Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

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Management of Recurrent of Management of Recurrent of Relapsed and Refractory Hodgkin Relapsed and Refractory Hodgkin Lymphoma Lymphoma Michael Crump, MD, FRCPC Division of Medical Oncology & Hematology Princess Margaret Hospital Department of Medicine, University of Toronto

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Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma. Michael Crump, MD, FRCPC Division of Medical Oncology & Hematology Princess Margaret Hospital Department of Medicine, University of Toronto. Outline of this talk. prognostic factors following disease recurrence - PowerPoint PPT Presentation

Transcript of Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Page 1: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Management of Recurrent of Relapsed Management of Recurrent of Relapsed and Refractory Hodgkin Lymphomaand Refractory Hodgkin Lymphoma

Michael Crump, MD, FRCPCDivision of Medical Oncology & Hematology

Princess Margaret HospitalDepartment of Medicine,

University of Toronto

Page 2: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Outline of this talkOutline of this talkOutline of this talkOutline of this talk

• prognostic factors following disease recurrence • role of local radiotherapy

• current results with ASCT

• strategies to improve ASCT outcome

• standard approaches – chemotherapy

• second transplants- reduced intensity allogeneic SCT

Page 3: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Recurrent HLRecurrent HL

• ~10-20% of early stage (I and II), 20-40% of pts with advanced disease

• Refractory: progression during or within 3 mos of completing therapy

Page 4: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Prognostic factors at relapsePrognostic factors at relapse

• age

• B symptoms

• performance status

• time to recurrence

• anemia

• extranodal sites

• primary treatment (RT v chemo)

… etc

Page 5: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Importance of time to Importance of time to recurrencerecurrence

GHSG: 472 pts with relapse / 4754

Median f/u 45 mos

FFTF survival

Early (< 1y) 33% 46%

Late (> 1y) 43% 79%

Josting et al. JCO 2002

Page 6: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Outcome of relapsed HL according to number of risk factors

(anemia, early relapse, stage III,IV)

Page 7: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Impact of clinical variables in transplant eligible patients

Age <60, KPS 90-100)

Page 8: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Outcome of Patients Experiencing Outcome of Patients Experiencing Relapse After ABVD x 2 + RT for Early-Relapse After ABVD x 2 + RT for Early-

Stage Favorable HLStage Favorable HL

• Uncommon occurrence: 3-5% of patients on recent trials of NCIC, GHSG

• eg: 42 / 1127 pts on GHSG trials– 8 ref, 7 early, 27 late (>12 m)– Rx: 4 RT, 14 chemo, 24 ASCT

Page 9: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Outcome of Patients Experiencing Outcome of Patients Experiencing Relapse After ABVD x 2 + RT for Early-Relapse After ABVD x 2 + RT for Early-

Stage Favorable HLStage Favorable HL

3y FFTF: 52%

3 y OS : 67%

Factors associated with poor outcome:

• anemia• advanced stage• early relapse

Sieniawski et al. J Clin Oncol 2007

Page 10: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Management of very late relapseManagement of very late relapse

• No risk factors (normal hemoglobin, limited stage), CR1 >5 y

→ chemotherapy + IFRT (EFRT?)

• eg BEACOPP x 4

• ASCT reserved for subsequent relapse

Page 11: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Primary Refractory HL

• New lesions or progression of prior lesions within 3 months of completing therapy

Josting A et al. J Clin Oncol 2000

Page 12: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Outline of this talkOutline of this talkOutline of this talkOutline of this talk

• prognostic factors following disease recurrence • role of local radiotherapy

• current results with ASCT

• strategies to improve ASCT outcome

• standard approaches – chemotherapy + rads

• second transplants- reduced intensity allogeneic SCT

Page 13: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Radiation After Relapse – Consider Radiation After Relapse – Consider it an Optionit an Option

• radiation as component of combined modalitytherapy for HL reduces the risk of local recurrence

• HL often recurs in nodal sites, and in sites not previously irradiated

• long-term disease control has been reportedafter RT for recurrent HL after primarychemotherapy (or CMT)

