Stem Cell Transplantation in Hodgkin’s Lymphoma Past, Present and Future

1. Amir Abbas Hedayati-AslPed. Hematologist Oncologist /BMTTehran University of Medical Sciences, HORC-SCTRoyan InstituteHematology & Oncology DepartmentCancer Personalized Medicine ProgramStem Cell Biology and Technology Department 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 LymphoidNeoplasms 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 supraclavicularlymphadenopathy 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 hilarlymphadenopathy 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/LYMPHOMASALVAGE 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 Relapsingafter 1st Line ChemotherrapyBNLI 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 PredictPoor Outcome in Pts with Rel/RefractoryHodgkin 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 HodgkinLymphoma 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 ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma afterASCT 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