An updated single center experience with plerixafor and granulocyte colony-stimulating factor for stem cell mobilization in light chain amyloidosis

Abstract

The use of granulocyte-colony stimulating factor (G-CSF) with or without chemotherapy to mobilize hematopoietic progenitor cells (HPCs) can result in significant morbidity in light chain (AL) amyloidosis patients. Plerixafor, a strong inducer and mobilizer of HPCs, can be used as an adjunct to G-CSF to improve mobilization efficiency. We describe the outcomes for combined G-CSF/plerixafor mobilized patients with AL amyloidosis. We reviewed data of 53 consecutive AL amyloidosis patients who underwent combined G-CSF/plerixafor HPC mobilization between May 2011 and October 2017 at our institution. We evaluated patients for HPC collection efficiency, perimobilization toxicity and postautologous hematopoietic cell transplantation (autoHCT) outcomes. Median CD34⁺ cell collection was 12.4 × 10⁶ cells/kg (range 2.5 × 10⁶ to 34.1 × 10⁶ cells/kg) and 45 (85%) patients had collections of ≥5.0 × 10⁶ CD34⁺ cells/kg. There were no mobilization failures or perimobilization mortality. During mobilization, 37 (70%) patients had weight gain (median 1.3 kg, range 0.1–4) but none >10% body weight, 5 (10%) patients had diarrhea, and one patient each had hypotension and cardiac arrhythmia. Among the 31 patients analyzed for CD34 collection efficiency (CE), the median CD34 CE was 47% (range 36–62). At 5 years follow-up 82% and 84% of patients were progression-free and alive, respectively. Our results suggest that G-CSF/plerixafor mobilization is safe, well tolerated, and effective in AL amyloidosis.

1 |. INTRODUCTION

High dose chemotherapy followed by autologous hematopoietic cell transplant (autoHCT) can provide durable responses and improved survival in a subset of patients with immunoglobin light chain (AL) amyloidosis.¹ Obtaining sufficient quantities of CD34⁺ cells is vital for successful engraftment after autoHCT. Hematopoietic progenitor cell (HPC) collection can be performed using chemotherapy and/or cytokines. Chemotherapy-based HPC mobilization can delay count recovery and is associated with increased risks for bleeding, infections, and mortality.² Granulocyte-colony stimulating factor (G-CSF) has been the standard of care for HPC mobilization in patients with AL amyloidosis, but G-CSF can lead to cardiac morbidity in patients with advanced amyloid heart disease.^3–5 In AL amyloidosis, G-CSF-only mobilization has been associated with significant morbidity, and even cases of mortality.⁶ Furthermore, up to 10% of patients with AL amyloidosis can have insufficient CD34⁺ cell collection with G-CSF alone or G-CSF plus chemotherapy-based HPC mobilization.⁴ Historically, the use of an alkylating agent for induction chemotherapy, advanced age, high white cell counts, low serum albumin, type of malignancy, type of cell separator used for apheresis and anemia have been shown to impact HPC yield and CD34 collection efficiency (CE).^7–10

Plerixafor is a strong mobilizer of HPCs from bone marrow to the blood stream. It is a partial antagonist of alpha chemokine receptor CXCR-4, which is responsible for homing of HPCs to bone marrow.^11,12 In a phase II study, plerixafor combined with G-CSF was shown to be efficient for CD34 mobilization and allowed for fewer apheresis sessions in patients with lymphoma and multiple myeloma.¹³ Several other small case series have highlighted the safety and efficacy of plerixafor-based stem cell mobilization in AL amyloid patients.^14,15 Our center adopted a combined G-CSF/plerixafor-based stem cell mobilization in patients with AL amyloidosis with the goal of reducing G-CSF and enhancing CE in AL amyloidosis. Earlier, we published our experience comparing outcomes of patients mobilized with G-CSF/plerixafor versus G-CSF alone in AL amyloidosis.¹⁶ In this retrospective analysis, we provide an update on the safety and efficacy of G-CSF/plerixafor regimen which we have adopted as a standard of care in AL amyloidosis since 2011. Anecdotally, we have observed low CD34+ cells viability due to high granulocyte content of the collected stem cell product, thus we also looked for factors potentially affecting mononuclear cell percentage (MNC%) and the CD34+ CE in addition to the total CD34 cell yield.

