Is there a role for allo transplant in Hodgkin Lymphoma?

Prof. Eldad J. Dann
Department of Hematology and Bone Marrow Transplantation; Blood
Bank and Aphaeresis Unit, Rambam Health Care Campus;
Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of
Technology, Haifa Israel
Disclosure of Interest: Nothing to Disclose
10/2013
Since we do not live in a black and white world, I think the actual
question is “How do we tailor the most appropriate therapy for
patients with relapsed or primary refractory Hodgkin lymphoma
(HL)?”
Why does allo SCT for HL remain a controversial issue?
How effective is the graft-versus-tumor effect in HL?
What is the role of newly available drugs in patients with relapsed
HL after auto SCT (ASCT) or primary refractory disease ?
Myeloablative allo HSCT in Hodgkin lymphoma
Seattle, the International Bone Marrow Transplant Registry, the Johns Hopkins
University, and the European Group for Blood and Marrow Transplantation
N=373, cumulative incidence of TRM is 52%.
The overall survival (OS) is 44%, PFS 20%, with a 57% relapse rate,
despite the use of high-dose chemotherapy and radiotherapy.
Reduced intensity conditioning
Institutions
N. of
pts
Early
TRM %
Cumulative
TRM %
PFS
%
OS
%
Relapse Ref. #
%
EBMT, 2002
UKCG, 2005
311
49
17
4
27
16
26
39
46
55
64
43
89
90
MDAH, 2005
SPCP, 2006
58
40
2
12
15
25
32
32
64
48
55
91
92
GITMO, 2007
FHCRC, 2007
32
27
3
11
3
39
18
32
51
81
47
93
94
Total
485
8
21
29
49
62
TRM: transplant-related mortality; PFS: progression-free survival; OS: overall survival; EBMT:
European Group for Blood and Marrow Transplantation; UKCG: United Kingdom Cooperative
Group; MDAH: M.D. Anderson Hospital; SPCP: Spanish Cooperative Panel; GITMO: Grouppo
Italiano Trapianto Midollo Osseo; FHCRC: Fred Hutchinson Cancer Research Center.
Brusamolino E et al, Haematologica, 2009
Allo SCT 133 (28%)
RIC-78%
Myeloablative (22%)
45 RIC-Allo SCT 20%
(ys 2000-2005)
Second ASCT 35 (8%)
Conventional chemo/
radiotherapy 268 (64%)
Conventional chemo/radiotherapy 195 (80%)
(ys 2000-2005)
Martinez C et al, Ann Oncol, 2013
At a median follow-up of 49 months, OS was 32% at 5 years. Independent risk
factors for OS were: early relapse (<6 months) after ASCT, stage IV, bulky disease,
poor performance status (PS), and age ≥50 years at relapse.
5-year OS in patients with: no risk factors  62% , 1 risk factor  37%, ≥2 factors 
12%.
This score was also predictive of the outcome in each group of rescue treatment
after ASCT failure.
Martinez C et al, Ann Oncol, 2013
Novel drugs for Hodgkin lymphoma
Antibody drug conjugate anti CD30+ and anti-microtubulin agent
Brentuximab Vedotin  ORR 70%, CR 32%
Histone deacetylase (HDAC) inhibitors: anti-proliferative effect on
HRS cells and alteration of cytokines and chemokines secretion.
Pan-HDAC inhibitors: vorinostat and panobinostat  ORR 27%
median response duration 6.9 months
Selective inhibitors: mocetinostat (decrease of serum TARC in
responders within 1 week)  ORR 33%; entinostat  ORR 16%,
stable disease (SD) 61%.
PI3K (phosphatidyl inositide 3 kinase/Akt/mTOR (mammalian
target of rapamycin): everolimus: ORR 35%, DS 27%, PFS 7.2
months; temsirolimus
Lenalidomide: ORR 19.5%, SD 13%
Bendamustine: ORR 57%
Adapted from Moskowitz AJ, Curr Onc Rep, 2012
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
Anas Younes, Ajay K. Gopal, Scott E. Smith, Stephen M. Ansell, Joseph D.
Rosenblatt, Kerry J. Savage,Radhakrishnan Ramchandren, Nancy L.
Bartlett, Bruce D. Cheson, Sven de Vos, Andres Forero-Torres,Craig H.
