REVIEW Role of Cytokines in the Treatment of Acute Leukemias

Role of cytokines in the treatment of acute leukemias: a review

F Ravandi

Department of Leukemia, University of Texas – MD Anderson Cancer Center, Houston, TX, USA

Myeloid growth factors, such as granulocyte colony-stimulat- Furthermore, the concomitant exposure of leukemic cells to ing factor and granulocyte–macrophage colony-stimulating cytarabine and growth factors results in an increased level of the factor, have been used to decrease the duration of chemother- active cytarabine-triphosphate (Ara-CTP) and increased DNA apy-induced neutropenia and thereby reduce the incidence and 11 severity of infections in various regimens used to treat acute uptake of radiolabeled cytarabine. myeloid leukemia and acute lymphoblastic leukemia. These growth factors have also been used to recruit dormant myeloid leukemia cells into the S phase of cell cycle in order to increase Use of growth factors after chemotherapy. A significant their susceptibility to the antileukemic effects of agents such as concern in the use of CSFs during AML induction therapy was cytarabine. Multiple prospective randomized trials have exam- the stimulation of residual normal precursors in the marrow, ined the benefit and safety of the addition of growth factors leading to increased susceptibility to chemotherapy and before, during, and after chemotherapy. A reduction in the consequent prolonged cytopenia. A further concern was the duration of neutropenia has been the most consistent finding; potential stimulation of leukemic cell growth. However, the this has not been associated with stimulation of leukemia cells, the main concern of using this strategy. Unfortunately, few safety of administration of growth factors before, during, and studies have reported a benefit in prolonging the duration of after induction chemotherapy has now been borne out by the disease-free survival or overall survival. Other cytokines, results of small exploratory studies as well as large randomized including interleukins and thrombopoietin, have also been trials (Tables 1 and 2). evaluated for their theoretical ability to recruit immune The most consistent finding in trials where either G- or mechanisms to eradicate residual leukemia burden after GM-CSF is administered after completion of chemotherapy has chemotherapy, and to stimulate platelet production. In this been acceleration of neutrophil recovery by approximately 2–7 review, we summarize the clinical experience with these growth 12–21 factors in treating acute leukemias. days. Owing to the lack of comparative trials, there are no Leukemia (2006) 20, 563–571. doi:10.1038/sj.leu.2404152; indications that one cytokine may be superior to the other in this published online 23 February 2006 regard. Similarly, the theoretical concern of an adverse effect on Keywords: G-CSF; GM-CSF; acute leukemia; clinical trials platelet recovery does not appear to be relevant. However, this strategy has not become the standard of care as it is not clear that such acceleration of neutrophil recovery is clinically meaningful.3 Such limited shortening of the duration of neutropenia has not been accompanied by a reduction in the Myeloid colony-stimulating factors incidence of documented, severe and fatal infections.12,15,20 Furthermore, in the majority of these studies, the complete Acute myeloid leukemia remission (CR) rate,12,15–19 disease-free survival (DFS),15–18,20 Myeloid colony-stimulating factors, including granulocyte and overall survival (OS)12,14–18 are not affected by growth colony-stimulating factor (G-CSF) and granulocyte–macrophage factor therapy. Some of these studies have demonstrated an colony-stimulating factor (GM-CSF), have been evaluated as increase in the CR rate,13,14 and even the OS, when using adjuncts in the treatment of patients with acute myeloid 13 1–4 growth factor therapy. However, it is likely that confounding leukemia (AML). A number of clinical trials have examined issues contribute to these differences.3 In the study by Rowe whether these agents can shorten the duration of chemotherapy- et al.,13 a higher rate of severe infections and a shorter median induced neutropenia and reduce the incidence of infections survival than expected in the placebo group were potential (Table 1). Other studies have evaluated the efficacy of these contributing factors to the differences in the OS. However, it agents to enhance the antileukemic effects of chemotherapy is also important to consider that the majority of these by recruiting dormant leukemia cells into a sensitive phase of studies report their data on an intent-to-treat basis and it is cell cycle (Table 2). This strategy has been based on the premise possible that the beneficial clinical effects of these cytokines that clonogenic leukemic cells are quiescent, and as a result, may be underestimated owing to their early discontinuation as a resistant to the effects of standard chemotherapeutic agents. As result of real or perceived toxicity. This is particularly important such, the use of growth factors may activate these cells and 5 in patients at the highest risk of infection-related mortality. thereby promote their responsiveness to chemotherapy. In vitro Uncontrolled22 as well as prospective randomized trials20 studies have demonstrated that the simultaneous exposure of have investigated the benefit of administering growth factors leukemic cells to cell-cycle-specific drugs such as cytarabine 6–10 after intensive consolidation chemotherapy in patients who and cytokines enhances the cytotoxic effects of the former. have achieved CR. In the study by Harousseau et al.,20 194 patients in CR after induction therapy were randomized to Correspondence: Dr F Ravandi, Department of Leukemia, Box 428, receive G-CSF (100 patients), or no G-CSF (94 patients) after two University of Texas – MD Anderson Cancer Center, 1515 Holcombe courses of intensive consolidation chemotherapy. The median Boulevard, Houston, TX 77030, USA. E-mail: [email protected] duration of neutropenia, the median duration of hospitalization Received 3 October 2005; revised 5 January 2006; accepted 16 and the median duration of antifungal therapy were reduced for January 2006; published online 23 February 2006 the G-CSF group, whereas the incidence of microbiologically Cytokine therapy in acute leukemias F Ravandi 564 Table 1 Prospective randomized trials of myeloid colony-stimulating factors postinduction therapy in AML

Reference Patients Age CSF type CSF Comments Neutropenia (n) (years) timing shortened by (days)

Stone et al.12 388 X60 GM-CSF A Shortened duration of neutropenia 2 Rowe et al.13 124 55–70 GM-CSF A Shortened duration of neutropenia, reduced 4, 7* infectious and treatment-related toxicity, improved OS Dombret et al.14 233 X65 G-CSF A Shortened duration of neutropenia, increased 6 CR rate Godwin et al.15 234 455 G-CSF A Shortened duration of neutropenia, decreased 15% (95% duration but not incidence of infections, shorter CI, 3–27%) duration of fever and antibiotic use

Heil et al.16 521 416 G-CSF A Shortened duration of neutropenia, reduction in 5 duration of fever, parenteral antibiotic use and hospitalization Zittoun et al.23 102 15–60 GM-CSF B, D, A Decreased CR rate Lowenberg et al.21 253 15–60 GM-CSF D, A Shortened duration of neutropenia 4 Bradstock et al.17 112 16–60 G-CSF A Shortened duration of neutropenia, reduction in 4 duration of antibiotic use Usuki et al.18 245 415 G-CSF A Shortened duration of neutropenia 6 Goldstone et al.19 226 456 G-CSF A Shortened duration of neutropenia 5 Harousseau et al.20 194 15–60 G-CSF A Shortened duration of neutropenia, intravenous 7 antibiotic/antifungal therapy and hospitalization Amadori et al.24 722 X61 G-CSF D, A Shorter duration of neutropenia, intravenous 5 antibiotic/antifungal therapy and hospitalization o80 Abbreviations: CSF, colony-stimulating factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; G-CSF: granulocyte colony-stimulating factor; A, after chemotherapy; B, before chemotherapy; D, during chemotherapy. *Recovery to 500/ml and 1000/ml, respectively.

