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The Value of Pegfilgastrim for the Therapy of Acute Myeloid Leukemia

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The Value of Pegfilgastrim for the Therapy of Acute Myeloid Leukemia The value of PegFilgastrim for the therapy of acute myeloid leukemia [haematologica reports] 2006;2(7):96-98 A.CIOLLI F. L EONI cute myeloid leukemia (AML) is a mal precursors in the marrow, leading to A.BOSI malignant disease resulting from increased susceptibility to chemotherapy Aacquired mutations that block the and consequent prolonged neutropenia. Department of Haematology, differentiation of primitive hematopoietic However the safety of administration of Careggi Hospital, Florence, Italy cells and thereby cause immature myeloid growth factors before, during and after precursors to accumulate. Patients are induction chemotherapy has now been often neutropenic as a result of the disease, borne out by the results of large random- and intensive chemotherapy will unavoid- ized studies.2 ably exacerbate myelosuppression. Howev- er, since the life expectancy is directly cor- Use of growth factors after related to the achievement of complete chemotherapy remission (CR), the goal of induction and Over the last decade, several randomized consolidation treatment is to induce CR and trials have analyzed whether recombinant prevent relapse. Infectious complications, growth factors can reduce the duration of mostly occurring during the first course of chemotherapy-induced neutropenia in AML treatment, are one of the major causes of patients without compromising the clinical death and the risk and severity of outcome. These studies varied in methodol- chemotherapy-induced myelosuppression ogy, assessed varied patient populations in increases with age. Older adults are less terms of refractory or de novo AML, and able to tolerate intensive chemotherapy produced somewhat inconsistent results. regimens, often have pre-existing haema- Generally, they showed that the use of tologic disorders, and are more likely to growth factors significantly shortened the have poor-risk cytogenetic abnormalities or duration of severe neutropenia, which also expression of the multidrug resistance phe- reduced the need for hospitalization and notype. The proportion of patients achiev- intravenous antibiotic use.3,4 Recently, data ing CR decrease with advancing age due of a large randomized, double-blind, place- either to the frailty of the elderly patients bo-controlled, phase III study of filgrastim or to the persistence of leukemia. in remission induction and consolidation Happily, hematopoietic growth factors therapy for adults with de novo acute such as recombinant granulocyte colony- myeloid leukemia have been published.5 The stimulating factor (G-CSF, filgrastim) authors, while confirming previous data3 on demonstrated to be effective in older indi- the safety and efficacy of filgrastrim in viduals affected by cancer who had to reducing the morbidity associated with receive curative chemotherapy: in a retro- AML treatment, demonstrated, after a spective review of clinical practices in the median follow-up of 7 years, that fil- USA filgrastim was associated with a 40% grastrim supportive therapy had no detri- reduction in the risk of febrile neutropenia mental effect on either disease free survival in CHOP treated non-Hodgkin lymphoma (DFS) or overall survival (OS). Patients patient.1 receiving filgrastim achieved the same CR The application of myeloid growth fac- rate as those receiving placebo, and the tors in AML has been delayed by their remissions were of similar duration. In con- potentially ability to stimulate the growth clusion, myeloid growth factors given after of myeloid blast cells since in vitro studies chemotherapy can consistently reduce the showed that the myeloid blasts expressed duration of neutropenia although they did receptors for G-CSF and GM-CSF. Two were not significantly modify the overall out- the major concerns in the use of colony come of AML. While some studies demon- stimulating factors during AML therapy: the strate an increase in CR rate and OS4,6 oth- potential stimulation of leukemic cell ers did not confirm these results.7,8 growth and the stimulation of residual nor- 96 haematologica reports 2006; 2(issue 7):May 2006 New Insights in Hematology Concomitant use of growth factors with ing the first year and started 48 hours before each chemotherapy course. Confirming a previous report (14), CR rate, OS In patients who are able to avoid therapy related and DFS were not affected in either younger or elder- mortality, relapse is the most important cause of treat- ly patients. Differences in the design of these trials ment failure. The likely cause of such failure is relat- and patients characteristics make comparison of these ed to the existence of a small proportion of quiescent studies difficult. However, this strategy has not been clonogenic blasts which has escaped the toxic effects consistently effective and no significant clinical ben- of chemotherapy. In vitro and in vivo studies have efit has been reported in the majority of the studies. demonstrated the ability of growth factors to recruit Thus, the priming with growth