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.Despite the generally excellent prognosis of children and adolescents with Hodgkin’s lymphoma (HL), approximately 15% of patients relapse. Aggressive chemotherapy followed by autologous bone marrow transplantation has been used with some improvement in survival.

1. Hedayati-Asl Amir
Mahak Cancer Children’s Hospital
Stem Cell Transplantation Department
Stem Cell
Transplantation for
Pediatric Lymphoma

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. Childhood NHL
• Classified as :
Intermediate (30%) disease
High grade (70%) disease
• Classified into four major subtypes:
Burkitt’s lymphoma (BL)
Lymphoblastic lymphoma (LL)
Diffuse large B-cell lymphoma (DLBL)
Anaplastic large cell lymphoma (ALCL)

5. Lymphoma
• As standardized treatment protocols show high
efficacy, an increasing effort has been undertaken
to reduce long-term side effects associated with
treatment.
• Use of gonadotoxic substances, such as
procarbazine, has been reduced.

6. • Hodgkin lymphoma is a highly curable (70 -90 %)
disease with modern chemotherapy ± radiation.
Kuruvilla J. ASH education book 2009

7. Relapsed and Refractory
• However, in children with relapsed and refractory
NHL, the prognosis is not as promising and the
best treatment approach for this poor risk group
continues to be a challenge.
• Between 25 and 30% of patients with advanced
stage HD still relapse and in subsets of this group,
the outcome is dismal.

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

9. 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.

10. Clinical Presentation (NHL)
• Approximately 70% of children with NHL present with
advanced disease and/or have metastatic involvement,
including BM, central nervous system and/or bone.
• Children with limited stage NHL have an excellent
prognosis with an estimated 5-year event-free survival
(EFS) of 90–95%. The prognosis for advanced stage
disease has also improved and varies based on subtype
(60–90% 5-year EFS).

11. 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.

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.

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

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.

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

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

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. BNLI ( UK group ) GHSG/EBMT group
Event Free Survival Freedom from treatment failure

36. Adverse Prognostic Factors after ASCT

37. Pre-Auto Transplant PET/Ga Scans Predict
Poor Outcome in Pts with Rel/Refractory
Hodgkin Lymphoma
Jabbour et al. Cancer
2007;109:2481

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

39. High Dose Chemotherapy Regimes in ASCT

40. 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)

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

42. 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

43. 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

44. Adjunctive Radiotherapy
• Adjuvant involved-field irradiation is widely
used either before or after autologous
hematopoietic cell transplantation.

45. Radiotherapy alone or with
chemotherapy in stage I-II
Hodgkin lymphoma

46. 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.

47. 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

48. 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

49. Brentuximab vedotin ( SGN-35)

50. 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

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

62. 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

66. EBMT Standard Indications for ASCT and
Allo-SCT in Lymphoid Malignancies

68. BMT for Non-Hodgkin’s Lymphoma
Indications
• Refractory disease
• Relapse
• High risk in CR1
• Lymphoblastic
• Burkitt’s
• Gamma delta-t-cell lymphoma

69. Stem cell transplantation for
childhood NHL
• Aggressive chemotherapy followed by autologous BMT
has been used with some improvement in survival.
• There is little consistency in therapeutic approaches and
there is no formal recommendation on the best approach
for this poor prognostic subgroup.

70. When to do stem cell
transplantation?
• Poor prognostic features have been defined as :
• (1) a delayed or partial response to first-line therapy
• (2) central nervous system or BM involvement at presentation
• (3) time to relapse from initial diagnosis.

71. Stem cell transplantation in
childhood NHL

72. SCT & NHL
• Most pediatric SCT programs will reserve SCT in children
with NHL to be used after the first relapse, progression or
induction failure.

73. Chemoresponse
• Chemoresponse is another important prognostic
indicator, and chemosensitive disease is
considered by many in the field as an essential
criterion for undergoing high-dose therapy and
AutoSCT.
• Histology may also play a role in response in
children and adolescents with relapsed/refractory
NHL.

