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Hematopoietic Growth Factors: What’s New in 2010?

VBCC - Other
Caroline Helwick

Chemotherapy-induced neutropenia is a risk associated with many common chemotherapy regimens. Especially when associated with fever—ie, febrile neutropenia (FN)—it is dose-limiting and sometimes life-threatening. Certainly, it increases resource utilization—including hospitalization—and cost. Myeloid growth factors can reduce the incidence, duration, and severity of neutropenic events and therefore are recommended for prophylaxis in some situations. It is important for payers to remain up to date on this important component of supportive care. To this end, this report describes recent recommendations and research findings that affect the optimum use of growth factors.

ESMO Updates Guidelines

In July, the European Society for Medical Oncology (ESMO) released an enhanced and revised set of clinical recommendations for cancer care, the 2010 ESMO Clinical Practice Guidelines, which contains a section on hematopoietic growth factors.1 The guidelines recommend hemato poietic growth factors for patients with a risk of FN ≥20% (listing chemotherapy regimens that pose this risk), or under special circumstances.

Primary prophylaxis is deemed justified for patients with reduced marrow reserve due to radiotherapy of >20% of the marrow, human immunodeficiency virus, or aged ≥65 years and receiving curative regimens. Secondary prophylaxis is advised for patients at risk for further infections considered life-threatening, patients with dose reductions of concern and treatment delays, and patients for whom lack of protocol adherence would compromise clinical outcomes. Other high-risk situations in which growth factors are indicated include autologous marrow transplant, allogeneic marrow transplant, and graft failure, the report states. Treatment with growth factors is advised for patients with protracted FN (>7 days), hypotension, sepsis, pneumonia or fungal infection, and for patients at risk for death from radiation injury. Growth factors with or without chemotherapy are an effective component of peripheral blood stem cell mobilization prior to transplant, the guidelines note.

The new guidelines are the first stage in the development of guidelines addressing 55 different clinical situations, including the therapeutic use of growth factors.

NCCN 2010 Guidelines

The selective use of colony-stimulating factors (CSFs) in patients at increased risk for neutropenic complications may enhance the cost-effectiveness of these agents, according to the 2010 guidelines of the National Comprehensive Cancer Network (NCCN).2 The indication for prophylactic CSF use depends on the risk of FN or other neutropenic events that can potentially compromise treatment. Based on chemotherapy regimen and patient-related risk factors, the patient is assigned to a high-risk group (>20% risk of FN) intermediate-risk group (10%-20% risk), or low-risk

group (<10% risk). For the high-risk group, NCCN has a category 1 recommendation for using CSF when the treatment intent is curative or to prolong survival and improve quality of life. For intermediate-risk patients with this intent, CSF should be considered. Prophylaxis is not recommended for low-risk patients.

There remains no consensus nomogram for risk assessment, but several risk factors are well established. New to the 2010 guidelines is the notation that a “prior episode of FN is a risk factor for poor clinical outcome or for developing infection-associated complications.”3 Also new is the addition of several regimens to those associated with high risk: hyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) for the treatment of multiple myeloma; antithymocyte globulin, rabbit/cyclosporine for the treatment of myelodysplastic syndrome; and doxorubicin/gemcitabine for the treatment of kidney cancer.4

Publications of Note

Aapro et al evaluated 254 elderly breast cancer patients receiving chemotherapy supported by pegfilgrastim (Neulasta) primary prophylaxis or current practice neutropenia management.5 FN incidence was 6% with pegfilgrastim prophylaxis, compared with 24% under current neutropenia practice; FN-related hospitalization incidence was 5% and 15%, respectively; and dose reductions were needed for 15% and 29%, respectively. Gerds et al conducted a phase 3 randomized, double-blind, placebo-controlled trial comparing efficacy, costs, and safety of single-dose pegfilgrastim versus daily filgrastim (Neupogen) after autologous peripheral stem cell transplantation in 78 patients.6 They found the 2 regimens to be equally effective in time to neutrophil engraftment, with no difference in clinical sequelae; however, pegfilgrastim achieved a cost-savings of $961 per patient over filgrastim.

