Developments in
supportive care of the
haematology patient
Nick Duncan
Haematology pharmacist
QE Hospital, Birmingham
Outline of session
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Stem cell stimulation
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Anti-infectives
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Plerixafor
Pegfilgrastim
Maribavir
Symptom control
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Aprepitant
Palifermin
New agents for GVHD
Stem cell stimulation
Current Mobilization Strategies for
Autologous Haematopoietic Stem Cell
Transplantation
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Growth factor alone - Filgrastim, Lenograstim
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Growth factor + Chemotherapy
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No agreed front-line choice – current failure rate
15-20%
Consequences of Sub-optimal
Mobilisation
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Failure to mobilise a sufficient number of
CD34+ cells may result in:
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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:
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Delayed, partial, or failed stem cell engraftment
Potential for increased risk of opportunistic infections
and/or bleeding
Limitations of Salvage Mobilisation
Strategies
Strategy
Complications
Repeat Mobilization
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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
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Associated with added toxicity or lack of
efficacy
Addition of
Chemotherapy
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Toxicity, neutropenic fever, admission costs
Traditional Bone
Marrow Harvest
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Slower engraftment
Increased cost, risk (due to anesthesia) and
pain for patient
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Plerixafor
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Recently approved by EMEA
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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
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A CXCR4 receptor antagonist
Mechanism of Action of Plerixafor
stem cell
CXCR4 SDF-1a
bone marrow
SDF-1a and CXCR4 play key
regulatory roles in stem cell
trafficking to, and retention by
the bone marrow.
Plerixafor blocks the CXCR4SDF-1a interaction, releasing
stem cells from the bone
marrow into the circulating
blood
Lapidot T and Petit I. Exp Hematol. 2002;30:973
Kaplan-Meier estimate of proportion of
patients reaching ≥ 5 × 106 CD34+ cells/kg
NHL Patients (%) achieving ≥ 5 million
CD34+ cells/kg by apheresis day
HR = 3.64, 95%CI (2.39, 5.45), P < 0.0001
65.6%
70
57.7%
60
50
40
Plerixafor + G-CSF
49.1%
27.9%
30
21.6%
20
14.2%
10
24.2%
Placebo + G-CSF
4.2%
0
1
2
3
4
Apheresis Day
DiPersio JF et al JCO 2009; Epub ahead of print
Myeloma patients (%) achieving ≥ 6 x
106 CD34+ Cells/kg by apheresis day
Kaplan-Meier Estimate of Proportion of
Patients Reaching ≥ 6 x 106 CD34+ cells/kg
HR = 2.54, P < .0001
100
86.8
90
Plerixafor + G-CSF
77.9
80
70
86.8
54.2
56.0
60
49.0
50
Placebo + G-CSF
35.3
40
17.3
30
20
10
0
1
2
3
4
Apheresis Day
DiPersio JF et al Blood 2009; 113: 5720-5726
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
Safety of Plerixafor – myeloma study
DiPersio JF et al Blood 2009; 113: 5720-5726
Plerixafor – practical issues
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Which patients to target?
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Needs to be given 6-11 hours pre-apheresis
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Admission required?
Recommended to be given at a dose of
0.24mg/kg/day for 2-4 days
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Costs £4,900 + VAT for a 24mg vial
Pegfilgrastim
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Currently licensed for FNE prophylaxis post
conventional chemotherapy. Interest in using
it for:
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PBSC mobilisation
Post SCT
Pegfilgrastim for stem cell
mobilisation
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Has been used alone (usually 12mg) or postchemo (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
Pegfilgrastim post SCT
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Number of small studies in autologous SCT
comparing pegfilgrastim (6mg on d+1 or d+5) with
conventional G-CSF.
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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
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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
Anti-infectives
CMV infection
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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
Maribavir (1)
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Maribavir is an oral agent with anti-CMV
activity
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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
Maribavir (2)
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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
Maribavir (3)
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Large phase III trial (681 patients) not yet published
but results released earlier this year
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Maribavir prophylaxis (100mg bd) failed to meet 1ry
and 2ry endpoints vs. placebo:
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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…….
Symptom control
Aprepitant
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An oral neurokinin-1 antagonist
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Licensed for prevention of N+V associated with
moderately and highly emetogenic chemo (+5HT3
antagonist and corticosteroid)
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Increasingly used in oncology
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High-dose chemotherapy is highly emetogenic so
should we be using aprepitant in haematology?
What do the guidelines say?
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ESMO guidelines 2008
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Highly emetogenic chemo
 5-HT3 antagonist + steroid + aprepitant to prevent acute
N+V.
 Steroid + aprepitant to prevent delayed N+V
NCCN guidelines 2008
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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.
What do the guidelines say?
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ASCO guidelines 2006
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As per ESMO for highly emetogenic chemo
Consider aprepitant with high-dose chemo
although lack of evidence in this group
Any data in haematology
patients?
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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
Any data in haematology
patients?
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Aprepitant (3/7) + ondansetron in 5 patients
receiving Bu/Cy. No vomiting and 2 patients
had 1 episode of nausea.
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Mittaine et al. EBMT 2007, Abstract 1026
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.
Current issues with aprepitant
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Lack of data in BMT population but may be worth
considering
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How to deal with multiple-day chemotherapy
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Little use of cisplatin in haematology
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Can it replace dexamethasone?
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Cost issues……
Cost issues
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Cost/day (£)
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Cost (£)
Comparative costs of antiemetics
(BNF 2008)
Data misleading due to NHS contract prices for
5-HT3 antagonists – large differential between
aprepitant and other agents
Mucositis as a complication of
SCT
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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)
Benefits of palifermin
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Pivotal trial – Spielberger R et al.
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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
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Langer et al. BMT 2008; 42: 275-9
Can palifermin influence GVHD
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Prevention of GI injury important in minimising
aGVHD
Animal models demonstrated benefits of palifermin
in incidence and severity of GVHD
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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)
Is there a role for palifermin?
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Trial data is reasonably strong but………..
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The drug is very expensive - >£700/dose
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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
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Conclusion - may have a role with TBI-based schedules but too
expensive for routine use
Management of GVHD
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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…….
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ATG, alemtuzumab, daclizumab,etanercept,
infliximab, pentostatin, MMF, budesonide, ECP,
thalidomide, imatinib, rituximab
Recent trials in GVHDbudesonide
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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 mildmoderate 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
Recent trials in GVHD imatinib
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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.
Recent trials in GVHD – antiTNF agents (1)
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Infliximab drug of choice at QEH for steroidrefractory gut aGVHD – Italian study showed
59% RR in 32 patients (mainly gut +/liverGVHD) – Patriarca F et al. Haematologica 2004; 89:
1352
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Potential issues:
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72% developed infection and 2 responding
patients died of fungal infection
10mg/kg/week for 4 weeks - £13,500 for 70kg
patient
Recent trials in GVHD – antiTNF agents (2)
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Etanercept has also shown promise against GVHD.
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Busca A et al. Am J Haematol 2007; 82: 45-52
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21 patients with steroid-refractory GVHD
52% RR (64% in gut GVHD)
High-rate of CMV reactivation and bacterial and fungal
infection
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Also been used 1st line (+ steroids) - 69% CR rate vs
33% with steroid alone – Levine J et al. Blood 2008; 111: 2470-2475
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25mg SC bw for 4/52, then weekly for 4/52
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cost = £1200.
Conclusions
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A number of interesting and novel recent
developments in supportive care
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Concerns:
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Affordability
Quality of the trial data especially in setting of
GVHD