Table 2 Prospective randomized trials of CSFs used in ‘priming’ AML for therapy

Reference Patients (n) Age (years) CSF type CSF timing Comments

Zittoun et al.23 102 15–60 GM-CSF B, D, A No response/survival benefit Lowenberg et al.32 326 X61 GM-CSF D, A No response/survival benefit Lowenberg et al.21 253 15–60 GM-CSF D, A No response/survival benefit Heil et al.33 80 15–75 GM-CSF B, D, A No response/survival benefit Witz et al.29 240 55–75 GM-CSF D, A Improved 2-year DFS Hast et al.34 93 35–90 GM-CSF B, D, A No response/survival benefit, increased side effects Uyl-de Groot et al.35 318 X60 GM-CSF B, D, A No response/survival benefit Ohno et al.36,* 58 16–66 G-CSF B, D, A No response/survival benefit Estey et al.91 215 Median 65 G-CSF D, A No response/survival benefit Lowenberg et al.30 640 18–60 G-CSF B, D Increased DFS and OS in standard-risk patients Rowe et al.40 245 455 GM-CSF B, D, A No response/survival benefit Thomas et al.37,* 192 o65 GM-CSF D Increased time to progression (trend) Lofgren et al.31 110 X60 GM-CSF B, D, A No survival benefit Buchner et al.92 895 16–83 G-CSF B, D No DFS or OS benefit Amadori et al.24 722 X61 G-CSF D, A Improved CR, no survival benefit o80 Abbreviations: CSF, colony stimulating factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; B, before chemotherapy; D, during chemotherapy; A, after chemotherapy; DFS, disease-free survival; OS, overall survival. *Studies in relapsed/refractory patients.

documented infections, the toxic death rate, the 2-year DFS and tion of high-dose cytarabine-containing chemotherapy, and a the 2-year OS were not affected by G-CSF administration.20 reduction in the duration of neutropenia of 4 days (P ¼ 0.0005) Considerable variation of the chemotherapy agents and their in patients who received the cytokine was reported.17 This is of dose/schedule used in these trials limits the ability to discern a similar magnitude to other studies employing standard-dose their potential effect on the outcome independent of the growth cytarabine.12–16,21,23 factor therapy (Table 3). However, a similar reduction in the Other problems with the direct comparison of these studies duration of neutropenia by several days suggests that the effect include the frequency of monitoring of the blood counts in the of the cytokines is independent of the regimen or schedule. For different studies, different age ranges of the study populations example, in a study by the Australian Leukemia Study Group (Table 1), lack of uniformity in time of initiation and duration of (ALSG), glycosylated G-CSF was administered after the comple- growth factor support, differing outcome of the placebo groups,

Leukemia Cytokine therapy in acute leukemias F Ravandi 565 Table 3 Chemotherapy schedules in various trials

Reference Chemotherapy schedule CSF type and dose

Stone et al.12 D 45 mg/m2 Â 3 days, A 200 mg/m2 Â 7 days GM-CSF 200 mg/m2 daily, start day 8 Rowe et al.13 D 60 mg/m2 Â 3 days, A 200 mg/m2 Â 7days GM-CSF 250 mg/m2 daily, start day 11 after AML-free marrow Dombret et al.14 D 45 mg/m2 Â 4 days, A 200 mg/m2 Â 7 days G-CSF 5 mg/kg daily, start day 9 Godwin et al.15 D 45 mg/m2 Â 3 days, A 220 mg/m2 Â 7 days G-CSF 400 mg/m2 daily, start day 11 if marrow blasts o5% on day 10 Heil et al.16 D 45 mg/m2 Â 3 days, A 220 mg/m2 Â 7 days, G-CSF 5 mg/kg daily, start day 8 E 100 mg/m2 Â 5 days Zittoun et al.23 D 45 mg/m2 Â 3 days, GM-CSF 5 mg/kg daily, start day 8 or day À1 A 200 mg/m2 Â 7 days Lowenberg et al.21 D 45 mg/m2 Â 3 days, GM-CSF 5 mg/kg daily, start day 8 or day À1 A 200 mg/m2 Â 7 days Lowenberg et al.32 D 30 mg/m2 Â 3 days, GM-CSF 5 mg/kg daily, start day before Daunorubicin A 200 mg/m2 Â 7 days Bradstock et al.17 Id 12 mg/m2 Â 3 days, G-CSF 5 mg/kg daily, start day 8 A 3 g/m2 Â 8 doses, E 75 mg/m2 Â 7 days Usuki et al.18 Variable G-CSF 200 mg/m2 daily, start 48 h after chemotherapy Goldstone et al.19 DAT versus ADE versus MAC for induction G-CSF 293 mg daily, start day +8 Harousseau et al.20 Id 8 mg/m2 Â 3 days, G-CSF 5 mg/kg daily, start day after chemotherapy A 200 mg/m2 Â 7 days ICC1: M 12 mg/m2 Â 2 days, A 3 g/m2 Â 8 doses ICC2: Am 150 mg/m2 Â 5 days, E 100 mg/m2 Â 5 days Lofgren et al.31 A 1000 mg/m2 twice daily Â 3 days, GM-CSF 200 mg/m2, start one day before chemotherapy M 12 mg/m2 daily Â 3, E 200 mg/m2 daily Â 3 Amadori et al.24 M 7 mg/m2 on days 1, 3 and 5, G-CSF 150 mg/m2 daily, during and after chemotherapy A 100 mg/m2 Â 7 days E 100 mg/m2 Â 3 days Abbreviations: A, cytarabine; D, daunorubicin; E, etoposide; Id, idarubicin; M, mitoxantrone; T, thioguanine, ICC, intensive consolidation chemotherapy; CSF, colony-stimulating factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; Am, amsacrine.

and diversity of decision-making process regarding antibiotic appropriate to consider initiating these growth factors in subsets therapy and hospitalization.3 Despite these differences, the of patients who are expected to have a prolonged and/or majority of these trials conclude that growth factors can be clinically complicated period of neutropenia, such as elderly safely administered after chemotherapy to patients with AML or heavily pretreated patients.3 However, such recommendation and they accelerate the recovery of neutrophils.19,20,24 Any is at best based on incomplete data and requires further disadvantage in their use would relate to the economics of such confirmation. a strategy and whether the benefits justify the significant cost that may be associated with such a universal approach. Several randomized studies have reported a beneficial effect Concomitant use of growth factors with chemotherapy. on the duration of fever, parenteral antibiotic use, and Relapse is the most important cause of treatment failure in AML. hospitalization (Table 1) suggesting that the use of growth This is particularly true for the younger patients who are able factors is of economical benefit.15,17,18,20 An analysis of the to avoid therapy-related mortality.27 The likely cause of such study from Southwest Oncology Group (SWOG) did not failure is the minimal residual disease that has escaped the demonstrate a reduction in the overall cost of supportive care cytotoxic effects of chemotherapy. Primary resistance to despite the beneficial effect of G-CSF on the duration of chemotherapy, particularly in the elderly patients, accounts for neutropenia and infections.15,25 However, according to a report another major cause of treatment failure and may be related to from the study by the Eastern Co-operative Oncology Group the existence of a small population of quiescent clonogenic (ECOG), the use of GM-CSF was associated with cost savings in blasts, which are resistant to chemotherapy.5 addition to a survival benefit and a reduction in duration of In vitro and in vivo studies have demonstrated the ability of neutropenia and severity of infections.13,26 Furthermore, the growth factors to recruit these quiescent cells into a phase of cell costs of therapy in the placebo groups in the two trials were cycle where these are more susceptible to the cytotoxic effects significantly different, leading to the suggestion that the cost of chemotherapy.11,28 Exposure of leukemic cells to growth analysis could be institution-specific.3 factors and cytarabine increases intracellular ara-CTP and DNA On the basis of the available data, no specific recommenda- uptake of radiolabeled cytarabine into the leukemic cells.6,7,9 tions regarding the use of G-CSF and GM-CSF in postinduction These preclinical studies provided the rationale for a number of period can be made with certainty. It is reasonable to assume trials investigating the safety and efficacy of concomitant that these agents are safe to administer and can shorten the administration of colony-stimulating factors with chemotherapy neutropenic period; it is, however, unclear whether their (Table 2). universal prophylactic administration translates into a clinical This strategy has not been consistently effective and benefit. On the basis of the available data, it may be more no significant clinical benefit has been reported in the majority