Similarly, several other studies found pegfilgrastim cost-effective over 6 days of filgrastim. In a study by Lyman et al, in patients with non-Hodgkin’s lymphoma receiving myelosuppressive chemotherapy, the incremental cost-effectiveness ratio (ICER) for pegfilgrastim was $2167/FN episode avoided.7 Adding a survival benefit derived from avoiding FN mortality yielded an ICER of $5532/life-year (LY) gained or $6190/quality-adjusted life-year (QALY) gained. When the potential benefit of optimized chemotherapy was included, the ICER was $1494/LY gained or $1677/QALY gained.

Italian investigators also concluded that primary prophylaxis with pegfilgrastim improved health outcomes with a “very limited cost increase” for the National Health Service payer. “Even when very low prices of filgrastim and high prices of pegfilgrastim were considered in the model, the resulting ICER remained well within the acceptable cost-effectiveness limit of €50,000/QALY,” Danova et al noted.8

Columbia University investigators reported that the sequential administration of sargramostim (Leukine) and filgrastim in 31 children undergoing myeloablative conditioning was safe and cost-effective and resulted in prompt myeloid engraftment.9 Sargramostim 250 mcg/m2 once daily was begun on the day of stem cell infusion, switching to filgrastim 10 mcg/kg once daily when white blood cells were ≥300/mm, for 2 days. Filgrastim was continued until the absolute neutrophil count (ANC) was ≥2500/mm3 for 2 days, then tapered to maintain ANC ≥1000/mm3. The sequential approach, versus filgrastim alone, was estimated to save $1311 per patient.

Naproxen was effective in reducing pegfilgrastim-induced bone pain in a randomized, double-blind, placebo-controlled trial of 510 cancer patients presented at the American Society of Clinical Oncology annual meeting.10 Mean AUC for pain was 7.71 for patients receiving placebo and 6.04 for those receiving naproxen 500 mg twice daily (P = .037). Naproxen reduced the overall pain incidence from 76% to 66% (P = .0085) and duration from 2.40 to 1.92 days (P = .009).

 

References

  1. Crawford J, Caserta C, Roila F. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol. 2010;21(suppl 5):v248-v251.
  2. National Comprehensive Cancer Network: NCCN Practice Guidelines in Oncology—v.1.2010. Available at: www.nccn.org/professionals/physicians_gls/PDF/myeloid_growth.pdf.
  3. National Comprehensive Cancer Network: NCCN Practice Guidelines in Oncology—v.1.2010. MGF-E. Available at: www.nccn.org/professionals/physicians_gls/PDF/myeloid_growth.pdf.
  4. National Comprehensive Cancer Network: NCCN Practice Guidelines in Oncology—v.1.2010. MGF-A. Available at: www.nccn.org/professionals/physicians_gls/PDF/myeloid_growth.pdf.
  5. Aapro M, Schwenkglenks M, Lyman GH, et al. Pegfilgrastim primary prophylaxis vs current practice neutropenia management in elderly breast cancer patients receiving chemotherapy. Crit Rev Oncol Hematol. 2010;74:203-210.
  6. Gerds A, Fox-Geiman M, Dawravoo K, et al. Randomized phase 3 trial of pegfilgrastim versus filgrastim after autologous peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2010;16:678-685.
  7. Lyman G, Lalla A, Barron R, Dubois RW. Cost effectiveness of pegfilgrastim versus 6-day filgrastim primary prophylaxis in patients with non-Hodgkin’s lymphoma receiving CHOP-21 in the United States. Curr Med Res Opin. 2009;25:401-411.
  8. Danova M, Chiroli S, Rosti G, Doan QV. Cost effectiveness of pegfilgrastim versus 6 days of filgrastim for preventing febrile neutropenia in breast cancer patients. Tumori. 2009;95:219-226.
  9. Waxman IM, Militano O, Baldinger L, et al. Sequential administration of sargramostim and filgrastim in pediatric allogeneic stem cell transplantation recipients undergoing myeloablative conditioning. Pediatr Transplant. 2009;13:464-474.
  10. Kirshner JJ, Heckler CE, Dakhil SR, et al. Prevention of pegfilgrastim-induced bone pain: a URCC CCOP randomized, double-blind, placebocontrolled trial of 510 cancer patients. Presented at: American Society of Clinical Oncology annual meeting; June 4-8; 2010. Chicago, IL. Abstract 9104.
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Last modified: May 28, 2014
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