Is chemotherapy alone sufficient for the treatment of Hodgkin’s lymphoma? The 1st World Congress on Controversies in Hematology (COHEM) Rome, Italy September 5, 2010

David J. Straus, M.D. Memorial Sloan-Kettering Cancer Center New York, NY USA

Hodgkin Lymphoma Historical Perspective • In HL, treatment with RT, RT+CT and CT has resulted in high cure rates for 30 years • It is unclear that results have improved over 30 years • The late toxicity associated with these treatments are significant • Unlike many other cancers, a major challenge is to achieve excellent treatment results with less toxicity

Hodgkin Lymphoma Survival MSKCC 1975-2000 1.0 0.9

Proportion Surviving

0.8 0.7 0.6 0.5 0.4 0.3

Patients: 746 (519 Alive) Median Overall Survival: 32.0 years Median Follow-up for Survivors: 21.6 years Range: 6.3 - 33.0 years

0.2 0.1 0.0 0

5

10

15

20

25

30

35

Years Since Treatment Start

Median age at initiation of treatment: 29 years (14-66 years)

Hodgkin Lymphoma Cause-Specific Survival MSKCC 1975-2000 0.4

Incidence of HL and non HL related death

0.2 0.1 0.0

Probability

0.3

DOD Died nonHL causes Died of Unknown

0

5

10

15 Years

20

25

30

Hodgkin Lymphoma Cause-Specific Survival MSKCC 1975-2000

0.4

Incidence of HL and non HL related death

0.2 0.1 0.0

Probability

0.3

DOD Died of SPM Died of Cardiac Died of Other Died of Unknown

0

5

10

15 Years

20

25

30

MSKCC Hodgkin Lymphoma Survival Study • Data from 233/519 survivors • Commonly reported specific late morbidities: – Second malignancies (24%) – Coronary artery disease (13%) – Varicella zoster reactivation (20%) – Osteoporosis (15%) – Chronic dental disease (27%).

Hodgkin Lymphoma Chemotherapy: Early Stages

MSKCC 90-44 Freedom From Progression 1.0

Proportion Progression-Free

0.8

0.6

ABVD+RT (76 pts, 11 failures) ABVD (76 pts, 12 failures)

0.4

P-value=0.70

0.2

0.0 0

20

40

60

80

Time to Progression in (months)

Straus et al. Blood 104: 3483-89, 2004

100

NCIC-CTG HD-6 (ECOG JHD6) Design

Exclude Low Risk IA1 with: • LP or NS • Bulk < 3 cm • ESR < 50 • high neck or epitrochlear

Exclude High Risk

CS I-IIA HD

Stratify

• Bulk > 10 cm • Bulk > 1/3 CTD • B symptoms • Abd. disease

Use • Age > 40 • ESR > 50 • MC / LD histology • > 4 sites

Randomize Meyer et al. J Clin Oncol 23: 4634-4642, 2005

NCIC-CTG HD-6 (ECOG JHD6) Design Randomize Standard Arm

Experimental Arm

• Favourable

• Both Strata

RT (M+PA/spleen)

ABVD x 2

• Unfavourable

If CR: x 2 more = 4

CMT (ABVD x 2 + RT)

If PR: x 4 more = 6

Assess Outcomes Primary: 12 yr OS Meyer et al. J Clin Oncol 23: 4634-4642, 2005

NCIC-CTG HD-6 (ECOG JHD6) Interim Results • 5-yr FFP: 93% STNI +/- 2 ABVD, 87% 4-6 ABVD (P=.006) • 5-yr EFS: 88% STNI +/- 2 ABVD, 86% 4-6 ABVD (P=.06) • 5-yr OS: 94% STNI +/- 2 ABVD, 96% 4-6 ABVD (P=.4)

Meyer et al. J Clin Oncol 23: 4634-4642, 2005

EORTC-GELA H9-F ASCO 2005 abs. 6505 • 783 pts. enrolled, early stop with >20% events, med. F/U 33 mo. • EBVPx6 4-yr EFS 70% • EBVPx6+20Gy IFRT 4-yr EFS 84% • EBVPx6+36Gy IFRT 4-yr EFS 87% p10cm) and/or B symptoms - Stage I/II and Bulky disease (>10cm) - Stage II and B symptoms

Before July 2005:

After July 2005:

ABVD x 6-8 cycles

ABVD x 6 cycles

Bulky tumors:

No residual mass – Observe

ABVD x 6 + RT

PET- neg - Observe

Residual mass > 2cm then PET/CT

PET- pos Consolidative RT

Progression-free survival PET-neg Bulky vs Non-bulky 1.0

Non- bulky

NPV Non-bulky .95

Bulky

.9

NPV Bulky .92

Cumulative Survival

.8

p=.42

.7 .6 .5 .4 .3 .2 .1 0.0 0

1

2

3

4

Progression Free Survival (y)

Savage et al. Blood 2007 110: Abstract 213

5

6

Hodgkin Lymphoma Chemotherapy: Late Stages

Kaplan-Meier Estimates of Event-free Survival among Patients in Complete Remission after Chemotherapy Who Were Randomly Assigned to Receive Either No Radiotherapy or Involved-Field Radiotherapy

Aleman, B. et al. N Engl J Med 2003;348:2396-2406

Kaplan-Meier Estimates of Overall Survival According to the Patients' Response to Initial Chemotherapy and to Whether They Underwent Randomization

Aleman, B. et al. N Engl J Med 2003;348:2396-2406

Hodgkin Lymphoma: Untreated US Intergroup Studies (CALGB, SWOG, ECOG) CALGB 50604 (Stages I/II non-bulky disease) AVBD x 2 cycles → PET scan • PET- → 2 more ABVD cycles • PET+ → 2 cycles escalated BEACOPP + IF RT

CALGB 50801 (Stages I/II bulky disease) ABVD x 2 cycles → PET scan • PET - → 4 more ABVD cycles • PET+ → 4 cycles escalated BEACOPP + IF RT

S0816 (Stages III/IV) ABVD x 2 cycles • PET- → 4 more ABVD cycles • PET+ → 6 cycles escalated BEACOPP

Hodgkin Lymphoma

Chemotherapy alone an option for most patients • Stages I/II – Non-bulky: possible slight increase in relapses with adequate CT only off-set by late complications of CMT – Bulky: CMT standard, but PET may define subgroup that does not need RT

• Stages III/IV – With adequate CT additional IFRT does not improve PFS or OS for patient who achieve CR after CT – IFRT may improve PFS for patients who achieve PR after CT

• Risk-adapted approach with interim PET may define a PET+ subgroup that would benefit from intensified Rx including RT for stages I/II

Trial

Phase III Trials of PET-Directed Therapy in Early Stage HL

Sponsor

Active

RAPID

UK

2003

H10

EORTC/ GELA

2006

Eligibility

Non-bulky I-II ABVD x 3:

If PET –ve → obs vs. 30 Gy RT If PET +ve → ABVD x1 + 30 Gy RT Favorable I-II ABVD x 3 + INRT vs. PET directed therapy ABVD x 2: If PET +ve, escBEACOPP x 2 + INRT If PET –ve ABVD x 2

Unfavor. I-II

HD16

GHSG

2009

Study Design

ABVD x 4 + INRT vs. PET directed therapy ABVD x 2: If PET +ve, escBEACOPP x 2 + INRT If PET –ve ABVD x 4

Favorable I-II ABVD x 2 +30 Gy IFRT vs. PET directed therapy ABVD x 2: If PET +ve 30 Gy IFRT If PET –ve ABVD x 2

HD17

GHSG

Pending Unfavor. I-II

escBEACOPP x2 + ABVD x2 + 20 Gy IFRT vs. PET directed therapy (EscBeaCOPP x 2. If PET +ve ABVD x 2 + 20 Gy INRT, if PET –ve ABVD x 2).

Trial

Phase III Trials of PET-Directed Therapy in Early Stage HL

Sponsor

Active

RAPID

UK

H10

EORTC/ 2006 GELA (Amended Aug. 2010)

HD16

GHSG

2003

2009

Eligibility

Study Design

Non-bulky I-II ABVD x 3:

If PET –ve → obs vs. 30 Gy RT If PET +ve → ABVD x1 + 30 Gy RT Favorable I-II ABVD x 3 + INRT vs. PET directed therapy ABVD x 2: If PET +ve, escBEACOPP x 2 + INRT If PET –ve ABVD x 1 + INRT

Unfavor. I-II

ABVD x 4 + INRT vs. PET directed therapy ABVD x 2: If PET +ve, escBEACOPP x 2 + INRT If PET –ve ABVD x 2 + INRT

Favorable I-II ABVD x 2 +30 Gy IFRT vs. PET directed therapy ABVD x 2: If PET +ve 30 Gy IFRT If PET –ve ABVD x 2

HD17

GHSG

Pending Unfavor. I-II

escBEACOPP x2 + ABVD x2 + 20 Gy IFRT vs. PET directed therapy (EscBeaCOPP x 2. If PET +ve ABVD x 2 + 20 Gy INRT, if PET –ve ABVD x 2).