Clinical impact and resource utilization after stem cell mobilization failure in patients with multiple myeloma and lymphoma

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Abstract

High-dose chemotherapy in conjunction with auto-SCT is the preferred treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma and newly diagnosed multiple myeloma. Failure to achieve optimal stem cell mobilization results in multiple subsequent attempts, which consumes large amounts of growth factors and potentially requires antibiotics and transfusions. We retrospectively reviewed the natural history of stem cell mobilization attempts at our institution from 2001 to 2007 to determine the frequency of suboptimal mobilization in patients with hematologic malignancy undergoing autologous transplant and analyzed the subsequent resource utilization in patients with initially failed attempts. Of 1775 patients undergoing mobilization during the study period, stem cell collection (defined by the number of CD34+ cells/kg) was ‘optimal’ (5 × 106) in 53%, ‘low’ (2–5 × 106) in 25%, ‘poor’ (<2 × 106) in 10%, and ‘failed’ (<10 CD34+ cells/μl) in 12%. In the 47% of collections that were less than optimal, increased resource consumption included increased use of growth factors and antibiotics, subsequent chemotherapy mobilization, increased transfusional support, more apheresis procedures, and more frequent hospitalization. This usually unappreciated resource utilization associated with stem cell mobilization failure highlights the need for more effective mobilization strategies.

Introduction

High-dose chemotherapy in conjunction with auto-SCT is widely recognized as the preferred modality of treatment for patients with relapsed or refractory Hodgkin disease1 or non-Hodgkin lymphoma2 at the time of chemotherapy-sensitive first relapse and for those with newly diagnosed multiple myeloma,3 whether there was a response to induction therapy or not.4 The primary source of stem cells for BM reconstitution is the peripheral blood.5 Harvesting of peripheral blood is convenient for the patient (an operative procedure with general anesthesia is not required) and allows for procurement of more cells expressing CD34, which is a marker for prompt engraftment after high-dose chemotherapy.6 The minimum number of cells required for successful engraftment after one course of high-dose chemotherapy is 2 × 106 CD34+ cells/kg.7, 8 However, some studies indicate that it is preferable to try to collect >5 × 106 CD34+ cells/kg to ensure prompt engraftment and decrease the need for long-term transfusional support after high-dose chemotherapy.9, 10 Although it is desirable to achieve 5 × 106 CD34+ cells/kg, failure to collect this number of cells is not a contraindication to high-dose chemotherapy.11

Typical strategies for stem cell mobilization include the use of filgrastim alone,12 filgrastim plus pegfilgrastim,13, 14 sargramostim,15, 16 or filgrastim combined with conventional chemotherapy,17 with apheresis commencing on recovery of the leukocyte count. In a significant proportion of patients receiving standard filgrastim, a requisite number of CD34+ cells can not be collected because of factors such as age,18, 19 extent of prior chemotherapy,20, 21 and exposure to specific medications including melphalan,22 purine nucleoside analogs,23, 24 and lenalidomide.25 The addition of chemotherapy to the filgrastim therapy tends to enhance the mobilization of stem cells but consumes resources, adds time, and increases the risks of neutropenic fever, hospitalization, and transfusions, which are problematic in patients scheduled to undergo subsequent high-dose chemotherapy.26, 27, 28 Mobilization failure rates vary from center to center, and failure to achieve optimal mobilization results in multiple subsequent attempts, which consumes large amounts of growth factors and potentially requires antibiotics and transfusions.

In this study, we aimed to review the natural history of stem cell mobilization attempts at our institution over a 7-year period to determine the frequency of suboptimal mobilization attempts and the subsequent utilization of resources in the population of patients with initially failed attempts.

Patients and methods

This study represents a single-center retrospective review of the transplant database at Mayo Clinic in Rochester, Minnesota, from 1 January 2001 through 31 December 2007. We searched the database for records of patients who had Hodgkin disease, non-Hodgkin lymphoma, or multiple myeloma and who received growth factor therapy with the express purpose of stem cell mobilization. Patients who did not authorize research use of their records were not included; no patients were excluded on any other basis. This study was approved by the Mayo Clinic Institutional Review Board.

