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Keywords:

  • Plerixafor;
  • germ cell tumor;
  • mobilization;
  • hematopoietic cell transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References

Study Objective

To evaluate the efficacy of plerixafor as a just-in-time therapy for patients with germ cell tumors who were identified as poor hematopoietic cell mobilizers after the initiation of apheresis.

Design

Case series.

Setting

National Cancer Institute–designated cancer center.

Patients

Nine patients with germ cell tumors who received plerixafor as an adjunct to granulocyte colony-stimulating factor (G-CSF) for hematopoietic cell mobilization in an attempt to prevent mobilization failure between January 2009 and December 2012.

Measurements and Main Results

Patients were heavily pretreated, having received at least four prior treatment cycles. A median of three total apheresis days (range 1–4 days) was required for all patients, but a median of two apheresis days (range 1–2 days) was needed after the initiation of plerixafor. A median of 0.9 × 106 CD34+ cells/kg (range 0.3–1.5 × 106 CD34+ cells/kg) was harvested with G-CSF mobilization alone; in addition, a median of 2.6 × 106 CD34+ cells/kg (range 0.6–32 × 106 CD34+ cells/kg) was harvested using plerixafor. All nine patients received high-dose carboplatin and etoposide followed by hematopoietic cell transplantation. The median time to neutrophil engraftment was 11 days (range 8–12 days). The median time to platelet engraftment was 16 days (range 10–22 days).

Conclusions

The use of plerixafor in addition to G-CSF as just-in-time therapy permits patients with germ cell tumors to pursue potentially curative therapy with high-dose chemotherapy followed by autologous stem cell rescue.

High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) rescue has become a standard therapy for patients with relapsed germ cell tumor.[1] High-dose chemotherapy consists of two cycles of carboplatin 700 mg/m2 of body surface area plus etoposide 750 mg/m2, both given intravenously 5, 4, and 3 days before the infusion of hematopoietic stem cells. A minimum of 1 x 106 CD34+ cells/kg of body weight is required for each cycle of high-dose chemotherapy. This treatment can lead to cure in nearly 60% of patients, with success of this treatment being dependent on collection of sufficient CD34+ cells for HCT.[1, 2] However, a subset of patients are predicted to be poor mobilizers, with hematopoietic cell mobilization failure rates approaching 30%.[3] Due to the risk of hematopoietic cell mobilization failure, additional methods of hematopoietic cell mobilization are needed. Plerixafor inhibits binding of stromal cell–derived factor-1α to its receptor, CXC chemokine receptor 4.[4] In patients with multiple myeloma and non-Hodgkin's lymphoma, CD34+ cell collection goals were achieved with less apheresis procedures when plerixafor was added to granulocyte colony-stimulating factor (G-CSF) than with G-CSF monotherapy.[5, 6] Plerixafor received approval by the United States Food and Drug Administration for use in combination with G-CSF for hematopoietic cell mobilization in patients with multiple myeloma and non-Hodgkin's lymphoma at a dose of 0.24 mg/kg subcutaneously once/day for up to four doses, approximately 11 hours before apheresis is initiated.[7]

Published case reports describe the use of plerixafor as a salvage mobilization strategy in patients with germ cell tumors after G-CSF mobilization failure.[2, 3, 8-10] Patients with germ cell tumors may be at an increased risk of mobilization failure due to platinum- and alkylator-based therapy exposure. Plerixafor mobilization strategies in patients with germ cell tumors vary based on timing of administration. The purpose of this study was to evaluate the efficacy of plerixafor as a just-in-time therapy for patients with germ cell tumors who were identified as poor hematopoietic cell mobilizers after the initiation of apheresis.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References

Study Design, Setting, and Definitions

This case series describes patients with germ cell tumors who were poor hematopoietic cell mobilizers treated at the Indiana University Simon Cancer Center (Indianapolis, IN), a National Cancer Institute–designated cancer center; the Indiana University institutional review board approved this study. Poor mobilizers are historically defined as those who collect less than 1.0 × 106 CD34+ cells/kg after multiple apheresis attempts.[4] Just-in-time therapy refers to initiating plerixafor as part of the mobilization regimen after the first day of collection as opposed to waiting for poor collection from multiple apheresis attempts with a subsequent second apheresis collection week. This strategy is used to prevent further delays in treatment timing, as a second apheresis schedule may take an additional few weeks for collection and cell processing.

Patient Characteristics

One hundred thirty patients underwent HCT at the Indiana University Simon Cancer Center between January 2009 and December 2012. Nine of these patients received plerixafor for CD34+ cell mobilization in combination with G-CSF. Of the nine patients, two received plerixafor before the first apheresis procedure as they were determined to be at high risk of mobilization failure; plerixafor was administered in four patients before the second apheresis procedure, in two patients before the third apheresis procedure, and in one patient before the fourth apheresis procedure.

