Plerixafor, solution for injection, 20 mg in 1 mL, 1.2 mL, Mozobil® - November 2011
Page last updated: 02 March 2012
Public Summary Document
Product: Plerixafor, solution for injection, 20
mg in 1 mL, 1.2 mL, Mozobil®
Sponsor: Genzyme Australasia Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
To request a S100 (Highly Specialised Drugs Program) Authority
Required listing for use of plerixafor in mobilisation of
haematopoietic stem cells to the peripheral blood for collection
and subsequent autologous stem cell transplantation (ASCT) in
patients with lymphoma and multiple myeloma who have failed
previous stem cell collection attempts.
Highly Specialised Drugs are medicines for the treatment of chronic
conditions, which, because of their clinical use or other special
features, are restricted to supply to public and private hospitals
having access to appropriate specialist facilities.
2. Background
This was the second consideration for this indication by the
PBAC.
At the November 2010 meeting, the PBAC rejected a submission
seeking a Section 100 (Highly Specialised Drugs Program) listing
for use of plerixafor, in combination with granulocyte-colony
stimulating factor (G-CSF), in mobilisation of haematopoietic stem
cells to the peripheral blood for collection and subsequent
autologous transplantation in patients with non-Hodgkin lymphoma
(NHL), Hodgkin lymphoma (HL) and multiple myeloma (MM) who meet
certain criteria.
For further details see the November 2010 Public Summary
Document.
3. Registration Status
Plerixafor was registered by the TGA on 31 May 2010 for use in
combination with G-CSF to mobilise haematopoietic stem cells (HSCs)
to the peripheral blood for collection and subsequent autologous
transplantation in patients with lymphoma and multiple
myeloma.
4. Listing Requested and PBAC’s View
Section 100 listing – Highly Specialised Drug
program
Public and Private Hospital Authority
Required
1. Patients with lymphoma who require ASCT and have failed previous
stem cell collection attempts.
2. Patients with multiple myeloma who require ASCT and have failed
previous stem cell collection attempts.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
High dose chemotherapy with autologous stem cell transplantation is
a highly effective treatment for patients with haematological
malignancies who are fit enough to undergo this form of therapy.
Before transplantation can take place, patients must undergo stem
cell mobilisation to increase the number of peripheral blood stem
cells available for collection and subsequent autologous
transplantation. Currently, most patients are mobilised with
granulocyte-colony stimulating factor (G-CSF) alone, or G-CSF with
chemotherapy.
The submission proposed that the place in therapy of plerixafor is
as second line therapy in combination with granulocyte-colony
stimulating factor (G-CSF) in mobilisation of haematopoietic stem
cells to the peripheral blood for collection and subsequent
autologous stem cell transplantation (ASCT) for lymphoma and
multiple myeloma patients who have failed previous attempts at stem
cell collection because they were unable to collect the minimum
CD34+ cell yield for transplant (2x106
CD34+ cells/kg) or were unable to proceed to apheresis
because of low peripheral blood CD34+ cell counts.
6. Comparator
The submission nominated G-CSF in combination with chemotherapy
(ifosfamide + carboplatin + etoposide for lymphoma; and
cyclophosphamide for multiple myeloma) as the comparator in
treating patients with lymphoma and multiple myeloma who have
failed previous stem cell collection attempts. This was as
previously agreed by the PBAC.
7. Clinical Trials
The basis of the re-submission was two arms of a retrospective
study using plerixafor plus G-CSF and chemotherapy plus G-CSF
(Pusic, 2008); five observational studies of patients receiving
plerixafor plus G-CSF (Calandra, 2008; Fowler, 2009; Micallef,
2009; Tricot, 2010; Duarte, 2011); one arm of a non-randomised
study of patients receiving chemotherapy plus G-CSF (Majado, 2003);
one observational study of patients receiving chemotherapy plus
G-CSF (McKibbin, 2007); and one arm of a retrospective study using
chemotherapy plus G-CSF (Goterris, 2005) in patients who have
failed previous stem cell collections.