factors in AML could these quiescent cells into a phase of cell cycle where not be recommended as standard of care.15 these are more susceptible to the cytotoxic drugs.9,10 Exposure of leukemic cells to growth factors before Pegylated filgrastim cytarabine increases intracellular ara-CTP and DNA The application of pegylation technology has creat- uptake of radiolabeled cytarabine into the leukemic ed a second generation molecule, pegfilgrastim, with cells.11 significantly altered pharmacokinetic properties. Peg- These preclinical studies provided the rationale for a filgrastim has the same mechanism of action as fil- number of trials investigating the safety and efficacy grastrim16 but the pegylation markedly reduces renal of concomitant administration of colony-stimulating clearance, leaving neutrophil-mediated clearance as factors with chemotherapy. Lowenberg et al.12 con- the major route of elimination.17 As a result, clearance ducted a multicenter trial where patients age 18-60 of pegfilgrastim is decreased and serum concentra- years with newly diagnosed AML received cytarabine- tions are sustained throughout the duration of neu- based chemotherapy with or without G-CSF. Overall, tropenia. In clinical studies with standard, multicycle a higher DFS was reported in the patients who received chemotherapy, a single subcutaneous (sc) dose of peg- G-CSF (42% vs 33% at 4 years, p=0.02) but the OS was filgrastim has been shown to have similar efficacy and not significantly better. A real advantage in the OS safety as daily sc doses of filgrastim in patients with was registered in the subset of standard risk patients solid tumors.18,19 Emerging evidence also suggests that ( OS at 4 years 45 vs 35%, p=0.02). The outcome for pegfilgrastim may be equally employed in the setting patients with unfavorable prognosis was not improved of chemotherapy for AML, dose-dense chemotherapy and the small number of patients in the favorable sub- and peripheral stem cell mobilization. group limited a meaningful analysis. A double-blind, randomized, active-controlled, clin- In a more recent study,8 722 newly diagnosed AML ical trial was conducted to assess the efficacy and elderly patients (age >60 years) were randomized into safety of pegfilgrastim relative to filgrastim in patients four arms:1no G-CSF, (2) G-CSF during chemotherapy,3 with de novo AML.20 To minimize inter-patient variabil- G-CSF after chemotherapy until neutrophils recovery,4 ity, patients with FAB M7 subtype, high-risk cytoge- G-CSF during and after chemotherapy. Patients who netics or leukemia secondary to myelodysplastic syn- received G-CSF after chemotherapy had a shorter time drome were excluded. Patients received 1 or 2 cours- to neutrophil recovery (median, 20 vs 25 days; p= < es of standard induction chemotherapy, and 1 course 0.001), a shorter hospitalization (mean, 27.2 vs 29.7 of consolidation therapy if complete remission was days; p=<0.001). CR rate was 58.3% for patients achieved. During days 6 through 8 of induction, receiving G-CSF during chemotherapy (groups 2+4) vs patients were randomized to receive either pegfilgras- 48.6% for the others (groups 1+3) p=0.009, suggest- tim or filgrastim (plus placebo-matched comparator) ing a possible priming effect. However, no significant in a 1:1 ratio. Pegfilgrastim was administered as a sin- differences were observed between the various groups gle, 6 mg, fixed dose, 24 hours after completing in terms of OS. The authors conclude that although chemotherapy. Filgrastim 5 µg/kg was administered priming with G-CSF can improve the CR rate, the use daily, beginning 24 hours after chemotherapy and con- of G-CSF during and/or after chemotherapy has no tinuing until the absolute neutrophil count (ANC) was 9 9 effect on the long-term outcome of elderly AML ≥10×10 /L for 3 consecutive days or ≥10×10 /L for 1 patients. Even less satisfactory results have been day. Median time to recovery from severe neutropenia reported in a recent update of the AMLCG 1999 trial was 22.0 days for each treatment group during induc- by the German group.13 In this study, patients 16 to 85 tion and 17.0 and 16.5 days during consolidation for years of age with de-novo or secondary AML received pegfilgrastim and filgrastim, respectively. two induction regimens, TAD/HAM or HAM/HAM, After a single injection, median pegfilgrastim serum standard consolidation, prolonged maintenance or concentrations remained above clinically relevant con- autologous stem cell transplantion. By randomization, centrations throughout the prolonged neutropenia and G-CSF was given with all chemotherapy courses dur- declined upon ANC recovery, consistent with a neu- haematologica reports 2006; 2(issue 7):May 2006 97 A. Ciolli et al. stimulating factor in adult patients (_ 55 to 70 years of age) with trophil-mediated clearance mechanism. Compared acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995;86:457-462. with 1 pegfilgrastim injection, a median of 16 filgras- 7. Lowenberg B, Zittoun R, Kerkhofs H, et al. On the value of inten- tim injections were required in induction and 13 in sive remission induction chemotherapy in elderly patients of 65+ consolidation to ensure ANC recovery.
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