Patient characteristics are outlined in Table 1. The median age of patients was 45 years (range 18–52 yrs). Three patients had mixed nonseminomatous germ cell tumors, two had nonseminomatous germ cell tumors, two had seminoma, one had probable adenocarcinoma of the esophagus with germ cell differentiation, and one had choriocarcinoma. All patients received at least four prior treatment cycles that included at least one platinum compound, alkylating agent, and etoposide.

Table 1. Patient Characteristics Before Mobilization Attempts
Patient123456789
  1. BEP = bleomycin etoposide cisplatin; EP = etoposide cisplatin; GCT = germ cell tumor; M = male; NSGCT = nonseminoma germ cell tumor; VeIP = vinblastine ifosfamide cisplatin; VIP = etoposide ifosfamide cisplatin; TIP = paclitaxel ifosfamide cisplatin.

  2. a

    Probable adenocarcinoma of esophagus with germ cell differentiation.

  3. b

    Whole brain radiation × 2 wks.

Age (yr)455223472949231849
SexMMMMMMMMM
DiseaseNSGCTSeminomaMixed NSGCTMixed NSGCTMixed NSGCTGCTaSeminomaNSGCTChorio-carcinoma
StageIIIIIIIIIIIIIIIIIIIIIIIIIII
Prior therapy regimens

3 × VIP

1 × BEP

4 × BEP

3 × VeIP

4 × VIP

3 × BEP

1 × VIP

3 × TIP

2 × BEP

2 × EP

4 × TIP

4 × VIP

5 × BEP

4 × TIP

4 × BEP

2 × VeIP

1 × BEP

4 × VeIP

RadiationNoNoNoNoNoNoYesbNoNo

Mobilization Regimens

The initial mobilization regimen was G-CSF at a dose of 10 µg/kg daily rounded to the dose of the nearest vial size (range 10–12 µg/kg) beginning 4 days before apheresis.[11] Peripheral blood CD34+ concentrations were not routinely performed before apheresis. Apheresis began on the fifth day of G-CSF administration. Plerixafor 0.24 mg/kg rounded to the dose of the nearest vial size (range 0.22–0.37 mg/kg) was initiated if a patient collected less than 1.5 × 106 CD34+ cells/kg after the first apheresis. The decision to proceed with apheresis was determined by the cellular therapy laboratory medical director or designee based on white blood cell count, with a cut-off of at least 10 × 103/mm3. Standard-dose G-CSF mobilization failure was defined as less than 1 × 106 CD34+ cells/kg collected within a 2-day period. The decision to increase G-CSF dose was based on the cellular therapy lab director in consultation with the clinical pharmacist. It is known that the minimum collection to ensure neutrophil and platelet engraftment is 1.0 × 106 CD34+ cells/kg.[4] As patients with germ cell tumor undergo tandem HCT,[1] the goal CD34+ collection from apheresis was 2 × 106 CD34+ cells/kg/patient, which would allow for 1.0 × 106 CD34+ cells/kg/ for each transplantation.[4] Ideally, a collection goal of at least 5 × 106 CD34+ cells/kg/patient for each transplantation is often sought.[4]

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References

Mobilization with Plerixafor

A median of three apheresis days (range 1–4 days) was needed for all patients, but a median of two apheresis days (range 1–2 days) was necessary after initiation of plerixafor. A median of 0.9 × 106 CD34+ cells/kg (range 0.3–1.5 × 106 CD34+ cells/kg) were collected with G-CSF mobilization alone; in addition, a median of 2.6 × 106 CD34+ cells/kg (range 0.6–32 × 106 CD34+ cells/kg) were collected using plerixafor. The overall median collection for the nine patients was 3 × 106 CD34+ cells/kg (range 1.6–32 × 106 CD34+ cells/kg). No difference was noted in the median number of cells collected in patients who received once/day versus twice/day G-CSF. Six of the nine patients achieved the goal collection of at least 2 × 106 CD34+ cells/kg during the apheresis procedures despite plerixafor administration. Figure 1 depicts the percentage of patients who achieved at least 1 × 106 CD34+ cells/kg after each day of apheresis with G-CSF mobilization alone and with G-CSF plus plerixafor. One patient had CD34+ cells collected before the first cycle of chemotherapy and HCT, and then remobilization was attempted after engraftment to collect cells for his second HCT. The two patients who did not attain CD34+ cell collection goals did proceed to the anticipated transplantation. No adverse drug events were reported, and toxicity mainly consisted of paresthesias associated with the apheresis procedure.

image

Figure 1. Apheresis CD34+ cell collection attainment with G-CSF alone and with G-CSF followed by just-in-time plerixafor. G-CSF = granulocyte colony-stimulating factor.

