Keywords
Hematopoietic stem cell transplantation - multiple myeloma - Non-Hodgkin lymphoma
- plerixafor
Introduction
High-dose chemotherapy combined with autologous hematopoietic stem cell transplantation
(auto-HSCT) is the standard of care for patients with relapsed or chemosensitive non-Hodgkin
lymphoma (NHL) and multiple myeloma (MM).[1],[2],[3]
Auto-HSCT improves hematologic recovery in patients by reconstituting hematopoiesis
following high-dose chemotherapy.[3] In patients with relapsed or chemosensitive NHL, high-dose chemotherapy with auto-HSCT
has been shown to increase disease-free survival, whereas in MM, a combination of
high-dose chemotherapy with auto-HSCT improves progression-free survival and overall
survival (OS).[4],[5],[6] In some situations, auto-HSCT is potentially curative.[7]
Employing an effective stem cell mobilization regimen plays a critical role in auto-HSCT.
The minimum number of cells generally acceptable for transplantation is ≥2 × 106 CD34 + cells/kg.[8] Transplanting fewer than this number of cells may result in delayed engraftment
of both platelets and neutrophils.[9] The target number of cells for a single transplant was defined by Weaver et al.
[10] as ≥5 × 106 CD34 + cells/kg, which is important for short-term outcomes, resulting in earlier
and more consistent neutrophil, and especially platelet engraftment compared with
transplants with lower cell doses.[11] In some studies, transplant doses of ≥5 × 106 CD34 + cells/kg have been associated with longer disease-free survival, and OS compared
with lower transplant doses.[12],[13] Obtaining a sufficient quantity of cells for auto-HSCT is difficult in approximately
20%–25% of patients.[14],[15],[16]
Until recently, there were two main approaches to stem cell mobilization that involved
the use of growth factors, such as granulocyte-colony-stimulating factor (G-CSF) alone
(G) or in conjunction with chemotherapy. The administration of chemotherapy before
the use of G-CSF produces a higher yield of stem cells for autologous transplantation,
but this is not effective for all patients. Around 5%–40% of patients fail to mobilize
an adequate number of CD34 + cells with commonly used regimens.[17] These include patients with NHL, elderly patients[18] who are heavily pretreated,[19],[20],[21] and patients with MM who previously received multiple cycles of lenalidomide or
underwent auto-HSCT.[22] Many patients with Hodgkin lymphoma (HL) who have received extensive cytotoxic chemotherapy
previously will turn out to be poor-mobilizers.[23]
Advancements in HL therapy have been documented since the introduction of combination
chemotherapy protocols and changes in irradiation strategies. Despite these advancements,
approximately 10% of HL patients remain refractory to these treatments in whom auto-HSCT
remains one of the most important alternative treatment modalities.[24]
Plerixafor is an additional option for use in auto-HSCT. G-CSF with plerixafor augments
the mobilization of CD34 + cells, particularly in patients who are considered poor
mobilizers.[25],[26],[27]
Plerixafor, a bicyclam derivative, is a small molecule which selectively and reversibly
antagonizes the CXCR4 chemokine receptor and blocks binding to its cognate ligand,
stromal cell-derived factor-1a (SDF-1a). The interruption of the CXCR4/SDF-1a interaction
results in mobilization of CD34 + cells to the peripheral blood, where they can be
collected for auto-HSCT.[28] The stem cells mobilized by the combination of G-CSF plus plerixafor have been shown
to differ from those mobilized by G-CSF alone, with a higher proportion of cells in
the growth phase, higher numbers of B- and T-lymphocytes, natural killer cells, dendritic
cells, and primitive CD34+ cells.[29],[30],[31],[32]
Methodology
This was a retrospective study conducted at HCG Cancer Centre, Bengaluru. The patients'
data were retrieved from the medical records from January 2017 to October 2018.
The following data were extracted: baseline characteristics, diagnosis, CD34+ cell
counts after plerixafor administration, and adverse events (if any). All patients'
data were transcribed onto the case report form maintaining patient anonymity.
The patients included were based on the following inclusion criteria: (1) age 18–78
years; (2) candidates to autologous stem cell transplantation (auto-SCT) for MM, NHL,
or HL; (3) who had failed to collect a minimum of 2 × 106 CD 34+ cells/kg or did not even proceed to apheresis based on a low peripheral blood
CD34+ count with mobilization with G-CSF; (4) adequate organ function to undergo apheresis
and transplantation; and (5) Eastern Cooperative Oncology Group Performance Status
0–2.
Exclusion criteria included: (1) diagnosis of any form of acute or chronic leukemia
(including plasma cell leukemia) or myelodysplastic syndrome; (2) comorbid conditions
which render the patient at high risk from treatment complications; (3) vasculitis
or autoimmune disorders; (4) brain metastases, carcinomatous meningitis, or any other
malignancy unless the patient had been disease-free for at least 5 years after curative
intent therapy; and (5) clinically significant heart disease.
Each patient's mobilization regimen was determined by the bone marrow transplant physician.
Patients received G-CSF as per the standard protocol, typically as a 10 mg/kg daily
s.c. injection each morning for 4 consecutive days. From the evening of the 4th day, patients received a single injection of s.c. plerixafor at the dose of 0.24
mg/kg, administered at least 11 h prior to the following day's apheresis schedule.
On the morning of the 5th day, G-CSF was administered, and apheresis began at approximately
10–12 h after plerixafor and at 1 h after G-CSF administration. The administration
of plerixafor + G-CSF and apheresis was repeated daily until the collection target
was achieved (sufficient cells for auto-SCT [minimum 2 × 106/kg]) or up to a maximum of four doses of plerixafor was given in total or the patient
had failed to mobilize enough peripheral blood stem cells to warrant continuation.