2 |. PATIENTS AND METHODS

We conducted this retrospective, IRB-approved study of 53 consecutive AL amyloidosis patients who received a G-CSF/plerixafor-based stem cell mobilization between May 2011 and October 2017 at the Froedtert and Medical College of Wisconsin Cancer Center. We studied baseline characteristics, pretransplant disease factors, and evaluated these patients for perimobilization toxicity, CD34+ yield, CD34+ CE, and post-autoHCT outcomes.

For a successful HPC mobilization, the minimum required collection was ≥2.0 × 10⁶ CD34+ cells/kg and the goal of collection was 5.0 × 10⁶ CD34+ cells/kg, to achieve efficient hematopoietic recovery at the time of transplantation. G-CSF was administered subcutaneously at a daily dose of 10 μg/kg of actual body weight for 3 days, starting on day −3 of mobilization. Plerixafor was administered at 0.24 mg/kg (renal dosing of 0.16 mg/kg) subcutaneously on day 3 of G-CSF (day −1 of mobilization), approximately 12 hours before the initiation of apheresis. Peripheral blood CD34+ cells counts were checked on day 4 of collection with target of ≥8 × 10⁶ CD34+ cells/kg.

Central venous catheters were used for HPC collection. All collections were performed using the mononuclear cell program on the COBE Spectra apheresis system. Citrate (ACD-A) was used as a default anticoagulation. In patients where there was concern for volume overload, heparin plus ACD-A was given to minimize volume given to patients. Four blood volumes were processed for each collection. CD34+ cell numbers in the apheresis products were performed at the Clinical Pathology Laboratory at Froedtert Hospital. The final products were cryopreserved and stored in liquid nitrogen.

The HPC dose targeted/infused was expressed as CD34+ cells/kg of recipient body weight. CD34+ CE was calculated on each of the collections performed as: CD34 CE = CD34+ yield/(precollection peripheral blood CD34+ count × blood volume processed). These data were available after 2014 (N = 31).

Patients were monitored for complications related to HPC mobilization by daily assessments including monitoring of vital signs and physical examination in the outpatient apheresis unit during mobilization. All patients were recommended to take loperamide 1 hour prior to the administration of pleraxifor as prophylaxis for anticipated diarrhea secondary to plerixafor. Calcium and magnesium supplements were also given on an as needed basis, during HPC collection. If patients were experiencing bone pains secondary to G-CSF, loratadine 10 mg once daily as needed was prescribed in addition to acetaminophen for symptom management.

2.1 |. Statistical analysis

Baseline demographic and disease characteristics were summarized using descriptive statistics. Amyloid staging and hematologic response was assigned per consensus guidelines for reporting of studies in AL amyloidosis.¹⁷ Overall and progression-free survival were calculated using Kaplan-Meier estimates from the date of autoHCT to disease progression or death/last follow-up, respectively. Patients were censored at last follow-up. The CD34+ CE and MNC% of the collection were used as a marker of CE and evaluated as continuous variables. Multiple linear regression was used to model total CD34 cell yield and CE outcomes as a function of multiple potential predictors, including age, AL stage, difference between involved and uninvolved free light chain (dFLC), red cell distribution width (RDW) and mean corpuscle volume (MCV). N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and troponin T were log-transformed to model effects of multiplicative changes; the coefficients should be interpreted as the effect of a 2-fold increase in the variable. Residual plots were examined to ensure modeling assumptions were met, but no notable deviations were found. Wilcoxon rank-sum test was used for continuous and ordinal variables. Exact chi-square test was used for categorical variables. A P < .05 was considered significant.

3 |. RESULTS

Baseline characteristics and outcomes are summarized in Table 1. Median age of patients was 61 years (range 39–75). Thirty (57%) patients had cardiac involvement, the median number of organs involved were 2 (range 1–4), and 29 (56%) patients had more than 2 organs involved. Twenty-four (45%), 16 (30%), 5 (10%) and 8 (15%) patients had AL amyloidosis stage 1, 2, 3 and 4, respectively, by the 2012 amyloidosis staging criteria.¹⁸ No patient was on dialysis or had solid organ transplant prior to transplant. Fifty-one (96%) patients received chemotherapy for AL amyloidosis before stem cell mobilization. Forty-six (87%) patients received cyclophosphamide, bortezomib and dexamethasone, 3 (6%) patients received bortezomib, lenalidomide and dexamethasone, 2 (4%) patients received miscellaneous regimens and 2 (4%) patients were untreated prior to stem cell mobilization. Hematological response prior to transplant was as follows: 10 (20%) patients had complete response (CR), 12 (24%) very good partial response (VGPR), 18 (35%) partial response (PR), 11 (21%) patients no response (NR).

