HODGKIN LYMPHOMA

Lalita Norasetthada, MD

Overview

Limited-stage disease Advanced-stage disease Challenging problems

Pregnancy HIV infection Elderly

Limited-Stage HL

Objectives in limited-stage HL To maximize the number of cures and

minimize late toxicity, particularly cardiovascular disease and 2nd cancers by optimizing the mix of available intervention

Unfavorable risk factors for Stage I-II HL

Risk GHSG EORTC NCIC

Age > 50 > 40

Histology MC or LD

ESR and B-Symptoms

> 50 if A; > 30 if B

> 50 if A; > 30 if B

> 50 orAny B-symptoms

Mediastinal mass

MMR > .33 MTR > .35 MMR > .33 or > 10 cm

Nodal sites > 2 > 3 > 3

Extranodal lesion

Any

GHSG HD7 trialEFRT vs 2 x ABVD + EFRT

7 year FFTF : 67% vs 88%

7 year OS : 92% vs 94%

Engert A, et al. J Clin Oncol. 2007; 25: 3495

GHSG HD8 trials :COPP/ABVD & EFRT vs COPP/ABVD & IFRT in limited-stage unfavorable HL

5-year OS : 90.8% vs 92.4%

5-year FFTF : 85.8% vs 84.2%

Engert A, et al. J Clin Oncol. 2003; 21: 3601

N = 532 N = 532

EORTC H8-F trialLimited-stage favorable HL

Early stage with favorable features randomly assigned to 3 MOPP-ABV plus

IFRT (n = 270) STNI (n = 272)

10-year EFS : 98% vs 74%

10-year OS : 97% vs 92%

Ferme C, et al. N Engl J Med. 2007; 357: 1916

EORTC H8-U trialLimited-stage unfavorable HL

Limited-stage with unfavorable features randomly assigned to 6 cycles MOPP-ABV

plus IFRT (n = 336) 4 cycles MOPP-ABV

plus IFRT (n = 333) 4 cycles MOPP-ABV

plus STNI (n = 327)

Ferme C, et al. N Engl J Med. 2007; 357: 1916

10-year EFS : 84% vs 88% vs 87%

10-year OS : 88% vs 85% vs 84%

GHSG HD10 trial : 2 vs 4 x ABVD plus 30 Gy vs 20 Gy IFRT in St I-II favorable HL randomized between

4 x ABVD & 30 Gy IF-RT (arm A) 4 x ABVD & 20 Gy IF-RT (arm B) 2 x ABVD & 30 Gy IF-RT (arm C) 2 x ABVD & 20 Gy IF-RT (arm D)

CR rate : 98.4% 2-year FFTF : 96.6% 2-year OS : 98.5%

Eich H, et al. Int J Radiat oncol Biol Phys. 2005; 63(suppl): S1

no statistical difference between arms

A meta-analysis: the influence of radiotherapy and chemotherapy on long term outcome of limited-stage HL 1974 patients treated in 8 randomized trials

comparing more vs less RT Reduction in RT field sized to IFRT has little if any

impact on survival

1,688 patients treated in 13 randomized trials comparing RT plus CT vs RT alone Addition of CT to RT produced large effect on

disease control but a small non-significant effect on overall survival

Specht L, et al. J Clin Oncol. 1998; 16: 830

GHSG HD14 : BEACOPP escalated in limited unfavorable HL

BEACOPP escalated x 2 + ABVD x 2 + IFRT

ABVD x 4 + IFRT

3-year FFTF 96% 90%

Disease progression

1.8% 5.9%

This more aggressive treatment strategy will become the new standard for early unfavorable HL patients within the GHSG

Whether the improved FFTF translates into an improved overall survival must be awaited