For PBAC’s view, see Recommendation and
Reasons.
The following trials had been published at the time of
submission:
| Trial ID / First author | Protocol title / Publication title | Publication citation | ||
|---|---|---|---|---|
| Retrospective study (includes chemotherapy plus G-CSF and plerixafor plus G-CSF) | ||||
| Pusic I et al | Impact of Mobilisation and Remobilisation Strategies on Achieving Sufficient Stem Cell Yields for Autologous Transplantation. | Biology of Blood and Marrow Transplantation 2008; 14:1045-1056. | ||
| Plerixafor plus G-CSF | ||||
| Calandra G et al | AMD3100 plus G-CSF can successfully mobilise CD34+ cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilisation with chemotherapy and/or cytokine treatment: Compassionate use data. | Bone Marrow Transplantation 2008; 41:331-338. | ||
| Fowler CJ et al | Rescue from failed growth factor and/or chemotherapy HSC mobilisation with G-CSF and plerixafor (AMD3100): An institutional experience. | Bone Marrow Transplantation 2009; 43:909-917 | ||
| Micallef I et al | Successful stem cell remobilization using plerixafor (Mozobil) with non-Hodgkin Lymphoma: Results from the plerixafor NHL Phase 3 study rescue protocol. | Biology of Blood and Marrow Transplantation 2009; 15: 1578-86. | ||
| Tricot G et al | Safety and efficacy assessment of plerixafor in patients with multiple myeloma proven or predicted to be poor mobilisers, including assessment of tumor cell mobilisation. | Bone Marrow Transplantation 2010; 45:63-68. | ||
| Duarte RF et al | Plerixafor plus granulocyte CSF can mobilize hematopoietic stem cells from multiple myeloma and lymphoma patients failing previous mobilization attempts: EU compassionate use data. | Bone Marrow Transplantation 2011; 46(1): 52-8. | ||
| Chemotherapy plus G-CSF | ||||
| Majado MJ et al | Second mobilization of peripheral blood progenitor cells in patients with poor first mobilization. | Transplantation Proceedings 2003; 35(5): 2027-8 | ||
| McKibbin T et al | Paclitaxel and filgrastim for hematopoietic progenitor cell mobilization in patients with hematologic malignancies after failure of a prior mobilization regimen. | Leukemia and Lymphoma 2007; 48(12): 2360-6. | ||
| Goterris R et al | Impact of different strategies of second-line stem cell harvest on the outcome of autologous transplantation in poor peripheral blood stem cell mobilizers. | Bone Marrow Transplantation 2005; 36(10): 847-53. | ||
Abbreviations: G-CSF, granulocyte-colony stimulating factor;
HL, Hodgkin lymphoma; MM, multiple myeloma; NHL, non-Hodgkin
lymphoma; PB, peripheral blood; US, United States
8. Results of Trials
The table below summarises the number of patients who achieved the
minimum number of CD34+ cells required for transplantation during
re-mobilisation. Transplantation using pooled cells from other
collections was allowed in most studies. The numbers of patients
achieving minimum target cell collections with
pooling were extracted from the relevant publications
during the evaluation. The proportions of patients achieving the
minimum target with pooling are higher compared to
the proportion of patients achieving the minimum target without
pooling.
