Treatment for HL has improved significantly since the ABVD chemotherapeutic combination was invented over 30 years ago . Despite using the same ABVD regimen in most patients treated in the first line, we now have a much better understanding of disease biology and the late side effects of therapy, and we have moved toward a personalized, risk-adapted approach. This approach promises to deliver low toxicities and high cure rates for lower risk patients while reserving aggressive regimens for those high risk patients who really need them. For the minority of patients who fail first-line therapy, novel drugs like the antibody-drug conjugate BV and immunotherapies with nivolumab and pembrolizumab have produced high response rates and durability of benefit. Further research is needed to determine whether these novel drugs could make life better for both patients with HL who are undergoing treatment and for the growing cohort of HL survivors.

1. Amir Abbas Hedayati-Asl
Hematologist, Oncologist & Ped. Stem Cell Transplantation
Cancer Stem Cell Group
Stem Cell Biology and Technology Department, Royan Institute
Stem Cell Transplantation in
Hodgkin’s Lymphoma
Past, Present and Future

2. Lymphoma
• Lymphoma is the third most common cancer in
children <15 years of age.
• The prognosis for children with newly diagnosed
chemosensitive non-Hodgkin’s lymphoma (NHL)
and Hodgkin’s disease (HD) has improved
significantly.

3. The Revised European–American Classification of Lymphoid
Neoplasms
Major histologic subtypes of HD:
Nodular lymphocyte predominant
Classical HD whose subtypes include
• Lymphocyte rich
• Nodular sclerosing
• Mixed cellularity
• Lymphocyte depleted
• ALCL Hodgkin’s-like
HD in children
Mixed cellularity
Nodular lymphocyte predominant
Nodular sclerosing

4. • Hodgkin lymphoma is a highly curable (70 -90 %)
disease with modern chemotherapy ± radiation.
• Despite the generally excellent prognosis of
children and adolescents with Hodgkin’s lymphoma
(HL), approximately 15% of patients relapse.
Kuruvilla J. ASH education book 2009

5. Relapsed and Refractory
• Between 25 and 30% of patients with advanced
stage HD still relapse and in subsets of this group,
the outcome is dismal.

6. Timeline of Landmark Developments in Hodgkin
Lymphoma Over the Last Decade

7. Stem Cell Transplantation
• Aggressive chemotherapy followed by
autologous bone marrow transplantation has
been used with some improvement in survival.

8. Best Approach?
• Some centers have investigated allogeneic
stem cell transplantation in pediatric patients
with recurrent/relapsed lymphoma.
• There is little consistency in therapeutic
approaches and there is no formal
recommendation on the best approach for this
poor prognostic subgroup.

9. Clinical Presentation (HD)
• Patients with HD commonly present with cervical
or supraclavicular lymphadenopathy and most will
present with some degree of mediastinal
involvement.
• Treatment is largely determined by :
– Disease stage
– Patient’s age at diagnosis
– The presence or absence of ‘B’ symptoms
– The presence of hilar lymphadenopathy and/or bulky nodal disease
– The rapidity of response to therapy.

10. Prognostic factors validation and
evaluation at the time of first failure
• Most commonly reported prognostic factors are time to treatment failure/CR
duration;
• CR duration as refractory (patients with progressive disease/partial
response/CR duration <3 months) versus early relapse (3–12 months) versus
late relapse >12 months.
• Many studies used <12 months versus >12 months as a cut off.
• Other factors include response to salvage chemotherapy, extranodal disease,
large mediastinal adenopathy, presence of B symptoms and elevated lactate
dehydrogenase
• Over the last 10 years, increasing numbers of patients have had FDG-PET
scans for response assessment. It has emerged that FDG-PET scan response
after salvage chemotherapy or disease status prior to HDC auto-SCT is an
important prognostic factor.

11. Staging Hodgkin Disease and Risk Factor

12. Clinical Presentation (HD)
• With current therapy,
• (DFS) in both children and adults with newly diagnosed
localized and advanced stage HD ranges between 85–
100 and 70–90%, respectively.

13. Patient 1
• 13 years old girl presented with left
supraclavicular lymph node enlargement for
1months with B symptoms.
• Lymph node biopsy confirmed the diagnosis of
classical Hodgkin lymphoma, nodular sclerosing.
• CT scan showed presence of bilateral
supraclavicular and mediastinal lymphadenopathy.