In our mobilization regimens, patients received filgrastim 10 μg/kg per day subcutaneously beginning on day 1, which was continued until the completion of apheresis. Apheresis began on day 5 if the peripheral blood CD34+ cell count exceeded 10/μl. Patients whose mobilization regimen included chemotherapy received CY 1.5 g/m2 on days 1 and 2; growth factor was started on day 3, with measurement of the peripheral blood CD34+ cell count when the peripheral blood WBC count exceeded 0.5 × 108/μl. Apheresis, performed using high-volume leukapheresis as described earlier,29 commenced if the CD34+ cell count exceeded 10/μl. Apheresis was performed using continuous flow, processing up to 20 l of blood with each procedure. CD34+ cell content was estimated by flow cytometry.

Patients were classified into four groups on the basis of the total yield of CD34+ cells obtained at the completion of the mobilization episode: optimal collection (5 × 106 CD34+ cells/kg), low collection (2 × 106 to <5 × 106 CD34+ cells/kg), poor collection (<2 × 106 CD34+ cells/kg), and failed collection (apheresis not attempted because of a peripheral blood CD34+ cell count <10/μl). If a count of 10 CD34+ cells/μl was not achieved, the dose of filgrastim was increased to 16 μg/kg twice daily. For the purpose of defining outcomes, if patients required an increased dose of growth factor after day 5, the collection was considered less than optimal, even if the subsequent total stem cell yield was adequate for a single round of high-dose chemotherapy.

Strategies for remobilization—defined as any attempt at stem cell mobilization after the first attempt—included increasing the dose of filgrastim to 16 μg/kg twice daily, combining filgrastim and sargramostim, adding chemotherapy (CY 1.5 g/m2 given over 2 consecutive days), or using plerixafor as a compassionate-use protocol or as part of a clinical trial.

The χ2 and Fisher's exact tests were used to compare differences among the patients for nominal variables, and nonparametric Wilcoxon rank sum statistics were used for continuous variables. P<0.05 was considered significant.

Results

Between 2001 and 2007, a total of 2660 patients underwent a stem cell mobilization attempt; of these, 1775 patients had a diagnosis of lymphoma or myeloma. Of these 1775 mobilizations, 93 were for Hodgkin disease, 685 for non-Hodgkin lymphoma, and 997 for multiple myeloma. The results of the CD34+ stem cell collections are given in Table 1. Attempted collections were less than optimal for 837 patients: 53 patients with Hodgkin disease (57%), 486 with non-Hodgkin lymphoma (71%), and 298 with multiple myeloma (30%). The earlier chemotherapy regimens administered before the first mobilization attempt for these 837 patients are shown in Table 2.

Table 1 Outcome of collection attempts
Table 2 Prior therapy in suboptimal mobilizations

Of the 837 patients with suboptimal collections, 310 patients (11 with Hodgkin disease, 158 with non-Hodgkin lymphoma, and 141 with multiple myeloma) underwent transplant with the collected cells, despite suboptimal yields, and no further mobilization attempts were made after the first. These 310 patients all had a yield of between 2 and 5 × 106 CD34+ cells/kg. The decision to proceed to myeloablative chemotherapy with <5 × 106 CD34+ cells/kg or to attempt remobilization was at the discretion of each treating physician. The other 527 patients with initially suboptimal collections underwent a total of 620 subsequent collection attempts (remobilizations). The main focus of this paper is an analysis of these 527 patients: 42 with Hodgkin disease, 328 with non-Hodgkin lymphoma, and 157 with multiple myeloma (Table 3).

Table 3 Characteristics of patients with suboptimal mobilization

Hodgkin disease

The median age of the 42 patients with Hodgkin disease who underwent remobilization was 40 years (interquartile range [IQR], 28–49 years), which is younger than both the non-Hodgkin lymphoma and multiple myeloma patients (P<0.001) (Table 3). Each patient had a median (IQR) of 3 (0–4) aphereses. During the first suboptimal mobilization attempt, 24 of the 42 patients with Hodgkin disease (57%) required an increase of growth factor: filgrastim 16 μg/kg twice daily was administered to these patients for a median (IQR) of 7 (3–8) days. One patient (2%) received chemotherapy mobilization with dexamethasone, doxorubicin, cytarabine, and cisplatin in addition to filgrastim. None received plerixafor. For the 24 patients who required increased doses of growth factor, the median (IQR) number of CD34+ cells ultimately collected was 0.95 × 106 (0–3.52 × 106) cells/kg.