Borchmann P, et al. ASH 2008: abstract

ABVDx6 & RT vs ABVD alone in St I-IIIA non-bulky disease

5-year FFP : 86% vs 84%5-year OS : 97% vs 90%, p= .08

Straus D, et al. Blood. 2004; 104: 3483

Response adapted therapy using FDG-PET : UK NCRN Rapid trials in St I-IIA Initial treatment : ABVD x 3 Re-assessment

if NR/PD, off study If CR/PR, PET scan performed

PET +ve PET -ve

4th cycle of ABVD then IFRT

IFRT

No further treatment

Randomization

(79%)(21%)

Radford J, et al. ASH 2008: Abstract

Treatment modality for limited stage HL

Combined chemotherapy with IFRT is the standard treatment of care Favorable disease : ABVD 2-4 cycles Unfavorable disease : ABVD 4-6 cycles

Chemotherapy alone can be the option in selected subgroup of patients with favorable non-bulky disease, if the long-term toxic risks of radiation are to be avoided, especially for patients younger than 40 years.

Advanced-stage HL

The landmark randomized trial by CALGB for advanced HL

MOPP (n =123)

MOPP/ABVD (n=123)

ABVD(n= 115)

P-value

CR rate 67 82 83 .006

5-year FFS

50 61 65

5-year OS

66 73 75 .28-ABVD for 6-8 months was as effective as 12 months of MOPP/ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkin's disease

- ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP.

Canellos GP, et al. N Engl J Med. 1992; 327: 1478

Intergroup trial : ABVD vs MOPP/ABVD for advanced HL

MOPP/ABVD(n = 433)

ABVD(n =419)

P-value

CR rate (%) 80 76 .16

5-year FFS (%) 66 63 .42

5-year OS (%) 81 82 .82

Pulmonary toxicity (> gr 2) (%)

30.6 24.5 .06

Hematologic toxicity ( > gr 3) (%)

74.6 63.6 <.001

Second malignancy (no.)

28 18 .13

MDS/leukemia 11 2 .011Duggan DB, et al. J Clin Oncol. 2003; 21: 607

UK NCRI Lymphoma Group Study, ISRCTN 64141244 : ABVD 6-8 + RT vs Standford V

ABVD (n- 261) Standford V (n= 259)

Gr III-IV Pulmonary toxicity (no.)

27 10

Gr III-IV non-pulmonary toxicity (%)

8 19

Overall response rate (%) 89 90

5-yr PFS 76 74

5-y OS 90 92

Involved field irradiation to sites of initial bulk disease (>5cm) or splenic deposits, and to residual

masses

Johnson P, et al. ASH 2008: abstract

GHSG HD9 : COPP/ABVD vs escalated- dose BEACOPP vs standard-dose BEACOPP in St IIB-IV

Diehl V, et al. N Engl J Med. 2003; 348; 2386Diehl V, et al J Clin Oncol 2007; 25(suppl 18): LBA8015

10-year FFTF : 64% vs 70% vs 82%10-year OS : 75% vs 80% vs 86%

GHSG HD12 final analysis : RCT comparing escalated BEACOPP x 8 vs escalated BEACOPP x 4 followed by standard-dose BEACOPP

Entire cohort

Escalated BEACOPP x 8 +/- RT

Escalated BEACOPP x 4 Standard BEACOPP x 4 +/- RT

Gr 3-4 anemia 65% 51%

Gr 3-4 thrombocytopenia

65% 51%

5-yr OS 91% NS NS

5-yr FFTF 85.5% NS NS

5-yr PFS 86.2% NS NS

Diehl V, et al. Blood. ASH 2008 : abstract

Risk-adapted BEACOPP regimen

Relapse or progression occurred in 27% of patients with interim positive PET/CT versus 2.3% of negative scans (P < .02)

5-year EFS and OS for patients with early unfavorable and standard risk vs patients with high risk : 84%, 90% vs 85%, 91%

