Relapsed Hodgkin's disease

1
Relapsed Hodgkin's disease

• Rama Suresh
• 2-20-04

2
Case presentation

• 20yr old male presented to PCP 1-02 with axillary
  mass. PCP also noticed a lymph node in his left
  neck.
• Left axillary node biopsy on 1-02 showed NSHD
• CT scan showed enlarged lymph node in the left
  neck, mediastinum,left axilla, low attenuation
  lesions in the spleen, the largest of which was 2
  cm. No splenomegaly.
• PET scan 2-02 showed increased uptake in
  bilateral SC area, peritracheal, sup mediastinal,
  left axilla, left hilum, crest of diaphragm lymph
  node area.
• BMBx 2-02 negative

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Case presentation

• ABVD chemo started
• CT scan 5-02 after 3 cycles of ABVD showed
  decrease in mediastinal node from 11cm to 7 cm as
  well as stable right hilar adenopathy. Lesion in
  the spleen had resolved
• Finished ABVD 6 cycles 8-02
• CT scan 8-02 showed 5x2.5 cm mediastinal mass
• PET scan 8-02 no increased uptake
• XRT to mantle, periaortic, splenic area with
  splenic boost between 9-02 to 11-02
• Was followed and in 8-03 CT scan showed increase
  in right hilar adenopathy, new nodular masses in
  the lung RLL, RML. He was lost to follow up until
  1-04 when CT scan showed numerous bilateral
  pulmonary nodules, RLL nodule increased from 3x
  1.5 cm to 6.2 x 2 cm, diffuse mediastinal
  adenopathy, suggestion of lymph node in the
  portal caval and celiac region.

4
Our patients albumin 4.2, HB 13.9, Male, Stage
IIIA, Age 18, WBC 9.5, L 14.4
International Prognostic Factors Project on
Advanced HD Hasenclever, D et al, NEJM 1998
3391506
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(No Transcript)
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Definitions

• Primary progressive HD never achieved CR
• Early relapse - within 12 months of CR
• Late relapse - after CR lasting gt12 months

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Diehl et al. ASH Education Program Book 2003
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Diagnosis

• CRu
• CT scan of chest/abdomen and pelvis ( Diagnostic
  accuracy 56) (Guay, C et al. J Nucl Med 2003
  44 1225 )
• PET scan (Diagnostic accuracy 92) (Guay, C et
  al. J Nucl Med 2003 44 1225 )
• Biopsy Clinical judgment
• Ann Arbor staging system substitutes the
  letters RS

9
Relapse after intial chemotherapy

• Stage I or II disease 10 to 15
• Stage III or IV disease 30 to 50

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Sites of relapse

• In a study looking at patterns of relapse after
  MOPP chemotherapy 75 were nodal sites and 92
  were at sites of prior disease. Central axial
  nodes and left SC area were the most common nodal
  site. New nodal sites tended to be adjacent to
  prior sites.

Young RC, Canellos GP et al. Cancer 1978 42 1001
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Sites of relapse

• In a study looking at 427 patients treated with
  MOPP or ABVD chemo, XRT was added to bulky or
  contiguous uninvolved sites in 38 of patients,
  23 relapsed and 71 of relapses were at nodal
  sites, 13 in previously irradiated nodes
• In patients who got XRT relapses will more likely
  occur in previously uninvolved nodal regions or
  extra nodal sites like lung and liver

Santoro A, Viviana S et al. Cancer Treat Rep
1986 70 343
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Prognostic factors in Salvage therapy ( Favorable
Factors)

• NCI, Bethesda age lt 30 yrs, CR duration gt 12
  months (J Clin Oncol 10 210, 1992)
• GELA, France CR gt 12 months, disease status at
  relapse ( untreated vs. refractory) ( Ann Oncol
  6 543, 1995)
• Hôpital Saint-Louis, Paris CR duration gt 12
  months, stage I or II at relapse ( Cancer 78
  1293, 1996)
• Cancer Control Agency, British Columbia no B
  symptoms at relapse, CR duration gt 12 months,
  Stage I-III at original diagnosis ( Blood 77
  2292, 1991)
• Instituto Nazionale Tumori, Milan nodal only
  relapse, CR duration gt 12 months, disease extent
  at relapse (J Clin Oncol 15 528, 1997)

Our pt relapsed within 12 months, Stage IV at
relapse, has relapsed in extra nodal sites
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Autologous transplantation

• Most significant factors
• Serum albumin lt 4
• HB lt 10.5 g
• Age gt 45
• Lymphocytopenia
• Ten year event free survival
• 0-1 factors-38
• 2-3 factors-23
• gt 4 factors-7

Bierman P.J. et al. Ann Oncol 13 1370, 2002
Our patient at relapse Albumin 4.4 ,Hb 14.5, age
20, ALC 1400
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Salvage chemotherapy (Conventional Dose)