Poen et al. Int J Rad Onc Bio Phys 1996Mundt et al. Int J Rad Onc Bio Phys 1995

Page 14: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Radiation as Salvage TherapyRadiation as Salvage Therapy

1) Josting et al (GHSG): non-randomized: 100 pts

62% advanced HL at dx68% prior radiotherapy40% in-field relapse

5 yr FFTF 28% OS 51%

2) Wirth et al (Melbourne): 16 pts - 2 or 3 prior regimens

5 yr FFS 14% OS 38%

1) J Clin Onc 20052) Int J Rad Onc Bio Phys 1997, 2005

Favourable outcome:Stage INo B sx

Page 15: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Outline of this talkOutline of this talkOutline of this talkOutline of this talk

• prognostic factors following disease recurrence • role of local radiotherapy

• current results with ASCT

• strategies to improve ASCT outcome

• standard approaches – chemotherapy + rads

• second transplants- reduced intensity allogeneic SCT

Page 16: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Autologous Stem Cell Transplant Autologous Stem Cell Transplant in HLin HL

• Standard of care for relapsed and/or refractory disease

• 2 RCTs demonstrated improvement in

3-year Freedom from Treatment Failure with ASCT vs conventional chemotherapy

• Schmitz, Lancet 2002: 75% vs 45%• Linch, Lancet 1993: 55% vs 34%

Page 17: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Autologous stem cell transplantation for Autologous stem cell transplantation for relapsed/refractory HLrelapsed/refractory HL

Autologous stem cell transplantation for Autologous stem cell transplantation for relapsed/refractory HLrelapsed/refractory HL

dexa-BEAM x 2R

dexa-BEAM x 2

dexa-BEAM x 2R

dexa-BEAM x 2n=161n=161

ASCTASCT 49%49% 57%57%

ChemoChemo 32%32% 56%56%

p = 0.02p = 0.02

ASCTASCT 49%49% 57%57%

ChemoChemo 32%32% 56%56%

p = 0.02p = 0.02

FFTF (7 y)FFTF (7 y) OSOSFFTF (7 y)FFTF (7 y) OSOS

Schmitz et al. ASCO, 2005Schmitz et al. ASCO, 2005

ASCT

dexa-BEAM x 2

ASCT

dexa-BEAM x 2n=117n=117

+ IFRT

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??Regimen

No. of Patients

CR%95% CI

PR%95% CI

ORR%95% CI%

Gr 3/4PMN/PLT

%

Toxic deaths %

Dexa-

BEAM

144 27

20-34

54

46-62

81

75-87

NS 5

1-9

Mini-

BEAM

55 49

35-63

33

21-47

82

69-91

86/60 2

0.1-10

ICE 65 26

16-39

59

46-71

85

74-92

NS 0

0-5

DHAPq2w 102 21

13-29

68

59-77

89

83-95

88/69 0

0-4

GDP 23 17

5-39

52

31-73

69

47-87

9/13 0

0-15GVD 38 11

3-2553

36-6964

46-7869/17 0

0-9

IEV 51 76

60-88

84

71-93

100/NS 0

MINE 157 NS NS 75

64-84

NS 5 (3)

IV 47 45

30-60

38

25-54

83

69-92

65/0 NS

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Long – term outcome: Long – term outcome: Royal Marsden HospitalRoyal Marsden Hospital

Ann Oncol 2008

5y 10yPFS 44% 37%OS 55% 49%`

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Multivariate Analysis: Prognosis determined by:

sensitivity to salvage chemotherapy

Hasenclever index

Page 21: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Predictors of outcome post-ASCT Predictors of outcome post-ASCT for relapsed/refractory HLfor relapsed/refractory HL

Predictors of outcome post-ASCT Predictors of outcome post-ASCT for relapsed/refractory HLfor relapsed/refractory HL