Leukemia Cytokine therapy in acute leukemias F Ravandi 566 of these trials (Table 2). In a study by Witz et al.29 conducted Similar studies in previously treated patients with relapsed or by the Groupe Ouest Est Leucemies Aigues Myeloblastiques refractory AML have also failed to demonstrate a significant (GOELAM), a significant improvement in the 2-year DFS in the benefit.36,37 However, these studies as well some uncontrolled patients who received GM-CSF during and after induction trials38,39 have demonstrated the safety of this approach with no chemotherapy as compared to the placebo group (48 versus evidence of an adverse effect on the outcome. However, Zittoun 21%; P ¼ 0.003) was noted. This was highly significant in the et al.23 reported a significant decrease in the CR rate when cohort of patients aged 55–64 years , but only marginal in GM-CSF was administered after chemotherapy (with or without patients X65 years of age. There was a trend toward a longer OS concomitant therapy during induction). This lower CR rate in the GM-CSF group (P ¼ 0.082). The investigators concluded appeared to be related to increased resistance and persistent that concomitant administration of GM-CSF with chemotherapy leukemia. shortened the time to neutrophil recovery and prolonged DFS Despite the existence of multiple clinical studies evaluating and OS, particularly in patients 55–64 years. The CR rate was the role of growth factors in priming the leukemic cells, few not improved.29 Lowenberg et al.30 conducted a multicenter studies have evaluated the cellular in vitro data, monitoring trial where patients age 18–60 years with newly diagnosed the attempted recruitment of the target leukemic blasts into AML received cytarabine-based chemotherapy with G-CSF the chemotherapy sensitive phase of cell cycle. In the report (321 patients) or without G-CSF (319 patients). The regimen by Rowe et al.,40 106 patients (including 53 patients receiving consisted of two cycles of chemotherapy with Cycle 1 including GM-CSF and 53 receiving placebo) had correlative samples cytarabine 200 mg/m2 daily on days 1–7 and idarubicin obtained on days 0 and 2 of the study. The mean change in 12 mg/m2 on days 6, 7, and 8. Cycle 2 consisted of cytarabine S phase percentage for placebo patients was 0.25%, and the 1000 mg/m2 every 12 h on days 1–6 and amsacrine 120 mg/m2 mean change with GM-CSF was 2.05% (P ¼ 0.003), confirming on days 4, 5, and 6. Granulocyte colony-stimulating factor was the intended effect of GM-CSF. However, this increase did not given concurrently with chemotherapy only. After a median differ between the patients attaining CR and those who did not, follow-up of 55 months, a higher rate of DFS was reported in the suggesting that priming for 48 h with GM-CSF, at the dose and patients in CR who received G-CSF (42 versus 33% at 4 years, timing of the study, did not have a sufficient effect to translate to P ¼ 0.02), owing to a reduced probability of relapse (relative clinical benefit.40 risk, 0.77; 95% confidence interval (CI) 0.61–0.99; P ¼ 0.04). Differences in the design of these trials including the Overall, the OS and DFS were not significantly better in the sequence of administration of growth factors, and differences G-CSF-treated patients (P ¼ 0.16).30 However, in the subgroup in the chemotherapeutic agents and patient characteristics of patients with standard risk disease, the OS at 4 years was make comparison of these studies difficult. Additional trials better for the patients receiving G-CSF (45 versus 35%; relative are necessary before the strategy of priming with growth factors risk of death, 0.75; 95% CI, 0.59–0.95; P ¼ 0.02) and DFS was could be recommended as standard of care.3,5 It may be the 45 versus 33% (relative risk, 0.70; 95% CI, 0.55–0.90; case that certain subsets of patients may benefit from such P ¼ 0.006). The outcome for patients with unfavorable prognosis strategy.41 It may therefore be more appropriate to design was not improved and the small number of patients in the studies in specific subgroups of patients.3 favorable subgroup limited a meaningful analysis. More recently, Lofgren et al.31 treated 110 consecutive patients aged 60 years and older with the combination of Acute lymphoblastic leukemia cytarabine 1 g/m2 twice daily, mitoxantrone 12 mg/m2 daily, The success in the treatment of acute lymphoblastic leukemia and etoposide 200 mg/m2 daily for 3 days. Patients were (ALL) in children and younger adults has largely been attributed randomized to receive or not receive GM-CSF 200 mg/m2 once to risk-adapted application of intensified regimens for induction daily beginning 1 day before start of chemotherapy and and consolidation therapy as well as improvements in suppor- continued until the absolute neutrophil count (ANC) was greater tive care.42,43 Adaptation of successful pediatric regimens has than 1.0 Â 109/l.31 Complete remission was achieved by 64% of led to significant improvements in remission induction for patients not receiving GM-CSF and 65% of patients who adults. However, the ability to maintain DFS has remained received the growth factor. Furthermore, the median remission disappointingly low for adults, with only 25–50% of these duration and the median OS were not statistically superior in the patients achieving long-term DFS.43,44 Further attempts in GM-CSF arm. The median time to neutrophil recovery was 25 improving disease outcome are based on a better understanding versus 17 days (P ¼ 0.03) in favor of GM-CSF-treated arm. Also, of the biology of ALL, and improved supportive care. fewer positive blood cultures were reported in this group. Infectious complications during the prolonged periods of In another recently published study, 722 patients with newly neutropenia have been a major cause of morbidity and diagnosed AML were randomized into four treatment arms: mortality. Several trials have investigated the role of growth (1) no G-CSF (glycosylated); (2) G-CSF during chemotherapy; factors in accelerating the neutrophil recovery.45–48 Prospective, (3) G-CSF after chemotherapy until recovery of neutrophils or randomized studies in children49–55 and adults56–61 with ALL day 28; and (4) G-CSF during and after chemotherapy.24 The CR have investigated the overall safety and benefit of administration rate was 48.9% in group (1), 52.2% in group (2), 48.3% in group of growth factors together with or after dose-intensive ALL (3), and 64.4% in group (4). Complete remission rate was therapy (Tables 4 and 5). The administration of growth factors in significantly higher in patients who received G-CSF during the majority of these studies reduced the hematological toxicity chemotherapy (58.3% in groups 2 þ 4, versus 48.6% in groups of dose intensification and led to better compliance with the 1 þ 3, P ¼ 0.009). No significant difference was reported for treatment schedule. Ohno et al.57 compared three doses of groups 1 þ 2 versus 3 þ 4. Patients who received G-CSF after G-CSF (2, 5, and 10 mg/kg per day) and recommended 5 mg/kg chemotherapy had a shorter time to neutrophil recovery and a per day as the optimal dose. Delorme et al.62 suggested that the shorter hospitalization (Po0.001 and Po0.001, respectively).24 improvement in chemotherapy dose intensity in children with However, several trials examining the role of ‘priming’, using high-risk ALL was not associated with an increase in the cost of either GM-CSF or G-CSF in newly diagnosed patients have not therapy. Pui et al.55 reported that the use of G-CSF in children reported any improvements in CR rate, DFS, or OS.21,32–35 with ALL was associated with a significantly lower incidence of