Limited stage, unfavorable/Advanced stage, IPS <2

Advanced stage, IPS > 3

Standard BEACOPP x 2

Escalated BEACOPP x 2

Restaging with PET or Ga67

Negative : Standard BEACOPP x 4

Positive : Escalated BEACOPP x 4

Dan E, et al. Blood. 2007;109:905

Chemotherapy for advanced HL ABVD x 6-8 cycles is generally recommended Escalated-dose BEACOPP x 4 should be considered

for high-risk patients with an IPS score > 4 If CR : Standard-dose BEACOPP x 4 If PR : Escalated-dose BEACOPP x 4

The ongoing EORTC 20012 trial is comparing escalated BEACOPP and ABVD in advanced HL

The recently completed E2496 intergroup trial compared the Stanford V regimen with ABVD + RT for advanced HL, results are awaited

NCCN. Practice Guidelines in Oncology-v.2 2009

EORTC 20884 trial : Role if IFRT in advanced HL

MOPP/ABVD x 6-8 cycles

CR PR

No further therapy IFRT

Aleman BMP, et al. N Engl J Med. 2003;109:2396

RandomizationIFRT

CR; no further Rx

CR; IFRT PR; IFRT

5-year EFS (%) 84 79 79

5-year OS (%) 91 85 87• IFRT did not improve outcome in patients achieving CR after chemotherapy • Consolidative IFRT is beneficial for patients experiencing PR after chemotherapy

GHSG HD15 : Response adapted therapy using FDG-PET; preliminary result

1-year PFS : 96% vs 86%

Multicenter RCT in advanced HL treated with standard-dose BEACOPP x 8 or escalated-dose BEACOPP x 6 or time-condensed BEACOPP-14 x 8

IFRT was restricted to patients with PET-positive after chemotherapy Negative predictive value of PET after chemotherapy : 94% (95% CI:

91-97)

Kobe C, et al. Blood. 2008; 112 : 3989

Role of IFRT after chemotherapy in advanced HL

Additional IFRT is beneficial for patients with residual disease after chemotherapy

IFRT is routinely recommended for patients with bulky disease

Consolidative IFRT can be omitted in PET negative patients after chemotherapy

HIV related HL

HIV related HL

HIV infection also increases the risk of classical Hodgkin lymphoma, with a relative risk of 8–10-fold compared to the general population

A greater proportion of the subtypes (mixed cellularity, lymphocyte depleted) with less favorable prognosis compared to the general population

The greater proportion of MC and LD subtypes is related to severe immunocompromise, while those with modest immunocompromise are more at risk for the NS subtype

Histology of HIV related cHL

MC LMP1

CD30 CD15

Grogg, et al. J Clin Path. 2007; 60 : 1365

HIV related HL

There is coincident EBV infection, with nearly all cases showing EBER and LMP-1 expression in the HRS cells

The composition of the reactive inflammatory infiltrate in HIV-related HL is often characterized by a predominance of CD8-positive T lymphocytes over CD4-positive lymphocytes, by contrast with the background in HL without HIV infection

Epidermiology of HIV-related HL and the effect of HARRT

Biggar et al. Blood. 2006; 108: 3786

HAART-related improvement in CD4 counts likely explain the increasing HIV related HL incidence since 1996

Characteristic of HIV related HL

Connors J. ASH Educational session. 2008

HIV related HL in HAART era

Patients treated in the pre-HAART era (1984–1996) were compared with those belonging to the HAART era (1997-2004)

By multivariate analysis patients without HAART had a 5.6-fold higher risk for 3-year mortality; HR 5.6, (95% CI 2.20–14.26)

Biggar, et al. Blood. 2006; 108: 3786

2-year OS 74% vs 34%, p <.0001

Response of HAART and survival outcomes

HR P-value

Response to HAART

.19 .0045

Age < 45 .23 .003

CR .30 .007

Kaplan Meier cumulative survival plot Multivariate analysis

2-year OS 89% vs 44%, p <.0001

Hoffman C, et al. Br J Haematol. 2004; 125: 445

Chemotherapy regimens for HIV-related HL

Standford V1

BEACOPP2 VEBEP3 ABVD4

No. 56 12 28 62

Stage III-IV (%)