• CR/PR at ASCT

• first remission >1 yr

• negative pre-ASCT

FDG-PET

• CR/PR at ASCT

• first remission >1 yr

• negative pre-ASCT

FDG-PET

• resistant to 2nd line chemo

• high # HL PI risk factors

• multiple relapses

• primary refractory HL

• resistant to 2nd line chemo

• high # HL PI risk factors

• multiple relapses

• primary refractory HL

Less favorableoutcome

Less favorableoutcome

More favorableoutcome

More favorableoutcome

Gopal AK, et al. Cancer 2008Sirohi B, et al. Ann Oncol 2008Wadehra N, et al. Biol Blood Marrow Transpl 2006Ferme C, et al. J Clin Oncol 2003

Gopal AK, et al. Cancer 2008Sirohi B, et al. Ann Oncol 2008Wadehra N, et al. Biol Blood Marrow Transpl 2006Ferme C, et al. J Clin Oncol 2003

Page 22: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

PMH: Mobilization and PMH: Mobilization and ASCTASCT

– PBSC Mobilization• Cyclophosphamide 2 g/m2 on day 1• Etoposide 200 mg/m2 days 1 – 3 • G-CSF 10 g/kg starting on day 6

– High-dose chemotherapy regimen• Etoposide 60 mg/kg on day -4• Melphalan 180 mg/m2 on day -3

– Involved field RT given if bulk disease ( 5 cm) present at relapse, 6-8 weeks post-ASCT

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Stem Cell Mobilization Stem Cell Mobilization EfficiencyEfficiency

GDPGDP Mini-BEAMMini-BEAM PP value value

# apheresis sessions(median, range)

1 (1 – 3) 1 (1 – 5) 0.23

Median CD34+ cellsX 106 /kg

11.1 (1.4 – 37.1)

5.5 (0 – 41.7) 0.0018

% patients with collection 2 X 106 /kg

97 82 0.07

Proportion collected in a single apheresis (%)

90 57 0.0043

% patients with collection > 5 X 106 /kg

97 57 0.0003

Proportion collected in a single apheresis (%)

73 36 0.004

Proportion requiring marrow harvest (%)

3 18 0.07Kuruvilla et al. Cancer 2006

Page 24: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Results – Response and Results – Response and SurvivalSurvival

    GDP Mini-BEAM p

Response Response Rate (%)Rate (%)(95% CI)(95% CI)

6262

(45 – 78%)(45 – 78%)

68

(52 – 83%)

0.610.61

Overall Overall SurvivalSurvival

18 mos (%)18 mos (%)

9090 8686 0.280.28

Progression-Progression-freefree

18 mos (%)18 mos (%)

7676 3636 0.0120.012

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0 5 10 15

0.0

0.2

0.4

0.6

0.8

1.0

Time (years)

Pro

babi

lity

Progression free rateSurvival

Time (years)

Pro

babi

lity

of S

urvi

val 1.0

0.8

0.6

0.4

0.2

0.0

0 5 10 15

Progression Free Survival Progression Free Survival vs Overall Survivalvs Overall Survival

Progression Free Survival

Overall Survival

n=323

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0 5 10 15

0.0

0.2

0.4

0.6

0.8

1.0

Time (years)

Pro

bab

ility

Incidence of progressionProbability of TRM death

Time (years)

Fai

lure

Rat

eCauses of Treatment FailureCauses of Treatment Failure

1.0 0.8

0.6

0.4

0.2

0.0

0 5 10 15

3 yr 5 yr 10 yr

Relapse 44% 46% 48%

TRM 6% 9% 15%

Page 27: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Competing Risks AnalysisCompeting Risks Analysis

3 yrs 10 yrs

Survival 68 % 39 %

Failure Free Rate 50 % 40 %

Probability of

2nd Cancer 5 % 12%

Leukemia 3 % 7 %

Solid Tumor 2 % 5 %

Page 28: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

ASCT for ASCT for refractoryrefractory HL: HL:

Author n PFS, yrs OS, yrsSweetenham, 1999

175 32% 5y 36% 5y

Ferme, 2002 101 60% 5y 71% 5y

Moskowitz, 2004 75 49% 10y 48% 10y

Princess Margaret 2009

73 49% 3y 75% 3y

Page 29: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Princess Margaret Hospital Princess Margaret Hospital experience—refractory HLexperience—refractory HL• 157 patients referred for ASCT 1999-2006• Response rate to salvage therapy

– refractory (n=73): 49% vs relapsed (84): 83% (p<.0001)

• 3 y FF2TF – refractory 49% vs relapsed 67% (p=0.21)

• Overall survival– refractory 75% vs relapsed 91% (p=0.097)

Page 30: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Princess Margaret Hospital Princess Margaret Hospital experienceexperience

0 2 4 6

0.0

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Su

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REF, n=73, 3y Survival=76%REL, n=84, 3y Survival=91%

Log-rank p-value=0.034

All patients, from time of treatment failure

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Princess Margaret Hospital Princess Margaret Hospital experienceexperience

Patients undergoing ASCT, from time of transplant

0 1 2 3 4 5 6 7

0.0

0.2

0.4

0.6

0.8

1.0

Time to death (years)

PF

S s

ince

AS

CT

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REF, n=58, 3y PFS=49%REL, n=77, 3y PFS=67%

Log-rank p-value=0.21

Page 32: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Outline of this talkOutline of this talkOutline of this talkOutline of this talk

• prognostic factors following disease recurrence • role of local radiotherapy

• current results with ASCT

• strategies to improve ASCT outcome

• standard approaches – chemotherapy + rads

• second transplants- reduced intensity allogeneic SCT

Page 33: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Treatment Intensification before Treatment Intensification before ASCT:ASCT:

High-dose sequential therapyHigh-dose sequential therapy

DHAP x2

CRPR

PBSC collection

MTX 8 g/m2 Etoposide 2 g/m2

Cyclo 4 g/m2 + gcsf

BEAM ASCT

Josting et al Ann Oncol 2005

Page 34: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

DHAP all relapsed refract.

n 102 85 17

CR (%) 21 24 12

PR (%) 66 68 53

fail (%) 13 8 35

Post ASCT

CR (%) 72 75 53

fail (%) 20 17 41

High-dose sequential therapy: High-dose sequential therapy: ResultsResults

Page 35: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

GHSG-EBMT randomized trial

Hematologica 2009; 94[suppl.2]:204 abstract 0501Hematologica 2009; 94[suppl.2]:204 abstract 0501

DHAP x2

CRPR

R

BEAM ASCT

HDS: cyclo, MTX,etoposide

BEAM ASCTn=284 n=240

3y FFTF PFS OS HDS 67% 69% 83%Standard 71% 72% 84%

Page 36: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Tandem autotransplants for high risk relapsed/refractory HL

GELA/SFGM H96 trial

• 245 pts 1995-2002

• High risk: refractory or 2 risk factors (early relapse, stage 3 or 4, rel in radiation field) → tandem transplant

• Intermediate risk: single risk factor → single transplant

Page 37: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Improvement in outcome with Improvement in outcome with tandem transplant?tandem transplant?

Morschhauser, JCO 2008

Page 38: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Outline of this talkOutline of this talkOutline of this talkOutline of this talk

• prognostic factors following disease recurrence • role of local radiotherapy

• current results with ASCT

• strategies to improve ASCT outcome

• standard approaches – chemotherapy

• reduced intensity allogeneic SCT

Page 39: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Systemic Chemotherapy: Systemic Chemotherapy: Single Agent or Combination?Single Agent or Combination?

