Early Stage Hodgkin
Lymphoma: Latest
Concepts & Controversies
Morton Coleman, M.D.
Director, Center for Lymphoma and
Myeloma
Weill Cornell Medical Center
New York Presbyterian Hospital
New York, New York
THE MAIN INTENT: LESS
TOXICITY
At least 85% of Hodgkin patients
can anticipate a cure. The charge:
cure even more patients with the
least impact on their well being
EARLY STAGE HODGKIN
HISTORY
• 5-10 yr. relapse rate lower for chemotherapy + IF
RT than EF RT alone (JCO 24: 3128-35, 2006; JC0
25: 3495-3502, 2007; NEJM 357: 1916-27, 2008)
• No difference in OS at 4-5-yrs. between ABVD
alone and ABVD + RT for patients with limited
stage non-bulky HL (Blood 104: 3483-89, 2004;
JCO 23: 4634-42, 2005)
• RT is associated with late 2nd malignancies and
cardiovascular events especially after 10 yrs. (JCO
21: 3431-9, 2003; NEJM 355: 1572-82, 2006; JCO
27 [Suppl.] abs. 8547, 2009
courtesy Straus,D
Kaplan–Meier Estimates of Overall Survival and Freedom from Disease
Progression.
Meyer RM et al. N Engl J Med 2012;366:399-408
Kaplan–Meier Estimates of Overall Survival and Freedom from Disease
Progression among Patients with an Unfavorable Risk Profile.
Meyer RM et al. N Engl J Med 2012;366:399-408
What role does PET Scans play
in this effort?
May interim PET/CAT scans
be of value or should scans
be used only at the end of
treatment?
In Vivo Treatment Sensitivity With
Positron Emission /Computed
Tomography After One Cycle of
Chemotherapy for Hodgkin
Lymphoma
Martin Hutchings, Lale Kostakoglu,
Morton Coleman, et al.
JCO 32: 2705-2711, 2014
FDG-PET: After one (two
treatments) versus two cycles
(four treatments) of therapy
Early determination of treatment
sensitivity in Hodgkin lymphoma:
FDG-PET/CT after one cycle of
therapy has a higher negative
predictive value than after two cycles
of therapy
Participating Nations
Denmark
United States
Italy
Poland
(Nine Institutions)
Patient Population:126 Pts.
• Stage I
8%
• Stage 2
46%
• Stage 3
19%
• Stage4
27%
• B Sxs
56%
• Bulky
37%
Comparison of the prognostic value
of PET 1 and PET 2: Progression Free
Survival at 2 Years
PET 1 PET2
• Negative predictive value 98% 91%
• Positive predictive value
63% 85%
• Sensitivity
94% 61%
• Specificity
86% 97%
• Concordance
>90%
Involved Field Radiotherapy Versus
No Further Treatment in Patients with
Early- Stage Hodgkin Lymphoma and
Negative PET Scan After 3 ABVD
Cycles: Resuts of the UK NCRI RAPID
Trial
Proc ASH 120,2012; Abstract 547
Radford J, Barrington S, Counsell N, et al
RAPID Trial Design
Initial treatment:
ABVD x 3
Reassessment:
571pts
if NR/PD, patient goes off study
if CR/PR, FDG-PET scan performed
PET-positive (145pts)
4th cycle ABVD then IFRT
Radford J, et al. Blood. 2012;120: Abstract 547.
PET negative (420 pts)
Randomization
IFRT
(209
pts)
No further
treatment
(211pts)
Outcomes After Median Follow-Up of
45.7 Months
PET negative;
randomized to
IFRT
(n = 209)
PET negative;
randomized to
NFT
(n = 211)
PET positive;
4th cycle
ABVD/IFRT
(n = 145)
Progressions
9
20
11
Deaths
8
1
8
PFS at 3 years
93.8%
90.7%
85.9%
OS at 3 years
97.0%
99.5%
93.9%
Radford J, et al. Blood. 2012;120: Abstract 547.
Summary
• 602 pts registered between 2003 and 2010
• 75% PET-negative at central review after ABVD x 3
• In the randomized PET-negative population, 3 yr PFS is
92.8% IFRT and 90% NFT
• Risk difference -3% is within the maximum allowable
difference of -7%
Radford J, et al. Blood. 2012;120: Abstract 547.
