AHSCT in Hodgkin lymphoma - indication and challenges. Bastian von Tresckow German Hodgkin Study Group Cologne University Hospital

AHSCT in Hodgkin lymphoma - indication and challenges Bastian von Tresckow German Hodgkin Study Group Cologne University Hospital

AHSCT in Hodgkin Lymphoma The role of AHSCT in HL Mobilisation failure and rescue strategies Interactive case study

AHSCT in first line therapy H97-HR trial for high risk advanced HL (Arakelyan et al. 1 ): VABEM+RT vs 4xABVD+BEAM and AHSCT; 158 pts. FFTF 79% vs 75%; OS 87% vs 86% @ 5 years HD01 trial for high risk advanced HL responding to ABVD (Federico et al. 2 and Carella et al. 3 ): 4 x conventional therapy vs AHSCT FFS 75% vs 79%; OS 84% vs 85% @ 10 years no role for AHSCT in first line for patients responding to initial therapy! 1. Arakelyan et al. Cancer. 2008 Dec 15;113(12):3323-30. 2. Federico et al. J Clin Oncol. 2003 Jun 15;21(12):2320-5. 3. Carella et al. Haematologica. 2009 Jan;94(1):146-8. Epub 2008 Nov 10.

AHSCT for relapsed/refractory HL patients BNLI (Linch et al. 1 ): BEAM versus minibeam, 40 pts. EFS @ 3years 53% versus 10%, (p=0,025) Years after randomisation Years after randomisation 1. Linch et al., Lancet. 1993 Apr 24;341(8852):1051-4.

AHSCT for relapsed/refractory HL patients HDR1 (Schmitz et al. 1 ): 4x DexaBEAM vs 2x DexaBEAM + BEAM and AHSCT, 166 pts. FFTF2 @ 3 years 34% vs 55% (p=0,019) 1. Schmitz et al., Lancet. 2002 Jun 15;359(9323):2065-71.

AHSCT for relapsed/refractory HL patients 2 cycles induction Ctx plus HDCT/APBSCT is standard of care, but PFS @ 3 years still is poor (around 50%)

Cologne dose-intensification strategy 2x DHAP + G-CSF PR or CR: continue Single agent HD Ctx - Cyclophosphamide - Mtx, Vcr - Etoposide BEAM + APBSCT

HDR2: Objectives and endpoints Objective: To improve the FFTF2 by 20% using additional sequential HDCT as compared to 2x DHAP + BEAM/APBSCT Endpoints: Freedom from treatment failure (FFTF) (primary) Progression free survival (PFS) Overall survival (OS) CR/CRu rate Severe toxicities (WHO grade 3/4) Secondary neoplasms

D H A P PBSC R E G I S T R A T I O N HDR2: European multicenter study (GHSG, EORTC) for relapsed HL Primary refractory and DAHP refractory patients were not included SD, PR, CR B E A M C Y C M T X VP 16 B E A M R A N D O M I S A T I O N Radiotherapy to residual disease D H A P Standard: 119 pts. Intensified: 122 pts.

Probability HDR2: PFS by treatment arm (final analysis 3-09) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 p = 0.505 0.1 Standard (at 3y: 72%) Intensified (at 3y: 67%) 0.0 0 12 24 36 48 60 Time [months] Pts. at Risk Standard 119 92 75 55 35 22 Intensified 122 90 75 53 34 22 Josting et al., J Clin Oncol. 2010 Dec 1;28(34):5074-80. Epub 2010 Oct 25.

GHSG-EORTC HDR2 trial summary HDR2 trial showed no advantage of an intensified induction chemotherapy. In contrast, there were more protocol deviations Toxicities dose reductions and a longer duration of treatment 2xDHAP plus BEAM/APBSCT is a brief and highly active treatment strategy for relapsed chemosensitive HL patients with a PFS @3 years of 72%

Tandem AHSCT for high risk HL H96 (Morschhauser et al. 1 ): non-randomized trial of tandem AHSCT in high risk patients 150 poor risk, 95 intermediate risk pts. Ifosfamide-based salvage + CBV-Mx/BEAM + TAM/BAM 1. Morschhauser et al. J Clin Oncol. 2008 Dec 20;26(36):5980-7. Epub 2008 Nov 17.

