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Stem Cells, Vol. 16, No. 4, 280-287, July 1998
© 1998 AlphaMed Press

Repeated Cycles of G-CSF-Combined Postremission Chemotherapy for Acute Myeloid Leukemia in a First Complete Remission: A Pilot Study

Kiyoyuki Ogata, Emi An, Keiko Kamikubo, Norio Yokose, Hideto Tamura, Takashi Yamada, Seiji Gomi, Kazuo Dan, Takeo Nomura

Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan

Key Words. G-CSF factor • Acute myeloid leukemia • Postremission chemotherapy

Dr. Kiyoyuki Ogata, Division of Hematology, Department of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113, Japan.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The cure rate of acute myeloid leukemia might increase if G-CSF were given concurrently with repeated postremission chemotherapy. However, this therapy might cause severe complications, including depletion of normal hematopoietic progenitors as a long-term toxicity. Thus, we conducted a pilot study of this strategy.

Twenty-six acute myeloid leukemia patients in a first complete remission (CR) were treated with two courses of consolidation chemotherapy (10-day BHAC-DMP, consisting of behenoyl cytosine arabinoside, daunorubicin, 6-mercaptopurine and prednisolone) and repeated maintenance-intensification therapy including eight cycles of six-day BHAC-DMP. G-CSF (filgrastim) was administered concurrently with these BHAC-DMP therapies. Toxicity during the therapeutic period was not significant in the study group compared with the historical control, treated with the same regimen without G-CSF. Neutrophil recovery after the consolidation therapy was more rapid in the study group than in the historical control (p = 0.066 and 0.024 for the first and second consolidation courses, respectively). Long-term toxicity, such as cytopenia, has not been seen in eight patients who have remained in CR for a long period (range: 39-58 months). At a median follow-up of 39 months, the predicted rate of 42-month CR duration for these 26 patients was 50% (95% confidence limits: 30% to 71%).

We conclude that G-CSF-combined repeated BHAC-DMP postremission therapy is feasible. Full elucidation of the clinical benefit of this strategy will require further study.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
The resistance of acute myeloid leukemia (AML) cells to chemotherapy may be due to two main mechanisms [1]. The first is modification of chemotherapeutic drug uptake and/or metabolism by the leukemic cells, and the second is that quiescent or slowly cycling leukemic cells escape exposure to the chemotherapeutic drugs, which are generally active only against cycling cells. These resistance mechanisms may affect the complete remission (CR) rate as well as the cure rate of AML in response to chemotherapy. Several hematopoietic growth factors stimulate the cell cycle of blasts and leukemic clonogenic cells in AML [2-6]. Thus, in attempts to overcome the second resistance mechanisms, several clinical studies administered G-CSF or GM-CSF concurrently with induction chemotherapy for AML [7-14]. However, no clear advantage of this strategy has been demonstrated to date.

Regarding G-CSF, Ohno et al. treated 58 patients with relapsed AML and myelodysplastic syndromes (MDS) with induction chemotherapy and concurrent G-CSF or a placebo [13]. Although the G-CSF arm had a higher CR rate (50% versus 37%), this was not statistically significant. Similarly, Estey et al. treated 112 patients with AML and MDS with G-CSF-combined induction chemotherapy and compared the results with a previous group treated with the same chemotherapy without G-CSF [9]. They noted that the G-CSF group had a slightly, but not significantly, higher CR rate (63% versus 53%) but also a relatively high rate of deaths before hematologic recovery. We believe that if G-CSF increases the efficacy of chemotherapy for AML cells by stimulating the leukemic cell cycle, this benefit would be more clearly demonstrable by examining the cure rate in trials in which de novo AML in a first CR is treated with G-CSF concurrently with postremission chemotherapy, compared with the prior approaches because of the following reasons. First, relapsed AML and MDS have a higher possibility of metabolic resistance, such as expression of p-glycoprotein [15]; thus, cell cycle activation may not increase the effect of chemotherapy in these populations. Secondly, the CR rate of de novo AML at the initial induction therapy is already high; thus, even if G-CSF-combined chemotherapy further increased the CR rate in this population it would be difficult to detect statistically. In contrast, the cure rate of AML in a first CR by chemotherapy is still low. Finally, even if G-CSF-combined chemotherapy increases the leukemic cell kill, it may be negated by early death caused by increased myelosuppression when G-CSF-combined chemotherapy is used for remission induction.