The initially suboptimal mobilizations in the 42 patients with Hodgkin disease were associated with 22 RBC transfusion episodes (52%). Patients received 1 (n=3), 2 (n=14), 3 (n=1), 4 (n=3), or >4 (n=1) units of packed RBCs with the mobilization attempt. Five of the 42 patients (12%) required plt transfusions. Three of the mobilization attempts were associated with bacteremia requiring parenteral antibiotics; this led to hospitalization of these patients during the mobilization attempt for 1, 3, and 4 days, respectively.

Among the 42 second mobilizations, cells were collected in 26 patients, although the cell yield remained suboptimal. Of the other 16 patients who had unsuccessful remobilization, 12 went onto BM harvest. Ultimately, 39 patients underwent transplant: 27 received peripheral blood stem cells, 5 received a combination of peripheral blood stem cells and BM, and 7 received BM alone. Transplant was never performed in three patients because of failure to procure sufficient cells.

Mean relapse-free survival and OS were both 86.5 months for the entire group. Neutrophil engraftment occurred at a mean of day 13, with plt engraftment (50 000/μl) at a mean of day 25. The mean duration of hospitalization post transplant was 6.5 days. Infections, including positive surveillance cultures for coagulase-negative staphylococci and Clostridium difficile, occurred in 15 of 39 patients (38%).

Non-Hodgkin lymphoma

In the 328 patients with non-Hodgkin lymphoma who had mobilization, the median (IQR) age was 59 (50–65) years, significantly younger than patients with myeloma and older than patients with Hodgkin disease (both P<0.001) (Table 3). The median (IQR) number of aphereses during remobilization was 3 (2–4), which was not significantly different than in the Hodgkin disease group, but was significantly less (P<0.001) than required in the multiple myeloma group (Table 3). As part of the effort to improve yields, growth factor was increased to 16 μg/kg twice daily during the initial suboptimal attempt in 152 of the non-Hodgkin lymphoma patients (46%) and was given for a median (IQR) of 6 (3–9) days. Eleven patients (3%) received plerixafor.

Parenteral antibacterials were administered for bacteremia or fever of unknown origin during 14 of 328 remobilization attempts (4.3%) in patients with non-Hodgkin lymphoma. Mobilization was associated with hospitalization in 18 patients (5%), with a median duration of 3 days (IQR, 2–9 days). RBCs were required (median [IQR], 2 [2–2] units) in 95 patients (29%), and 34 (10%) required a plt transfusion during mobilization.

A second independent remobilization attempt was made in 64 patients, and 5 had a third attempt. The median CD34+ cell yield for all collections was 2.56 × 106 (IQR, 0.66–4.26 × 106) CD34+ cells/kg. One patient was treated with the Vanderbilt regimen, with stem cells collected on rebound from neutropenia, and a ‘low’ collection outcome was achieved (2.63 × 106 CD34+ cells/kg). Another patient was treated with rituximab, ifosfamide, carboplatin, and etoposide and, on rebound from neutropenia, had a ‘failed’ collection (<10 CD34+ cells/μl).

Seventy-six patients (23%) underwent BM harvesting. Ultimately, 278 patients underwent SCT: 53 received both stem cells and BM, 21 received BM alone, and 204 received stem cells alone. Fifty patients had only failed collections and never had SCT.

For the entire group, mean relapse-free survival was 29.6 months and OS was 69 months. Neutrophil engraftment occurred at a mean of day 11.5, and plt engraftment (50 000/μl) occurred at a mean of day 21.5. The mean duration of hospitalization post transplant was 6.4 days. Infections, including positive surveillance cultures for coagulase-negative staphylococci and C. difficile occurred in 109 of 278 patients (39%).