Patients achieving ≥ 2 x 106 CD34+
cells/kg
| Lymphoma | MM | Total population (no pooling) | Total population (with pooling) | ||
|---|---|---|---|---|---|
| NHL | HL | ||||
| Plerixafor plus G-CSF, n/N (%) | |||||
| Calandra (2008) | 38/63 (60) | 13/17 (77) | 25/35 (71) | 76/115 (66) | NR |
| Fowler (2009) | 10/10 (100) | 1/2 (50) | 6/6 (100) | 18/20 (90) | 18/20 (90) |
| Micallef (2009) | 37/62 (60) | NA | NA | 37/62 (60) | NR |
| Pusic (2008) | NR | NR | NR | 13/18 (72) | 15/18 (83) |
| Tricot (2010) | NA | NA | 15/20 ( 75 ) | 15/20 (75) | NR |
| Duarte (2011) | 15/24 (63) | 27/32 (84) | 42/56 (75) | NR | |
| Combined mean | 114/178 (64) | 73/93 (78) | 201/291(69) | 33/38 (87) | |
| Chemotherapy plus G-CSF, n/N (%) | |||||
| Majado (2003) | NR | NR | NR | 4/8 (50) | 4/8 (50) |
| McKibben (2007) | 4/17 (24) | NA | 2/7 (29) | 7/26 (27) | 17/26 (65) |
| Goterris (2005) | NR | NR | NR | 21/41 (51) | 31/41 (76) |
| Pusic (2008) | NR | NR | NR | 9/34 (26) | 18/34 (53) |
| Combined mean | 4/17 (24) | 2/7 (29) | 41/109 (38) | 70/109 (64) | |
Abbreviations: HL, Hodgkin lymphoma; MM, multiple myeloma; NA,
not applicable; NHL, non-Hodgkin lymphoma; NR, not
reported
The PBAC considered that results obtained by application of the
minimum threshold to the pooled cell numbers is more applicable to
Australian clinical practice, as pooling of cells is standard
practice in Australia. The percentage of patients achieving greater
than or equal to 2 × 106 CD34+ cells/kg from Pusic
(2008) yields a total population (with pooling) of 83% (Plerixafor
+ G-SCF) versus 53% (Chemo+G-SCF). However, the results using the
combined mean of Pusic (2008) and the five observational studies
are 87% versus 64% respectively, which may be a more appropriate
basis for comparison.
Lymphoma
The proportion of patients with lymphoma receiving plerixafor and
achieving greater than or equal to 2 × 106 CD34+
cells/kg ranged from 60% to 92%.
Two studies provided data for NHL and HL separately (Calandra,
2008; Fowler, 2009). There were no consistent trends for
differences in response for the two diseases, although numbers in
the HL cohorts were small.
For chemo-mobilisation, 4 out of 17 (24%) of NHL patients from
McKibben (2007) successfully achieved greater than or equal to 2
× 106 CD34+ cells/kg during the second collection.
However, if the
combined
collection was considered, the
proportion of NHL patients who successfully collect greater than or
equal to 2 × 106 CD34+ cells/kg increases to 65%
(11/17).
Multiple myeloma
The proportion of patients receiving plerixafor plus G-CSF
collecting greater than or equal to 2 × 106 CD34+
cells/kg ranged from 71% to 100%.
For chemo-mobilisation, 2 of 7 (29%) MM patients achieved greater
than or equal to 2 × 106 CD34+ cells/kg during the
second collection attempt (derived from McKibben, 2007). If the
combined collection is considered, the proportion of patients who
successfully collect greater than or equal to 2 ×
106 CD34+ cells/kg is substantially higher, i.e. 57%
(4/7) patients.
Total population (no pooling)
The proportion of patients achieving greater than or equal to 2
× 106 CD34+ cells/kg in the total population (no
pooling) of patients receiving plerixafor for the second
mobilisation ranged from 60% to 90%. This population included
patients with other diagnoses e.g. leukaemia.
For chemo-mobilisation, the proportion of patients achieving the
minimum collection for the total population ranged from 26% to 51%.
The re-submission attributed the range of results to the
heterogeneity of the populations. However, the substantial
variation in the results for the total population undergoing
chemo-mobilisation highlights the uncertainty surrounding the
estimate, particularly given that the re-submission used the
results from the lower end of the reported range to inform the
economic evaluation.
Total population (with pooling previous mobilisation
attempts)
The proportion of patients treated with plerixafor achieving
greater than or equal to 2 × 106 CD34+ cells/kg
ranged from 83% to 90%
with pooling
of cells; compared to
60% to 90% for second mobilisation attempt only.