However, the feasibility of G-CSF-combined postremission chemotherapy is unknown. Because G-CSF acts on not only myeloid lineage cells but also on primitive hematopoietic progenitors [16, 17], G-CSF-combined postremission therapy may cause depletion of normal hematopoietic stem cells, especially when the therapy is given repeatedly. Other unexpected adverse effects also must be considered [18-25]. Therefore, we have conducted the present pilot study.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Subjects
The subjects enrolled in this study were AML patients who achieved a first CR in response to BHAC-DMP induction chemotherapy (the first-line therapy in our institution) [26], consisting of behenoyl cytosine arabinoside (BHAC), daunorubicin (DNR), 6-mercaptopurine (6-MP) and prednisolone (PSL), during the 1993-1995 period in our institution. Of 31 AML patients who received BHAC-DMP during this period, 23 patients achieved CR and 21 of those 23 patients agreed to enroll in this study. Acute promyelocytic leukemia (M3) cases who achieved a first CR in response to all-trans retinoic acid in this period were also included (five patients achieved CR and all five were enrolled). Informed consent was obtained from the patients or a family member, and the study was approved by the Institutional Review Board of Nippon Medical School (Tokyo, Japan).

The historical controls were AML patients who achieved a first CR in response to the same induction chemotherapy during the 1989-1992 period in our institution and received the same postremission therapy except that G-CSF was not used. Of 46 AML patients who received BHAC-DMP during this historical control period, 30 patients achieved CR and 29 of those 30 were treated with the same postremission therapy.

Patients having prediagnosed MDS were excluded from both groups. Disease diagnosis was performed according to the criteria of the French-American-British (FAB) Cooperative Group [27-29]. The definitions of CR and relapse are according to the standard criteria [30].

Subjects were classified as high risk and standard risk according to the reported prognostic factors affecting CR duration [31-35]. The presence of at least one of the following findings was defined as high risk in this study: the presence of unfavorable bone marrow chromosomal aberrations, FAB subtypes M0, M5 or M6, and requirement for two or more courses of BHAC-DMP therapy to achieve CR. Unfavorable chromosomal aberrations were defined as deletion of all or part of chromosome 5 and/or 7, t(9;22), abnormalities of chromosome 11 and complex abnormalities. Cases who did not meet the high risk criteria were defined as standard risk.

Treatment Protocol ( Fig. 1)
When CR was obtained, all patients received two courses of consolidation chemotherapy with 10-day BHAC-DMP; that is, BHAC (170 mg/m2/d, two-h infusion, days 1-10), DNR (25 mg/m2/d, bolus injection, days 1-4), 6-MP (70 mg/m2/d, orally, days 1-10) and PSL (20 mg/m2/d, orally, days 1-10). The therapy was administered as soon as possible after both the neutrophil and platelet counts had recovered. Then, maintenance-intensification therapy was administered for two years using two different regimens, given alternately at six-week intervals. The first regimen was VEMP, consisting of cyclophosphamide (550 mg/m2/d, bolus injection, days 1 and 8), vincristine (1.4 mg/m2/d, bolus injection, days 1 and 8), 6-MP (70 mg/m2/d, days 1-14) and PSL (20 mg/m2/d, days 1-14). The second regimen was six-day BHAC-DMP; that is, BHAC (170 mg/m2/d, days 1-6), DNR (25 mg/m2/d, days 1-2), 6-MP (70 mg/m2/d, days 1-6) and PSL (20 mg/m2/d, days 1-6). A total of eight cycles of each VEMP and six-day BHAC-DMP therapy was given during the two years. We applied this two-year therapy based on the results of a multicenter study, which showed that when similar BHAC- and anthracycline-based repeated regimens were applied, the duration of the first CR of AML was significantly longer than in patients who received 12 cycles of therapy (1.5-year therapy) compared with four cycles of therapy (six-month therapy) [36]. Patients 70 years of age or older received two-thirds of each drug dosage during the postremission therapy. Regardless of the patient's age, when a severe infection or prolonged high grade fever was observed during the neutropenic period of this postremission therapy, the dose of chemotherapy was reduced to 70%-80% of the original dose.



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  		Figure 1. Scheme of G-CSF-combined postremission chemotherapy.

