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Emerging Trends In Managing AML

Hematopoietic growth factors in the treatment of acute myeloid leukemia

by: Maria R. Baer, MD

Table of Contents
Responsiveness of Acute Meyloid Leukemia Cells to Growth Factors

Use of Growth Factors After Incubation Therapy

Use of G-CSF After HIDAC-Based Induction Therapy

Use of Growth Factors After Postremission Therapy

Growth-Factor Priming: Laboratory Studies

Growth-Factor Priming: Clinical Studies

Growth-Factor Priming: Biological Effects

Conclusions

References

Treatment results for acute myeloid leukemia (AML) have improved significantly, with an increasing number of patients achieving long-term, disease-free survival. Nevertheless, various patient groups still fare poorly with current approaches. These high-risk groups comprise those patients whose leukemia cells have prognostically unfavorable cytogenetic abnormalities, those with antecedent hematologic disorders or prior cytotoxic therapy, and older patients. Drug resistance and the patient's inability to survive or tolerate potentially curative therapy, most commonly due to infectious complications, are some of the reasons for poor treatment outcome.

Therapeutic challenges in AML include improving treatment results among patients who have a poor prognosis with current regimens, as well as increasing the cure rate for all patients. New strategies designed to improve outcome have been fueled by the availability of recombinant hematopoietic growth factors. These growth factors are given to AML patients following completion of chemotherapy, with the goal of attenuating hematologic toxicity. This beneficial effect may also allow escalation of therapy, which in turn may overcome drug resistance. These growth-factor applications are similar for AML and other malignancies. Administering hematopoietic growth factors to AML patients is, however, potentially problematic in that these factors have the capacity to stimulate proliferation of AML cells in vitro and may therefore promote regrowth of leukemia cells after chemotherapy in vivo.

The fact that growth factors stimulate proliferation of AML cells is the basis for a therapeutic application unique to this disease. In recent studies, growth factors have been given to patients before and during chemotherapy to recruit AML cells into active cell cycle in order to increase their sensitivity to cell-cycle-specific chemotherapy. Although substantial in vitro data demonstrate the potential for beneficial effects, administering growth factors to "prime" cells before chemotherapy in the clinical setting could adversely affect treatment outcome by expanding leukemic populations or promoting growth of resistant leukemia cells.

RESPONSIVENESS OF ACUTE MYELOID LEUKEMIA CELLS TO GROWTH FACTORS

Specific binding of granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) to leukemia cells can be demonstrated in most cases of AML. These growth factors stimulate DNA synthesis and clonogenic growth in most cases in which receptors are present. To exemplify, data combined from four studies indicated that G-CSF receptors were present in 70 of 72 (97%) cases of AML and in vitro proliferative responses to G-CSF were apparent in 42 of 63 cases (67%).1-4 Findings are similar for GM-CSF and IL3.1,3,5

The few cases in which leukemia cells have receptors for, but do not respond to, growth factors in in vitro assays may indicate the presence of leukemic cells that are truly unresponsive. Alternatively, available in vitro assays may be inadequate to support growth in these cases, or requisite co-stimulatory factors may not be present.

USE OF GROWTH FACTORS AFTER INDUCTION THERAPY

Studies published to date investigating the effect on clinical outcome of growth-factor administration following chemotherapy have yielded mixed results. These trials differ with respect to choice of growth factor and corresponding dosage regimen, patient age and other risk factors, stage of disease (ie, newly diagnosed, refractory or relapsed) and chemotherapeutic regimen, including agents and doses used. It is unclear as to which variables explain the discrepant findings.

Ohno et al6 conducted the first randomized trial of growth-factor administration following AML chemotherapy. In this study, patients with relapsed or refractory leukemia were randomly assigned to receive or not receive G-CSF at a daily dose of 200 µg/m", beginning 2 days after completion of cytarabine, mitoxantrone and etoposide chemotherapy, until neutrophil counts reached 1.5 ◊109/L. Marrow aplasia was documented before initiation of G-CSF.