For chemo-mobilisation, the data on the proportions of patients
successfully mobilising the minimum collection
with pooling
are more consistent with the reporting for Majado (2003) and
McKibben (2007). Of the failed mobilisers undergoing
chemo-mobilisation, 50% to 76% of patients achieved the minimum
number of cells with pooling of cells from previous collections.
This was substantially higher than the proportions of patients who
collect the minimum target cells during the second mobilisation
attempt only (26% to 51%).
Transplantation using pooled cells from other collections was
allowed in most studies, thus the proportion of patients proceeding
to transplantation was often higher than the proportion of patients
achieving the target cell yield after re-mobilisation. The table
below summarises the data on the proportion of patients proceeding
to transplantation.
Patients proceeding to transplantation
| Lymphoma n/N (%) | MM n/N (%) | Total population n/N (%) | ||
|---|---|---|---|---|
| NHL | HL | |||
| Plerixafor plus G-CSF | ||||
| Calandra (2008) | 45/63 (71) | 15/17 (88) | 27/35 (77 ) | 87/115 (76) |
| Fowler (2009) | 9/10 (90) | 1/2 (50) | 5/6 (83) | 17/20 (85) |
| Micallef (2009) | 52/62 (84) | NA | NA | 52/62 (84) |
| Pusic (2008) | NR | NR | NR | 15/18 (83) |
| Tricot (2010) | NA | NA | 17/20 (85) | 17/20 (85) |
| Duarte (2011) c | NA | NA | NA | |
| Chemotherapy plus G-CSF | ||||
| Majado (2003) | NR | NR | NR | NR |
| McKibben (2007) | NR | NA | NR | 16/26 (62) |
| Goterris (2005) | NR | NR | NR | 23/41 (56) |
| Pusic (2008) | NR | NR | NR | 18/34 (53) |
Abbreviations: HL, Hodgkin lymphoma; MM, multiple myeloma; NA,
not applicable; NHL, non-Hodgkin lymphoma; NR, not
reported
For the total population, 76% to 85% of patients receiving
plerixafor proceeded to transplantation. The re-submission claimed
that 53% to 62% of patients undergoing chemo-mobilisation proceeded
to transplantation.
Overall, plerixafor appears to increase the number of patients
proceeding to transplantation compared to chemo-mobilisation; but
the magnitude of the benefit is unclear as estimates are from small
non–randomised and uncontrolled studies.
The median days of apheresis for most observational cohorts
receiving plerixafor ranged from 2 to 3 days, with the exception of
7 days in Tricot (2010). For the comparator of chemo-mobilisation,
the median number of days of apheresis ranged from 2 to 3
days.
Pusic (2008) was the only study which facilitated a point of
comparison of the number of days of apheresis with the two
mobilisation strategies. The median number of apheresis days was
longer for plerixafor-treated patients (2.5 days) versus patients
undergoing chemo-mobilisation (2 days) in Pusic (2008).
The re-submission presented new toxicity data from Duarte (2011) on
plerixafor; and for chemo-mobilisation from McKibben (2007) and
Goterris (2005). The most common adverse events reported for
plerixafor in the trials and studies include gastrointestinal
disorders (diarrhoea, nausea), injection site reactions (erythema,
pruritis) and dizziness. The additional safety data from Duarte
(2011) are consistent with this pattern of adverse events.
For chemo-mobilisation, there were reports of febrile neutropenia
leading to hospitalisation, anaemia (some requiring transfusion),
and thrombocytopenia in McKibben (2007). One patient developed
sepsis resulting in death. However, the dose of paclitaxel used was
higher than the maximum dose recommended in the PI. The adverse
events reported by Goterris (2005) were likely to be related to the
high dose chemotherapy (HDT) supported by ASCT, and were not
directly comparable to adverse events related to
chemo-mobilisation.