Moskowitz, Joseph M. Connors, Andreas Engert, Emily K. Larsen, Dana A.
Kennedy, Eric L. Sievers,
and Robert Chen,
J Clin Oncol 30:2183-2189. © 2012 by American Society of Clinical Oncology
N=102
Age*
31 yr (1577)
Gender
48 M / 54 F
ECOG status
0
42 (41%)
1
60 (59%)
Refractory to frontline therapy
72 (71%)
Refractory to most recent treatment
43 (42%)
Prior chemotherapy regimens*
3.5 (113)
Prior radiation
67 (66%)
Prior ASCT
102 (100%)
Time from ASCT to first post transplant relapse*
6.7 mo (0131)
* Median (range)
Tumor Size (% Change from Baseline)
94% (96 of 102) of patients achieved tumor reduction
Individual Patients (n=98)*
% Patients Free of PD or Death
Overall survival
Median (wks)
not reached
PFS per investigator
39.1
PFS per IRF
25.1
Median (range) cycles of treatment = 9 (116)
Time (Weeks)
Results: The ORR was 75% with complete remission (CR) in 34% of patients. The median
progression-free survival time for all patients was 5.6 months, and the median duration of
response for those in CR was 20.5 months. After a median observation time of more than 1.5
years, 31 patients were alive and free of documented progressive disease. The most common
treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue,
neutropenia, and diarrhea.
The 129 patients (median age, 32 years; range, 18 to 75 years) were
heavily pretreated with a median of 4 (range 2-7) prior systemic
regimens, and 41% did not respond to the regimen immediately
preceding panobinostat. Tumor reductions occurred in 96 patients
(74%). Objective response was achieved by 35 patients (27%),
including 30 (23%) partial responses and 5(4%) complete
responses. The median TTR was 2.3 months, median DOR was 6.9
months, and median PFS was 6.1 months. The estimated 1-year
overall survival rate was 78%.
Bendamustine 120mg/m2; days 1 and 2 every 28 days for up to 6 cycles
Eligibility for first cycle: ANC>1.0, Plt>100K
Eligibility for subsequent cycles: ANC>1.0, Plt >75K;
Pegfilgrastim was administered with each cycle.
Restaging with PET and CT after cycles 2, 4, 6.
Of the 36 patients enrolled, 34 were evaluable for response. Patients
had received a median of 4 prior treatments, and 75% had relapsed
after ASCT. The ORR by intent-to-treat analysis was 53%, including 12
complete responses (33%) and 7 partial responses (19%). The ORR
was 56% including patients with prior refractory disease, prior
ASCT, and prior allo SCT; however, no responses were seen in
patients who relapsed within 3 months of ASCT.
Moskowitz AJ et al, JCO 2013
Progressed (6)
Potentially eligible
for allogeneic stem
cell transplant
n=16
Responded to
bendamustine
n=10 (63%)
CR: 5, PR: 5
Median follow-up for survived patients: 36 months
Median PFS: 5.2 months
Median time to bendamustine response: 7 weeks
Number of bendamustine cycles prior to transplant: 4
Progressed
prior to
transplant
referral (5)
Met criteria for
transplant (5)
Refused
transplant (2)
Completed
transplant (3)
18% of eligible
patients
or 9% of all
analyzed patients
Moskowitz A et al JCO 2013
Lenalidomide 25mg/d x 21d
12/35 patients had cytoreductive
response, median time to treatment
failure 15 months
Median PFS 4 month and
median OS 20 month
Fehniger et al, Blood 2011
Ramchadren R, The Oncologist, 2012
Conclusions
2/3 of patients relapsing following ASCT are not going to benefit from
allo SCT due to short time to relapse, B symptoms, advanced disease,
chemo-refractory disease.
Currently, many new drugs are investigated and some have
demonstrated impressive response rate like Brentuximab Vedotin,
with 75% response rate and 20% long-term response.
While Allo SCT is curative for some of the patients with long time to
relapse from ASCT and chemo sensitive disease, the graft-versus
lymphoma effect is weak and DLI and GVHD are the trade off of
progression free survival.
Both the physician and patient should be aware of limitations of
available therapeutic choices and the options in terms of costs
(quality of life) versus benefits. Both issues should be discussed.
Thank You