Developments in supportive care of the haematology patient

1. Developments in supportive care of the haematology patient Nick Duncan Haematology pharmacist QE Hospital, Birmingham

2. Outline of session • Stem cell stimulation • Plerixafor • Pegfilgrastim • Anti-infectives • Maribavir • Symptom control • Aprepitant • Palifermin • New agents for GVHD

3. Stem cell stimulation

4. Current Mobilization Strategies for Autologous Haematopoietic Stem Cell Transplantation • Growth factor alone - Filgrastim, Lenograstim • Growth factor + Chemotherapy • No agreed front-line choice – current failure rate 15-20%

5. Consequences of Sub-optimal Mobilisation • Failure to mobilise a sufficient number of CD34+ cells may result in: • Increased number of days of apheresis • Need for bone marrow harvest • Ineligibility for transplantation • Additional burden on patients • Use of sub-optimal apheresis product may lead to: • Delayed, partial, or failed stem cell engraftment • Potential for increased risk of opportunistic infections and/or bleeding

6. Limitations of Salvage Mobilisation Strategies

7. Plerixafor • Recently approved by EMEA • In combination with G-CSF to enhance mobilisation of haematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma whose cells mobilise poorly. • Novel mechanism of action • A CXCR4 receptor antagonist

8. stem cell CXCR4 SDF-1a bone marrow Mechanism of Action of Plerixafor SDF-1 and CXCR4 play key regulatory roles in stem cell trafficking to, and retention by the bone marrow. Plerixafor blocks the CXCR4-SDF-1a interaction, releasing stem cells from the bone marrow into the circulating blood Lapidot T and Petit I. Exp Hematol. 2002;30:973

10. NHL Patients (%) achieving ≥ 5 million CD34+ cells/kg by apheresis day Plerixafor + G-CSF Kaplan-Meier estimate of proportion of patients reaching ≥ 5 × 106 CD34+ cells/kg Placebo + G-CSF DiPersio JF et al JCO 2009; Epub ahead of print

11. Myeloma patients (%) achieving ≥ 6 x 106 CD34+ Cells/kg by apheresis day Plerixafor + G-CSF Placebo + G-CSF Kaplan-Meier Estimate of Proportion of Patients Reaching ≥ 6 x 106 CD34+ cells/kg DiPersio JF et al Blood 2009; 113: 5720-5726

12. Transplant Outcomes: Number of Days to Neutrophil & Platelet Engraftment DiPersio JF et al JCO 2009; Epub ahead of print DiPersio JF et al Blood 2009; 113: 5720-5726

13. Safety of Plerixafor – myeloma study DiPersio JF et al Blood 2009; 113: 5720-5726

14. Plerixafor – practical issues • Which patients to target? • Needs to be given 6-11 hours pre-apheresis • Admission required? • Recommended to be given at a dose of 0.24mg/kg/day for 2-4 days • Costs £4,900 + VAT for a 24mg vial

15. Pegfilgrastim • Currently licensed for FNE prophylaxis post conventional chemotherapy. Interest in using it for: • PBSC mobilisation • Post SCT

16. Pegfilgrastim for stem cell mobilisation • Has been used alone (usually 12mg) or post-chemo (usually 6mg) for autologous stem cell mobilisation in myeloma and lymphoma patients • Appears comparable to conventional G-CSF but studies all small • Pegfilgrastim mobilised stem cells may result in faster count recovery – Tricot G et al. Haematologica 2008; 93: 1739-42

17. Pegfilgrastim post SCT • Number of small studies in autologous SCT comparing pegfilgrastim (6mg on d+1 or d+5) with conventional G-CSF. • Equivalence demonstrated wrt count recovery • Some studies demonstrated superiority wrt incidence and duration of FN - (e.g. Martino M et al. Eur J Haematol 2006; 77: 410-5) • One fully published study in allograft recipients – Ocheni S et al. Leuk Lymphoma 2009; 50: 612-8 • Neutrophil recovery slightly faster (15 vs 16 days) with pegfilgrastim vs lenograstim • No difference wrt incidence and duration of FN. • In conclusion, drug cost likely to impact on choice of agent