Multiple myeloma

Mobilization data

For the 157 patients with multiple myeloma who had remobilizations, the median age was 63 years (Table 3), which was significantly older than the other two patient groups (P<0.001). Myeloma patients also had significantly fewer prior chemotherapy regimens than the other groups (median, 1 vs 2; P<0.001) and had a lower initial mobilization failure rate than patients with non-Hodgkin lymphoma (30 vs 71%). The group was 64% male; there was no significant difference in sex among the three groups (P=0.12). Myeloma patients required a median (IQR) of four (2–6) aphereses, significantly more than for non-Hodgkin lymphoma (P<0.001). For 96 of the myeloma patients (61%), the dosage of growth factor was increased to 16 μg/kg twice daily during their initial suboptimal mobilization attempt. The median (IQR) duration of high-dose filgrastim for these patients was 7 (4–9) days.

Three patients with myeloma were on plerixafor trials for the remobilization attempt. Chemotherapy (single-agent CY) was used for the remobilization attempt in 37 of 157 patients (24%). In the patients with myeloma, parenteral antibacterials (for neutropenic fever, bacteremia [usually line-associated], or fever of unknown origin) were required during 9 of 37 chemotherapy-based remobilization attempts (24%), whereas they were required for only 6 of 120 non-chemotherapy-based remobilization attempts (5%). The median duration of parenteral antibacterial therapy was 5 days (range, 2–14 days) for patients who had chemotherapy-based remobilization vs 4 days (range, 1–16 days) for those with non-chemotherapy-based remobilization. RBC transfusions, using a median of 2 units (IQR, 2–4 units), were required in 46 of 157 patients (29%): 28 of 37 patients (76%) with chemotherapy-based remobilization and 18 of the 120 (15%) not receiving chemotherapy (P<0.001). Plt transfusions were required in 30 of 157 patients (19%): 20 of 37 (54%) with chemotherapy-based remobilization and 10 of 120 (8%) not receiving chemotherapy (P<0.001).

The median total yield of CD34+ cells for the 157 myeloma patients undergoing remobilization was 3.95 × 106 cells/kg (IQR, 1.51–5.37 × 106 cells/kg). In all, 18 patients (11%) required hospitalization during the remobilization procedure (median [IQR] duration, 6 [3–10] days), of whom 11 (61%) had CY mobilization. Of the 157 patients who had remobilizations, 73 underwent >1 attempt to remobilize stem cells—10 had 3 attempts and 4 had 4 attempts. A remobilization attempt was eventually successful (cells were collected, although with suboptimal yields) in 39 of these 73 patients. None underwent a marrow harvest. Eventually, 101 (64%) of the 157 collections led to stem cell transplant; cell dose was inadequate for transplant in the other 56 patients (36%).

Pretransplant factors that were not predictive of poor mobilization included sex, chemotherapy responsiveness, plasma cell labeling index, BM plasma cell percentage, creatinine value, age, and metaphase cytogenetics. Those with poor mobilization had more chemotherapy regimens before transplant (P=0.002) and a higher mean β2-microglobulin value (3.52 vs 2.67 μg/ml; P=0.053).

Post-transplant outcomes

In the myeloma cohort, we directly compared patients with (n=699) and without (n=298) optimal mobilization. No differences between the groups were seen in terms of absolute neutrophil engraftment and median time to engraftment (median for both, day 13; P=0.83). Median time to plt engraftment, defined as 50 000/μl, was at day 15 for both groups; however, the number of patients with slower engraftment was higher in those with poor mobilization. The percentage of patients achieving 50 000/μl was 85% at day 20 and 94% at day 30 in those with optimal mobilization vs 77 and 89%, respectively, for those with suboptimal mobilization (P=0.01 by Kaplan–Meier analysis). Incidence of bacteremia (35 vs 33%; P=0.10) and duration of hospitalization (4 days vs 3 days; P=0.10) were not different between the two groups.

Relapse-free survival was similar in myeloma patients with and without optimal mobilization (17.7 vs 19.8 months; P=0.85). OS was significantly longer in the optimal mobilization group (71.2 vs 57.8 months; P=0.04, log-rank test). The two groups were not balanced, however, as those with suboptimal mobilization had more prior chemotherapy regimens pretransplant (P=0.006, Kruskal–Wallis rank sum test) and higher pretransplant β2-microglobulin levels (P=0.03). Cox proportional hazards multivariate survival analysis indicated that both β2-microglobulin level and number of pretransplant chemotherapy regimens remained predictive of OS (P<0.001), but poor mobilization did not (P=0.25).