TABLE 1.

Baseline characteristics

Characteristic	All patients (n = 53)
Age, years (median)	61 (39–75)
Male	29 (55%)
Serum creatinine, mg/dl (median)	0.98 (0.27–6.29)
dFLC, mg/dl (median)	10.4 (0.22–1039.2)
24 h urine protein, g (median) (N = 45)	1.85 (0.065–24)
AL (lambda)	40 (76%)
AL stage
1	24 (45%)
2	16 (30%)
3	5 (9%)
4	8 (15%)
Concurrent diagnosis
Multiple myeloma	8 (15%)
Waldenstrom macroglobulinemia	1 (2%)
Cardiac involvement	30 (57%)
Renal involvement	37 (70%)
Liver involvement	5 (9.4%)
Peripheral nervous system involvement	5 (9.4%)
Autonomic nervous system involvement	4 (7.5%)
Other organ	14 (26.4%)
Median number of organs involved (range)	2 (1–4)
>2 organs involved	29 (60%)
Mean (SD) NT pro-BNP at diagnosis	1936 ± 3390
Mean (SD) troponin T at diagnosis	0.04 ± 0.08
Prior chemotherapy	51 (96%)
Type of chemotherapy prior to mobilization	N = 51
Cyclophosphamide, bortezomib, dexamethasone	46 (90%)
Bortezomib, lenalidomide, dexamethasone	3 (6%)
Other	2 (4%)
Median (range) KPS	90 (60–100)
Amyloid hematological response prior to stem cell mobilization
CR	9 (18%)
VGPR	9 (18%)
PR	18 (36%)
NR	12 (24%)
NA (no prior therapy)	2

Abbreviations: AL, light chain amyloidosis; CR, complete response; dFLC, delta free light chain; KPS, Karnofsky performance status; NR, no response; plt, platelet; PR, partial response; PRBC, packed red blood cells; VGPR, very good partial response.

Mobilization characteristics and perimobilization toxicity are shown in Table 2. Thirty-seven (70%) patients underwent stem cell mobilization as an outpatient, whereas 16 (30%) patients were preemptively admitted for HPC mobilization due to advanced cardiac disease and concern for cardiac arrhythmias or worsening heart failure. The median collection of total CD34+ cells was 12.4 × 10⁶ cells/kg (range 2.5–34.1 × 10⁶ cells/kg) and 45 (85%) patients had collections of ≥5.0 × 10⁶ CD34+ cells/kg. The median CD34+ cells collection on day 1 was 8.6 × 10⁶ cells/kg (range 1.4–25.3 × 10⁶ cells/kg). Twenty-seven (51%), 15 (28%) and 7 (13%) patients achieved HPC mobilization goal (≥5 × 10⁶ CD 34+ cells/kg) with 1, 2 and 3 sessions of apheresis, respectively. There were no mobilization failures and all patients had collection of at least >2 × 10⁶ CD34+ cells/kg. Four (8%) patients did not achieve the targeted goal of ≥5 × 10⁶ CD34+ cells/kg collection; among them, one patient had concurrent diagnosis of Waldenstrom Macroglobulinemia and had 3 lines of therapy before mobilization, one patient received bortezomib/lenalidomide/dexamethasone combination, and the remaining two had cyclophosphamide, bortezomib and dexamethasone induction chemotherapy before stem cell mobilization. Patients underwent a median number of 2 apheresis sessions (range 1–3). Among the 31 patients analyzed for CD34 CE, the median CD34+ CE was 47% (range 36–62). Among the 46 patients analyzed for MNC% of HPC collection, the median MNC% was 61% (range 16–94). The HPC mobilization procedure was well tolerated and no perimobilization mortality was observed. Thirty-seven (70%) patients had weight gain, with a median value of 1.3 kg (range 0.1–4 kg). No patient had weight gain >10% from precollection baseline weight. Five (10%) patients had diarrhea, among them 4 (8%) patients had grade 1 and 1 (2%) patient had grade 2 diarrhea. One (2%) patient had asymptomatic hypotension with systolic blood pressure of <90 mm Hg and responded to fluid resuscitation. One (2%) patient had an episode of atrial fibrillation with ventricular rate of less than 100/minute and no intervention was required. One (2%) patient required blood product transfusion during mobilization. On multiple linear regression, age, AL amyloidosis stage, log NT-proBNP, log troponin T, high RDW, high MCV, and abnormal dFLC did not correlate with total CD34 yield, CD34 CE and MNC% (Table 3).