18. Anti-infectives

19. CMV infection • CMV reactivation a major issue post allogeneic SCT • Pre-emptive ganciclovir mainstay of management but toxicity concerns • Lack of gold-standard prophylaxis – aciclovir, valaciclovir, ganciclovir? • Interest in new agents

20. Maribavir (1) • Maribavir is an oral agent with anti-CMV activity • Inhibits viral DNA assembly and egress of viral particles from infected cells • Favourable toxicity profile – no renal or BM effects • Interest in using for CMV prophylaxis • Promising data published 2008

21. Maribavir (2) • Winston et al. Blood 2008; 111:5403 • 111 allograft recipients randomised to maribavir (200-800mg/day) or placebo • At 100 days incidence of CMV infection was 15-19% vs. 39% • Significant reduction in need for pre-emptive ganciclovir • Toxicity – N+V, taste disturbances

22. Maribavir (3) • Large phase III trial (681 patients) not yet published but results released earlier this year • Maribavir prophylaxis (100mg bd) failed to meet 1ry and 2ry endpoints vs. placebo: • Rate of CMV disease: 4.4% vs. 4.8% • Need for anti-CMV therapies: 38% vs. 40.5% • GVHD incidence and mortality comparable • Not sure what the future holds for this drug…….

23. Symptom control

24. Aprepitant • An oral neurokinin-1 antagonist • Licensed for prevention of N+V associated with moderately and highly emetogenic chemo (+5HT3 antagonist and corticosteroid) • Increasingly used in oncology • High-dose chemotherapy is highly emetogenic so should we be using aprepitant in haematology?

25. What do the guidelines say? • ESMO guidelines 2008 • Highly emetogenic chemo • 5-HT3 antagonist + steroid + aprepitant to prevent acute N+V. • Steroid + aprepitant to prevent delayed N+V • NCCN guidelines 2008 • As per ESMO for highly emetogenic chemo. An option for some patients receiving moderately emetogenic chemo. • TBI - 5-HT3 antagonist + steroid • For multiple-day chemotherapy advises that can give aprepitant 125mg day 1 then 80mg days 2-5.

26. What do the guidelines say? • ASCO guidelines 2006 • As per ESMO for highly emetogenic chemo • Consider aprepitant with high-dose chemo although lack of evidence in this group

27. Any data in haematology patients? • Bubalo JS et al. ASCO 2007, abstract 9112 • 30 patients receiving Cyclo/TBI or Bu/Cy allograft • Randomised to aprepitant or placebo (plus ondansetron +/- dex) • Received aprepitant from d-7 to d+4 • Complete or major response rate: 14/15 vs 7/15 (p=0.014) • No emesis seen in 10/15 vs. 5/15 (p = ns) • No difference wrt cyclophosphamide kinetics or toxicity

28. Any data in haematology patients? • Mittaine et al. EBMT 2007, Abstract 1026 • Aprepitant (3/7) + ondansetron in 5 patients receiving Bu/Cy. No vomiting and 2 patients had 1 episode of nausea. • Domingues et al. EBMT 2008, Abstract 1235 • Domingues et al. EBMT 2009, Abstract 1202 • Aprepitant (days -5, -2, +1) + ondansetron in 8 patients receiving BEAM. Concluded that highly effective.

29. Current issues with aprepitant • Lack of data in BMT population but may be worth considering • How to deal with multiple-day chemotherapy • Little use of cisplatin in haematology • Can it replace dexamethasone? • Cost issues……

30. Cost issues • Data misleading due to NHS contract prices for 5-HT3 antagonists – large differential between aprepitant and other agents

31. Mucositis as a complication of SCT • Incidence of mucositis with SCT conditioning regimens 70-80% • Consequences include pain, infection risk, inadequate nutrition, prolonged hospitalisation • Management mainly supportive • Now have option of palifermin (recombinant human keratinocyte growth factor)