Download figure to PowerPoint

One patient did not have engraftment data available at the time of this writing. Neutrophil engraftment data were reported for 13 of 14 HCTs, and platelet engraftment data were reported for 12 of 14 HCTs. Neutrophil engraftment was defined as the first date of three lab values on different days with an absolute neutrophil count (ANC) of 500 cells/mm3 or more after ANC nadir. Platelet engraftment was defined as the first date of three lab values on different days with platelet count of 20,000/mm3 or more after nadir and with no platelet transfusions in the previous 3 days. The median time to neutrophil engraftment was 11 days (range 8–12 days). The median time to platelet engraftment was 16 days (range 10–22 days). Of the available data, the engraftment durability was reported for platelets and neutrophils for six patients at day 30 after second or only HCT, for three patients at day 100 after second HCT, and for two patients at day 365 after second HCT.

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References

Although we are not the first to report the use of plerixafor to mobilize hematopoietic cells in patients with germ cell tumors, we may be the first to report its use as a just-in-time therapy at the first mobilization attempt. This varies from remobilization efforts that occur after the first week of mobilization failure as reported previously.[2, 3, 8-10] This differentiates our experience from previously published cases by incorporating an adaptive mobilization model allowing plerixafor to be incorporated based on less-than-ideal first day CD34+ cell collection rather than rescheduling apheresis sessions for the following weeks and potentially delaying high-dose chemotherapy and HCT with curative intent.

We provide additional evidence on the efficacy of plerixafor for hematopoietic cell mobilization in patients with germ cell tumors. Engraftment sustainability can occur with the use of plerixafor-mobilized hematopoietic cells as evidenced by our data at day 100 and day 365 after HCT. Use of plerixafor-mobilized hematopoietic cells did not adversely affect time to engraftment as evidenced by appropriate ANC and platelet engraftment time periods. One of the limitations of the retrospective nature of this report is the difficulty in assessing adverse drug events given the lack of documentation.

Patients who fail initial mobilization efforts often require multiple mobilization attempts, which can lead to increased health care costs and delays in undergoing HCT.[5] If patients with germ cell tumors are delayed in receiving HCT or are unable to achieve sufficient hematopoietic cells for transplantation, they may be denied potential curative therapy. It is generally accepted that heavily treated patients may be at risk of hematopoietic cell mobilization failure.[3] The nine patients in our report received a median of six treatment cycles (range 4–9 cycles) before presenting for mobilization, which is expected in patients undergoing chemotherapy for germ cell tumors.

Conclusion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References

The data from this case series, in addition to previous reports, support the addition of plerixafor to G-CSF to mobilize hematopoietic cells in patients with germ cell tumors who are not reaching CD34+ cell collection goals. The just-in-time approach permits patients to pursue potentially curative therapy with high-dose carboplatin and etoposide followed by autologous stem cell rescue.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. References
  • 1
    Einhorn LH, Williams SD, Chamness A, Brames MJ, Perkins SM, Abonour R. High-dose chemotherapy and stem-cell rescue for metastatic germ cell tumors. N Engl J Med 2007;357:3408.
  • 2
    Worel N, Apperley JF, Basak GW, et al. European data on stem cell mobilization with plerixafor in patients with nonhematologic diseases: an analysis of the European consortium of stem cell mobilization. Transfusion 2012;52:2395400.
  • 3
    Kobold S, Isernhagen J, Hübel K, et al. Plerixafor is effective and safe for stem cell mobilization in heavily pretreated germ cell tumor patients. Bone Marrow Transplant 2010;46:105360.
  • 4
    Rosenbeck LL, Srivastava S, Kiel PJ. Peripheral blood stem cell mobilization tactics. Ann Pharmacother 2010;44:10713.
  • 5
    DiPersio JF, Stadtmauer EA, Nademanee A, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 2009;113:57206.
  • 6
    DiPersio JF, Micallef IV, Stiff PJ, et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma. J Clin Oncol 2009;27:476773.
  • 7
    Genzyme Corporation. Mozobil [package insert]. Swindon, UK: Genzyme Corporation; 2010.
  • 8
    Tuffaha H, Adel-Rahman FA. Successful stem-cell mobilization and transplantation using plerixafor in a patient with a germ cell tumor. Hematol Oncol Stem Cell Ther 2010;3:2035.
  • 9
    Saure C, Wiegelt C, Schroeder T, et al. Plerixafor enables successful hematopoietic stem cell collection in an extensively pretreated patient with testicular cancer. Acta Haematol 2010;124:2358.
  • 10
    Horwitz ME, Long G, Holman P, Libby E, Calandra GC, Schriber JR. Efficacy and safety of hematopoietic stem cell remobilization with plerixafor+G-CSF in adult patients with germ cell tumors. Bone Marrow Transplant 2012;47:12836.
  • 11
    Amgen Inc. Neupogen [package insert]. Thousand Oaks, CA: Amgen Inc; 2013.