Neutrophil recovery was significantly more rapid in 48 patients (including 30 with AML) who received G-CSF than in 50 (including 31 with AML) who did not. Median number of days from completion of chemotherapy to attainment of 1.0 ◊109/L neutrophils was 22 v 34 in corresponding groups (P = .0002). Incidence of fever was similar for the two groups, but documented infections were significantly less frequent in patients who received G-CSF (P = .028). Complete remission rates were 50% v 36% in G-CSF-treated patients and those who did not receive G-CSF; this difference was not statistically significant. Incidences of early regrowth of leukemic cells and early relapse were not different between the two groups (P = .899).6

Büchner et al7treated 25 newly diagnosed patients > 65 years of age, as well as 11 in early or second relapse, with GM-CSF at a dose of 250 µg/m"/d, beginning on Day 4 after completion of cytarabine, daunorubicin and 6-thioguanine or high-dose cytarabine (HIDAC) and mitoxantrone chemotherapy. As in Ohnoĺs study,6 marrow aplasia was documented before initiation of GM-CSF.

Neutrophil recovery was significantly accelerated in patients who received the growth factor after either chemotherapeutic regimen, compared to historical controls (P = .009 and .043 for the two groups, respectively). Specifically, differences in median time to recovery between GM-CSF-treated patients in the two chemotherapy groups and historical controls were 6 and 9 days for the two regimens. Incidence of early death was significantly lower (P = .009) for patients who received the growth factor (14%), compared to historical controls (39%). Complete remission rates were 50% for GM-CSF-treated patients v 32% for controls (P =.09), while remission duration was similar for the two groups.7,8

In an Eastern Cooperative Oncology Group (ECOG) study recently reported by Rowe et al,9 124 newly diagnosed AML patients (age range: 55 to 70 years) received cytarabine 100 mg/m" by continuous infusion and daunorubicin 60 mg/m" daily for 3 days and then, following documentation of marrow aplasia on Day 10, were randomized to receive GM-CSF 250 µg/m"/d or placebo until neutrophil recovery. GM-CSF or placebo was also administered following consolidation, which consisted of a single course of high-dose cytarabine (1.5 g/m") every 12 hours for 12 doses.

GM-CSF had a significant, favorable effect on time to recovery of 0.5 ◊ 10 9/L neutrophils (11 days after the start of growth factor v 14 days after the start of placebo; P = .01) and 1.0 ◊10 9/L neutrophils (12 days v 18 days, respectively; P = .001), as well as on the incidence of infectious toxicity (24% grade 3 and 4% grade 5 on the GM-CSF arm v 32% grade 3, 8% grade 4 and 8% grade 5 on the placebo arm; P =.019). Complete remission rates were 61% for patients treated with the growth factor and 46% for those who received placebo. Median survival was 325 days v 135 days in corresponding groups (P = .035); this difference in survival was predominantly due to the difference in toxicity.

In a Cancer and Leukemia Group B (CALGB) study,10 388 newly diagnosed patients > 60 years of age were randomized to receive GM-CSF 5 µg/kg/d or placebo after induction chemotherapy, which consisted of cytarabine 200 mg/m"/d for 7 days and daunorubicin 45 mg/m"/day for 3 days. GM-CSF or placebo was administered starting on the day after completion of chemotherapy (Day 8) and continuing until recovery of 1.0 ◊109/L neutrophils. No significant difference in duration of neutropenia was observed between the two treatment groups (16 days for GM-CSF v 17 days for placebo). There also were no significant differences in rates of infectious complication or complete remission.

Although several differences are apparent between the chemotherapeutic and growth-factor regimens used in the ECOG and CALGB studies, the major difference is in duration of neutropenia induced by chemotherapy in the absence of growth factor. In particular, the higher anthracycline dose in the ECOG study resulted in a longer duration of neutropenia compared to the CALGB regimen, despite the higher cytarabine dose in the latter trial. This longer period of neutropenia in the ECOG study was shortened by GM-CSF.

In contrast, the hematologic toxicity from the CALGB regimen was less considerable and was not attenuated by GM-CSF. In this context, it is notable that the regimens used in the studies conducted by Ohno et al6 and Büchner et al7 produced substantial hematologic toxicity in the absence of growth factor.

There has been great concern that growth factors given to AML patients to attenuate hematologic toxicity may promote the growth of residual leukemic cells after chemotherapy, thus increasing the rate of remission induction failure or early relapse. Although data are still limited, studies published to date support the conclusion that G-CSF or GM-CSF administered to AML patients after induction chemotherapy, with effective cytoreduction documented by marrow aplasia, does not increase the risk of remission induction failure due to persistent leukemia, risk of rapid regrowth of leukemia, or relapse rate.