Commentary
• These data are similar to those reported from
Argentina several years ago for all stages of
disease when PETs were obtained after 3
cycles (Pavlosky, et al.)
• CAUTION: Were the deaths in the IFRT arm
‘flukes’ and not related to the IFRT? If so,
would the data and conclusions be different.
Radford J, et al. Blood. 2012;120: Abstract 547.
An Individual Patient-Data
Comparison of Combined Modality
Therapy and ABVD Alone for
Patients with Limited Stage Hodgkin
Lymphoma
A study of the NCIC (HD 6) and the
German Hodgkin Study Group (HD 10
&11)
Hay AE, Klimm B, Chen BE, et al
Annals of Oncology 24 (12) 3065-3069, 2013
GHSG Early-Stage HL Risk Factors
Favorable: CS IA,IB, IIA, IIB without risk factors
Unfavorable: CS IA, IB, with at least one of
the risk factors a-d given below
or CS IIB with risk factor c, d, or both given below:
and IIA
a) Large mediastinal mass (≥1/3 of maximum
transverse thorax diameter)
b) Extranodal involvement
c) High erythrocyte sedimentation rate (≥50 mm/h
in patients without B-symptoms, ≥30 mm/h in patients with Bsymptoms)
d) 3 or more involved lymph node areas
Eich HT, et al. J Clin Oncol. 2011;28:4199-4206.
HD.6 Trial
Patients with Clinical Stage I-IIA Hodgkin Lymphoma
Study schema of a
randomized trial
comparing a
strategy that
includes radiation
therapy with
ABVD in patients
with limited-stage
Hodgkin
lymphoma
Exclude low-risk patients
Exclude high-risk patients
Stage IA with single node of
Hodgkin lymphoma and all of:
• Lymphocyte predominant or
nodular sclerosis histology
• Bulk <3cm
• ESR <50 mm/hour
• Disease involving high neck or
epitrochlear region only
Patients with either:
• Bulk >10 cm or ≥1/3 chest wall
diameter, or
• Intra-abdominal disease
Favorable or unfavorable cohort
Stratify
Randomly
Assign
Unfavorable cohort patients have
any of:
• Age ≥40 years
• ESR ≥50 mm/hour
• Mixed cellularity or lymphocyte
deplete histology
• ≥4 sites of disease
Treatment that includes
radiation therapy
• Favorable cohort: subtotal
nodal radiation therapy
• Unfavorable cohort:
combined modality therapy
with ABVD x 2 cycles plus
subtotal nodal radiation
therapy
Meyer RM, et al. N Engl J Med. 2012;366:399-408.
ABVD as a single modality
• Both cohorts: ABVD x 2 cycles
• IF CR or CRu, ABVD x 2 more
cycles (total 4 cycles)
• If <CR or CRu, ABVD x 4 more
cycles (total 6 cycles)
Comparison of NCIC CTG HD.6 and GHSG
HD10 and HD11 Staging, Eligibility and
Preferred Arms
2 ABVD + 20 Gy IFRT
Early,
favorable
HD10
4 ABVD + 30 Gy IFRT
Early,
unfavorable
HD11
Advanced
GHSG
4 – 6 ABVD alone
NCIC CTG
HD.6
Favorable
Unfavorable
Not necessarily to scale
Hay AE, et al. Blood. 2012;120: Abstract 549.
Advanced
Comparison of NCIC CTG HD.6 and GHSG
HD10 and HD11 Staging, Eligibility and
Preferred Arms
Very good prognosis
Early,
favorable
HD10
B or Bulk
Early,
unfavorable
HD11
Advanced
GHSG
NCIC CTG
HD.6
Favorable
Unfavorable
Advanced
Not necessarily to scale
Hay AE, et al. Blood. 2012;120: Abstract 549.
Attribution of Death: All Patients
Cause of Death
Number
Med. F/U
GHSG HD10/11
406
7.6 Years
NCIG CTG HD.6
182
11.2 Years
Hodgkin lymphoma
Immediate toxicity
5
2
4
1
Second cancer
Cardiac
Other
2
4
6*
3
2
0
Total
19
10
*Other deaths were: 1 suicide, 1 respiratory failure, 1 cerebral hemorrhage,
1 progression of NHL, 2 unknown
Hay AE, et al. Blood. 2012;120: Abstract 549.