Discussion

High-dose chemotherapy is the standard of care for patients with multiple myeloma and chemosensitive relapsed non-Hodgkin lymphoma.30, 31 The data presented here suggest that the fraction of patients that have a less-than-optimal first collection is substantial: 30% in multiple myeloma, 71% in non-Hodgkin lymphoma, and 57% in Hodgkin disease.

The literature is not often clear about the hidden additional and unappreciated resource requirements associated with failure to have an optimal initial stem cell collection. A high proportion of patients that have poor CD34+ cell counts in the blood require a doubling of the dose of growth factor, with the associated pharmacy requirements, for a median of 6 to 7 days. The additional aphereses required in patients who have poor stem cell yields also add substantial consumption of resources when mobilization is not successful on the first attempt. Other resource considerations often omitted include the need for hospitalization, which was seen in 5–11% of the patients in our study. Moreover, during some reattempts at mobilizing stem cells, RBCs and plt support were required; parenteral antibiotics were needed when fever developed in 7% of patients with Hodgkin disease, 4% with non-Hodgkin lymphoma, and 24% with multiple myeloma who underwent mobilization using a chemotherapy pulse.

Even when multiple mobilization attempts,32 growth factor dose increases, and chemotherapy mobilization were used, not all patients were able to undergo transplantation. When stem cell mobilization was not immediately optimal, subsequent attempts to mobilize failed completely in 3 of 42 patients (7%) with Hodgkin disease (3% of the original Hodgkin disease cohort), 56 of 157 (36%) with multiple myeloma (6% of the original myeloma cohort), and 50 of 328 (15%) with non-Hodgkin lymphoma (7% of the original non-Hodgkin lymphoma cohort). These percentages represent the failure rates for remobilizations and reflect the high incidence of failure if mobilization is suboptimal on the first attempt. In this type of situation, all resources consumed are essentially wasted.

Cost information exists but is variable because of the extensive variation in daily hospitalization costs and drug acquisition costs both across countries and over time. In a study from Australia, the costs associated with high-dose therapy were estimated to be A$37 490, far lower than costs reported in the United States.33 Pharmacy costs were substantial, the largest proportions of which were the costs of chemotherapy (40%), G-CSF (36%), and antibiotics (15%). In a prospective cost analysis of stem cell mobilization, the mean total cost was $32 160 (range, $19 092–$50 550).26 Average total costs were higher than DRG reimbursement.

Resources can be conserved merely by setting minimal thresholds of peripheral blood CD34+ cell counts before commencing leukapheresis. This alone has been reported to save $67 660 by decreasing unnecessary leukapheresis.34 In one study, administration of low-dose (300 μg per day) G-CSF was delayed after beginning CY and paclitaxel to enhance stem cell yields.35 G-CSF was administered for 9 days at a mean cost of $1260 per patient; no increases in rates of hospitalization, fever, or catheter-related bacteremia were seen.

Attempts to facilitate stem cell mobilization have included the use of EPO in combination with G-CSF after mobilization chemotherapy with ifosfamide, epirubicin, and etoposide;36 pegfilgrastim;14 dexamethasone, CY, etoposide, and cisplatin;37 or CY, doxorubicin, and dexamethasone.38 Cytokine-only mobilization regimens were well tolerated, but the utility is limited by lower stem cell yield.39 Multiple studies have shown that the addition of a chemotherapy agent to cytokine mobilization improves collections, but this leads to increased toxicity, morbidity, transfusion requirement, and hospitalization, as reflected in our myeloma population.40, 41 Investigational mobilization agents include pegylated G-CSF42 and SCF.43 In a multicenter analysis, age, sex, diagnosis, prior chemotherapy regimens, cumulative alkylator dose, precollection infections, and time from last chemotherapy were all predictive of yield.44