14. Reed-Sternberg Cells

15. CD15/CD 30 Immunostain

16.  BMA : no marrow infiltration.
 Normal CBC, Albumin level, ESR.
 Diagnosis : Classical Hodgkin lymphoma,
nodular sclerosing, stage IIB.
 She received 6 cycles of ABVD and achieved CR.
 However, 2 years later, she presented with left
cervical lymphadenopathy.
 Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma, nodular sclerosing.
 CT scan : cervical, mediastinal and left hilar
lymphadenopathy.

17. • She received gemcitabine, vinorelbine
chemotherapy and then underwent
autologous stem cell transplant with CEAM
and eventually achieved complete remission
and remained in CR.
• CEAM regimen: alternative regimen, modified BEAM-like regimen
(lomustine, etoposide, cytarabine, and melphalan), in which carmustine
(BiCNU IV) was substituted by oral lomustine (CCNU: 2 chloroethyl
cyclohexyl nitrosourea).

18. Patient 2
• 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness
of breath.
• Noted to have bilateral cervical and axillary lymphadenopathy.
• Left axillary lymph node biopsy confirmed the diagnosis of Classical
Hodgkin Lymphoma, Nodular Sclerosing type.
• CT scan showed presence of bilateral cervical, axillary, mediastinal
lymph nodes enlargement with mediastinal mass 15 x 10 cm , pleural
effusion with paraaortic , inguinal lymphadenopathy and
hepatosplenomegaly.

19. • Hb 9.7 g/L, WBC 12000
• Albumin 2.8 g/dL
• BMA : no evidence of marrow infiltration.
• Diagnosis : Classical Hodgkin lymphoma, nodular
sclerosing, Stage IVB, bulky disease .
• Treated with 8 cycles of escalated ABVD, and RT
• However, repeat CT scan showed mediastinal mass, 8cm
x 9cm.
• Treated with ESHAP then refer for ASCT

20. SCT for childhood HD
• Indications for stem cell transplant in Hodgkin Lymphoma
• Autologous stem cell transplant in Hodgkinl ymphoma.
• Myeloablative allogeneic stem cell transplant
• Reduced-Intensity conditioning SCT
• Role of novel agents – Brentuximab in HSCT

21. High-risk patients with HD
• Refractory to initial therapy
• Primary induction failure
• Relapse after primary initial chemotherapy
• High-risk patients with HD who are refractory to initial therapy, primary
induction failure and relapse after primary initial chemotherapy (especially if
first CR <12 months duration) have a minimal chance for long term survival
with salvage chemotherapy alone with a reported 5- to 10-year OS of 25%.

22. Stem cell transplantation in
childhood Hodgkin’s disease

23. Prognostic Factors
• Disease status
• Chemoresponsiveness to salvage chemotherapy
• Tumor bulk
• Remission duration
• Extranodal relapse
• Performance status
• Relapse in previous radiation field

24. Major Prognostic Factor
• The length of first remission is a major prognostic
factor in attaining a durable second remission with
chemotherapy alone in relapsed HD.
• Studies have shown that patients who relapse after more
than 12 months from diagnosis can enter a durable CR2
with standard chemotherapy regimens.

25. Pediatric Literature
• Extranodal disease at the time of relapse
• Large mediastinal mass going into AutoSCT
• Resistant disease predict for poor OS, EFS and
PFS
• Additional poor prognostic
– Lactate dehydrogenase (LDH) ratio of more than one
– Interval from diagnosis to AutoSCT of <15 months
– Female sex

26. Not all Relapsing Patients do so Well after an
Autologous Stem Cell Transplantation and related to
multiple factors

27. Children and Adolescents
at risk for long-term complications including:
 Myelodysplastic syndrome (MDS)
 AML
 Breast cancer

28. Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10% of patients with limited-stage disease.
Armitage JO. N Engl J Med. 2010;363(7)

29. HODGKIN’S DISEASE/LYMPHOMA
SALVAGE REGIMENS
Regimen Patients CR/PR to ASCT
DHAP 102 87% 60%
(dexamethasone, ara-C, cisplatin)
Mini-BEAM 89 77% 82%
(BCNU, etoposide, ara-C, melphalan; 2 series)
Dexa-BEAM 225 75% 75%
(above plus dexamethasone; 3 series)
GDP 34 62% 88%
(gemcitabine, dexamethasone, oxaloplatin)
ICE 65 84% 86%
(ifosfamide, carboplatin, etoposide)
GND 38 64% --
(gemcitabine, vinorelbine, liposomal doxorubicin)

30. SALVAGE REGIMENS
There are no Significantly Better Salvage Chemotherapy Regimens to Treat
Relapsed Patients with HL. About 50% of patients relapsing after the first line
chemotherapy can be rescued by an autologous stem cell transplant.

