Developments in supportive care of the haematology patient

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Developments in supportive care of the
haematology patient

• Nick Duncan
• Haematology pharmacist
• QE Hospital, Birmingham

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Outline of session

• Stem cell stimulation
• Plerixafor
• Pegfilgrastim
• Anti-infectives
• Maribavir
• Symptom control
• Aprepitant
• Palifermin
• New agents for GVHD

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Stem cell stimulation
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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

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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

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Limitations of Salvage Mobilisation Strategies
Strategy Complications
Repeat Mobilization High product volume when combined with previous collection Higher cost morbidity Associated with high failure rate
Alternative Cytokines Higher dose of G-CSF Combine G-CSF with GM-CSF Associated with added toxicity or lack of efficacy
Addition of Chemotherapy Toxicity, neutropenic fever, admission costs
Traditional Bone Marrow Harvest Slower engraftment Increased cost, risk (due to anesthesia) and pain for patient
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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

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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. 200230973
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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
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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
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Transplant Outcomes Number of Days to Neutrophil
Platelet Engraftment
PLERIXAFOR PLACEBO

Median time to neutrophil engraftment (days) NHL 10 Myeloma 11 NHL 10 Myeloma 11
Median time to platelet engraftment (days) NHL 20 Myeloma 18 NHL 20 Myeloma 18
DiPersio JF et al JCO 2009 Epub ahead of
print DiPersio JF et al Blood 2009 113 5720-5726
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Safety of Plerixafor myeloma study
DiPersio JF et al Blood 2009 113 5720-5726
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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

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Pegfilgrastim

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

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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

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Pegfilgrastim post SCT

• Number of small studies in autologous SCT
  comparing pegfilgrastim (6mg on d1 or d5) 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

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Anti-infectives
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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

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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

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Maribavir (2)

• Winston et al. Blood 2008 1115403
• 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 NV, taste disturbances

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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.

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Symptom control
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Aprepitant

• An oral neurokinin-1 antagonist
• Licensed for prevention of NV 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?

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What do the guidelines say?

• ESMO guidelines 2008
• Highly emetogenic chemo
• 5-HT3 antagonist steroid aprepitant to
  prevent acute NV.
• Steroid aprepitant to prevent delayed NV
• 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.

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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

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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 d4
• Complete or major response rate 14/15 vs 7/15
  (p0.014)
• No emesis seen in 10/15 vs. 5/15 (p ns)
• No difference wrt cyclophosphamide kinetics or
  toxicity

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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.

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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

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Cost issues

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

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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)

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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
  (plt0.001)
• Duration of mucositis (grade 3/4) 3 vs 9 days
  (plt0.001)
• Significant reduction in opioid and TPN
  requirements
• Recent allograft study reported similar findings
• Langer et al. BMT 2008 42 275-9

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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)

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Is there a role for palifermin?

• Trial data is reasonably strong but..
• The drug is very expensive - gt700/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

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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

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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

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Recent trials in GVHD - imatinib

• Magro L et al. BMT 2008 42 757-60
• Sclerodermatous cGVHD historically difficult to
  treat incidence of about 11
• Imatinibs 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.

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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

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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.

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Conclusions

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