Outcomes: All Patients
GHSG
HD10/11
NCIG CTG
HD.6
406
7.6 Years
182
11.2 Years
8-yr TTP
93%
8-yr PFS
8-yr OS
Endpoint
Number
Med. F/U
HR
(95% CI)
GHSG
PD/OS
NCIC CTG
PD/OS
87%
0.44 (0.24, 0.78)
25/0
23/0
89%
86%
0.71 (0.42, 1.18)
25/13
23/4
95%
95%
1.09 (0.49, 2.40)
19
10
Hay AE, et al. Blood. 2012;120: Abstract 549.
Overall Commentary
• Combined modality therapy (CMT) improves
disease control by 4%-7%
• Could this difference in control have been
obviated by the use of PET scans after one cycle
of therapy since there was a 7% difference in
PET negative results between cycles 1 and 2,
much less cycle 3?
• The relatively long term outcomes associated
with IFRT remain to be clarified
Omitting Radiotherapy in Early
Positron Emission TomographyNegative Stage I/II Hodgkin
Lymphoma Is Associated With an
Increased Risk of Early Relapse:
Clinical Results of the Preplanned
Interim Analysis of the Randomized
EORTC/LTSA/FIL H10 Trial
• Raemaekers, J.M.M., Andre, Marc P.E.,
Federico, M. JCO 32:1188-1194, 2014
Study design of European Organisation for Research and Treatment of Cancer,
Lymphoma Study Association, and Fondazione Italiana Linfomi H10 20551 trial of
patients age 15 to 70 years with untreated supradiaphragmatic clinical stage I/II
Hodgkin lymphoma
Raemaekers J M et al. JCO 2014;32:1188-1194
2014 by American Society of Clinical Oncology
Flowchart of patients included in interim analysis.
Raemaekers J M et al. JCO 2014;32:1188-1194
2014 by American Society of Clinical Oncology
Results: Progression
Favorable: no RT – 9 (5%)
with RT-1 (0.5%)
Unfavorable: no RT-16 (5%)
with RT-7 (2.6%)
Study is now closed.
Abstract No: CT-08
Early-Stage Hodgkin's Disease:
The Utilization of Radiation
Therapy and Its Impact on
Overall Survival
Rahul R. Parikh, M.D.1, Joachim Yahalom, M.D.2,
James A. Talcott, M.D.3, Michael L. Grossbard, M.D.3,
& Louis B. Harrison, M.D.4
Mt. Sinai Beth Israel Medical Center & Mt. Sinai St. Luke’s-Roosevelt Hospitals, Mount Sinai Health System,
Department of Radiation Oncology, New York, NY
2 Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, NY
3 Mt. Sinai Beth Israel Medical Center & Mt. Sinai St. Luke’s-Roosevelt Hospitals, Mount Sinai Health System,
Department of Hematology-Oncology, New York, NY
4 Department of Radiation Oncology, Moffitt Cancer Center and Research Institute,
Tampa, FL
1
Background
National Cancer Database
(NCDB)






Joint program of the Commission on Cancer and the
American Cancer Society
Prospectively collected; Nationwide outcomes database
covering 75% of all newly diagnosed cancers (>1,500 U.S.
hospitals);
Not population-based dataset
Not geographically limited (care in all states included)
Reflects contemporary treatment programs
RT specifics available for analysis (modality, dose, fx,
volume/site)
Aims of the Study
Primary Endpoint:
 Determine relationship between use of RT
and overall survival in patients with earlystage Hodgkin’s Disease
 Secondary Endpoints:
 Determine the trends of utilization rates of
RT
 Determine other factors (socioeconomic
factors, timing of chemotherapy, co-morbid
conditions) associated with overall survival
Methods
Hodgkin’s Disease, Stage I/II, diagnosed 1998-2011
(N = 41,420)
 Median f/u = 6.4 years;
 Median age = 37 years (range: 18-90)
 Multi-agent chemotherapy given to 96% of the pts
Did NOT receive Radiation
Therapy
Received Radiation Therapy as
part of CMT
(N = 20,897, 51%)
(N = 20,523, 49%)
 Median RT dose = 30.6 Gy
 Evaluated clinical features & survival outcomes
 The association between RT use, co-variables, and outcome was
assessed in a multivariate Cox proportional hazards model.