A second tentative conclusion from these studies is that growth factors may have a more pronounced effect when administered after induction regimens that result in a greater degree of hematologic toxicity, and thus may allow escalation of chemotherapy. Whether or not growth factors can attenuate hematologic toxicity may also be a function of the cytotoxic agents administered and the mechanisms by which they produce toxicity. Further work is needed to explore these hypotheses.

USE OF G-CSF AFTER HIDAC-BASED INDUCTION THERAPY

Several groups have studied HIDAC-based regimens as remission induction therapy in newly diagnosed AML in the absence of growth factors.11-14HIDAC has been shown to have a favorable impact on remission rates11,12 and remissions are more frequently achieved with a single course of therapy.11 A beneficial effect of HIDAC on remission duration has also been suggested.13 However, the finding that HIDAC-based regimens caused more substantial hematologic toxicity, compared with standard dose cytarabine-based induction therapy, in randomized studies limited its use as initial induction therapy.13,14

At the Roswell Park Cancer Institute, we wished to determine whether G-CSF could attenuate the hematologic toxicity associated with HIDAC and anthracycline induction chemotherapy. Idarubicin was chosen as the anthracycline to be used in conjunction with HIDAC in our study because data from several clinical trials demonstrated its efficacy in AML remission induction therapy,15-20 and because in vitro data suggested better uptake and retention as well as greater cytotoxicity of idarubicin in multidrug-resistant leukemia cell lines.21

Remission induction therapy in the Roswell Park study consisted of cytarabine 3 g/m" intravenously over 1 hour every 12 hours for 12 doses, with idarubicin 12 mg/m" over 30 minutes daily on days 2, 3 and 4 of cytarabine administration. Patients > 50 years of age received 1.5 g/m" cytarabine because of their increased risk of cerebellar toxicity with the 3 g/m" dose.22 Patients were given G-CSF subcutaneously at a daily dose of 10 µg/kg, beginning on the day following completion of chemotherapy and continuing until the absolute neutrophil count rose to > 5.0 ◊109/L on 2 consecutive days.

Early experience with the Roswell Park induction regimen has been reported.23 In a subsequent interim analysis of treatment results for 41 patients with de novo AML, remission rate with a single course of induction therapy was 75%, with a 15% incidence of treatment failure due to resistant disease and a 10% mortality rate during induction. Complete remission occurred in 86% of patients < 60 years of age and in 65% of those <= 60 years of age. Mortality rate during induction was similar in the two age groups (9% and 10%), while a higher incidence of treatment failure due to resistant disease was evident in the older group (25% v 5%; unpublished data).

Results of a single course of induction therapy with the regimen used at Roswell Park were at least as good as those achieved with standard dose cytarabine-based regimens. Importantly, in a large CALGB study,24 one third of patients required two induction courses with standard dose cytarabine-based therapy to achieve remission. In contrast, the Roswell Park study showed that comparable remission rates were achieved with only a single course of HIDAC and idarubicin, followed by G-CSF.

Data from the Roswell Park study strongly suggest that G-CSF is useful in attenuating the hematologic toxicity of HIDAC-based induction therapy. Median time from initiation of chemotherapy to recovery of 0.5 ◊109/L neutrophils was 20 days (range: 17 to 28 days) among patients with de novo AML who achieved remission after receiving chemotherapy with HIDAC and idarubicin, followed by G-CSF. Median time to recovery of 1.5 ◊109/L neutrophils was 21 days (range: 19 to 29 days). Thus, hematologic toxicity of HIDAC/idarubicin chemotherapy, followed by G-CSF, was comparable to that of standard-dose cytarabine and idarubicin or daunorubicin chemotherapy20 and was substantially less than that observed with HIDAC and daunorubicin induction therapy without growth factors.11

USE OF GROWTH FACTORS AFTER POSTREMISSION THERAPY

Substantial data demonstrate that intensive postremission therapy in AML patients who achieve complete remission improves remission duration and increases the fraction of patients who achieve long-term, disease-free survival. Beneficial approaches include high-dose cytarabine chemotherapy 24,25 and allogeneic as well as autologous bone marrow transplantation.26,27 As with induction regimens, dose intensity of postremission therapy is limited by hematologic toxicity. To date, little is known about the efficacy of growth factors in attenuating the hematologic toxicity resulting from postremission chemotherapy in AML.