The number of CD34+ cells collected during each apheresis session was recorded. Descriptive
statistics were used to analyze the data.
Results
The study included a total of 32 consecutive patients in whom the mobilization was
performed using G-CSF plus plerixafor following previous mobilization failure with
G-CSF alone. Patients were heavily pretreated and received a median of two lines of
different chemotherapy regimen before mobilization with G-CSF plus plerixafor. The
demographic, clinical characteristics, and mobilization data are summarized in [Table 1].
Table 1
Demographic/clinical characteristics of the study cohort (n=32)
|
n (%)
|
|
MM – Multiple myeloma; HL – Hodgkin lymphoma; NHL – Non- Hodgkin lymphoma
|
|
Number of patients
|
32
|
|
Age (years), median (range)
|
41.4 (21-63)
|
|
Gender
|
|
|
Male
|
20 (45.45)
|
|
Female
|
12 (54.54)
|
|
Primary diagnosis
|
|
|
NHL
|
11
|
|
MM
|
11
|
|
HL
|
10
|
|
Prior lines of chemotherapy, average
|
2
|
Mobilization
In 31 (96.8%) patients, a minimum threshold for peripheral stem cells, defined as
2 × 106 CD34+ stem cells, was collected following G-CSF + plerixafor mobilization
procedure. A median of 1.5 and 2 days was required to mobilize 2 × 106 CD34+ stem
cells in MM and NHL, respectively.
In 8 (72.72%) patients with MM, an optimal threshold for peripheral stem cells, defined
as 6 × 106 CD34 + stem cells, was collected following G–P mobilization procedure,
requiring a median of 2.5 days for mobilization.
In 6 (54.54%) patients with NHL, an optimal threshold for peripheral stem cells, defined
as 5 × 106 CD34 + stem cells, was collected following G–P mobilization procedure,
requiring a median of 2 days for mobilization. [Table 2] depicts the mobilization features of the patients.
Table 2
Mobilization features
|
Mobilization features
|
MM (n=11)
|
NHL (n=11)
|
HL (n=10)
|
|
MM – Multiple myeloma; HL – Hodgkin lymphoma; NHL – Non-Hodgkin lymphoma
|
|
Cumulative CD34+ cells/kg×106 collected
|
10.21
|
7.32
|
6.73
|
|
Median number of patients collecting minimal cell dose (≥2×106 CD34+ cells/kg) (%)
|
11 (100)
|
10 (90.90)
|
10 (100)
|
|
Days to collect minimal cell dose, median
|
1.5
|
2
|
2.4
|
|
Number of patients collecting optimal cell dose (≥5×106 in NHL and≥6×106 in MM CD34+ cells/kg) (%)
|
8 (72.72)
|
6 (54.54)
|
7 (70)
|
|
Days to collect optimal cell dose, median
|
2.5
|
2.8
|
2.8
|
No major adverse events were observed during this study.
Discussion
Our data confirm that plerixafor in combination with G-CSF is an effective alternative
measure for poor mobilizers with G-CSF alone in NHL, HL, and MM patients. Plerixafor
was well tolerated by our patients which is in accordance with other studies reporting
only mild side effects associated with plerixafor.[33]
The mobilization efficacy of plerixafor has been demonstrated in combination with
G-CSF for primary mobilization in adult patients with MM or NHL in two Phase III,
multicenter, randomized, placebo-controlled trials.[34],[35] Fifty-nine percent of adults with NHL were able to achieve the primary endpoint
collection of 5 × 106 CD34 cells/kg, and 87% of them were able to reach the secondary endpoint collection
of 2 × 106 CD34 cells/kg. Target stem cell collection of ≥5 × 106 CD34+ cells/kg was achieved within 4 apheresis days in the plerixafor plus G-CSF
group.[34]
In the MM trial, the primary collection endpoint of 6 × 106 CD34 cells/kg was met by 72% of participants versus 34% in placebo group, and 95%
of them were able to reach the secondary endpoint collection of 2 × 106 CD34 cells/kg. Target stem cell collection of ≥6 × 106 CD34+ cells/kg was achieved within 2 apheresis days in the plerixafor plus G-CSF
group.[35] In both studies, patients tolerated plerixafor, and for patients who underwent auto-HSCT,
their hematopoietic recovery process and engraftment status were unremarkable. In
both studies, auto-HSCT after mobilization with plerixafor and placebo resulted in
successful engraftment of neutrophils and platelets. The durability of grafts was
similar for plerixafor and placebo through 12 months of follow-up. Both regimens were
associated with similar survival rates at 12 months posttransplantation.[34],[35]
Our experiences showed that most patients with HL with poor mobilization following
G-CSF alone showed favorable responses to the addition of plerixafor, which might
have averted costly and time-consuming remobilization attempts and contributed to
the successful mobilization of CD34+ cells.
Several pharmacoeconomic studies have shown that plerixafor, when given to poor mobilizers,
decreased mobilization failure rates at an acceptable increase in costs for patients
with MM and NHL.
Our study is limited by its retrospective nature and relatively small patient population
size. Despite these limitations, our data have shown that plerixafor is an effective
and safe mobilization agent in patients with NHL and MM who have failed mobilization
with G-CSF alone.
Conclusion
Plerixafor is indicated along with Granulocyte-Colony Stimulating Factor (G-CSF) to
mobilize hematopoietic stem cells in patients with NHL or MM, who failed the mobilization
with G-CSF alone. This single-centre retrospective study reiterates that plerixafor
is an effective and safe mobilization agent in patients with NHL, MM, and HL who have
failed mobilization with G-CSF alone.