 Survival was estimated using the Kaplan-Meier method.
Univariate Survival Analysis (OS)
Prognostic Factor HR (95% CI)
p-value
RT
<0.0001*
No
1.00 (Ref.)
Yes
0.51 (0.48-0.54)
Age (years) at
Diagnosis
≤ 40
> 40
Gender
Male
Female
Stage
1
2
Presence of “B”
Symptoms
No
Yes
Charlson/Deyo comorbidity score
0
1
2
Transplant Proc.
No
Yes
<0.0001*
0.19 (0.180.20)
1.00 (Ref.)
<0.0001*
1.00 (Ref.)
0.81 (0.76-0.86)
<0.0001*
1.00 (Ref.)
0.70 (0.66-0.74)
<0.0001*
1.00 (Ref.)
1.65 (1.46-1.87)
<0.0001*
1.00 (Ref.)
3.14 (2.76-3.57)
5.19 (4.23-6.36)
1.00 (Ref.)
1.64 (1.15-2.35)
0.012*
Prognostic Factor
Timing of Chemotherapy
≤30 days from dx
>30 days from dx
Education (% not HS grad)
≥ 29%
20-28.9%
14-19.9%
<14%
Household Income
< $30,000
$30,000-34,999
$35,000-45,999
≥ $46,000
Insured Status
Insured (Medicare,
Private / Managed
Care)
Not Insured / Medicaid
Facility Type
Comm. Cancer Prog.
Comprehen Cancer Prog
Academic/Res. Prog.
Other
HR (95% CI)
p-value
<0.0001*
0.67 (0.640.72)
1.00 (Ref)
<0.0001*
1.00 (Ref.)
0.84 (0.76-0.92)
0.75 (0.69-0.82)
0.62 (0.56-0.67
1.00 (Ref.)
0.92 (0.83-1.01)
0.79 (0.72-0.87)
0.62 (0.57-0.68)
<0.0001*
<0.0001*
1.00 (Ref.)
5.27 (4.97-5.59)
<0.0001*
1.00 (Ref.)
0.84 (0.77-9.23)
0.66 (0.60-0.73)
0.96 (0.77-1.19)
Factors Associated with Overall Survival (MVA)
HR LCL UCL
Utilization of RT (yes vs. no)
0.47 0.43 0.53
Age (≤40 vs. >40)
0.23 0.20 0.26
Race (black vs. white)
0.93 0.79 1.11
Race (other vs. white)
0.81 0.69 0.91
Insured status (Uninsured vs. Insured)
3.48 3.13 3.87
Stage (1 vs. 2)
0.89 0.77 1.02
B Symptoms (yes vs. no)
1.72 1.50 1.97
Transplant performed (yes vs. no)
2.66 1.59 4.45
Co-morbidity score (1 vs. 0)
1.94 1.69 2.23
Co-morbidity score (2 vs. 0)
2.93 2.34 3.65
Timing of chemo (≤30 days vs.
>30days)
0.84 0.76 0.94
0.1
1.0
Inc. Overall Survival
10.0
Dec. Overall Survival
Overall Survival by RT use
84%
76%
RT Utilization
90
56%
80
1998
70
41%
2011
`
Percent of patients receiving RT
100
60
50
40
30
20
10
0
1998
2000
2002
2004
2006
Year of Diagnosis
2008
2010
Reason for No Radiation
Freq.