Leukemia Cytokine therapy in acute leukemias F Ravandi 567 Table 4 Pediatric studies of growth factors in ALL

Reference Patients (n) CSF type Result

Welte et al.49 34 G-CSF Reduced incidence and duration of febrile neutropenia, reduced incidence of culture-confirmed infections and duration of antibiotic use Laver et al.50 56 G-CSF Reduced duration of neutropenia during continuation phase Clarke et al.51 17 G-CSF Reduced duration and severity of neutropenia and duration in hospital Michel et al.52 67 G-CSF Increased chemotherapy dose intensity, reduced duration of neutropenia, fever, intravenous antibiotics and hospitalization, prolonged thrombocytopenia, No benefit for EFS Little et al.53 46 G-CSF Reduced rate of hospitalization Heath et al.54 287 G-CSF Reduced duration of neutropenia, no benefit in incidence of febrile neutropenia, duration of hospitalization, therapy completion time, EFS, or OS Pui et al.55 164 G-CSF Reduced duration of hospitalization and fewer documented infections Abbreviations: CSF, colony-stimulating factor; G-CSF: granulocyte colony-stimulating factor; DFS, disease-free survival; OS, overall survival

Table 5 Studies of growth factors in adult ALL

Reference Patients (n) CSF type Result

Ottmann et al.56 67 G-CSF Reduction of duration of neutropenia, reduced delays and earlier completion Ohno et al.57 41 G-CSF Faster neutrophil recovery, reduced incidence of febrile neutropenia Geissler et al.58 53 G-CSF Reduction in duration of neutropenia, reduced incidence of febrile neutropenia and documented infections Larsen et al.59 198 G-CSF Reduction of duration of neutropenia and thrombocytopenia and hospitalization, higher CR rate and fewer deaths during induction, no effect on DFS and OS Ifrah et al.60 67 GM-CSF Improved incidence of mucositis during induction Holowiecki et al.61 64 G-CSF Reduced duration of neutropenia, lower infection rate, faster completion of induction- consolidation, shorter hospital stay, higher 2-year survival, lower 2-year relapse rate Abbreviations: CSF, colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; DFS, disease-free survival; OS, overall survival. documented infections, shorter median hospital stays, and fewer Clinical responses have been reported, but generally these were delays in starting consolidation chemotherapy.55 In the study by only observed in patients with limited disease.66,67 Toxicity in Larsen et al.,59 there were no detectable differences during the the form of fever, hypotension, vascular leak, thrombocytope- induction course for the neutrophil recovery end points or nia, rash, and sepsis has generally been acceptable, in particular hospitalization between patients younger or older than 60 years. for lower dose regimens.69 Platelet recovery was significantly faster for patients X60 years Owing to the higher likelihood of efficacy of such biological of age, who received G-CSF (17 days versuss 26 days; P ¼ 0.04) therapy in patients with minimal residual disease, IL-2 has also In this age group, the CR rate (81 versuss 55%) and induction been investigated as maintenance therapy in second or later mortality rate (10 versuss 25%) were in favor of patients who remission,70,71 or after autologous or allogeneic transplanta- received G-CSF; although these differences were not statistically tion.72–77 On the basis of the efficacy of IL-2 in these trials, it significant, probably due to the small number of patients.59 They was hypothesized that the use of IL-2 in first CR might be suggested that the impact of growth factor therapy is likely to be relatively more beneficial.78 Cortes et al.78 administered IL-2 most apparent in the subset of patients who would otherwise 4.5 Â 105 U/m2 daily by continuous infusion for 12 weeks, plus have the slowest recovery, including the elderly, the malnouri- boluses of 1 Â 106 U/m2 on day 8 and weekly thereafter to 18 shed and those patients who had received other myelosuppres- patients with AML in first CR and compared them to historical sive medication or had ongoing infections.59 In summary, the controls. Although IL-2 administration was feasible and toler- use of growth factors accelerates neutrophil recovery, and may able, no statistically significant improvements in DFS and CR allow an increase in chemotherapy dose intensity. In some duration was reported.78 A study by CALGB examined the studies, this has been associated with an improved CR rate and tolerability of IL-2 after intensive chemotherapy in 35 elderly survival. patients with AML in first CR.79 Patients received low-dose IL-2 (1 Â 106 IU/m2/day subcutaneously for 90 days) or low dose IL-2 with intermittent pulse doses (6–12 Â 106 IU/m2/day subcuta- Other cytokines used in acute leukemias neously for 3 days) every 14 days for a maximum of five pulses. Both regimens were well tolerated with similar toxicity profile Interleukin-2 including grade 1–2 fatigue, fever, nausea, anemia, injection site Interleukin-2 (IL-2) has been of limited use in the treatment of reactions, and thrombocytopenia. Grade 3–4 hematological hematological malignancies, mainly because of the inability toxicity was uncommon.79 The median OS for the group was 1.1 to mount a host-cell-mediated immune response as a result of years. Similarly, Sievers et al.80 administered IL-2 9 Â 106 IU/m2 host-related and chemotherapy-induced immunosuppression. daily by continuous infusion intermittently to 21 children in CR The known ability of IL-2 to recruit T-cells and in particular and reported reasonable tolerability. The results of a study of natural killer (NK) cells, as well as the efficacy of the immune IL-2 in the late post-CR setting conducted by CALGB are as system to eradicate minimal residual leukemia provided the yet not available. At present, the exact role of IL-2 in the rational for a number of studies of IL-2 in acute leukemias.63–68 management of patients with acute leukemia remains unclear.