• Early relapse Crossover therapy(MOPP vs. ABVD)
  CR 35, FFS 20 at 3-5 yrs (NEJM 327 1478, 1992)
• Late relapse Previous regimen or other
  appropriate regimen CR 50-80, FFS 50 at 5 yrs
  (JCO 15 528, 1997)

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Early relapse conventional dose chemotherapy

• Several regimens (ESHAP, DHAP, ICE, ASHAP, VIM-D,
  CAPE/PALE, ABDIC, CAV, EIP, EVA, MINE, MIME, mini
  BEAM, Dexa BEAM, VIP, CEVD)
• Commonly used ESHAP, ICE

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ESHAP

• 22 pts ( 5 PP, 17 relapse)
• 3 cycles of ESHAP
• Suitable for transplant- CBVauto PBSCT
• Unsuitable for transplant 3 more cycles of
  ESHAP
• ESHAP alone 9 CR, 7PR ( ORR 73)
• Auto PBSCT 9 patients, 7patients were disease
  free at 50 months
• Grade 3-4 myelotoxicity in 59
• OS 35, DFS 27 at 3 years

Aparicio J et al. Ann Oncol 1999 10 593
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ICE

• Usually used as preparative regimen for PBSCT
  (cytoreduction and PBPC mobilization)
• RR 66
• Response to ICE predicted OS after PBSCT (CR vs.
  PR - 65 vs. 30)
• DLT Grade 3-4 thrombocytopenia 29
• Grade 4 neutropenia 13
• Median number of CD 34cells collected 8.4 x
  106/Kg

(Moskowitz, CH et al. J Clin Oncol 1999 17
3776)
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Table 9. Characteristics of patients best treated
with high dose chemotherapy/hematopoietic stem
cell transplantation (HDC/HSCT) for relapse of
Hodgkins lymphoma after primary chemotherapy.

Diehl et al. ASH Education Program Book 2003
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Table 10. Reasons for preference of growth factor
mobilized peripheral blood stem cells for high
dose chemotherapy/hematopoietic stem cell
transplantation (HDC/HSCT) in Hodgkins lymphoma.
Diehl et al. ASH Education Program Book 2003

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BNLI trial

• BEAMauto PBSCT vs. mini BEAM
• Relapsed or refractory
• 40 patients
• 3 yr EFS 53 vs 10
• Closed early as patients refused non PBSCT arm
• No difference in OS patients who failed mini
  BEAM was offered ABMT

Linch D et al. Lancet 1993 341 1051
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GHSG/EBMT trial

• Relapsed
• 4 cycles Dexa BEAM or 2 cycles of Dexa BEAM
  followed by high dose BEAM auto PBSCT
• Only patients who had response to first 2 cycles
  of Dexa BEAM continued on the study
• 161 patients enrolled
• 117 chemosensitive
• 3 yr DFS 55 vs. 34
• DFS survival better in early and late relapse
  patients with PBSCT
• OS was not significantly different

Schmitz N et al. Lancet 359 2065, 2002
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Autologous transplantation

• BEAM, CBV used as high dose regimens
• Acute toxicity can be lethal in 5-25 of
  patients, mainly due to lung toxicity (BCNUgt
  600mg/m2, prior XRT )
• TBI based regimens usually avoided

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GHSG experience
Diehl et al. ASH Education Program Book 2003
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IBMTR data
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Primary progressive HD

• GHSG retrospective study on 206 patients
• Standard salvage chemo 5 yr FF2F 17, OS 26
• High dose chemo 5 yr FF2F 31, OS 43 ( but only
  33 of patients received high dose chemo) ---
  poor stem cell harvest, poor PS and older age
• Prognostic factors low KPS, age gt 50 yrs,
  failure to attain temporary remission to first CT
  ( 5 yr survival 0-55)

Josting A, et al, Blood 96(4) 1280, 2000
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Long term follow up from British Columbia since
1985
Diehl et al. ASH Education Program Book 2003
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Allogeneic transplant trials
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Reduced intensity conditioning Allogeneic
transplantation

• patients too small
• Heavily pretreated ( gt 50 at least 2 lines of
  treatment, RT before allo PBSCT, gt 50 progressed
  with auto PBSCT, gt 50 transplanted in resistant
  disease)
• Conditioning regimen Mostly Fludarabine

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Non Myeloablative Allogeneic PBSCT

• Retrospective study on 188 patients
• NHL and HD from EBMT
• 84 Fludarabine based regimens
• 10 BEAM

Robinson SP et al. Blood 100(13) 4310, 2002
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Robinson SP et al. Blood 100(13) 4310, 2002
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Robinson SP et al. Blood 100(13) 4310, 2002
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Robinson SP et al. Blood 100(13) 4310, 2002
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Relapse after ABMT

• Second ABMT
• Mini allo
• Various regimens which include drugs like VP 16,
  nitrosoureas, gemcitabine, vinorelbine
• Monoclonal anti-CD30 antibody - being studied
• EBV specific cytotoxic Tlymphocytes generated
  ex-vivo can be reinfused to target EBV positive
  tumor cells - being studied