32. ASCT as standard therapy for HL Relapsing
after 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al. Lancet 1993

33. Linch et al.Lancet 1993;341:1051
( UK Group )
Schmitz et al. Lancet 2002;359:2065
( EBMT German Group )

34. HD R1 Trial ( GHSG/EBMT )
( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al. Lancet 2002

35. Adverse Prognostic Factors after ASCT

36. Pre-Auto Transplant PET/Ga Scans Predict
Poor Outcome in Pts with Rel/Refractory
Hodgkin Lymphoma
No single standard prognostic system for relapsed HL.
Higher incidence of recurrence post ASCT is associated with :
* less than a CR to 2nd line therapy ( by CT/PET )
* Duration of CR<12 months
* Advanced stage / Extranodal disease
Jabbour et al. Cancer
2007;109:2481

37. PET-CT is desirable at diagnosis and
essential at restaging

38. High Dose Chemotherapy Regimes in ASCT

39. Preparative Regimen
• CBV (cyclophosphamide, BCNU [carmustine], etoposide [VP-16])
• BEAM (BCNU, etoposide, cytarabine [Ara-C], and melphalan)
• Fractionated total body radiation has often been given in
conjunction with etoposide and cyclophosphamide.
• Some centers use CCNU (lomustine) as an alternative to BCNU,
because of a lower incidence of respiratory complications .(CEAM)

40. Choice of Donor Cell
• Peripheral blood stem cells (PBSCs) are the
donor cells of choice
• More rapid hematologic recovery and
shortened hospital stay

41. Identification of high risk
patients in first remission
• Although controversial and investigational,
there is a limited literature on the use of
autologous hematopoietic cell
transplantation in high risk patients with
advanced disease in first remission

42. Autologous SCT in Chemoresistant Hodgkin
Lymphoma
N: 64
􀂃 Median age : 22 year old
􀂃 Stage III/IV : 77%
􀂃 Prior Radiotherapy : 50%
􀂃 Median f/u: 4.2 years
􀂃 Chemoresistant : < 50%
reduction in tumor bulk
after salvage chemo
Estimated 5 years PFS : 17% OS : 31 %
Gopal et al. Cancer 2008; 113:1344

43. Adjunctive Radiotherapy
• Adjuvant involved-field irradiation is widely used
either before or after autologous hematopoietic cell
transplantation.
• There are no randomized trials indicating survival
benefit, but several studies have shown that adjuvant
irradiation can control limited residual disease and may
contribute to improved prognosis.

44. TREATMENT OF RELAPSE
FOLLOWING TRANSPLANTATION
• Only highly selected patients can tolerate a second
autologous transplant.
• Single agent chemotherapy is often used in this setting
• Local regional irradiation or allogeneic HCT may also be
of benefit.

45. Tandem ASCT
N = 245
􀂃 Stratified by risk factors :
- CR < 12 months
- Stage III/IV at relapse
- Relapse in previous XRT area
􀂃 Poor risk →≥ 2 risk factors → Double SCT
􀂃 Intermediate risk →1 risk factors → single SCT

46. New Therapeutic Options for Relapsed Patients.
AntiCD30 MoAb
– SGN-35(Brentuximab Vedotin) is a CD30-targeted
antibody conjugated to an auristatin E derivative
(MMAE)
– MMAE is a potent anti-tubulin agent selectively
delivered to CD-30 positive cells via antibody-drug
conjugate technology

47. Brentuximab vedotin ( SGN-35)
Inclusion of new drugs in the ASCT setting:
• As part of salvage therapy before ASCT
• Maintenance therapy after ASCT

48. Pivotal Phase II ,single arm, multicenter study of
Brentuximab vedotin ( SGN-35) in patients with
relapsed or refractory Hodgkin Lymphoma after
ASCT
n=102
􀂃 1.8mg/kg q3 week up to 16 cycles.
􀂃 Primary end point : ORR
􀂃 Median age : 31 (75% between 18-39 )
􀂃 Median duration of follow up : 9 months
􀂃 Objective response rate : 75%
􀂃 CR : 34%
􀂃 Side effects : peripheral sensory neuropathy,
neutropenia, diarrhoea, nausea, fatigue.
Chen et al. JCO 2011 ASCO meeting abstract 8031

51. Myeloablative Allogeneic Stem
Cell Transplant

52. Allogeneic
graft vs host lymphoma effect

53. Allo SCT
• Several studies have suggested that
there may be a significant GvLy effect
after high-dose therapy and AlloSCT.