9. Clinical Claim
The re-submission claimed that plerixafor, administered in
conjunction with G-CSF, can be an effective means to salvage
patients who have previously failed standard [peripheral blood stem
cell] mobilisation attempts. The re-submission also claimed that
plerixafor is generally safe and well-tolerated.
The PBAC considered that there was a lack of comparator data
available to quantify the extent of the benefit of plerixafor over
chemo-mobilisation. The PBAC noted that the results for
chemo-mobilisation may not be representative of current clinical
practice and may underestimate the efficacy of
chemo-mobilisation.
In regard to safety, the PBAC considered the claim was reasonable
if plerixafor plus G-CSF was used instead of chemo-mobilisation.
However, it was difficult to quantify the rate of febrile
neutropenia and transfusion-related interventions from
chemo-mobilisation based on the supporting data provided. No
long-term safety data was presented.
10. Economic Analysis
An updated modelled economic evaluation was presented.
For PBAC’s view, see Recommendation and
Reasons.
The structure of the model was the same as for failed mobilisers in
the November 2010 submission, which was a decision analysis applied
separately for the lymphoma and MM population. The re-submission
presented an incremental cost per successful mobilisation (Step 1
of the stepped economic evaluation). The base-case presented was a
cost-utility analysis (Step 3 of the stepped economic
evaluation).
The results for Step 1 of the economic evaluation produced an
incremental cost per additional patient achieving successful
mobilisation between $15,000 and $45,000 in lymphoma patients and
less than $15,000 in MM patients.
The incremental cost per additional successful mobilisation is
lower for MM patients, because of the additional costs associated
with the comparator for treating the adverse event of febrile
neutropenia with cyclophosphamide (not included in lymphoma) and
the greater incremental benefit, compared with lymphoma. No
cost-offsets are claimed for ICE salvage chemotherapy and
subsequent risk of febrile neutropenia for lymphoma patients.
Sensitivity analyses of Step 1 for lymphoma and MM patients were
conducted during the evaluation with alternative estimates.
The results of the sensitivity analyses indicated that the
incremental cost per additional successful mobilisation for the
lymphoma population was sensitive to the proportion of patients
that successfully mobilise (particularly for chemo-mobilisation),
the number of days of apheresis, the number of vials of plerixafor
per day, and the claimed cost offset from the differing number of
days of G-CSF pre-apheresis between arms.
The results of the sensitivity analyses indicated that the
incremental cost per additional successful mobilisation for the MM
population was sensitive to the proportion of patients that
successfully mobilise, the risk of neutropenia and associated
costs, the number of days of apheresis and the number of vials of
plerixafor per day.
The results for Step 3 of the economic evaluation produced an
incremental cost per quality-adjusted life year (QALY) gained
between $15,000 and $45,000 for lymphoma patients and between
$45,000 and $75,000 for MM patients.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost to the PBS was estimated by the submission
to be less than $10 million per year in Year 5. The estimate was
considered uncertain.
For PBAC’s view, see Recommendation and Reasons.
12. Recommendation and Reasons
The PBAC noted that the intent of requested restriction is to
include patients who have failed previous attempts at peripheral
blood stem cell collection as well as those who are currently
failing, i.e. “immediate rescue”, which was
acknowledged by the sponsor in its Pre-PBAC Response. Therefore,
the restriction would be required to accommodate the different
populations.
As previously agreed, the PBAC accepted the comparators for this
submission, G-CSF in combination with chemotherapy (ifosfamide +
carboplatin + etoposide for lymphoma and cyclophosphamide for
multiple myeloma) in patients who have failed previous stem cell
collection attempts.
The PBAC considered that the clinical management algorithm
presented in the submission did not adequately represent current
clinical practice in Australia. The PBAC expected that it would be
more similar to the clinical algorithm presented by Herbert at al
(2011). In this algorithm, plerixafor is used pre-emptively for
predicted poor mobilisers, as well as immediate salvage where the
yield of CD34+ cells for patients undergoing apheresis is
considered to be suboptimal. The PBAC noted that minimal data are
presented in the submission for the “immediate rescue”
population.