32. Benefits of palifermin • Pivotal trial – Spielberger R et al. NEngl J Med 2004; 351: 2590-8 • 212 autograft patients receiving high dose chemo + TBI randomised to palifermin (60mcg/kg) or placebo • Incidence of mucositis (grade 4) – 20% vs 62% (p<0.001) • Duration of mucositis (grade 3/4) – 3 vs 9 days (p<0.001) • Significant reduction in opioid and TPN requirements • Recent allograft study reported similar findings • Langer et al. BMT 2008; 42: 275-9

33. Can palifermin influence GVHD • Prevention of GI injury important in minimising aGVHD • Animal models demonstrated benefits of palifermin in incidence and severity of GVHD • Blazer B et al. Blood 2006; 108: 3216-22 • Palifermin vs. placebo in 100 allograft recipients • No difference wrt GVHD, relapse or survival • Longer follow up failed to demonstrate any differences between arms (Levine et al. Biol Blood Marrow Transplant 2008; 14: 1017-21)

34. Is there a role for palifermin? • Trial data is reasonably strong but……….. • The drug is very expensive - >£700/dose • Practice at QEH has been to give it to private patients undergoing SCT. • About 25 patients treated to date • Collected data on first 13 patients and demonstrated no clear benefits compared to matched control-group (Khan, Duncan BOPA 2007). Lower-risk population? • Majority of patients developed a rash • Conclusion - may have a role with TBI-based schedules but too expensive for routine use

35. Management of GVHD • GVHD is the most frequent complication after allogeneic SCT. • Steroids the mainstay of treatment but steroid refractory GVHD has a mortality of 70% so need for effective 2nd line/alternative therapies • Lots of treatment options……. • ATG, alemtuzumab, daclizumab,etanercept, infliximab, pentostatin, MMF, budesonide, ECP, thalidomide, imatinib, rituximab

36. Recent trials in GVHD- budesonide • Andree H et al. BMT 2008; 42: 541-6 • 13 patients with cGVHD affecting the gut • Some had received systemic steroid previously • Received budesonide 3mg tds for median 5/12 • 7 patients achieved CR and 1 PR. • Consider as alternative to systemic steroid in mild-moderate cGVHD but caution re recurrence when treatment stopped. • Also shown efficacy in combination with systemic steroids in aGVHD of the gut – Bertz H et al. BMT 1999; 24: 1185-9

37. Recent trials in GVHD - imatinib • Magro L et al. BMT 2008; 42: 757-60 • Sclerodermatous cGVHD historically difficult to treat – incidence of about 11% • Imatinib’s inihibition of PDGF and TGF pathways may be of benefit – inhibits fibroblasts growth and collagen production • 2 patients with refractory sclerodermatous GVHD treated with imatinib 400mg/day • Both had very good response with no tolerability issues • AT QEH, one patient with severe ocular cGVHD received imatinib for relapsed CML. GVHD improved dramatically.

38. Recent trials in GVHD – anti-TNF agents (1) • Infliximab drug of choice at QEH for steroid-refractory gut aGVHD – Italian study showed 59% RR in 32 patients (mainly gut +/- liverGVHD) – Patriarca F et al. Haematologica 2004; 89: 1352 • Potential issues: • 72% developed infection and 2 responding patients died of fungal infection • 10mg/kg/week for 4 weeks - £13,500 for 70kg patient

39. Recent trials in GVHD – anti-TNF agents (2) • Etanercept has also shown promise against GVHD. • Busca A et al. Am J Haematol 2007; 82: 45-52 • 21 patients with steroid-refractory GVHD • 52% RR (64% in gut GVHD) • High-rate of CMV reactivation and bacterial and fungal infection • Also been used 1st line (+ steroids) - 69% CR rate vs 33% with steroid alone – Levine J et al. Blood 2008; 111: 2470-2475 • 25mg SC bw for 4/52, then weekly for 4/52 • cost = £1200.

40. Conclusions • A number of interesting and novel recent developments in supportive care • Concerns: • Affordability • Quality of the trial data especially in setting of GVHD