Tandem AHSCT for high risk HL Poor risk: Primary refractory disease Or 2 risk factors* at first relapse Intermediate risk: One risk factor* *Risk factors: Early relapse Stage III or IV at relapse Relapse within previously irradiated sites Morschhauser et al. J Clin Oncol. 2008 Dec 20;26(36):5980-7. Epub 2008 Nov 17.

Tandem AHSCT for high risk HL H96 (Morschhauser et al. 1 ): FF2F 46% and OS 57% @5years OS 45% @5years for salvage-refractory pts. Tandem AHSCT is an option for high risk patients, especially those not reaching CR after salvage Ctx 1. Morschhauser et al. J Clin Oncol. 2008 Dec 20;26(36):5980-7. Epub 2008 Nov 17.

AHSCT in Hodgkin Lymphoma The role of AHSCT in HL Mobilisation failure and rescue strategies Interactive case study

Mobilisation failure in HL Regimen Number of patients (n) Mobilisation failure (%) Reference DHAPq2wk 102 4 Josting 2002 ICE 66 14 Moskowitz 2004 IGEV 90 1.3 Santoro 2007 Josting A et al. Ann Oncol. 2002 Oct;13(10):1628-35. Moskowitz C et al. Br J Haematol. 2004 Mar;124(5):645-52. Santoro A et al. Haematologica. 2007 Jan;92(1):35-41.

Mobilisation failure in HL Mobilisation failure in HL is rare but challenging Rescue strategies are needed to allow for AHSCT (only curative treatment!) Tandem AHSCT highlights the need for effective mobilisation

Mobilisation failure in HL -rescue strategies- Alternative chemotherapy regimen (single-hd or combination) cons: toxicity, delay of AHSCT, costs pros: tumour reduction, stem cell purging (?) Bone marrow harvest cons: general anaesthesia, painful, no tumour salvage, slower engraftment, higher rate of infections pros: high rate of successful harvests Plerixafor cons: costs pros: high success rate, safe and tolerable, high stem cell yield

Plerixafor in HL Feasibility of mobilisation and AHSCT has been shown in a prospective phase II trial in HL patients (Cashen et al. 1 ) European compassionate use programme: 54 HL patients received plerixafor after mobilisation failure, 44 (81,5%) successfully mobilised stem cells (Huebel et al. 2 ) Plerixafor mobilisation is an effective rescue strategy in Hodgkin Lymphoma 1. Cashen et al. Biol Blood Marrow Transplant. 2008 Nov;14(11):1253-61. 2. Huebel et al. Bone Marrow Transplant. 2011 Aug;46(8):1045-52. Epub 2010 Oct 25.

AHSCT in Hodgkin Lymphoma The role of AHSCT in HL Mobilisation failure and rescue strategies Interactive case study

Interactive case study Male, 21 years old, Hodgkin Lymphoma CS IIB with large mediastinal mass and involvement of left supraclavicular region Treatment: 6 x ABVD partial response (PET+) 2 x BEACOPPesc progressive disease left supraclavicular region Salvage therapy and AHSCT was planned

Which salvage therapy would you use? 1. DHAP? 2. ICE? 3. IGEV? 4. Dexa-BEAM? 5. None, bone marrow harvest or steady state mobilisation and straight AHSCT?