 
The patients in the study group received recombinant human G-CSF (filgrastim) by daily s.c. injection, which is biologically more potent than i.v. injection [37]. For the two courses of consolidation therapy, G-CSF administration was initiated two days before the start of each chemotherapy at a dose of 75-150 µg/day, and the complete blood cell count was determined daily while the blood chemistry was determined at least twice a week. To achieve cell cycle activation of leukemic cells without adverse reactions due to hyperleukocytosis, the maximum daily dose of G-CSF was set at 300 µg. This dose was given provided that the leukocyte count in the peripheral blood did not exceed 40.0 x 109/l during the 10-day consolidation therapy. When the leukocyte count exceeded this level, G-CSF was reduced to a half-dose or stopped if necessary, and thereafter the dose was increased when the leukocyte count became lower than 25.0 x 109/l. After completing the 10-day chemotherapy, the maximum daily dose of G-CSF was set at 150 µg. This maximum dose was allowed for patients whose neutrophil count was less than 0.5 x 109/l; otherwise, a smaller G-CSF dose was given. G-CSF was stopped when the neutrophil count reached 1.0 x 109/l for two successive days. For maintenance-intensification therapy, G-CSF was given during the six-day BHAC-DMP regimen. In this case, G-CSF was given only during the chemotherapy, and the dose of G-CSF was determined based on the G-CSF dose used in the consolidation therapy of each patient.

Platelet transfusions were given to maintain the platelet count above 20 x 109/l after the consolidation therapy, while during the maintenance-intensification therapy they were given only if extensive petechiae or mucosal bleeding was evident.

Analyses
The criteria of the World Health Organization were used to analyze toxicity [38]. Differences between the two groups of data were evaluated using the chi-square test for categorical variables and the Mann Whitney-U test for continuous variables. The duration of CR was calculated from the date of CR to the date of relapse. Because no patients died before relapse, the CR duration was the same as the disease-free survival in this study. Patients who underwent bone marrow transplantation (BMT) or who were lost to follow-up were censored at the date of BMT or the last follow-up. Kapplan-Meier product limit estimates were performed to determine the CR duration. For comparison of the CR duration, the log-rank test was used. A p value of less than 0.05 was considered to be statistically significant. The median follow-up for patients alive at the time of analysis was 39 months (range 22-58 months) for the study group and 70 months (range 61-83 months) for the historical control group.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patients and Therapeutic Evolution
Table 1 summarizes the characteristics of the two groups of patients. The sex, age and leukocyte counts at diagnosis were similar between the two groups. The G-CSF group had five patients with high risk FAB subtypes (M0, M5 and M6), while the control group had one such patient (p = 0.06). The control group had six patients who required two courses of induction chemotherapy, while the G-CSF group had two such patients (p = 0.17). Both groups had quite similar numbers of high-risk and standard-risk patients (four control group cases were not classified as to the risk category because they lacked chromosome data).


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  		Table 1. Patient characteristics
 
Of the 26 patients enrolled in the G-CSF study, eight cases (age [years]: median 40, range 20-66) have completed all schedules, i.e., two courses of consolidation and eight cycles each of VEMP and six-day BHAC-DMP therapy. Among those eight cases, seven remain in CR, whereas one relapsed. One patient decided to stop the therapy after receiving two consolidation courses and six cycles each of VEMP and six day BHAC-DMP therapy. This patient has remained in CR for 39 months. Ten cases relapsed during the maintenance-intensification therapy. Four cases are still undergoing the maintenance-intensification therapy. One case (M3) was lost to follow-up after remaining in CR for 15 months on this G-CSF-combined therapy. One case (M6) received BMT after remaining in CR for 15 months on this therapy. One case (M5, 43 years old) switched to the same chemotherapy without G-CSF after remaining in CR for 11 months; this change was due to prolonged myelosuppression after each cycle of G-CSF-combined therapy. However, the degree of myelosuppression was similar even after switching the therapy, and this patient relapsed seven months later.

The given daily dose of G-CSF (mean ± SD calculated from the mean G-CSF dose of each patient) was 117 ± 50 µg/m2, 121 ± 48 µg/m2 and 110 ± 43 µg/m2 for the first consolidation, the second consolidation and intensification therapies, respectively (the doses for the consolidation therapies are the data from the first day of G-CSF administration to the last day of the chemotherapy). The peak leukocyte counts (mean ± SD, x 109/l) were 34.3 ± 11.3 and 31.9 ± 11.5 for the first and second courses of consolidation therapy, respectively.