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GND-CALGB 59804

• Phase I/II trial
• 76 patients with recurrent or refractory HD
• 28 patients had prior PBSCT
• The Phase I portion of the study identified G
  1000 mg/m2 d1, 8, N 20 mg/m2 D1, 8, and D 15
  mg/m2 D1, 8 Q21 days as the MTD for patients
  without a prior transplant and G 800 mg/m2 D1, 8,
  N 15 mg/m2 D1, 8 and D 10 mg/m2 D 1, 8 Q21 days
  as the MTD for pts having had a prior transplant
• DLT Febrile Neutropenia and mucositis

Bartlett N. et al. ASCO 2003 Abstr 2275
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GND-CALGB 59804

• Phase II planned interim analysis
• ORR 58 (for the first 19 patients without prior
  transplant)
• ORR68 ( for the first 19 patients with prior
  transplant)
• Neutropenia 69, Thrombocytopenia 17, febrile
  neutropenia 9, mucositis 9, pulmonary toxicity
  17

Bartlett N. et al. ASCO 2003 Abstr 2275
36
SGN-30

• mAb against CD 30, AC10 was able to inhibit the
  growth of HD cell lines in vitro
• The variable regions from AC10 were cloned into
  an expression construct containing the human ?1
  heavy chain and ? light chain constant regions.
• SGN-30, chimeric antibody
• Growth arrest in G1 phase and DNA fragmentation
  consistent with apoptosis in HD cell line L540cy
• Mouse models of disseminated HD treated with
  SGN-30 - increased survival

Wahl AF et al. Cancer
Research 62 3736, 2002
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SGN-30 Phase 1 data

• Relapsed on refractory CD30 malignancies( HD,
  ALCL)
• 13 patients
• Doses ranging from 1 to 15mg/kg
• Volume of distribution same as blood and other
  mAb
• Half life approx 25 days
• Response was observed in 1 patient at a low titer
  of 1100
• Single dose of SGN-30 was well tolerated
• 1 patient experienced infusion reaction Grade II

Carabasi MA et al. ASCO 2003 Abstr 722
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Phase I/II study of SGN-30

• Phase 1 study has been completed
• Cohorts of 6 patients received 6 weekly infusions
  of SGN-30 at doses of 2, 4, 8, 12mg/kg
• 24 patients
• 21 HD, 2 ALCL, 1 DLBCL
• Median 5 prior therapies
• 70 post transplant
• Nausea 13, pyrexia 13, anorexia 8, myalgia 8,
  headache 8, pruritis 8
• Grade 3/4 events anemia 2 patients, Herpes
  Zoster 1 patient
• Preliminary response data through the 8mg/kg
  cohort
• 5 stable disease, 1 patient with ALCL had CR
• Half life approx 3 weeks

Bartlett NL et al. ASH 2003 Abstract 2390,
Poster Board Session 561-II
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Phase I/II study of a fully human anti- CD30 mAb
MDX-060

• Fully human IgG1? mAb that recognizes CD30 with
  nanomolar affinity, mediated killing of HD and
  ALCL cell lines in vitro and xenograft tumor
  models
• Phase I completely enrolled (Open label, dose
  escalation)
• Cohorts of 3-6 patients received 0.1 to 10mg/kg
  weekly for 4 weeks
• 21 patients (HD16, ALCL3, Other2)
• No MTD has been identified
• Phase II portion expanded cohorts will receive
  drug at 10 or 15mg/kg
• 1 patient with history of chronic GVHD had grade
  3 elevation of liver transaminases
• Efficacy assessment yet to be completed but one
  patient with ALCL in the 1mg/kg cohort had CR to
  therapy of 4 months duration
• Half life yet to be determined

Ansell
S et al. ASH 2003 Abstract 632
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EBV specific cytotoxic T lymphocytes

• EBV proteins present in malignant HR-S cells in
  about 40 of patients
• HD tumors use strategies to avoid CTL
• EBV specific CTL generated ex-vivo using
  autologous EBV transformed B cells as stimulator
  cells. CTLs marked with retroviral vector
  encoding the neomycin resistance gene (Neo)
• EBV specific CTL infused in 13 patients with
  multiple relapses of HD
• CTL homed to sites of malignancy and persisted
  for up to 10 months
• EBV specific immunity increased and viral load
  decreased
• Resolution of B symptoms in 3 of 4 patients
• 8 patients got this as treatment. 5 of them had
  mixed tumor responses and survived 5 to 15 months
  after CTL infusion. 1 patient had stable disease
  for 18 months and then had allo PBSCT . 2
  patients died of PD
• 4 of 5 patients who got CTL as adjuvant therapy
  post PBSCT are alive and well 8M to 2 yrs after
  CTL infusions. 1 patient died of PD 3 months post
  CTL infusion

Rooney CM et al. Annals of Hematology
81(S2)39,2002
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Acknowledgements

• Dr. Nancy Bartlett
• Dr. Steven Devine