54. • 3 year OS and DFS were 21% and 15% with 3
year probability of relapse 65%.
(Gajewski JL et al. JCO 1996;14 :572-578 )
• Peniket AJ et al reported 4 year OS, PFS, TRM
were 24%, 16%, 52%.
( Peniket AJ et al. BMT 2003;31:667-678 )
High treatment related mortality ( up to 50% )
and poor long term results.

55. Reduced Intensity Conditioning
Allogeneic Stem Cell Transplant

56. RIC vs Myeloablative
NRM at 3 mth : 28%(MA)vs 15% (RIC)
1 year : 46% vs 23%
Sureda et al. JCO 2008;26:455

57. Allo-SCT in children and adolescents with
recurrent HL
The type of conditioning had no impact on NRM. RIC
regimens were associated with an increased risk of
progression, with a lower PFS.
Claviez et al. Blood 2009

58. Impact of cGVHD after alloSCT in relapse
rate and PFS
Sureda et al. JCO 2008;26:455

59. • Prospective, multicenter, phase II study Primary refractory disease
after two lines of chemotherapy, relapses after first-line therapy with a
short complete remission (<12 months), multiply relapsed patients and
patients who relapsed after an ASCT.
Sureda et al. Haematologica 2012;97(2)

60. RIC-Allo in RR HL

63. HSCT in HL
• Autologous SCT :
Relapsed or Primary refractory disease
• Allogeneic SCT :
Chemosensitive relapse following
HDCT/ASCT if time to relapse >1 year.

64. Allo-SCT vs ASCT. Advantages and Disadvantages
• Advantages:
– Infusion of a tumor-free cell product
– Graft-versus-HL effect
• Disadvantages:
– Higher non-relapse mortality
– Availability of a histocompatible
donor

65. • Patients with relapsed and progressive
disease post HDC auto-SCT can benefit
from newer agents like BV and PD-1
blockade.
• Should patients achieving CR after BV or
nivolumab be continued on these agents, or
should they be offered consolidative auto-
or allo-SCT?

66. • Patients who are eligible for treatment for post HDC auto-SCT
failure may consume significant resources.
• Newer agents like BV, nivolumab, and pembrolizumab are
significantly expensive as compared to chemotherapy.
• In addition, these agents are not easily available due to high price
and registration requirements in different countries. Due to a
limited demand/market in various countries, pharmaceuticals
may not be interested in seeking registration for low volume
supply in many countries.
• Many patients responding to BV and not planned to have second
SCT may end up continuing BV for 12–16 cycles. The same is
true for nivolumab that is intended to be continued until disease
progression.

72. Conclusion:
• Treatment for HL has improved significantly since the ABVD
chemotherapeutic combination was invented over 30 years ago .
• Despite using the same ABVD regimen in most patients treated in the
first line, we now have a much better understanding of disease biology
and the late side effects of therapy, and we have moved toward a
personalized, risk-adapted approach.
• This approach promises to deliver low toxicities and high cure rates for
lower risk patients while reserving aggressive regimens for those high
risk patients who really need them.
• For the minority of patients who fail first-line therapy, novel drugs like
the antibody-drug conjugate BV and immunotherapies with nivolumab
and pembrolizumab have produced high response rates and durability
of benefit.
• Further research is needed to determine whether these novel drugs
could make life better for both patients with HL who are undergoing
treatment and for the growing cohort of HL survivors.

73. Conclusion:
• Although HDC auto-SCT is standard for refractory and
relapsed HL, emerging newer treatments, salvage
therapies, post HDC auto-SCT consolidation and
managing post HDC auto-SCT failure landscape is rapidly
changing.
• Changing treatment guidelines based on small phase
I/phase II trials should be discouraged. These issues can
best be answered in properly designed randomized phase
III clinical trials.