At the Roswell Park Cancer Institute, we have administered high-dose etoposide and cyclophosphamide intensification therapy followed by G-CSF to patients achieving complete remission with the HIDAC/idarubicin/G-CSF induction regimen detailed above. Hematologic toxicity is being compared to that in a previous series of patients receiving the same intensification regimen without growth factors.28 Relatively little is known about the role of growth factors in allowing escalation of postremission therapy. This is an important area of study, given the demonstrated benefit of intensive postremission therapy in prolonging remissions and producing cures.

GROWTH-FACTOR PRIMING: LABORATORY STUDIES

Cytarabine is a cell-cycle-specific cytotoxic agent that is incorporated into S-phase cells. Given that growth factors increase the fraction of AML cells in S phase, it was hypothesized that stimulating AML cells with growth factors before or during exposure to cytarabine should enhance sensitivity to this agent. Several studies have demonstrated that in vitro stimulation of AML cells with GM-CSF, IL-3 or G-CSF increases clonogenic cell kill by cytarabine.29-33 Ara-CTP levels and Ara-CTP to dCTP ratios are higher in AML cells exposed to growth factors.30,33,34 Moreover, growth factors may also enhance cytarabine sensitivity by additional mechanisms unrelated to cell cycle.35,36

Stimulation of AML cells with growth factors enhances sensitivity to other chemotherapeutic agents besides cytarabine.36,37 Exposure of AML cells to IL-3, GM-CSF and G-CSF prior to exposure to daunorubicin increases daunorubicin cytotoxicity.37 The mechanism by which growth factors enhance sensitivity of AML cells to anthracyclines likely involves increases in topoisomerase II levels.38

GROWTH-FACTOR PRIMING: CLINICAL STUDIES

Pilot studies have shown that administering growth factors to AML patients before and during chemotherapy was feasible and was effective in recruiting AML cells into S phase. Bettelheim et al39 treated 18 newly diagnosed de novo AML patients with GM-CSF before, during and after cytarabine and daunorubicin chemotherapy. Recruitment of marrow cells into active cell cycle was observed, with a 1.5- to 10-fold increase in percent S-phase cells. Complete remission occurred in 83% of these patients. Findings of another pilot study were similar.40

Results of an early controlled clinical trial of growth-factor priming in AML suggested an adverse, rather than a beneficial, effect. Estey et al41 reported a lower rate of complete remission and a higher incidence of resistant disease in 56 previously untreated patients receiving GM-CSF for up to 8 days before cytarabine and daunorubicin chemotherapy, compared to historical control patients who were matched for prognostic factors and who were treated with the same cytarabine schedule without GM-CSF. Remission induction failure in GM-CSF-treated patients was most commonly due to persistent leukemia, suggesting that in vivo administration of GM-CSF may decrease, rather than increase, sensitivity to cytarabine and daunorubicin.

Several trials have failed to demonstrate a difference in clinical outcome for patients receiving growth-factor priming before chemotherapy. Archimbaud et al42 demonstrated that GM-CSF in conjunction with timed-sequential chemotherapy did not affect remission rate in 22 patients with refractory AML, compared to historical controls. Ohno et al43 found that 2-day administration of G-CSF to 28 refractory AML patients before chemotherapy with behenoyl cytosine arabinoside, etoposide and mitoxantrone produced no statistically significant difference in complete remission rate (50% for patients with growth-factor priming v 37% of 30 patients receiving placebo; P = .306) and no statistically significant difference in duration of complete remission.43 Similarly, Estey et al44 found that G-CSF given to 112 previously untreated patients for 1 day prior to fludarabine and high-dose cytarabine chemotherapy had no effect on complete remission rate (63% for patients who received G-CSF v 53% of 85 patients who did not; P = .50).

Results from a single clinical trial by Büchner et al,45 have suggested a beneficial effect of priming before chemotherapy. Previously untreated patients who received GM-CSF for 24 hours before both induction and consolidation therapy and those without GM-CSF priming had similar complete remission rates, but the former group had a longer duration of complete remission. Probability of continuous complete remission after 2 years was 39% for 34 patients who received growth-factor priming, compared to 17% for 29 patients who did not (P = .024).

Thus, controlled clinical trials of growth-factor priming published to date have variously reported no effect as well as positive and negative effects on treatment outcome. These trials differ with respect to priming strategies, including choice of growth factor and corresponding dosage regimen. Patient populations and chemotherapeutic regimens (choice of cytarabine dose and incorporation of other agents) have also varied. Chemosensitivity is expected to differ among newly diagnosed, refractory and relapsed patients, as well as between low- and high-risk patients; however, little is known about any differences in growth-factor responsiveness in these patient groups. It also should be noted that growth factors have been administered during and after chemotherapy, as well as before, in priming trials; clinical outcomes may be influenced by each of these interventions.