Systemic Chemotherapy: Systemic Chemotherapy: Single Agent or Combination?Single Agent or Combination?

vinca alkyloids 46-59% 6-8 m

gemcitabine 22-64% 6-9 m

gemcitabine –rituximab 61% 3 m

gemcitabine, vinorelbine,PEG-liposomal dox. 75% 8.5 m

Response rate vs. Disease controlRR (%) PFS (med)

Page 40: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Problem with Combination Therapy: MyelosuppressionProblem with Combination Therapy: MyelosuppressionProblem with Combination Therapy: MyelosuppressionProblem with Combination Therapy: Myelosuppression

MTD: (mg/m2)Gemcitabine 800 1000Vinorelbine 15 20Peg-liposomal-doxorubicin 10 15

Gr 4 neutropenia (%) 24 35Gr 3/4 platelets 43 14

treatment onschedule, full dose (%) 26 32

response rate (%) 75 61FS (median) 8.5 ---

Prior SCT No prior SCT(n = 37) (n = 43)

eg) GVD

Bartlett N, et al. Ann Onc, 2008

Page 41: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Outline of this talkOutline of this talkOutline of this talkOutline of this talk

• prognostic factors following disease recurrence • role of local radiotherapy

• current results with ASCT

• strategies to improve ASCT outcome

• standard approaches – chemotherapy

• reduced intensity allogeneic SCT

Page 42: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Allogeneic Stem Cell TransplantationAllogeneic Stem Cell TransplantationFollowing Relapse from ASCT for HLFollowing Relapse from ASCT for HL

Allogeneic Stem Cell TransplantationAllogeneic Stem Cell TransplantationFollowing Relapse from ASCT for HLFollowing Relapse from ASCT for HL

Pro• young patient population – going for cure• HL similar to other indolent B-cell lymphomas

- long survival after relapse- demonstrated GV–lymphoma effect in CLL,

follicular NHL

Con• published data from myeloablative alloSCT:

- high treatment-related mortality- GVHD, regimen-related

- little impact of GVHD on relapse rate

Page 43: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Myeloablative Allo Transplants After ASCTMyeloablative Allo Transplants After ASCT (IBMTR 1990-99)(IBMTR 1990-99)

Myeloablative Allo Transplants After ASCTMyeloablative Allo Transplants After ASCT (IBMTR 1990-99)(IBMTR 1990-99)

At 3 yrs:

• treatment related mortality 22% (16-31)

• relapse risk 52% (43-61)

• progression-free survival 25% (18-33)

- risk of treatmentrelated mortality higher forunrelated donors

Freytes, et al. Blood 2004

Page 44: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

2 Gy TBI2 Gy TBI

Bu

Flu

Bu

Flu+ +

FluFlu

FluFlu CnICnIMelMel

ATG, -CD52 DLI

Reduced IntensityRegimens:

Page 45: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Recent Results with Reduced IntensityAllogeneic Transplantation for Relapsed HL

Peggs 49 44 5 16 (2 y) 32 (4y) 56 (4 y)

Sureda 89 55 85% ≥ 3 23 (1 y) 18 (3 y) 35 (3 y)

Alderlini 40 30 5 22 (18 m) 55 (18 m) 61 (18 m)

Armand 36 34 4 15 (3 y) 22 (3 y) 56 (3 y)

Alvarez 40 29 55% ≥ 3 25 (1 y) 32 (2 y) 48 (2 y)

Prior Prior regimens Tx-related

n ASCT (median) mortality PFS OS

Abbreviations: n: number of allogeneic transplants; ASCT autologous stem cell transplantlPFS: progression-free survival; OS: overall survival

Page 46: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

1) Response to Donor Lymphocyte Infusion1) Response to Donor Lymphocyte Infusion1) Response to Donor Lymphocyte Infusion1) Response to Donor Lymphocyte Infusion

Armand 2008 13 NS 2/13 NS

Peggs 2005 16 3 9/16 5/16

Alderlini 2008 14 11 6/14 1/14

DLI after Relapse-Author n chemo Response Free

2)2) Decreased relapse, improved PFS withDecreased relapse, improved PFS with chronic GVHDchronic GVHD

spontaneous Sureda A, et al. JCO 2008

Armand P, et al. BBMT 2008

and after DLI Peggs KS, et al. Lancet 2005

2)2) Decreased relapse, improved PFS withDecreased relapse, improved PFS with chronic GVHDchronic GVHD

spontaneous Sureda A, et al. JCO 2008

Armand P, et al. BBMT 2008

and after DLI Peggs KS, et al. Lancet 2005

Is there a graft vs. HL effect after RIT? Is there a graft vs. HL effect after RIT?