74. SCT in Lymphoblastic Lymphoma
• Relapsed BL and diffuse large B-cell lymphoma
had a better survival following high-dose therapy
and AutoSCT compared to patients with relapsed
LL.
• Pediatric patients with relapsed LL had a
survival of 39% following high dose
therapy and AutoSCT

75. B-cell lymphoma
• Dismal prognosis for those patients with B-cell NHL who
relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
•The major factor determining survival in this study was the
remission status of patients before AutoSCT

76. ALCL
• The prognosis for children who develop progressive or
recurrent disease is poor with <50% DFS.
• These results raise the question whether AutoSCT in CR1
should be considered for pediatric patients who present
with high-risk ALCL

77. Relapsed ALCL
• The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by
AutoSCT or AlloSCT in children and adolescents with
relapsed ALCL after BFM frontline therapy.

78. (GvLy)
• These results favor a potential allogeneic graft vs
lymphoma (GvLy) response.
• Further classification and larger trials are needed for this
heterogenous ALCL subtype to determine an appropriate
risk-stratified treatment approach for pediatric ALCL.

79. Allo vs Auto
• There was a similar DFS between AlloSCT vs AutoSCT in patients
with LL.
•There was a significantly decreased risk of relapse following AlloSCT

80. Non-MA AlloSCT
• Non-MA non-toxic regimens to reduce
regimen-related morbidity and mortality
with MA AlloSCT.
• But still achieve a GvLy disease effect is
currently under investigation.

81. Future Investigations following SCT
• Focus on reducing minimal residual disease
• Targeted adoptive cellular immunotherapy to reduce disease
relapse
Use of targeted therapy such as:
Monoclonal antibodies including rituximaab (anti-CD20)
Epratuzamab (anti-CD22)
SGN-30 (anti-CD30)
Immunotoxin therapy (denileukin diftitox)
Anti-CD22-calichimiacin

82. Targeted Cellular Therapies
• EBV-specific cytotoxic T-cell lymphocytes for HD
• Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or
natural killer cells for B-cell NHL.
• And the end :
Reducing the burden of lymphoma prior and post-SCT

83. ASCT for HD
• We report our experience with high-dose
chemotherapy and autologous SCT and
outcome in children with Hodgkin’s
disease.

84. • Twenty-one patients aged 8 to 25 years
(median 14 years, M/F = 15/6)
• Status at transplant was:
• (CR2): n = 11
• (CR>2): n = 7
• partial remission (PR): n = 3

85. Conditioning Regimen-CBV
• Cyclophosphamide, Carmustine and Etoposide
(CBV): 7 pts
Cyclophosphamid 1500 mg/m2
× 4
BCNU 300 mg/m2
× 1
Etoposide 250 mg/m2
× 4

86. Conditioning Regimen-CEAM
• CCNU, Etoposide, Cytarabine and Melphalan
(CEAM): 14 pts
CCNU 200 mg/m2
on day -3
Etoposide 1000 mg/m2
on day -3 and -2
Cytarabine 1000 mg/m2
on days -3, -2
Melphalan 140 mg/m2
on day -1

87. Result:
• The median mononuclear cell dose was 5.4
× 108
/ kg.
• The median time to absolute neutrophil
count > 0.5 × 109
/L was 11 days.
• The median time to platelet count > 20 × 109
was 14 days.

88. Result:
• Grade 2 and grade 3 mucositis was seen in
60% our patients.
• Transplant-related mortality at 100 days not
occurred.
• Only one patient relapsed 18 months after
transplant.
• Twenty one children remain alive.

89. Conclusion:
• ASCT is feasible, in HD
• Low early toxicity
• Result in durable remissions
• Should be considered for children with advanced
HD.
• Long-term survivors must continue to be closely
followed.