Although effects on treatment response have been variable, priming studies reported to date show that administering growth factors to patients with active AML before chemotherapy does not delay blood count recovery in those who achieve remission. Treatment with growth factors before AML chemotherapy could enhance hematologic toxicity by recruiting normal stem cells into active cell cycle before their exposure to cytotoxic agents. Although of potential concern, enhanced hematologic toxicity has not been evident following priming in any of the studies published so far.

GROWTH-FACTOR PRIMING: BIOLOGIC EFFECTS

Pilot studies have shown that administering growth factors to AML patients before and during chemotherapy was feasible and was effective in recruiting AML cells into S phase. Bettelheim et al39 treated 18 newly diagnosed de novo AML patients with GM-CSF before, during and after cytarabine and daunorubicin chemotherapy. Recruitment of marrow cells into active cell cycle was observed, with a 1.5- to 10-fold increase in percent S-phase cells. Complete remission occurred in 83% of these patients. Findings of another pilot study were similar.40

Results of an early controlled clinical trial of growth-factor priming in AML suggested an adverse, rather than a beneficial, effect. Estey et al41 reported a lower rate of complete remission and a higher incidence of resistant disease in 56 previously untreated patients receiving GM-CSF for up to 8 days before cytarabine and daunorubicin chemotherapy, compared to historical control patients who were matched for prognostic factors and who were treated with the same cytarabine schedule without GM-CSF. Remission induction failure in GM-CSF-treated patients was most commonly due to persistent leukemia, suggesting that in vivo administration of GM-CSF may decrease, rather than increase, sensitivity to cytarabine and daunorubicin.

Several trials have failed to demonstrate a difference in clinical outcome for patients receiving growth-factor priming before chemotherapy. Archimbaud et al42 demonstrated that GM-CSF in conjunction with timed-sequential chemotherapy did not affect remission rate in 22 patients with refractory AML, compared to historical controls. Ohno et al43 found that 2-day administration of G-CSF to 28 refractory AML patients before chemotherapy with behenoyl cytosine arabinoside, etoposide and mitoxantrone produced no statistically significant difference in complete remission rate (50% for patients with growth-factor priming v 37% of 30 patients receiving placebo; P = .306) and no statistically significant difference in duration of complete remission.43 Similarly, Estey et al44 found that G-CSF given to 112 previously untreated patients for 1 day prior to fludarabine and high-dose cytarabine chemotherapy had no effect on complete remission rate (63% for patients who received G-CSF v 53% of 85 patients who did not; P = .50).

Results from a single clinical trial by Büchner et al,45 have suggested a beneficial effect of priming before chemotherapy. Previously untreated patients who received GM-CSF for 24 hours before both induction and consolidation therapy and those without GM-CSF priming had similar complete remission rates, but the former group had a longer duration of complete remission. Probability of continuous complete remission after 2 years was 39% for 34 patients who received growth-factor priming, compared to 17% for 29 patients who did not (P = .024).

Thus, we have shown that in vivo G-CSF priming increases cell cycling and expands leukemic cell populations in most cases of AML. It is not yet known whether G-CSF priming will favorably or adversely affect remission duration or survival.

CONCLUSIONS

The use of hematopoietic growth factors in conjunction with, or as part of, therapy for AML is still in its infancy. Based on work to date, it appears that hematopoietic growth factors can contribute substantially to AML therapy. However, much remains to be learned about choice and schedule of growth factors to maximize short-term clinical outcomes. In addition, little is known about the long-term effects of growth factors. Given these unknowns, it should be stressed that, for the present, growth- factor administration should be undertaken within the context of clinical trials.

Author

MARIA R. BAER, MD, IS ASSOCIATE PROFESSOR, DEPARTMENTS OF HEMATOLOGIC ONCOLOGY AND BONE MARROW TRANSPLANTATION, DIVISION OF MEDICINE, ROSWELL PARK CANCER INSTITUTE, BUFFALO, NEW YORK.

ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
MARIA R. BAER, MD, DIVISION OF MEDICINE,
ROSWELL PARK CANCER INSTITUTE,
ELM AND CARLTON STREETS,
BUFFALO, NEW YORK 14263.

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