71 92 71 100

CD4 (/uL) 238 205 257 129

HARRT Yes Yes Yes (25%) Yes

G-CSF Yes Yes NS 20%

CR (%) 81 100 75 87

Survival, % (year)

51 (3) NA 86 (2) 76 (5)

Spina, et al. Blood. 2002; 100: 19871; Hartman P, et al. Ann Oncol. 2003. 14: 15622

Spina M, et al. Blood. 2005; 106: 100a3; Xicoy B, et al. Haematologica. 2007; 92: 191 4

Additional therapy in HIV related HL

HAART Opportunistic infection prevention Hematopoietic growth factor Psychological support

HL during Pregnancy

HL during pregnancy

Two patients need to be managed Mother : optimally controlling lymphoma Fetus : avoiding toxicity and allowing the

normal term delivery

Information about the best approach to management of coincident HL and pregnancy is limited

HL and birth outcomes : a Danish nation wide cohort study

Langagergaard V, et al. Br J Cancer. 2008; 98: 183

Dx within 2 yr prior to pregnancy

Dx during Preg

Staging in HL during pregnancy Avoiding the use of imaging that requires

radiation CXR with proper shielding and abdominal

ultrasonography MRI Abdominal and pelvic CT should be avoided FDG-PET can cross the placenta and reach

the fetus, it may involve higher radiation exposure than regular CT and its use cannot be recommended during pregnancy

HL during pregnancy

As a general rule any treatment, radiation or chemotherapy should be avoided during the first trimester unless severely threatening symptoms are present

More than 50% of patients can continue the pregnancy to term without any treatment for the lymphoma

Management HL during pregnancy

If treatment are required Radiation Single agent chemotherapy Combined chemotherapy

RT during pregnancy

From 2 case series : 11 patients with limited-stage received supradiaphargmatic RT with special shielding 10 patients achieved CR without evident fetal injury

When conventional doses of radiotherapy are administered, a distance of over 30 cm from the field edges will limit the total exposure of the fetus to only 4-20 cGy

Therefore, radiotherapy may be considered in specific circumstances such as lymphoma confined to the neck or axillary lymph nodes

Exposure to 10-20 cGy of radiation is considered as the threshold dose for severe congenital malformation when given during organogenesis

Gelb AB, et al. Cancer1996; 78: 304; Nisce LZ, et al. J Clin Oncol. 1986; 9: 146;

Kal HB, et al. Lancet Oncol 2005; 6: 328

Radiation exposure during the second and third trimesters is associated with a carcinogenic effect that may include an increased risk for the development of leukemia and solid tumors within the first decade of life

Another concern is the increased risk of neurodevelopmental impairment, including a decrease in the IQ and even severe mental retardation

RT during pregnancy

Kal HB, et al. Lancet Oncol 2005; 6: 328

Chemotherapy during pregnancy

Chemotherapy during the first trimester may increase the risk of spontaneous abortions, fetal death and major malformations

The fetus is extremely vulnerable from the 2nd -8th week of gestation, during which organogenesis occurs

Between the 14th to 16th weeks of gestation the risk of severe malformations or mental retardation is reduced significantly

Cardonick E, et al. Lancet Oncol 2004; 5: 283; Leslie KK, et al. Obstet Gynecol Clin North Am 2005; 32: 627

Second and third trimester exposure is not associated with malformations but increases the risk of Fetal or neonatal death IUGR Pre-term delivery Low birth weight

These complications may be associated with adverse long-term effects such as neurodevelopmental impairment, increased rate of cardiovascular risk factors

Cardonick E, et al. Lancet Oncol 2004; 5: 283; Leslie KK, et al. Obstet Gynecol Clin North Am 2005; 32: 627

Chemotherapy during pregnancy

Case series: HL during pregnancy

24 cases of HL during pregnancy 12 cases received MOPP, MOP or cyclophosphamide during

