

– Transplant conditioning regimens in drug resistance– Combination therapy– Earlier treatment in poor prognosis patients

Documents

The Evolving Role of Transplantation in Lymphoma Stephen Mackinnon Royal Free Hospital / University College London