Page 47: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

ConclusionsConclusions

• Outcome of second-line therapy is determined by clinical factors, as much as by treatment– Not to mention biology…

• ASCT is the standard of care for all patients (suitable age, PS) with few exceptions– Late relapse, localized… think CMT

Page 48: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

ConclusionsConclusions

• Novel agents are currently being tested that may be incorporated into primary or second line treatment– HDAC inhibitors, mTOR, antibody-chemo

conjugates…

• Reduced intensity transplants need to be evaluated in carefully conducted trials

Page 49: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma
Page 50: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

RelapsedHL post-ASCT

Localized (stage I or IIA)

No prior RT

Localized (stage I or IIA)

No prior RT

Systemic recurrencestage III or IV

or relapse in priorradiation field

Systemic recurrencestage III or IV

or relapse in priorradiation field

Extended fieldradiation

Extended fieldradiation

RI allotransplant ifresponse to

chemotherapy

RI allotransplant ifresponse to

chemotherapy

≤ 6 mosfrom ASCT

≤ 6 mosfrom ASCT

≥ 6 mosFrom ASCT

≥ 6 mosFrom ASCT

Clinical trialof new agent

Clinical trialof new agent Young

good PS

Younggood PS

Single agentor combination chemotherapy

Single agentor combination chemotherapy

HLAmatched

donor

HLAmatched

donorClinical trialsof new agent

at progression

Clinical trialsof new agent

at progression

ASCT (if response,>5 yrs from

1st transplant)

ASCT (if response,>5 yrs from

1st transplant)

In summary:An algorithm

Page 51: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

relapsedHL post-ASCT

Localized: (stage I,IIA)

no prior RT orrelapse out of field

systemic recurrencestage III or IV

or relapse in priorradiation field

extended fieldradiation

Page 52: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

systemic recurrencestage III or IV

or relapse in priorradiation field

< 6 mosfrom ASCT

≥ 6 mosfrom ASCT

clinical trialof new agent

Page 53: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

RIT ifresponse to

chemotherapy

≥ 6 mosfrom ASCT

younggood PS

single agentor combinationchemotherapy

HLAmatched

donor clinical trialsof new agent

at progression

ASCT (if response,>5 yrs from

1st transplant)

Page 54: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

ConclusionsConclusions

• Numerous treatment options available– but cure is but cure is uncommonuncommon: take time to manage expectations, : take time to manage expectations,

discuss realistic goalsdiscuss realistic goals

• Disease control possible with radiation (sometimes) and chemotherapy (sometimes)– Keep it simple; reserve combinations for when transplant is

goal (chemosensitive)

• Exciting new agents entering or in clinical trials!– encourage patient, physician participation

• Allotransplant needs further study in well-designed phase II trials

Page 55: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Autologous Transplant at PMHAutologous Transplant at PMH• Salvage therapy to best response

mini-BEAM, GDP, DHAP

• Conditioning

etoposide 60 mg/kg Day -4

melphalan 160-180 mg/m2 Day -3

• Stem Cell Source

bone marrow – 46%

peripheral stem cells – 49%

• Post-transplant radiotherapy – 26%

Page 56: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Results – Patient CharacteristicsResults – Patient Characteristics

No. patients 323

ASCT 1986 – 1995 148

ASCT 1996 – 2005 175

Male 61 %

Age 33 yrs (16-67)

Histology

NS 73 %

Prior therapy

> 2 lines chemotherapy 11 %

radiotherapy 32 %

Page 57: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Results – Patient OutcomesResults – Patient Outcomes

Median follow-up 4.7 yrs (1-17)

Vital Status

Dead 47 % (154)

Disease Status

Relapse 45 % (146)

Outcome

Treatment Failure 53 % (170)

Page 58: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Second Cancer RiskSecond Cancer Risk

• Increases with every 10 year increment in age at time of transplant

Hazard Ratio

Second Cancer 1.9 (1.4-2.6)