Leukemia Cytokine therapy in acute leukemias F Ravandi 568 Pegylated rHuMGDF blasts in transformation (RAEBt).87 There was no statistically Recombinant human megakaryocyte growth and development significant difference between the three study arms with regards factor (rHuMGDF) is a potent thrombopoietic agent and has to response rate and degree of cytopenia, and the authors been modified by the addition of a polyethylene glycol moiety concluded that the combination of low-dose cytarabine and to increase its circulating half-life. Randomized, placebo- GM-CSF or IL-3 cannot be recommended for routine use in this controlled trials examining the role of pegylated rHuMGDF population.87 Palifermin is an N-terminal, truncated version (PEG-rHuMGDF) in acute leukemia therapy have been repor- of endogenous keratinocyte growth factor with keratinocyte- ted.81,82 Archimbaud et al.82 randomized 108 adult patients stimulating activity.88 In a randomized study, the effects of with de novo AML to receive one of two dose schedules of PEG- palifermin were compared with placebo in 212 patients with rHuMGDF or placebo. There was no effect on the median time hematological cancers undergoing chemotherapy.89 Palifermin to transfusion-independent platelet recovery (420 Â 109/l). reduced the duration and severity of oral mucositis after Similarly, there was no apparent effect on the stimulation of intensive chemotherapy and radiotherapy. Its role in the leukemia, time to neutrophil recovery or red blood cell treatment of patients with acute leukemia outside the setting transfusion requirements.82 Schiffer et al.81 randomized newly of transplantation remains unclear. Newer agents such as AMG- diagnosed AML patients to receive either 2.5 or 5 mg/kg/day of 531, a thrombopoietin receptor ligand are undergoing further PEG-rHuMGDF or a placebo after completion of chemotherapy. evaluation.90 A higher platelet count in remission was achieved after cytokine therapy, but there was no improvement in platelet transfusion requirements or CR rate. The drug was tolerated well in both Conclusions studies.81,82 Further development of PEG-rHuMGDF has been hindered by reports of development of cytopenias with Increased understanding of the role of a number of cytokines neutralizing antibodies to thrombopoietin after its use to support and chemokines has led to the evaluation of their role as multicycle chemotherapy.83 adjuncts in the management of patients with hematological malignancies. A number of clinical trials have examined the role of myeloid colony-stimulating factors in treating patients with Interleukin-11 acute leukemias and have, in general, suggested a beneficial Human IL-11 is a multipotential cytokine that is involved in effect by reduction of duration of neutropenia as well as an numerous biological activities including hematopoiesis and also improvement in dose intensity of chemotherapy. However, the displays anti-inflammatory properties. Interleukin-11 has been majority of these studies have not reported a meaningful benefit approved for the treatment of chemotherapy-induced thrombo- in increasing the OS or DFS. A recent trial did show an cytopenia. Estey et al.84 treated 51 patients (X60 years) with improvement in OS and DFS in patients with standard-risk AML AML or advanced MDS with gemtuzumab ozogamicin (GO) when G-CSF was administered during induction chemo- with or without IL-11. Addition of IL-11 to GO was associated therapy.30 Overall, however, the exact clinical role of colony- with an increased CR rate, but no survival benefit was reported. stimulating factors in the management of acute leukemias Furthermore, when compared with historical patients treated in remains undefined. the same institution with standard chemotherapy, no benefit A number of other cytokines have also been evaluated for could be demonstrated for GO/IL-11-treated patients.84 Admin- their theoretical effects in recruiting the immune system to istration of IL-11 has been reported to reduce the incidence of eradicate minimal residual leukemia. In general, the application bacteremia in patients with acute leukemias undergoing of these agents has been limited owing to the difficulties chemotherapy.85 In a randomized, double-blind, placebo- inherent to the biological function and delivery of such controlled study, 40 patients with hematological malignancies pleiotropic agents, where doses needed to achieve the desired (including 21 with AML and 14 with ALL), who were under- immune enhancement are generally associated with significant going chemotherapy received either recombinant human IL-11 side effects. Newer cytokines and megakaryocyte-stimulating (rhIL-11) 50 mg/kg or placebo by daily subcutaneous injection factors are likely to provide us with more options in treating from the day before starting chemotherapy until resolution of patients with hematological malignancies recovering from neutropenia or day 21.85 Significantly fewer patients receiving chemotherapy. the cytokine developed bacteremia than those receiving the placebo (P ¼ 0.02). Time to the first bacteremic event was also longer for the patients who received rhIL-11 than for those References who received placebo (P ¼ 0.03).85 The authors concluded that rhIL-11 reduces the frequency of bacteremia possibly by 1 Schiffer CA. Hematopoietic growth factors as adjuncts to the gastrointestinal cytoprotective or immunological mechanisms. treatment of acute myeloid leukemia. Blood 1996; 88: 3675–3685. 2 Geller RB. Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 1996; 14: 1371–1382. Other cytokines 3 Estey EH. Growth factors in acute myeloid leukaemia. Best Pract A number of other cytokines have been evaluated as adjuncts Res Clin Haematol 2001; 14: 175–187. 4 Rowe JM, Liesveld JL. Hematopoietic growth factors in acute to the treatment of patients with acute leukemia. Interleukin-3 leukemia. Leukemia 1997; 11: 328–341. (IL-3) was evaluated in combination with induction chemo- 5 Schiffer CA. Hematopoietic growth factors and the future of therapy including daunorubicin or mitoxantrone and cytarabine therapeutic research on acute myeloid leukemia. N Engl J Med in 20 patients with AML and was reported to be tolerated with 2003; 349: 727–729. acceptable toxicity.86 More recently, the investigators at the 6 Miyauchi J, Kelleher CA, Wang C, Minkin S, MCculloch EA. EORTC reported the results of a randomized study of low-dose Growth factors influence the sensitivity of leukemic stem cells to cytosine arabinoside in culture. Blood 1989; 73: 1272–1278. cytarabine, either alone or in combination with GM-CSF or 7 Cannistra SA, Groshek P, Griffin JD. Granulocyte–macrophage IL-3 in 180 patients with myelodysplastic syndrome (MDS) colony-stimulating factor enhances the cytotoxic effects of cytosine including 73 patients with refractory anemia with excess arabinoside in acute myeloblastic leukemia and in the myeloid

