Stem Cell Procurement

Growth factor plus preemptive (‘just-in-time’) plerixafor successfully mobilizes hematopoietic stem cells in multiple myeloma patients despite prior lenalidomide exposure

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Abstract

Lenalidomide is associated with suboptimal autologous hematopoietic stem cell (AHSC) mobilization. We hypothesized that growth factor plus preemptive plerixafor is an effective strategy for AHSC mobilization in multiple myeloma (MM) despite prior exposure to lenalidomide. We retrospectively reviewed patient characteristics and mobilization outcomes of 89 consecutive MM patients undergoing first mobilization with filgrastim or pegfilgrastim +/− preemptive plerixafor using a previously validated algorithm based on day 4 peripheral blood CD34+ cell count (PB-CD34+) and mobilization target. Outcomes were analyzed according to the extent of prior exposure to lenalidomide: no prior exposure (group A, n=40), 1– 4 cycles (group B, n=30) and >4 cycles (group C, n=19). Multivariate analysis yielded only age and number of cycles of lenalidomide as negatively associated, and mobilization with pegfilgrastim as positively associated with higher PB-CD34+. Only 45% of patients in group A required plerixafor vs 63% in groups B and 84% in C, P=0.01. A higher proportion of patients in group A (100%) met the mobilization target than in groups B (90%) or C (79%), P=0.008. All patients yielded at least 2 × 106 CD34+/kg. Growth factor mobilization with preemptive plerixafor is an adequate upfront mobilization strategy for MM patients regardless of prior exposure to lenalidomide.

Introduction

High dose chemotherapy with autologous hematopoietic SCT (AHSCT) is one of the cornerstones for the treatment of younger patients with newly diagnosed multiple myeloma (MM).1, 2, 3 Over the last decade, novel drugs, particularly immunomodulatory (IMID) agents and proteasome inhibitors, have been incorporated into the pre-transplantation induction therapy and have improved the rate of complete response both before and after autologous transplantation.4, 5, 6

The use of the IMID lenalidomide in the induction regimen was early identified as a risk factor for poor AHSC mobilization.7, 8, 9, 10 This negative effect, noticed particularly with growth factor mobilization, is at least partially overcome with the use of chemotherapy mobilization,11, 12, 13 although this strategy carries higher cost and toxicity.14, 15, 16, 17

The CXCR4-SDF1-binding inhibitor plerixafor dramatically enhances filgrastim-based CD34+ mobilization in patients with MM,18 but is expensive, limiting its use in all patients undergoing mobilization. Preliminary experience suggests that the majority of lenalidomide-exposed patients failing filgrastim mobilization will adequately mobilize CD34+ cells with filgrastim plus plerixafor.10, 19, 20 Moreover, there were no mobilization failures among the few reported lenalidomide-treated patients who underwent upfront mobilization with filgrastim plus plerixafor.20, 21

In this study, we examine 89 patients with MM (49 previously exposed to lenalidomide) who proceeded to steady state growth factor-based AHSC mobilization with preemptive (‘just in time’) use of plerixafor depending on peripheral blood CD34+ enumeration on the 4th day of mobilization and following a previously validated and published algorithm.14, 22, 23 The goals of the study are to determine if growth factor plus preemptive plerixafor overcomes the negative effect of lenalidomide on AHSC mobilization, and to estimate the impact of prior lenalidomide on plerixafor use, mobilization cost and resource utilization.

MATERIALS AND METHODS

We have developed a cost-based decision making algorithm to determine whether or not to add plerixafor to an ongoing filgrastim-based mobilization of autologous HSC aiming at best cost-effectiveness (preemptive or ‘just-in-time’ approach). The development and validation of this algorithm has been described elsewhere,22, 24 as well as the performance of this algorithm in the setting of pegfilgrastim-based mobilization.23 Steady state filgrastim-based and pegfilgrastim-based mobilization were performed in two consecutive cohorts and the choice of growth factor was not influenced by any patient or disease characteristic.

We identified all MM patients undergoing autologous HSC mobilization since the implementation of this algorithm, and reviewed charts to retrieve patient and disease characteristics as well as mobilization outcomes. This study was approved by the institutional review board at the Medical University of South Carolina.