In our transplant cohort, remobilization strategies differed on the basis of the underlying disease. In multiple myeloma, patients with poor collections immediately received CY pulsing to enhance yield.39, 45 These patients generally were in first partial response with only 4 months of prior induction therapy. In the lymphoma cohort, collection attempts began after proof of chemosensitive disease after relapse by using either rituximab with ifosfamide, carboplatin, and etoposide or rituximab with dexamethasone, cytarabine, and cisplatin. The preference in our clinical group was to increase the dose or combine growth factors;46 if that failed, BM was harvested, with only a few patients receiving chemotherapy pulse mobilization.47 Ultimately, only 50 of the original 1775 patients did not go on to high-dose therapy. Success rates were similar with either technique, but resource utilization was greater with chemotherapy-pulsed mobilization. Overall, sufficient cells for high-dose therapy can be collected in most patients,48 but the resources expended to collect the cells vary widely on the basis of diagnosis, age, and prior therapy.49, 50 The nature of our referral population made it impossible to determine which features at diagnosis might correlate with low collection yields.

Pusic et al.51 reported 182 mobilization failures out of 976 (19%). In our cohort, separating patients by diagnosis and by the terms low, poor, and failed collection, collections were considered optimal in only 43% of patients with Hodgkin disease, 70% with multiple myeloma, and 29% with non-Hodgkin lymphoma. In a recent placebo-controlled trial in patients with multiple myeloma, a threshold of 6 × 106 CD34+ cells/kg was reached with growth factor alone in only 34% of patients, which is comparable with our results.52 These low success rates indicate the need for improved modalities to help enhance CD34+ cell yields. The failure rates for growth factor only and chemotherapy mobilization were similar in the study by Pusic et al.51

It is technically possible to perform safe transplantation with as few as 1 × 106 CD34+ cells/kg. Unfortunately, engraftment times, particularly for plts, can be affected when the stem cell infusion is <5 × 106 CD34+ cells/kg.53 This results in increased RBC and plt support after the transplant, with its inherent resource consumption, which is not often reported in the literature. Plerixafor has recently been introduced as a CXCR4 inhibitor that helps improve stem cell yield and is approved to be administered the evening before apheresis to enhance yield of cells.54, 55 The exact patient subset for appropriate use of plerixafor has yet to be defined, and whether it should be used in conjunction with chemomobilization is as yet unclear.56

With regard to transplant outcomes, the difference in time to plt engraftment in myeloma patients with optimal vs suboptimal collection is somewhat confounded by the fact that the total number of CD34+ cells infused was higher in the optimal mobilization group: a median of 4.60 vs 4.36 × 106 cells/kg. Therefore, it is unclear what function, if any, suboptimal mobilization had in plt engraftment, other than the lower infused CD34+ cell numbers. Outcomes after transplant in patients with Hodgkin disease and non-Hodgkin lymphoma were not noticeably different from those of other patients in our experience.57, 58, 59

A limitation associated with this type of retrospective review is lack of control for interphysician variability. If a patient, after three collections, had a yield of 4.5 × 106 CD34+ cells/kg and the responsible physician elected to stop and proceed with conditioning, this would have been classified as suboptimal, but not subject to remobilization. This subjective factor cannot be controlled for in our study. Moreover, the decision to attempt a BM harvest as a source of stem cells was not used for patients with myeloma, which may partly account for the high ultimate failure rate in those with suboptimal yields after a first attempt.

In summary, one-third of the patients with multiple myeloma and more than half of patients with lymphoma in our study had a less-than-optimal stem cell collection on the first attempt. The consequences of having a low, poor, or failed collection include marked increases in the amount of growth factor used, repeat mobilization using chemotherapy, hospitalization, transfusion, and antibiotic consumption. It does not seem that, once sufficient cells have been collected, an initial suboptimal collection has any effect on PFS, OS, engraftment, or infection. The number of prior chemotherapy regimens was the only factor identified to predict poor mobilization. These data can be used as a baseline for comparison with newer mobilization strategies.

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Acknowledgements

We thank Norine Huneke and LeAnn Batterson for expert data management and Denise Chase for expert manuscript preparation. This study was supported in part by a grant from Genzyme Inc.

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Correspondence to M A Gertz.

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Keywords

  • growth factors
  • stem cell mobilization
  • SCT

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