%
Radiation was not part of the planned initial treatment strategy
18,482
86.30
Radiation was contraindicated
Radiation recommended but not administered
Radiation recommended but refused by the patient
Radiation recommended, unknown whether delivered
Unknown if recommended or administered
Total
185
1,041
279
872
561
21,420
0.86
4.86
1.30
4.07
2.62
100.00
Conclusions

Largest contemporary dataset of patients with earlystage HD (n=41,420)

The use of RT is associated with improved 10-yr OS
(84% vs. 76%, HR=0.51, p<0.00001) BUT THIS MAY
BE DUE TO A POPULATION WITH AN INHERENT
BETTER PROGNOSIS

Utilization of RT has decreased by 15% from 1998 to
2011 (5641%; not part of initial treatment strategy)
Specific factors (socioeconomic, insurance status,
facility type) were associated with underutilization of RT
which may be targeted to improve patient access to RT,
IF RT IS INDEED INDICATED
Brentuximab Vedotin Mechanism
of Action
Brentuximab vedotin (SGN-35) ADC
monomethyl auristatin E (MMAE), potent antitubulin agent
protease-cleavable linker
anti-CD30 monoclonal antibody
ADC binds to CD30
ADC-CD30 complex
traffics to lysosome
MMAE is released
MMAE disrupts
microtubule network
G2/M cell
cycle arrest
Apoptosis
Frontline Therapy With
Brentuximab Vedotin Combined
with ABVD or AVD in Patients with
Newly Diagnosed Advanced-Stage
Hodgkin Lymphoma
Abstract 798, ASH 2012
Ansell SM, Connors JM, Park SI, et al
Study Design
• Phase I, multicenter, dose-escalation study
• Major eligibility criteria
– Treatment-naïve HL patients
– Age ≥18 to ≤60 years
– Stage IIA bulky disease or Stage IIB-IV disease
• Treatment design
– 28-day cycles (up to 6 cycles) with dosing on Days 1 and 15
– Dose escalation cohorts – I-6, II-13, III-6, IV-6, expansion-20
Cycle 1
Cycle 3
Cycle 2
Brentuximab Vedotin
A(B)VD
6 Cycles +/- XRT
0
2
4
6
Weeks
Ansell SM, et al. Blood. 2012;120: Abstract 798.
8
10
12
Response Results at End of Front-Line
Therapy
ABVD with
brentuximab vedotin
N = 22
AVD with
brentuximab vedotin
N = 25
Complete remission
21 (95)
24 (96)
Progressive disease
0
1 (4)
1b (5)
0
Response per Investigatora
Response at end of front-line
therapy, n (%)
Not evaluable due to AEs
a Assessed using Cheson 2007
b Patient had a Grade 5 event of pulmonary toxicity prior to the end of front-line therapy
•
•
Response results at end of front-line therapy:
◦ ABVD cohorts: 21 of 22 CR (95%)
◦ AVD cohorts: 24 of 25 CR (96%)
In addition, 1 patient withdrew consent and 3 patients were lost to
follow-up prior to completion of front-line therapy and were not
evaluable for response
Ansell SM, et al. Blood. 2012;120: Abstract 798.
CONCLUSIONS: EARLY STAGE HL
PET SCANS HAVE ALLOWED THE REDUCTION OF
CHEMOTHERAPY CYCLES IN EARLY STAGE HL.
COMBINED MODALITY THERAPY (CMT)PROVIDES ABOUT
ABOUT A 5% (+/- 3%)ADVANTAGE OVER CHEMOTHEAPY
ALONE IN PFS ALTHOUGH OS ADVANTAGE REMAINS TO BE
PROVEN.
THE LONG TERM TOXICITY OF LIMITED OR NODAL FIELD RT IS
STILL UNKNOWN. ACUTE TOXICITY MAY PLAY A ROLE IN
REDUCING OS?
PET SCANS AFTER 1 CYCLE MAY REDUCE THE PFS
ADVANTAGE OF CMT.
PATIENT SELECTION IS CRITICAL IN DECIDING WHAT RX TO
ADMINISTER.
WILL BRENTUXIMAB VEDOTIN REPLACE THE ‘NEED’ FOR RT?
Acknowledgment
Clinical Research (Cornell)
Jia Ruan, M.D., Ph.D.
Richard Furman, M.D.
John P. Leonard, M.D.
Peter Martin, M.D.
Maureen Joyce, R.N.
Patricia Glenn, R.N.
Jamie Ketas
Jessica Hansen
Karen Weil
Jennifer O’Loughlin
Laboratory Research
Ari Milneck, M.D., Ph.D.(Cornell)
Katherine Hajjar, M.D. (Cornell)
Shahin Rafii, M.D. (Cornell)
Translational Core
Maureen Lane, Ph.D. (Cornell)
Maureen Ward
Biostatistician
Madhu Mazumdar, Ph.D. (Cornell)
Lymphoma Research Foundation
ASCO Foundation (YIA, CDA)
NIH / NHLBI
THANK YOU FOR
YOUR ATTENTION