Mobilization Protocol

Our algorithm dictates the use of plerixafor, starting on the 4th day of growth-factor mobilization, depending on peripheral blood CD34+ count (PB-CD34+) and patient-specific target CD34+ (T-CD34+) collection total. Patients received subcutaneous filgrastim (at the dose of 10 μg/kg per day) daily for 4 days or subcutaneous pegfilgrastim (at a single dose of 12 mg) on day 1. On day 4, a tunneled apheresis catheter was implanted and PB-CD34+ was checked. If PB-CD34+ exceeded a certain target-specific threshold (14 CD34+/mm3 for T-CD34+ of 3 × 106 CD34+/kg; 25 CD34+/mm3 for T-CD34+ of 6 × 106 CD34+/kg), apheresis was started immediately and repeated daily until T-CD34+ was met or the patient underwent 4 days of collection. In the event of PB-CD34+, equal or inferior to the pre-specified threshold, daily subcutaneous plerixafor (at the dose of 240 μg/kg per day) was started on the evening of the 4th day and apheresis started on the following morning (day 5). Daily filgrastim (unless pegfilgrastim mobilization), apheresis and plerixafor continued until T-CD34+ was met, typically 6 × 106 CD34+/kg (enough for two transplant procedures), 3 × 106 CD34+/kg (aiming at collection for one transplant only) or patients had four daily apheresis sessions. The apheresis equipment used was COBE Spectra, software version 6.1 (Gambro BCT, Lakewood, CO, USA). Each apheresis session consisted in the processing of at least three total blood volumes.

CFU-GM assay

CFU-GM assay as performed in our institution has been described elsewhere.25 CFU-GMs were enumerated on each apheresis product but this information was not utilized for decision making.

Cost analysis

For the estimated cost analysis, we utilized medication cost according to the listed average wholesale price for each product. The estimated costs were: filgrastim US$ 328.70 for 300 μg vial and US$ 523.62 for 480 μg; pegfilgrastim US$ 4218 for 6 mg syringe and plerixafor US$ 8032.50 for 24 mg vial. The daily charges associated with apheresis (including physician, facility, equipment and cryopreservation fees) were based on our program’s historical charges of US$ 6922.00 per day of apheresis. Personnel costs associated with injection teaching and/or growth factor administration were not included in the analysis.

Statistics

We reported proportions with 95% confidence intervals and made comparisons between proportions using Fisher’s exact test. We described continuous numerical variables on the basis of median and interquartile range (IQR) and compared continuous variables among multiple groups using Kruskal–Wallis non-parametric test. We performed multivariate analysis for factors associated with PB-CD34+ on the 4th day of mobilization utilizing linear regression model. The cumulative proportion of patients meeting the mobilization target was calculated using 1-Kaplan–Meier. In all inference analyses, two-sided P values of less than 0.05 were considered to indicate statistical significance.

Results

Population

A total of 89 MM patients underwent HSC mobilization between November 2008 and October 2011 using steady state growth factor +/− preemptive plerixafor as previously described. These patients were analyzed in three distinct groups according to the extent of prior exposure to lenalidomide: no prior exposure (group A, n=40), 1– 4 cycles (group B, n=30) and >4 cycles (group C, n=19). Table 1 summarizes patient, disease and mobilization characteristics for these three groups. Essentially, the three groups were similar in terms of patient demographics and disease characteristics. The main difference among groups, with the obvious exception of prior therapies, was the more frequent use of pegfilgrastim mobilization in group A than in groups B and C.

Table 1 Characteristics of patients included

Peripheral blood CD34+

The PB-CD34+ count on the 4th day of mobilization is a strong predictor of the apheresis yield22, 26 and therefore used in this algorithm and in others27, 28 to determine whether or not to add plerixafor to the ongoing mobilization. As the actual number of CD34+ cells collected will obviously be influenced by the use or not of plerixafor (expected to cause a three to fivefold increase in CD34+ yield), PB-CD34+ is likely the best outcome in this setting to study factors affecting CD34+ mobilization. In fact, there was a meaningful reduction of PB-CD34+ associated with the extent of the exposure to lenalidomide (Figure 1). The median PB-CD34+ count was 27 (IQR 13.75–44.5), 14.5 (IQR 10.25–27) and 10/mm3 (IQR 5–17) for groups A, B and C, respectively (P<0.001).