New data for plerixafor plus G-CSF presented in this re -
submission are from Duarte (2011), as identified during the
evaluation and presented in the November 2010 Commentary, and
additional data from Tricot (2010) due to the extension of the
definition of a “failure” in the re-submission. Three
additional studies of patients receiving chemotherapy plus G-CSF
(comparator) are also presented in the re-submission (Majado, 2003;
McKibben, 2007; Goterris, 2005). The PBAC noted that the evidence
presented in the re-submission to support the requested listings is
derived from non-randomised studies (often data from one arm of the
study) and observational cohorts and that these studies may be
subject to bias (e.g. selection bias) and confounding.
The PBAC considered that results obtained by application of the
minimum threshold to the pooled cell numbers is more applicable to
Australian clinical practice, as pooling of cells is standard
practice in Australia. The PBAC noted that the percentage of
patients achieving greater than or equal to 2x106 CD34+
cells/kg from Pusic (2008) yields a total population (with pooling)
of 83% (Plerixafor + G-SCF) versus 53% (Chemo+G-SCF). However, the
results using the combined mean of Pusic (2008) and the five
observational studies are 87% versus 64% respectively, which may be
a more appropriate basis for comparison.
The PBAC noted the economic model in the resubmission is based on
mobilisation success rates (ie proportion of patients achieving
greater than or equal to 2 x 106 CD34+ cells/kg). The
PBAC considered that patients proceeding to transplant was the more
relevant outcome, noting that the incremental benefit of plerixafor
using mobilisation success data (40% lymphoma; 49% MM) is higher
than if the proportion of the total population proceeding to
transplant is used (14-32%).
The PBAC noted the main economic uncertainties. It further
considered that the greatest uncertainties remain around the
assumed survival benefits accruing from additional lymphoma and
myeloma patients proceeding to autologous transplantation. The PBAC
noted that the transplant benefit data for lymphoma are out of date
as they pre-date use of rituximab, inclusion of which is considered
standard care for patients with B-cell lymphoma, particularly
diffuse large B-cell lymphoma. The PBAC also noted that the
modelled greatest gains in life years for lymphoma patients treated
with plerixafor compared to chemo-mobilisation is during the
relapse health state (incremental life years gained 0.849) rather
than the remission health state (incremental life-years gained
0.649), which is implausible. Taken together with the other key
issues highlighted in the ESC advice, these matters meant that
steps 2 and 3 of the economic evaluation are very uncertain.
The PBAC considered that the incremental cost per quality-adjusted
life year (QALY) gained between $15,000 and $45,000 for lymphoma
patients and between $45,000 and $75,000 for MM patients are highly
uncertain due to the considerable uncertainty associated with the
economic model. Unlike Step 1, where incremental costs are lower
per additional successful mobilisation in myeloma patients, the
incremental cost per QALY gained is lower in lymphoma patients than
myeloma patients. This is predominately due to the larger apparent
QALY gains during the remission and relapse health states, which
are largely driven by the modelled greater gain in life years for
lymphoma patients (based on NHL data) compared to MM
patients.
The PBAC considered that there is major uncertainty arising from
the low quality of clinical data about the incremental numbers of
patients proceeding to transplant and from the attempt to translate
these increments into life years gained (LYG). The latter requires
many highly uncertain assumptions and the PBAC considered that
collectively these render the model inappropriate. As stated in the
November 2010 PBAC Minutes, a simple and conservative comparison of
costs of mobilisation on a per patient basis should also be
provided, rather than a claim of highly uncertain transplant
benefits.
The PBAC therefore rejected the submission on the basis of a high
and uncertain cost-effectiveness ratio.
The PBAC also acknowledged and noted the consumer comments on this
item.
Recommendation:
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Genzyme is disappointed by the decision but is committed to
continuing to work with the PBAC to ensure that Mozobil is made
available on the PBS for eligible patients with lymphoma and
multiple myeloma.