TABLE 2.

Mobilization results and perimobilization toxicity

Parameters	All patients (n = 53)
Total CD34+ ×106 cells/kg collected (median)	12.4 (2.5–34)
CD34+ ×106 cells/kg collected on day 1 (median)	8.6 (1.4–25.3)
Number of patients with CD34+ collection ≥5 × 106 cells/kg	45 (85%)
Median number of apheresis session, days (range)	2 (1–3)
Number of patients achieving target goal of mobilization (≥5 × 106 cells/kg) on day 1 of collection	27 (51%)
Mononuclear cells (MNC) collected (median)a	61% (16–94)
CD34 collection efficiency (median) (n = 31)b	47% (36–62.5)
Inpatient mobilization	16 (30%)
Perimobilization toxicity
Weight gain, kg	37 (70%)
Median, kg (range)	1.3 (0.1–4)
>10% weight gain from baseline	0
Diarrhea	5 (10%)
Grade 1	4 (8%)
Grade 2	1 (2%)
Cardiac arrhythmia (grade 1)	1 (2%)c
Hypotension (grade 1)	1 (2%)
Blood product transfusion (plt or PRBC)	1 (2%)
Death	0

^a46 patient’s stem cells analyzed for MNC %.

^b31 patient’s stem cells analyzed for CD34 collection efficiency.

^cAtrial fibrillation.

TABLE 3.

Multiple linear regression model of predictors

Variable	Parameter estimate	SE	P value
(a) Predictors of total CD34 cell yield
High RDW during mobilization	1.53	2.06	.5
High MCV during mobilization	−3.55	2.40	.2
Abnormal dFLC at collection	−1.21	3.29	.7
Age	0.02	0.13	.9
AL stage	2.56	1.59	.1
log2(NT-proBNP)a	−1.00	0.59	.1
log2(troponin T)a	−0.83	1.25	.5
(b) Predictors of CD34 CE
High RDW during mobilization	−3.08	2.63	.3
High MCV during mobilization	1.40	3.20	.7
Abnormal dFLC at collection	3.62	4.52	.4
Age	−0.18	0.18	.3
AL stage	1.65	2.16	.5
log2(NT-proBNP)a	−0.47	0.81	.6
log2(troponin T)a	−0.71	1.62	.7
(c) Predictors of MNC%
High RDW during mobilization	1.47	6.19	.8
High MCV during mobilization	4.74	7.29	.5
dFLC at collection	−9.45	9.70	.3
Age	−0.58	0.38	.1
AL stage	−6.22	4.82	.2
log2(NT-proBNP)a	1.48	1.87	.4
log2(troponin T)a	1.68	3.74	.7

Abbreviations: AL, immunoglobin light chain amyloidosis; CE, collection efficiency; dFLC, difference in involved and uninvolved free light chain; MCV, mean corpuscle volume; MNC%, mononuclear cells percentage; RDW, red cells distribution width.

^aNT-proBNP and troponin T were log-transformed to model effects of multiplicative changes; the coefficients should be interpreted as the effect of a 2-fold increase in the variable.

In terms of post-autoHCT outcomes, the median time to neutrophil recovery was 14 days (range 9–21) and the median time to platelet engraftment was 14 days (range 9–19). Day 100 transplant-related mortality was 0. Forty-four (85%) patients had a VGPR or better at day 100 post-autoHCT. The median progression-free survival was not reached (NR), and at 5 years 82% of patients had sustained hematological responses. Similarly, the median overall survival was NR and at 5 years 84% of patients were alive. The median duration of follow-up of surviving patients was 23.3 months and 12/53 (23%) patients had died at last follow-up on the study.