Toxicity
Table 2 summarizes the data on toxicity recorded during the therapeutic period. Neutrophil recovery after the consolidation therapy was shorter in the G-CSF group than in the control group. No other toxicity data showed a significant difference between the two groups. During the two consolidation courses, documented infections occurred in seven cases of the G-CSF group (bacteremia = 1; perianal abscess = 1; enteritis = 2; urinary tract infection = 1; pharyngitis = 1; and gingivitis = 1) and in 13 cases of the control group (bacteremia = 2; pneumonia = 2; perianal abscess = 2; nasal abscess = 1; enteritis = 1; urinary tract infection = 2; pharyngitis = 1; and gingivitis = 2). Platelet recovery after the consolidation therapy was similar in both patient groups.


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  		Table 2. Toxicity
 
We were unable to monitor the recovery of the peripheral blood cell count after the maintenance-intensification therapy, which was given on an outpatient basis. During the maintenance-intensification phase, documented infections occurred in two cases of the G-CSF group (bacteremia = 1 and gingivitis = 1) and in one control group case (pneumonia). Two G-CSF group cases received platelet transfusions during the maintenance-intensification therapy. The number of patients who required reduction of the chemotherapy dose was four and two for the G-CSF and control groups, respectively (p = 0.31).

Nonhematologic toxicity was infrequent except for paresthesias due to vincristine, and all were tolerable in the G-CSF group. Relapse was the only cause of death in the study population. Long-term toxicity was examined in eight patients who have remained in CR for a long period (CR duration: 39-58 months; seven completed all of the therapeutic schedules, while one received two consolidation courses and six cycles each of VEMP and six-day BHAC-DMP therapy). The peripheral blood cell counts of all these patients have been normal; the ranges of the recent data for these eight cases are hemoglobin 12.8-15.8 g/dl, platelets 130-210 x 109/l, neutrophils 2.1-5.6 x 109/l and lymphocytes 1.3-2.7 x 109/l. No long-term hematologic and nonhematologic toxicity have been observed in these patients.

CR Duration
Two patients in the G-CSF group were censored after remaining in CR for 15 months (one was due to BMT and the other was lost to follow-up), while one patient in the control group was censored after remaining in CR for six months due to being lost to follow-up. At a median follow-up time of 39 months for the G-CSF group, 12 patients have remained in CR whereas the other 12 patients relapsed. The predicted rate of a 42-month CR duration for all 26 patients in the G-CSF group was 50% (95% confidence limits [CL], 30% to 71%), which is better than that of the control group (25%: 95% CL, 9% to 41%), but the difference was not statistically significant (p = 0.21, Fig. 2A). When only the standard risk patients of both groups were analyzed, the predicted rate of a 42-month CR duration was 63% (95% CL, 39% to 88%) for the G-CSF group (n = 18) and 29% (95% CL, 8% to 51%) for the control group (n = 17) (p = 0.17, Fig. 2B). This better trend of CR duration for the G-CSF group was not changed when patients over 50 years old, a factor which may be associated with a short CR duration [35, 36], or M3 patients were excluded from the standard risk patients (G-CSF group versus control group: excluding cases >=50 years old, 67% [n = 10] versus 36% [n = 11]; excluding M3 cases, 49% [n = 13] versus 30% [n = 13]). The CR duration of high-risk patients was similar between the G-CSF and control groups (data not shown). Only one of the eight relapse-free long-term survivors of the G-CSF group was a high-risk patient (FAB M0).



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  		Figure 2. CR duration for all patients (A) and the standard-risk patients (B).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Despite administration of various types of postremission chemotherapy, chemotherapy alone cures only 25% to 30% of patients with AML in a first CR [39, 40]. Although autologous or allogeneic BMT may increase the cure rate of AML, these transplants show a 10%-20% treatment-related mortality rate. Further, age limitations for both transplants and the requirement for an HLA-matched donor for allogeneic BMT restrict the application of these treatments. Based on this background, we conducted this pilot study, which may be the basis for designing a G-CSF-combined chemotherapeutic strategy capable of increasing the cure rate of adult AML. Although prior studies of G-CSF-combined induction chemotherapy did not show a clear advantage [9, 13], there are theoretical reasons, as described in the Introduction, in support of the study of G-CSF-combined postremission chemotherapy for de novo AML in a first CR. We confirmed previously that in vitro G-CSF stimulates the cell cycle of blasts (i.e., by decreasing G0 phase blasts and/or increasing S phase blasts) in most AML cases, and that combined use of G-CSF and cytosine arabinoside reduces the number of G0 phase blasts [6].