Figure 1
figure1

Peripheral blood CD34+ on the 4th day of mobilization with growth factor (filgrastim or pegfilgrastim) according to extent of prior exposure to lenalidomide. Median is indicated by horizontal bar.

To minimize possible imbalances between the groups in the distribution of other factors known to affect mobilization efficacy (and therefore PB-CD34+), we performed a multivariate analysis including age, gender, number of prior lenalidomide cycles, number of prior lines of therapy, presence of CR or VGPR, percentage of plasma cells in the BM at the time of mobilization and mobilization with pegfilgrastim as independent variables, and PB-CD34+ as the dependent variable. Only age, number of prior cycles of lenalidomide (negative association) and mobilization with pegfilgrastim (positive association) remained in the final model and were independently associated with higher PB-CD34+ count on the 4th day of mobilization (Table 2).This finding strongly suggests that the differences in PB-CD34+ among the three groups is not simply a function of imbalance on other factors, particularly the use of pegfilgrastim mobilization.

Table 2 Multivariate analysis of factors affecting PB–CD34+ on the 4th day of growth factor mobilization

Plerixafor use

The mobilization target was 6 × 106 CD34+/kg for 95% of patients in group A, 83% of patients in group B and 74% of patients in group C. For all remaining patients the mobilization target was 3 × 106 CD34+/kg. As all patients followed the same algorithm thresholds for preemptive use of plerixafor, the lower PB-CD34+ seen with greater exposure to lenalidomide resulted in higher rates of plerixafor use. Only 45% (95% CI 31–60%) of patients in group A received plerixafor vs 63% (95% CI 46–78%) in group B and 84% (95% CI 62–94%) in group C, P=0.01.

Mobilization outcomes

The median yield of CD34+ collected was 8.1 × 106 CD34+/kg (IQR 7.3–10.7) in group A, 7.4 × 106 CD34+/kg (IQR 6.1–10.4) in group B and 7 × 106 CD34+/kg (IQR 4.8–8.3) in group C. In fact, the smallest collection was 2.7 × 106 CD34+/kg for a patient in group C. A higher proportion of patients in group A (100%, 95% CI 91–100%) met their mobilization targets than in groups B (90%, 95% CI 74–97%) or C (79%, 95% CI 57–91%), P=0.008 (Figure 2). The median collection in terms of percentage of the pre-established goal was 135% (IQR 122–178%) in group A, 135% (IQR 112–178%) in group B and 119% (IQR 100–142%) in group C, P=0.10. Patients in group A yielded a median of 1.73 × 106 (IQR, 1.3–2.41 × 106) CFU-GM/kg vs 1.49 × 106 (IQR, 1.18–1.97 × 106) in group B and 1.24 × 106 (IQR, 1.02–1.93 × 106) in group C, P=0.16.

Figure 2
figure2

Cumulative proportion of MM patients meeting the prespecified T-CD34+ according to extent of prior exposure to lenalidomide (1-Kaplan–Meier).

None of the patients in any of the three groups failed mobilization (defined by failure to collect 2 × 106 CD34+/kg, sufficient to undergo one transplantation procedure), and none of the patients required remobilization.

Cost and resource utilization

HSC collection was completed after a median of 1.5 (IQR 1–2) daily apheresis sessions in group A, 1.5 (IQR 1–2) in group B and 2 (IQR 1–2.5) in group C. Figure 3 summarizes the apheresis yield in the three groups. No patient underwent more than four daily sessions or weekend sessions.

Figure 3
figure3

Median (+/− s.d.) apheresis yield for each day of collection according to prior exposure to lenalidomide.

The estimated cost of mobilization and collection was similar between groups A (median US$ 22 280, IQR 18 105–23 390) and B (22 280, IQR 19 459–27 614) but substantially higher in group C (35 023, IQR 22 075–37 268).