Leukemia Cytokine therapy in acute leukemias F Ravandi 569 blast crisis phase of chronic myeloid leukemia. Leukemia 1989; 3: 22 Moore JO, Dodge RK, Amrein PC, Kolitz J, Lee EJ, Powell B et al. 328–334. Granulocyte-colony stimulating factor (filgrastim) accelerates 8 Bhalla K, Holladay C, Arlin Z, Grant S, Ibrado AM, Jasiok M. granulocyte recovery after intensive postremission chemotherapy Treatment with interleukin-3 plus granulocyte–macrophage for acute myeloid leukemia with aziridinyl benzoquinone and colony-stimulating factors improves the selectivity of Ara-C mitoxantrone: Cancer and Leukemia Group B study 9022. Blood in vitro against acute myeloid leukemia blasts. Blood 1991; 78: 1997; 89: 780–788. 2674–2679. 23 Zittoun R, Suciu S, Mandelli F, de Witte T, Thaler J, Stryckmans P 9 te Boekhorst PA, Lowenberg B, Vlastuin M, Sonneveld P. Enhanced et al. Granulocyte–macrophage colony-stimulating factor asso- chemosensitivity of clonogenic blasts from patients with acute ciated with induction treatment of acute myelogenous leukemia: a myeloid leukemia by G-CSF, IL-3 or GM-CSF stimulation. randomized trial by the European Organization for Research and Leukemia 1993; 7: 1191–1198. Treatment of Cancer Leukemia Cooperative Group. J Clin Oncol 10 Inatomi Y, Toyama K, Clark SC, Shimizu K, Miyauchi J. 1996; 14: 2150–2159. Combinations of stem cell factor with other hematopoietic growth 24 Amadori S, Suciu S, Jehn U, Stasi R, Thomas X, Marie JP et al. Use factors enhance growth and sensitivity to cytosine arabinoside of of glycosylated recombinant human G-CSF (lenograstim) during blast progenitors in acute myelogenous leukemia. Cancer Res and/or after induction chemotherapy in patients 61 years of age 1994; 54: 455–462. and older with acute myeloid leukemia: final results of AML-13, 11 Hiddemann W, Kiehl M, Zuhlsdorf M, Busemann C, Schleyer E, a randomized phase-3 study. Blood 2005; 106: 27–34. Wormann B et al. Granulocyte–macrophage colony-stimulating 25 Bennett CL, Hynes D, Godwin J, Stinson TJ, Golub RM, factor and interleukin-3 enhance the incorporation of cytosine Appelbaum FR. Economic analysis of granulocyte colony stimulat- arabinoside into the DNA of leukemic blasts and the cytotoxic ing factor as adjunct therapy for older patients with acute effect on clonogenic cells from patients with acute myeloid myelogenous leukemia (AML): estimates from a Southwest leukemia. Semin Oncol 1992; 19 (Suppl 4): 31–37. Oncology Group clinical trial. Cancer Invest 2001; 19: 603–610. 12 Stone RM, Berg DT, George SL, Dodge RK, Paciucci PA, 26 Bennett CL, Stinson TJ, Tallman MS, Stadtmauer EA, Marsh RW, Schulmann P et al. Granulocyte–macrophage colony-stimulating Friedenberg W et al. Economic analysis of a randomized placebo- factor after initial chemotherapy for elderly patients with primary controlled phase III study of granulocyte–macrophage colony acute myelogenous leukemia. Cancer and Leukemia Group B. stimulating factor in adult patients (455 to 70 years of age) with N Engl J Med 1995; 332: 1671–1677. acute myelogenous leukemia. Eastern Cooperative Oncology 13 Rowe JM, Andersen JW, Mazza JJ, Bennett JM, Paietta E, Hayes FA Group (E1490). Ann Oncol 1999; 10: 177–182. et al. A randomized placebo-controlled phase III study of 27 Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. granulocyte–macrophage colony-stimulating factor in adult N Engl J Med 1999; 341: 1051–1062. patients (455 to 70 years of age) with acute myelogenous 28 Cannistra SA, DiCarlo J, Groshek P, Kanakura Y, Berg D, Mayer RJ leukemia: a study of the Eastern Cooperative Oncology Group et al. Simultaneous administration of granulocyte–macrophage colony-stimulating factor and cytosine arabinoside for the (E1490). Blood 1995; 86: 457–462. 14 Dombret H, Chastang C, Fenaux P, Reiffers J, Bordessoule D, treatment of relapsed acute myeloid leukemia. Leukemia 1991; 5: 230–238. Bouabdallah R et al. A controlled study of recombinant human 29 Witz F, Sadoun A, Perrin MC, Berthou C, Briere J, Cahn JY et al. A granulocyte colony-stimulating factor in elderly patients after placebo-controlled study of recombinant human granulocyte– treatment for acute myelogenous leukemia. AML Cooperative macrophage colony-stimulating factor administered during and Study Group. N Engl J Med 1995; 332: 1678–1683. after induction treatment for de novo acute myelogenous leukemia 15 Godwin JE, Kopecky KJ, Head DR, Willman CL, Leith CP, Hynes in elderly patients. Groupe Ouest Est Leucemies Aigues Myelo- HE et al. A double-blind placebo-controlled trial of granulocyte blastiques (GOELAM). Blood 1998; 91: 2722–2730. colony-stimulating factor in elderly patients with previously 30 Lowenberg B, van Putten W, Theobald M, Gmur J, Verdonck L, untreated acute myeloid leukemia: a Southwest oncology group Sonneveld S et al. Effect of priming with granulocyte colony- study (9031). Blood 1998; 91: 3607–3615. stimulating factor on the outcome of chemotherapy for acute 16 Heil G, Hoelzer D, Sanz MA, Lechner K, Liu Yin, Papa G et al. A myeloid leukemia. N Engl J Med 2003; 349: 743–752. randomized, double-blind, placebo-controlled, phase III study of 31 Lofgren C, Paul C, Astrom M, Hast R, Hedenius M, Lerner R et al. filgrastim in remission induction and consolidation therapy for Granulocyte–macrophage colony-stimulating factor to increase adults with de novo acute myeloid leukemia. The International efficacy of mitoxantrone, etoposide and cytarabine in previously Acute Myeloid Leukemia Study Group. Blood 1997; 90: untreated elderly patients with acute myeloid leukaemia: 4710–4718. a Swedish multicentre randomized trial. Br J Haematol 2004; 17 Bradstock K, Matthews J, Young G, Lowenthal R, Baxter H, Arthur 124: 474–480. C et al. Effects of glycosylated recombinant human granulocyte 32 Lowenberg B, Suciu S, Archimbaud E, Ossenkoppele G, Verhoef colony-stimulating factor after high-dose cytarabine-based induc- GE, Vellenga E et al. Use of recombinant GM-CSF during and after tion chemotherapy for adult acute myeloid leukaemia. Leukemia remission induction chemotherapy in patients aged 61 years and 2001; 15: 1331–1338. older with acute myeloid leukemia: final report of AML-11, 18 Usuki K, Urabe A, Masaoka T, Ohno R, Mizoguchi H, Hamajima a phase III randomized study of the Leukemia Cooperative Group N et al. Efficacy of granulocyte colony-stimulating factor in the of European Organisation for the Research and Treatment of treatment of acute myelogenous leukaemia: a multicentre rando- Cancer and the Dutch Belgian Hemato-Oncology Cooperative mized study. Br J Haematol 2002; 116: 103–112. Group. Blood 1997; 90: 2952–2961. 19 Goldstone AH, Burnett AK, Wheatley K, Snith AG, Hutchinson 33 Heil G, Chadid L, Hoelzer D, Seipelt G, Mitrou P, Huber C et al. RM, Clark RE. Attempts to improve treatment outcomes in acute GM-CSF in a double-blind randomized, placebo controlled trial in myeloid leukemia (AML) in older patients: the results of the United therapy of adult patients with de novo acute myeloid leukemia Kingdom Medical Research Council AML11 trial. Blood 2001; 98: (AML). Leukemia 1995; 9: 3–9. 1302–1311. 34 Hast R, Hellstrom-Lindberg E, Ohm L, Bjorkholm M, Celsing F, 20 Harousseau JL, Witz B, Lioure B, Hunault-Berger M, Desablens B, Dahl IM et al. No benefit from adding GM-CSF to induction Desablens B et al. Granulocyte colony-stimulating factor chemotherapy in transforming myelodysplastic syndromes: better after intensive consolidation chemotherapy in acute myeloid outcome in patients with less proliferative disease. Leukemia 2003; leukemia: results of a randomized trial of the Groupe Ouest-Est 17: 1827–1833. Leucemies Aigues Myeloblastiques. J Clin Oncol 2000; 18: 35 Uyl-de Groot CA, Lowenberg B, Vellenga E, Suciu S, Willemze R, 780–787. Rutten FF et al. Cost-effectiveness and quality-of-life assessment of 21 Lowenberg B, Boogaerts MA, Daenen SM, Verhoef GE, Hagenbeek GM-CSF as an adjunct to intensive remission induction chemo- A, Vellenga E et al. Value of different modalities of granulocyte– therapy in elderly patients with acute myeloid leukemia. Br J macrophage colony-stimulating factor applied during or after Haematol 1998; 100: 629–636. induction therapy of acute myeloid leukemia. J Clin Oncol 1997; 36 Ohno R, Naoe T, Kanamaru A, Yoshida M, Hiraoka A, Kobayashi T 15: 3496–3506. et al. A double-blind controlled study of granulocyte colony-