1st trimester Spontaneous abortion : 2 Fetal malformation : 5

10 cases receiving combined chemotherapy after 1st trimester delivered normal infants

Based on this observation and the known carcinogenicity of alkylating agent such as mechlorethamine, cyclophosphamide, procarbazine and chlorambucil should be avoided

Ebert U, et al. Pharmacol Ther. 1997; 74: 207

ABVD regimen in pregnancy 2 case series involving 13 cases

No fetal adverse outcomes after receiving ABVD during first, second and third trimesters

Anselmo AP, aet al. Fetal Diagn Ther. 1999; 14: 102; Cardonick E, et al. Lancet Oncol. 2004; 5: 283

Single agent : Vinblastine > 75% response rate in treatment naïve HL patients

and modest toxicity

Reported to be teratogenicity in mice No similar effect reported in human at doses

therapeutic for lymphoma

The combination of high level of effectiveness, minimal acute toxicity and low likelihood of negative effect on the fetus make vinblastine a useful agent to suppress HL during pregnancy

Armstrong JG, et al. Science. 1964; 143: 703 Lacher MJ, et al. Ann Intern Med. 1964; 61: 113

Rosenzweig AI, et al. Ann Intern Med. 1964; 61: 108 Connors J, et al. ASH Educational session. 2008

Management after delivery Patients who have been able to complete the

pregnancy without treatment Repeat full staging Consider appropriate therapy according to stage

of lymphoma

Patients who have been treated with vinblastine Multi-agent chemotherapy 6-8 cycles as accurate

staging cannot be performed

Connors J, et al. ASH Educational session. 2008

Suggesting algorithm for the treatment of HL during pregnancy

Perek D, et al. Hematologica. 2007; 92: 1230

HL in elderly

GHSG: HL in elderly

Age < 60, n = 3879 Age > 60, n = 372

Median Age (years) 31 65

Stage III-IV (%) 40 48

B-symptom (%) 43 50

Bulky disease (%) 60 49

PS < 70 (%) 3 11

IPS > 4 (%) 11 13

Histology (%) NS MC

6619

4135

Engert, et al. J Clin Oncol. 2005; 23: 5052

Engert, et al. J Clin Oncol. 2005; 23: 5052

GHSG: HL in elderly

Dose intensity and the outcomes in elderly patients

Langren O, et al. Haematologica. 2007; 88: 438

Factors contributing to poorer outcomes in elderly

Less favorable histologic subtypes Co-morbidity Delayed diagnosis Inadequate adherence to treatment

protocols Failure to maintain dose intensity

Chemotherapy regimen for HL in elderly

Engert A, et al. J Clin Oncol. 2005; 23: 50521; Feltl D, et al. Leuk Lymphoma. 2006: 47: 15182

Kolstad A, et al. Leuk Lymphoma ; 2007; 48: 5703; Ballova V, et al. Ann Oncol. 2005 4 Levis A, et al. Ann Oncol. 2004; 16:1245; Mcpherson N, et al. LeuK Lymphoma. 2002: 43: 13956

1

23

4 5 6

ABVD compared with other chemotherapy regimens in elderly

Connors J. ASH Educational session. 2008

Management for HL in elderly Chemotherapy regimens

No special regimen superior ABVD remains the goal standard

Anticipate increase toxicity Hematologic Pulmonary Cardiac Neurologic

Hemopoietic growth factors

Can bleomicin be omitted in patients with compromised pulmonary function?

Canellos G, et al. J Clin Oncol. 2004; 22: 1533

Overall treatment plan for HL in elderly

Favorable non-bulky limited stage ABVD x 2 + IFRT

Unfavorable limited stage or advanced stage HL ABVD until 2 cycles past CR (minimum 6)

Patients with quite advanced age and too frail to receive chemotherapy Radiation

Connors J. ASH Educational session. 2008

THE END