Leukemia 1.9 (1.3-2.9)

Solid Tumour 1.8 (1.1-3.2)

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0 2 4 6 8

0.0

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ASCT in 1996 - 2005

Time (years)

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0 5 10 15

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0.6

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ASCT in 1986 - 1995

Time (years)

Pro

bab

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Incidence of progressionProbability of TRM death

ASCT 1986 – 1995

ASCT 1996 – 2005

0 5 10 15

0.8

0.6

0.4

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0.0

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Fai

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Page 60: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Identifying Prognostic Groups:Identifying Prognostic Groups:Multivariate Predictors of OutcomeMultivariate Predictors of Outcome

Identifying Prognostic Groups:Identifying Prognostic Groups:Multivariate Predictors of OutcomeMultivariate Predictors of Outcome

0 10 20 30 40 50 60

0.0

0.2

0.4

0.6

0.8

1.0

Progression Free Survival time (Months)

Pro

port

ion

Pro

gres

sion

Fre

e

Risk (Median PFS)

Low (14 m)Medium (6 m)High (4 m)

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

Overall Survival time (Months)P

ropo

rtio

n A

live

Risk (Median OS)

Low (36 m)Medium (21 m)High (9 m)

PFS:• >2 cycles salvage• extra-nodal sites at relapse

No risk factor : 14 m1 RF: 6 m2 RFs: 4 m

OS:• >2 cycles salvage• anemia at relapse

No risk factor : 36 m1 RF : 21 m2 RFs: 9 m

Al Farsi, et al, submitted

Page 61: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Time to Relapse after ASCT as a Time to Relapse after ASCT as a Predictor of Outcome/Guide to TherapyPredictor of Outcome/Guide to Therapy

• interval between ASCT and relapse is a strong predictor survival: recent series:

- Constans, et al, ASH 2004 (abstract 1649)

- Dean, et al, ASH 2007 (abstract 1903)

- Horning, et al ICML 2008 (abstract 118)

• median time to relapse 6-10 mos• outcome significantly worse

for pts with relapse <6-12 mos

from ASCT

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

Overall Survival time (Months)P

ropo

rtio

n A

live

Relapse 0-3 moRelapse 3-6 moRelapse 6-12 moRelapse >12 mo

Page 62: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Princess Margaret HospitalPrincess Margaret HospitalRadiation for Relapse Post-ASCTRadiation for Relapse Post-ASCT

39 pts: rads as first therapy

13 : extended field (mantle, inv Y)

26 : involved field (2: n = 5)

median PFS: 7 m OS: 41 m

vs. chemotherapy: PFS 6 m OS: 23 m

p = 0.18

Page 63: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Factors Associated with Outcome of Second Factors Associated with Outcome of Second SCT with Non-myeloablative ConditioningSCT with Non-myeloablative Conditioning

n = 147Prior auto: 135 (92%)Hodgkin lymphoma: 35 (24%)- response to chemo (CR/PR) : 20

refractory: 15

3 yr FFS 3 yr OS

HL 8%

35%

Mantle cell 57%

64%

Follicular 28%

31%

Barron, et al. J Clin Onc 2006

Page 64: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Reduced Intensity Allotransplant:Reduced Intensity Allotransplant:Superior to Standard RSuperior to Standard Rxx??

Cases: Phase II multicentre trial of RIT for HLin UK

Peggs, et al. Lancet 2005

Controls: - single institution (UCLH)- HL, relapsed post-ASCT- responded to next treatment- survived one yr post relapse

Thomson, et al. BMT 2008

Flu + Mel + alemtuzumab

Page 65: Management of Recurrent of Relapsed and Refractory Hodgkin Lymphoma

Reduced Intensity Allotransplant:Reduced Intensity Allotransplant:Superior to Standard RSuperior to Standard Rxx??

Outcome:

Overall survival - 5 yr from ASCT: Standard Rx 15% RIT 65%

RIT

no RIT

Thomson, et al. BMT 2008