Leukemia Cytokine therapy in acute leukemias F Ravandi 570 stimulating factor started two days before induction chemotherapy 52 Michel G, Landman-Parker J, Auclerc MF, Mathey C, Leblanc T, in refractory acute myeloid leukemia. Kohseisho Leukemia Study Legall E et al. Use of recombinant human granulocyte colony- Group. Blood 1994; 83: 2086–2092. stimulating factor to increase chemotherapy dose-intensity: 37 Thomas X, Fenaux P, Dombret H, Delair S, Dreyfus F, Tilly H et al. a randomized trial in very high-risk childhood acute lymphoblastic Granulocyte–macrophage colony-stimulating factor (GM-CSF) leukemia. J Clin Oncol 2000; 18: 1517–1524. to increase efficacy of intensive sequential chemotherapy with 53 Little MA, Morland B, Chisholm J, Hole A, Shankar A, Devine T etoposide, mitoxantrone and cytarabine (EMA) in previously et al. A randomised study of prophylactic G-CSF following MRC treated acute myeloid leukemia: a multicenter randomized UKALL XI intensification regimen in childhood ALL and T-NHL. placebo-controlled trial (EMA91 Trial). Leukemia 1999; 13: Med Pediatr Oncol 2002; 38: 98–103. 1214–1220. 54 Heath JA, Steinherz PG, Altman A, Sather H, Jhanwar S, Halpern S 38 Rossi HA, O’Donnell J, Sarcinelli F, Stewart FM, Quesenberry PJ, et al. Human granulocyte colony-stimulating factor in children Becker PS. Granulocyte–macrophage colony-stimulating factor with high-risk acute lymphoblastic leukemia: a Children’s Cancer (GM-CSF) priming with successive concomitant low-dose Ara-C Group Study. J Clin Oncol 2003; 21: 1612–1617. for elderly patients with secondary/refractory acute myeloid 55 Pui CH, Boyett JM, Hughes WT, Rivera GK, Hancock ML, leukemia or advanced myelodysplastic syndrome. Leukemia Sandlund JT et al. Human granulocyte colony-stimulating factor 2002; 16: 310–315. after induction chemotherapy in children with acute lymphoblastic 39 He XY, Pohlman B, Lichtin A, Rybicki L, Kalaycio M. Timed- leukemia. N Engl J Med 1997; 336: 1781–1787. sequential chemotherapy with concomitant granulocyte colony- 56 Ottmann OG, Hoelzer D, Gracien E, Ganser A, Kelly K, Reutzel R stimulating factor for newly diagnosed de novo acute myelogenous et al. Concomitant granulocyte colony-stimulating factor and leukemia. Leukemia 2003; 17: 1078–1084. induction chemoradiotherapy in adult acute lymphoblastic leuke- 40 Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, mia: a randomized phase III trial. Blood 1995; 86: 444–450. Makary AZ et al. A phase 3 study of three induction regimens and 57 Ohno R, Tomonaga M, Ohshima T, Masaoka T, Asou N, Oh H of priming with GM-CSF in older adults with acute myeloid et al. A randomized controlled study of granulocyte colony leukemia: a trial by the Eastern Cooperative Oncology Group. stimulating factor after intensive induction and consolidation Blood 2004; 103: 479–485. therapy in patients with acute lymphoblastic leukemia. Japan 41 Jahns-Streubel G, Reuter C, Auf der Landwehr U, Unterhalt M, Adult Leukemia Study Group. Int J Hematol 1993; 58: 73–81. Schleyer E, Wormann B et al. Activity of thymidine kinase and of 58 Geissler K, Koller E, Hubmann E, Niederwieser D, Hinterberger W, polymerase alpha as well as activity and gene expression of Geissler D et al. Granulocyte colony-stimulating factor as an deoxycytidine deaminase in leukemic blasts are correlated with adjunct to induction chemotherapy for adult acute lympho- clinical response in the setting of granulocyte–macrophage blastic leukemia–a randomized phase-III study. Blood 1997; 90: colony-stimulating factor-based priming before and during TAD- 590–596. 59 Larson RA, Dodge RK, Linker CA, Stone RM, Powell BL, Lee EJ 9 induction therapy in acute myeloid leukemia. Blood 1997; 90: et al. A randomized controlled trial of filgrastim during remission 1968–1976. induction and consolidation chemotherapy for adults with acute 42 Pui CH, Campana D, Evans WE. Childhood acute lymphoblastic lymphoblastic leukemia: CALGB study 9111. Blood 1998; 92: leukaemia–current status and future perspectives. Lancet Oncol 1556–1564. 2001; 2: 597–607. 60 Ifrah N, Witz F, Jouet JP, Francois S, Lamy T, Linassier C et al. 43 Faderl S, Jeha S, Kantarjian HM. The biology and therapy of adult Intensive short term therapy with granulocyte–macrophage-colony acute lymphoblastic leukemia. Cancer 2003; 98: 1337–1354. stimulating factor support, similar to therapy for acute myeloblastic 44 Hoelzer D, Gokbuget N. Recent approaches in acute lympho- leukemia, does not improve overall results for adults with acute blastic leukemia in adults. Crit Rev Oncol Hematol 2000; 36: lymphoblastic leukemia. GOELAMS Group. Cancer Oct 15; 1999: 49–58. 86 (8):1496–1505.. 45 Kantarjian HM, Estey E, O’Brien S, Anaissie E, Beran M, Pierce S 61 Holowiecki J, Giebel S, Krzemien S, Krawczyk-Kulis M, Jagoda K, et al. Granulocyte colony-stimulating factor supportive treatment Kopera M et al. G-CSF administered in time-sequenced setting following intensive chemotherapy in acute lymphocytic leukemia during remission induction and consolidation therapy of adult in first remission. Cancer 1993; 72: 2950–2955. acute lymphoblastic leukemia has beneficial influence on early 46 Bassan R, Lerede T, Di Bona E, Rossi G, Pogliani E, Rambaldi A recovery and possibly improves long-term outcome: a randomized et al. Granulocyte colony-stimulating factor (G-CSF, filgrastim) multicenter study. Leuk Lymphoma 2002; 43: 315–325. after or during an intensive remission induction therapy for adult 62 Delorme J, Badin S, Le Corroller AG, Auvrignon AA, Auclere MF, acute lymphoblastic leukaemia: effects, role of patient pre- Gandemer V et al. Economic evaluation of recombinant human treatment characteristics, and costs. Leuk Lymphoma 1997; 26: granulocyte colony-stimulating factor in very high-risk childhood 153–161. acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2003; 25: 47 Ottmann OG, Ganser A, Freund M, Heil G, Hiddenmann W, Heit 441–447. W et al. Simultaneous administration of granulocyte colony- 63 Lotzova E, Savary CA, Herberman RB. Inhibition of clonogenic stimulating factor (Filgrastim) and induction chemotherapy in growth of fresh leukemia cells by unstimulated and IL-2 stimulated acute lymphoblastic leukemia. A pilot study. Ann Hematol 1993; NK cells of normal donors. Leuk Res 1987; 11: 1059–1066. 67: 161–167. 64 Oshimi K, Oshimi Y, Akutsu M, Takei Y, Saito H, Okada M et al. 48 Kantarjian HM, O’Brien S, Smith TL, Cortes J, Giles FJ, Beran M Cytotoxicity of interleukin 2-activated lymphocytes for leukemia et al. Results of treatment with hyper-CVAD, a dose-intensive and lymphoma cells. Blood 1986; 68: 938–948. regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000; 65 Margolin K, Forman SJ. Immunotherapy with interleukin-2 after 18: 547–561. hematopoietic cell transplantation for hematologic malignancy. 49 Welte K, Reiter A, Mempel K, Pfetsch M, Schwab G, Schrappe M Cancer J Sci Am 2000; 6 (Suppl 1): S33–S38. et al. A randomized phase-III study of the efficacy of granulocyte 66 Foa R, Meloni G, Tosti S, Novarino A, Fenu S, Gavosto F et al. colony-stimulating factor in children with high-risk acute lympho- Treatment of acute myeloid leukaemia patients with recombinant blastic leukemia. Berlin-Frankfurt-Munster Study Group. Blood interleukin 2: a pilot study. Br J Haematol 1991; 77: 491–496. 1996; 87: 3143–3150. 67 Meloni G, Foa R, Vignetti M, Guarini A, Fenu S, Tosti S et al. 50 Laver J, Amylon M, Desai S, Link M, Schwenn M, Mahmoud H Interleukin-2 may induce prolonged remissions in advanced acute et al. Randomized trial of r-metHu granulocyte colony-stimulating myelogenous leukemia. Blood 1994; 84: 2158–2163. factor in an intensive treatment for T-cell leukemia and advanced- 68 Meloni G, Vignetti M, Pogliani E, Invernizzi R, Allione B, Mirto S stage lymphoblastic lymphoma of childhood: a Pediatric Onco- et al. Interleukin-2 therapy in relapsed acute myelogenous logy Group pilot study. J Clin Oncol 1998; 16: 522–526. leukemia. Cancer J Sci Am 1997; 3 (Suppl 1): S43–S47. 51 Clarke V, Dunstan FD, Webb DK. Granulocyte colony-stimulating 69 Goodman M, Cabral L, Cassileth P. Interleukin-2 and leukemia. factor ameliorates toxicity of intensification chemotherapy for Leukemia 1998; 12: 1671–1675. acute lymphoblastic leukemia. Med Pediatr Oncol 1999; 32: 70 Bergmann L, Heil G, Kolbe K, Lengfelder E, Puzicha E, Martin H 331–335. et al. Interleukin-2 bolus infusion as late consolidation therapy in

