Developments in supportive care of the

haematology patient

Nick Duncan

Haematology pharmacist

QE Hospital, Birmingham

Outline of session

Stem cell stimulation Plerixafor Pegfilgrastim

Anti-infectives Maribavir

Symptom control Aprepitant Palifermin New agents for GVHD

Stem cell stimulation

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%

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

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

Plerixafor

Recently approved by EMEARecently 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

SDF-1CXCR4

stem cell

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

27.9%

49.1%

57.7%

65.6%

4.2%

14.2%

21.6%24.2%

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10

20

30

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Apheresis Day

HR = 3.64, 95%CI (2.39, 5.45), P < 0.0001

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NHL Patients (%) achieving ≥ 5 million CD34+ cells/kg by apheresis day

DiPersio JF et al JCO 2009; Epub ahead of print

Myeloma patients (%) achieving ≥ 6 x 106 CD34+ Cells/kg by apheresis day

54.2

77.986.8 86.8

17.3

35.3

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Apheresis Day

HR = 2.54, P < .0001

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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 printDiPersio 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

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

Pegfilgrastim

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

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

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

Anti-infectives

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

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

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

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…….

Symptom control

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?

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.

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

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

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.

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……

Cost issues

Comparative costs of antiemetics (BNF 2008)

02468

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(£)

Cost/day (£)

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

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)

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

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)

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

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

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

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.

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

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.

Conclusions

A number of interesting and novel recent developments in supportive care

Concerns: Affordability Quality of the trial data especially in setting of

GVHD