4 |. DISCUSSION

We describe our institutional experience of combined G-CSF/plerixafor-based mobilization in AL amyloidosis patients. The new data solidify the results of our earlier report, as well as other reports on the safety and efficacy of this approach.^12,16 The CD34+ cell CE in AL amyloidosis was in the same range as reported in different studies across different diseases.^10,19–21

Peripheral HPC mobilization using G-CSF or G-CSF plus chemotherapy is a cause of significant morbidity in patients with AL amyloidosis.^3–5,22,23 Cytokine-based mobilization has been shown to be associated with fluid overload requiring ICU transfers and life threatening hypotensive episodes.^4,5 Thus there is considerable interest in reducing the cumulative cytokine (G-CSF) dose in AL and shortening collection days. Since 2011, we have adopted a combined G-CSF/plerixafor regimen to mobilize our AL patients in order to reduce exposure to G-CSF and shorten the time to mobilization. In our series, cardiac adverse events (hypotension, cardiac arryhtmia) were observed in only 2 (4%) patients. This was likely achieved by reducing G-CSF exposure and upfront plerixafor administration to improve CE. Our data show that 79% of AL patients achieved the HPC goal within 2 days of apheresis. A significant proportion of patients with AL amyloidosis have renal involvement and associated renal insufficiency. Cyclophosphamide, which is commonly used for HPC mobilization, is mainly excreted from the kidneys and can lead to increased toxicity in patients with renal amyloid. In this context, it has been shown that plerixafor can be safely used in patients with renal insufficiency with optimal CD34⁺ cell yield.²⁴ In our cohort, 70% patients had renal AL involvement. We did not see any overt renal toxicity, mobilization or engraftment failures. Acknowledging the selection bias of a retrospective analysis, our clinical experience suggests that limiting exposure to G-CSF and avoiding chemotherapy is justified, especially to improve the safety of mobilization in patients with advanced cardiac and renal amyloid.

In our earlier report,¹⁶ we compared HPC mobilization outcomes between G-CSF versus G-CSF/plerixafor and focused on stem cell yield and perimobilization toxicity. In the current analysis, we expand on our experience in a larger cohort of patients and show that G-CSF/plerixafor-based HPC mobilization is safe and effective. Moreover, we also explored CD34+ CE in patients with AL amyloidosis and factors that could potentially affect CE. To the best of our knowledge, no studies have specifically examined CD34+ CE in AL amyloidosis. The median CD34+ CE reported in our study is in the same range as those reported in several studies for different malignancies (40%−50%).^10,20,21 We did not find an association between AL amyloidosis-related factors (stage, dFLC, and cardiac biomarkers) with the total CD34+ yield and CE. Nearly all of our patients received pretransplant induction, thus we could not evaluate the impact of induction therapy on yield or CE. In a cohort of 731 peripheral blood stem cell donors for allogeniec bone marrow transplantation, Wang et al reported that donors with microcytic anemia (MCV < 80 fl) were associated with inefficient CE. It is difficult to make direct comparisons with this study as it was conducted in healthy donors; nonetheless, we could not replicate their findings in patients with AL amyloidosis and low MCV. Further studies are warranted in a larger group of patients to evaluate factors specific to AL amyloidosis which may impact HPC CE.

Increased HPC mobilization costs are always a concern with the addition of plerixafor, and is one reason for its restricted use globally. Our own previous analysis showed that the addition of plerixafor increased costs in this setting.²⁵ In other settings, however, plerixafor usage has demonstrated significant reduction in mobilization failure rates, days of apheresis, use of transfusion resources, and rates of inpatient mobilizations.¹¹ In addition, given the safety and efficacy data, despite the additional cost, we have continued with this institutional approach in our AL amyloidosis patients.

In a disease such as AL amyloidosis, peritransplant morbidity is of high concern. Minimizing G-CSF exposure during mobilization with use of plerixafor provides safe and efficient collections has allowed us to conduct safe HPC mobilization with manageable morbidity and no peritransplant mortality in AL amyloidosis. In conclusion, our single center experience of combined G-CSF/plerixafor mobilization for AL amyloidosis suggests this approach being safe and effective, though a multicenter prospective phase 1 or 2 study is warranted to replicate our findings.