Discussion

Despite the many treatment advances in the past decade, MM remains an incurable disease with median survival of only 44 months from the time of diagnosis.29 High dose chemotherapy with AHSCT has become a standard treatment for younger and fit MM patients, as it is capable of providing sustained remission with improvement in both event-free survival1, 2, 3, 30 and overall survival.1, 2, 30 The alkylating agent melphalan, a mainstay of MM therapy, has been shown to hamper stem cell collection and is avoided in the initial management of transplant-eligible patients.31, 32, 33 Therefore, any novel agents used in the treatment of MM in transplant-eligible patients must likewise be evaluated for possible deleterious effects on HSC mobilization and collection.

Introduced in 2004, the thalidomide-analog lenalidomide was quickly incorporated in the frontline management of transplant-eligible MM patients.4, 5 The mechanisms of action of lenalidomide are complex and not fully understood, but appear to include immunomodulatory, antiangiogenic and direct antineoplastic effects.34 Clinically significant neutropenia and thrombocytopenia are well-described toxicities of lenalidomide therapy. These observations led to the concern that prior therapy with lenalidomide could impair HSC mobilization.

Kumar et al.7 made the initial observation that lenalidomide treatment could have a negative impact on HSC mobilization. In this retrospective analysis, patients receiving prior lenalidomide had lower total CD34+ collection, lower daily CD34+ collection yield and higher number of apheresis sessions required when compared with patients receiving non-lenalidomide-containing regimens. Importantly, the detrimental effect of lenalidomide on HSC mobilization was associated with the extent of exposure, leading to the recommendation that transplant-eligible, lenalidomide-treated patients should undergo HSC collection during the first 6 months of therapy. Multiple subsequent and independent reports confirmed the detrimental effect of lenalidomide on mobilization, with mobilization failure rates up to 25%8, 9, 10 along with a dose-dependent effect.9, 10

The use of CY plus growth-factor mobilization is often employed in MM with intent to obtain better CD34+ yield while still providing anti-MM therapy, although the relevance of the latter has never been demonstrated. Nevertheless, chemotherapy mobilization is associated with significant morbidities, including increased risk of infection and rate of hospitalization and excessive cost.15, 16, 17, 24, 35

Retrospective studies have been performed evaluating the role of CY plus filgrastim mobilization after lenalidomide-containing treatment regimens. Collectively, the data reveal that mobilization with CY and filgrastim results in an increased number of CD34+ cells collected and reduced rate of mobilization failure when compared with mobilization with filgrastim alone.12, 13 Additionally, it has been demonstrated that the majority of lenalidomide-treated MM patients who fail filgrastim mobilization will yield an adequate number of CD34+ cells when subjected to CY plus filgrastim mobilization.11 Therefore, the upfront use of CY and filgrastim mobilization can partially overcome the detrimental effect of lenalidomide even though it is associated with substantial morbidity and still carries a failure rate of approximately 10%.13, 21

When used concomitantly with growth factor, plerixafor improves the yield of CD34+ collection, and has been shown to successfully mobilize CD34+ cells in patients failing or likely to fail standard mobilization with growth factor or growth factor combined with chemotherapy.36, 37 In a recent phase 3 study, the addition of plerixafor on and beyond the 4th day of filgrastim administration reduced the number of apheresis days and increased the yield of CD34+ cells mobilization in MM patients18 when compared with filgrastim alone. Although upfront utilization of plerixafor is very effective, it also adds to the cost and complexity of mobilization. Consequently, several groups have developed algorithms for preemptive (‘just in time’) use of plerixafor based mostly on PB-CD34+ count.22, 38, 39 Our algorithm has a very high success rate while still avoiding the use of plerixafor in nearly half the patients.14, 22

There are limited data on the use of filgrastim plus plerixafor mobilization in patients treated with lenalidomide. Data coming from remobilization series suggest that the majority of lenalidomide-treated patients failing upfront mobilization with filgrastim will successfully mobilize with filgrastim plus plerixafor.10, 19, 20 Limited data on upfront use of filgrastim plus plerixafor for all patients treated with lenalidomide suggest a near 100% mobilization success rate.20, 21, 40

