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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
Age
EORTC
NCIC
> 50
> 40
Histology
MC or LD
ESR and BSymptoms
> 50 if A;
> 30 if B
> 50 if A;
> 30 if B
> 50 or
Any B-symptoms
Mediastinal mass
MMR > .33
MTR > .35
MMR > .33 or
> 10 cm
Nodal sites
>2
>3
>3
Extranodal lesion
Any
GHSG HD7 trial
EFRT 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
N = 532
N = 532
5-year FFTF : 85.8% vs 84.2%
5-year OS : 90.8% vs 92.4%
Engert A, et al. J Clin Oncol. 2003; 21: 3601
EORTC H8-F trial
Limited-stage favorable HL

Early stage with
favorable features
randomly assigned
to
10-year EFS : 98% vs 74%
3
MOPP-ABV plus
IFRT (n = 270)
 STNI (n = 272)
10-year OS : 97% vs 92%
Ferme C, et al. N Engl J Med. 2007; 357: 1916
EORTC H8-U trial
Limited-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)
10-year EFS : 84% vs 88% vs 87%

Ferme C, et al. N Engl J Med. 2007; 357: 1916
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%
Straus D, et al. Blood. 2004; 104: 3483
5-year OS : 97% vs 90%, p= .08
Response adapted therapy using FDGPET : 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 (21%)
4th cycle of ABVD
then IFRT
Radford J, et al. ASH 2008: Abstract
PET -ve (79%)
Randomization
IFRT
No further treatment
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/ABV ABVD
D (n=123) (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 74.6
( > gr 3) (%)
63.6
<.001
Second malignancy
(no.)
28
18
.13
MDS/leukemia
11
2
.011
Duggan DB, et al. J Clin Oncol. 2003; 21: 607
UK NCRI Lymphoma Group Study, ISRCTN
64141244 : ABVD 6-8 + RT vs Standford V

Involved field irradiation to sites of initial bulk
disease (>5cm) or splenic deposits, and to residual
masses
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
Johnson P, et al. ASH 2008: abstract
GHSG HD9 : COPP/ABVD vs escalated- dose
BEACOPP vs standard-dose BEACOPP in
St IIB-IV
10-year FFTF : 64% vs 70% vs 82%
10-year OS : 75% vs 80% vs 86%
Diehl V, et al. N Engl J Med. 2003; 348; 2386
Diehl V, et al J Clin Oncol 2007; 25(suppl 18): LBA8015
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
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

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%
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
Randomization
No further therapy
IFRT
IFRT
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
Aleman BMP, et al. N Engl J Med. 2003;109:2396
GHSG HD15 : Response adapted therapy
using FDG-PET; preliminary result

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)
1-year PFS : 96% vs 86%
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 8–10fold 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
Grogg, et al. J Clin Path. 2007; 60 : 1365
MC
LMP1
CD30
CD15
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

HAART-related improvement in CD4 counts likely explain the
increasing HIV related HL incidence since 1996
Biggar et al. Blood. 2006; 108: 3786
Characteristic of HIV related HL
Connors J. ASH Educational session. 2008
HIV related HL in HAART era


Patients treated in the preHAART 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 3year 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
Kaplan Meier cumulative
survival plot
2-year OS 89% vs 44%, p <.0001
Hoffman C, et al. Br J Haematol. 2004; 125: 445
Multivariate analysis
HR
Pvalue
Response to HAART
.19
.0045
Age < 45
.23
.003
CR
.30
.007
Chemotherapy regimens for HIVrelated 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;
Spina M, et al. Blood. 2005; 106: 100a3;
Hartman P, et al. Ann Oncol. 2003. 14: 15622
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
Dx within 2 yr prior to pregnancy
Dx during Preg
Langagergaard V, et al. Br J Cancer. 2008; 98: 183
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
RT during pregnancy

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
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
Chemotherapy during pregnancy

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
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
66
19
41
35
Engert, et al. J Clin Oncol. 2005; 23: 5052
GHSG: HL in elderly
Engert, et al. J Clin Oncol. 2005; 23: 5052
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
2
4
5
3
1
Engert A, et al. J Clin Oncol. 2005; 23: 50521;
Kolstad A, et al. Leuk Lymphoma ; 2007; 48: 5703;
Levis A, et al. Ann Oncol. 2004; 16:1245;
Feltl D, et al. Leuk Lymphoma. 2006: 47: 15182
Ballova V, et al. Ann Oncol. 2005 4
Mcpherson N, et al. LeuK Lymphoma. 2002: 43: 13956
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

Unfavorable limited stage or advanced
stage HL
 ABVD

x 2 + IFRT
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