Leukemia Cytokine therapy in acute leukemias F Ravandi 571 2nd remission of acute myeloblastic leukemia. Leuk Lymphoma 82 Archimbaud E, Ottmann OG, Yin JA, Lechner K, Dombret H, Sanz 1995; 16: 271–279. MA et al. A randomized, double-blind, placebo-controlled study 71 Meloni G, Vignetti M, Andrizzi C, Capria S, Foa R, Mandelli F. with pegylated recombinant human megakaryocyte growth and Interleukin-2 for the treatment of advanced acute myelogenous development factor (PEG-rHuMGDF) as an adjunct to chemo- leukemia patients with limited disease: updated experience with therapy for adults with de novo acute myeloid leukemia. Blood 20 cases. Leuk Lymphoma 1996; 21: 429–435. 1999; 94: 3694–3701. 72 Soiffer RJ, Murray C, Cochran K, Cameron C, Wang E, Schow PW 83 Basser RL, O’Flaherty E, Green M, Edmonds M, Nichol J, et al. Clinical and immunologic effects of prolonged infusion of Menchaca DM et al. Development of pancytopenia with low-dose recombinant interleukin-2 after autologous and T-cell- neutralizing antibodies to thrombopoietin after multicycle chemo- depleted allogeneic bone marrow transplantation. Blood 1992; 79: therapy supported by megakaryocyte growth and development 517–526. factor. Blood 2002; 99: 2599–2602. 73 Soiffer RJ, Murray C, Gonin R, Ritz J. Effect of low-dose interleukin- 84 Estey EH, Thall PF, Giles FJ, Wang XM, Cortes JE, Beran M 2 on disease relapse after T-cell-depleted allogeneic bone marrow et al. Gemtuzumab ozogamicin with or without interleukin 11 in transplantation. Blood 1994; 84: 964–971. patients 65 years of age or older with untreated acute myeloid 74 Klingemann HG, Phillips GL. Is there a place for immunotherapy leukemia and high-risk myelodysplastic syndrome: comparison with interleukin-2 to prevent relapse after autologous stem cell with idarubicin plus continuous-infusion, high-dose cytosine transplantation for acute leukemia? Leuk Lymphoma 1995; 16: arabinoside. Blood 2002; 99: 4343–4349. 397–405. 85 Ellis M, Zwaan F, Hedstrom U, Poynton C, Kristensen J, Jumaa P 75 Robinson N, Sanders JE, Benyunes MC, Beach K, Lindgren C, et al. Recombinant human interleukin 11 and bacterial infection in Thompson JA et al. Phase I trial of interleukin-2 after unmodified patients with [correction of] haematological malignant disease HLA-matched sibling bone marrow transplantation for children undergoing chemotherapy: a double-blind placebo-controlled with acute leukemia. Blood 1996; 87: 1249–1254. randomised trial. Lancet 2003; 361: 275–280. 76 Blaise D, Attal M, Pico JL, Reiffers J, Stoppa AM, Bellanger C et al. 86 Wielenga JJ, Vellenga E, Groenewegen A, Sonneveld P, Low- The use of a sequential high dose recombinant interleukin 2 enberg B. Recombinant human interleukin-3 (rH IL-3) in combina- regimen after autologous bone marrow transplantation does not tion with remission induction chemotherapy in patients with improve the disease free survival of patients with acute leukemia relapsed acute myelogenous leukemia (AML): a phase I/II study. transplanted in first complete remission. Leuk Lymphoma 1997; Leukemia 1996; 10: 43–47. 25: 469–478. 87 Zwierzina H, Suciu S, Loeffler-Ragg J, Neuwirtova R, Fenaux P, 77 Attal M, Blaise D, Marit G, Payen C, Michallet M, Vernant JP et al. Beksac M et al. Low-dose cytosine arabinoside (LD-AraC) vs Consolidation treatment of adult acute lymphoblastic leukemia: LD-AraC plus granulocyte/macrophage colony stimulating factor a prospective, randomized trial comparing allogeneic versus vs LD-AraC plus Interleukin-3 for myelodysplastic syndrome autologous bone marrow transplantation and testing the impact patients with a high risk of developing acute leukemia: of recombinant interleukin-2 after autologous bone marrow final results of a randomized phase III study (06903) of the transplantation. BGMT Group Blood 1995; 86: 1619–1628. EORTC Leukemia Cooperative Group. Leukemia 2005; 19: 78 Cortes JE, Kantarjian HM, O’Brien S, Giles F, Keating MJ, Freireich 1929–1933. EJ et al. A pilot study of interleukin-2 for adult patients with acute 88 Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson myelogenous leukemia in first complete remission. Cancer 1999; SA. Purification and characterization of a newly identified growth 85: 1506–1513. factor specific for epithelial cells. Proc Natl Acad Sci USA 1989; 79 Farag SS, George SL, Lee EJ, Baer M, Dodge RK, Becknell B et al. 86: 802–806. Postremission therapy with low-dose interleukin 2 with or without 89 Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, intermediate pulse dose interleukin 2 therapy is well tolerated Kewalramani T et al. Palifermin for oral mucositis after intensive in elderly patients with acute myeloid leukemia: Cancer therapy for hematologic cancers. N Engl J Med 2004; 351: and Leukemia Group B study 9420. Clin Cancer Res 2002; 8: 2590–2598. 2812–2819. 90 Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharma- 80 Sievers EL, Lange BJ, Sondel PM, Krailo MD, Gan J, Liu-Mares W cokinetics of AMG 531, a novel thrombopoietin receptor ligand. et al. Feasibility, toxicity, and biologic response of interleukin-2 Clin Pharmacol Ther 2004; 76: 628–638. after consolidation chemotherapy for acute myelogenous leuke- 91 Estey EH, Thall PF, Pierce S, Cortes J, Beran M, Kantarjian H et al. mia: a report from the Children’s Cancer Group. J Clin Oncol Randomized phase II study of fludarabine + cytosine arabinoside + 1998; 16: 914–919. idarubicin +/À all-trans retinoic acid +/À granulocyte colony- 81 Schiffer CA, Miller K, Larson RA, Amrein PC, Antin JH, Zani VJ stimulating factor in poor prognosis newly diagnosed acute et al. A double-blind, placebo-controlled trial of pegylated myeloid leukemia and myelodysplastic syndrome. Blood 1999; recombinant human megakaryocyte growth and development 93: 2478–2484. factor as an adjunct to induction and consolidation therapy 92 Buchner T, Berdel WE, Hiddemann W. Priming with granulocyte for patients with acute myeloid leukemia. Blood 2000; 95: colony-stimulating factor – relation to high-dose cytarabine in 2530–2535. acute myeloid leukemia. N Engl J Med 2004; 350: 2215–2216.

Leukemia