We arbitrarily set the upper limit of leukocytes in the peripheral blood at 40 x 109/l to avoid adverse reactions due to extreme leukocytosis, and the G-CSF dose was modified to achieve this. The mean daily dose of G-CSF given in each therapeutic phase of this study ranged from 110 µg/m2 to 121 µg/m2. Because our subjects received G-CSF after having achieved CR, we were unable to prove whether the cell cycle of AML blasts was indeed stimulated in vivo in these subjects. Little data have been published regarding the in vivo effect of G-CSF on human AML blasts [41], but the following data support that AML blasts were stimulated in vivo by G-CSF in our subjects. Ashida et al. injected G-CSF (150 µg/body/day, s.c.) into two AML patients for a few days and documented that this treatment increased S phase blasts and DNA synthesis of blasts in both cases [42]. Jinnai et al. injected G-CSF s.c. into two AML patients (2 µg/kg/day for one case and 5 µg/kg/day for the other case), and this treatment induced a marked increase in the peripheral blast cell count in both cases [43]. We previously injected G-CSF (100 µg/m2/day, s.c. for one week) into one patient with AML transformed from MDS and demonstrated a decrease in G0 phase blasts and an increase in S phase blasts in response to this treatment [44].

We administered repeated G-CSF-combined BHAC-DMP therapy to 26 AML patients in a first CR. During the therapeutic period, there was no significant toxicity in the study group compared with the control group, and all patients tolerated this therapy well except for one M5 case. It is unclear whether the prolonged myelosuppression seen in this case was due to the G-CSF therapy, because the chemotherapy alone continued to cause prolonged myelosuppression in this patient. Heil et al. reported that when GM-CSF or a placebo was given concurrently with induction chemotherapy and two subsequent courses of consolidation chemotherapy for AML patients, platelet recovery was delayed in the GM-CSF arm [45]. A similar finding was reported by Büchner et al. in AML patients treated with GM-CSF-combined chemotherapy [46]. In contrast, our G-CSF-combined chemotherapy did not show any delay in platelet recovery after two consolidation courses. Nevertheless, because two cases in the present G-CSF group received platelet transfusions during the maintenance-intensification period, there is a possibility that platelet recovery during this period may be delayed in the G-CSF group. Several nonhematologic toxicities probably associated with G-CSF have been reported [18-25]. Interstitial pneumonia has occasionally been reported in patients with various cancers who received chemotherapy and G-CSF. We also encountered six patients with non-Hodgkin's lymphoma who received chemotherapy and G-CSF and developed interstitial pneumonia. In our series of 52 non-Hodgkin's lymphoma patients, this complication developed only in subjects who suffered from extreme leukocytosis due to G-CSF [47]. However, this complication was not observed in this AML study. Nonhematologic toxicities specific for G-CSF observed in this study were bone pain and Sweet's syndrome, both of which were tolerable. One patient developed leg edema, which also might be associated with G-CSF [23]. Long-term hematologic toxicity due to depletion of normal hematopoietic progenitor cells was one of our concerns at the start of this pilot study. Nevertheless, the peripheral blood cell counts have been normal in the eight cases who have remained in long-term CR at a follow-up period of 39-58 months. Taken together, we conclude that the G-CSF-combined BHAC-DMP postremission therapy is well tolerated and probably has no significant long-term toxicity.

The advantage of G-CSF-combined postremission chemotherapy on the CR duration of AML remains speculative. The subjects treated with the G-CSF-combined chemotherapy showed a better trend for the CR duration than the control group. Nevertheless, there is a possibility that this better trend may be caused by a hidden prognostic difference between the two groups of patients, the different follow-up period for the two groups and/or the small number of patients studied. To clarify the advantage of the G-CSF-combined postremission chemotherapy on the CR duration in AML, a large randomized study comparing this strategy and the conventional therapy is needed.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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accepted for publication April 16, 1998.




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