Our study is the largest one to date to report the performance of first mobilization with growth factor plus preemptive use of plerixafor in MM patients previously exposed to lenalidomide. It confirms the feasibility of incorporating ‘just in time’ algorithm in clinical practice with 100% compliance. The negative effect of lenalidomide on mobilization was once more confirmed by the clear correlation between lenalidomide exposure and PB-CD34+, here underlined by the multivariate analysis including other factors possibly affecting mobilization. We found that the vast majority of patients with 1–4 (90%) and >4 (79%) prior cycles of lenalidomide met their mobilization target. Importantly all patients yielded >2 × 106 CD34+/kg (considered the minimal cell dose to safely proceed to transplantation) and all but one patient yielded >3 × 106 CD34+/kg. Mobilization was more expensive in patients receiving more than four cycles of lenalidomide, driven by the higher need for plerixafor and slightly longer duration of collection. This extra cost is likely justifiable by helping to avoid the risks and financial burden of remobilization.

The group from the Mayo clinic has recently reported the summary of their accumulated experience in mobilizing MM patients previously exposed to lenalidomide including a cohort of patients mobilized with filgrastim plus preemptive plerixafor.21 Their experience confirms the still relatively high (10%) rate of mobilization failures in patients undergoing CY plus filgrastim mobilization. A total of 10 patients in their series underwent mobilization with filgrastim and plerixafor (no failures) and 34 patients underwent initial mobilization with filgrastim plus preemptive use of plerixafor. In contrast to our experience, there were mobilization failures in the preemptive plerixafor cohort (6%). We suspect the disparity in mobilization outcomes between our preemptive series and the one reported by the Mayo group may be attributed to the differences in threshold for use of plerixafor.38 The choice of a lower threshold by that group may have precluded the use of plerixafor in patients with borderline (but yet above the threshold) CD34+ count on the 4th day of mobilization leading to multiple suboptimal collections.

Even though our series supports the idea that successful mobilization is possible for virtually all patients with MM, it is important to notice some peculiarities of mobilization after exposure to lenalidomide. Even though patients with 1–4 prior cycles of lenalidomide were more likely to require preemptive plerixafor, there were only minor differences in mobilization outcomes between this group and the group of patients with no prior lenalidomide exposure. In contrast, mobilization in patients with >4 prior cycles of lenalidomide required plerixafor in the vast majority of patients, was more expensive and resulted in fewer patients meeting the mobilization target. This finding reinforces the recommendation that MM patients who are transplant candidates should undergo autologous HSC mobilization before more than four cycles of a lenalidomide-containing regimen are administered. However, patients who do receive more than four cycles of lenalidomide before mobilization are still very likely to successfully mobilize on first attempt using growth factor and preemptive plerixafor, avoiding the cost and toxicity associated with chemotherapy mobilization. It is possible, however, that the number of CD34+ cells obtained with the proposed approach is suboptimal. Transplantation with <5 × 106 CD34+cells/kg has been associated with delayed hematological recovery and greater resource utilization in some41, 42 but not all43 series. Prospective randomized trials comparing plerixafor-based mobilization with chemomobilization or comparing different cell doses for autologous HSCT are necessary.

In summary, steady state growth factor mobilization with a validated algorithm for preemptive use of plerixafor is an adequate upfront mobilization strategy for MM patients regardless of prior exposure to lenalidomide. Chemotherapy mobilization is not needed in this population.

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Correspondence to L J Costa.

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Competing interests

LJC received honorarium from Sanofi-Genzyme. The other authors declare no conflict of interest.

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Costa, L., Abbas, J., Hogan, K. et al. Growth factor plus preemptive (‘just-in-time’) plerixafor successfully mobilizes hematopoietic stem cells in multiple myeloma patients despite prior lenalidomide exposure. Bone Marrow Transplant 47, 1403–1408 (2012) doi:10.1038/bmt.2012.60

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Keywords

  • multiple myeloma
  • stem cell
  • mobilization
  • plerixafor
  • lenalidomide

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