Which salvage therapy would you use? DHAP: well tolerated, high ORR (88%), short (2 x 2weeks), good results in the large HD-R2 study ICE: well tolerated, high ORR (85%) but high rate of mobilisation failure (in HL) IGEV: well tolerated, high ORR (81%), effective mobilisation, but long (4 x 3weeks) Dexa-BEAM: used in HD-R1 but toxic, stem cell toxic, crossresistant to BEAM Straight AHSCT: used in BNLI but disadvantages of bone marrow harvest/no salvage therapy

Interactive case study Salvage treatment: 3 x IGEV, no successful stem cell mobilisation Response: SD (CT-scan) Salvage radiotherapy: 30 Gy left supraclavicular region and right supraclavicular and axillary region Response: PET+ PR

Procedure? 1. Allogeneic transplant? 2. Mobilisation with polychemotherapy (e.g. DHAP)? 3. Mobilisation with single-hd (e.g. cyclophosphamide)? 4. Steady-state mobilisation and HDCT? 5. G-CSF + Plerixafor (with or without Ctx)?

Procedure? Allo-Tx: no role in HL patients before Auto-Tx Mobilisation with polychemotherapy: non-cross-resistant substances might improve the response Mobilisation with single-hd: high mobilisation potential, tumour reduction Steady state mobilisation: no further tumour reduction, lower mobilisation potential G-CSF + Plerixafor: very high mobilisation potential in combination with Ctx, suitable for poor mobilisers

Risk factors for poor mobilisation Age > 60 Progressive disease Severe BM involvement Previous Ctx and/or Rtx Type of Ctx Previously failed mobilisation attempts Platelet count < 100,000 /µl before apheresis Neutropenic fever during mobilisation Huebel et al., Bone Marrow Transplant 2011

Interactive case study 2nd salvage treatment: DHAP, no successful stem cell mobilisation the patient was admitted to our hospital

Procedure? 1. 2 nd mobilisation attempt with chemotherapy + G- CSF only? 2. Mobilisation with polychemotherapy + G-CSF + plerixafor? 3. Mobilisation with cyclophosphamide + G-CSF + plerixafor? 4. Mobilisation with etoposide + G-CSF + plerixafor?

Interactive case study Single high dose therapy: etoposide 500mg/m²/d d1-4 + lenograstim 10µg/kg BW/d

Interactive case study d14:plerixafor 240µg/kg BW apheresis d15: 6,591 x10 6 CD34+ cells/kg BW

Procedure? 1. BEAM and AHSCT? 2. Alternative regimen (e.g. CBV-Mx, Mel/Eto) and AHSCT? 3. Auto-Allo Tx? 4. Double-AHSCT (e.g. BEAM/BAM)?

Interactive case study Double AHSCT: 1. BEAM 2. BAM PET-CT: CR with PET- residual disease <2cm

Procedure? 1. Maintenance therapy? 2. No further therapy?

Maintenance in HL Benefit of maintenance therapy in HL has not been demonstrated (e.g. Young et al. 1 ) Currently ongoing: AETHERA (Brentuximab vedotin for HL patients after AHSCT with high risk of relapse) 1. Young et al. Lancet. 1973 Jun 16;1(7816):1339-43.

Interactive case study Final treatment outcome: patient remains in CR (follow-up: 5 years)

What to do in case of relapse? 1. Allo-Tx? 2. 2 nd Auto-Tx? 3. Palliative treatment with chemotherapy or experimental substance?

What to do in case of relapse? Allo-Tx: RIC-allo might be suitable for chemosensitive, young patients in good general condition 2nd Auto-Tx: an option for late relapse after AHSCT (Smith et al. 1 ) Palliative treatment: emerging role of new substances (HDAC-inhibitors, mtor-inhibitors and brentuximab vedotin) 1. Smith et al. Biol Blood Marrow Transplant. 2008 Aug;14(8):904-12.

Thank you for your attention

AHSCT in first line therapy HD0801 trial: AHSCT in IIB-IV patients PET positive after 2 x ABVD 6 x ABVD +/-RT vs. AHSCT possible role of AHSCT in first line in the future?