rhugm-csf after High-Dose Chemotherapy in Post-Remission Acute Leukemia

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1 rhugm-csf after High-Dose Chemotherapy in Post-Remission Acute Leukemia Rafael Hurtado, Myrna Candelaria, Florencia Vargas, Abraham Majluf, Federico Bolaiios, Juan R. Labardini Departament of Hemato-Oncology, Instituto Nacional de la Nutricion, Salvador Zubiran, Mexico City, Mexico Key Words. rhugm-csf Acute leukemia Post-remission chemotherapy AML ALL Abstract. Post-remission high-dose chemotherapy has been an important advance in the treatment of adult acute leukemia (AAL). Without the use of colony-stimulating factors (CSFs) in this program, the mortality rate varies from 5 to 17%, and infectious complications arise in more than 5%. These findings limit the widespread use of such forms of therapy. The use of high-dose ara-c (HIDAC) alone or in combination with other drugs is the most common regimen studied, however neither other drug combinations nor the addition of supporting CSFs have been extensively explored. For this reason we studied the effect of high-dose cyclophosphamideetoposide (CECY) plus recombinant human granulocyte-macrophage (rhugm)-csf with the intention of decreasing morbimortality and prolonging disease-free survival (DFS). Since 1992 we have included 51 complete remission patients with AAL in the CECY plus rhugm-csf protocol. The maximal myelosuppression occurred in a mean of 6.4 days, and the mean days required for absolute neutrophil count recovery was 13 days and for platelets 21 days (p <.1). No toxic deaths occurred and only two serious infectious complications were seen. After two years of follow-up, 5% of de novo acute myelogenous leukemia patients had relapsed at 13 months, and 5% of de novo adult acute lymphocytic leukemia patients had relapsed at 15 months. In a recent update, we have not seen a significant difference when compared to historic groups. The CECY protocol does not appear to be superior in prolonging DFS compared to HIDAC as a post-remission strategy for newly diagnosed AAL. The main difference was the Correspondence: Dr. Rafael Hurtado M., Hospital Angeles del Pedregal, Camino a Santa Teresa No. 155, Desp. 243 Col. Heroes de Padierna CP17 Mexico City, Mexico. Received September 9, 1994; accepted for publication September 9, OAlphaMed Press /95/$5./ absence of toxic deaths and minimal serious infectious complications in the CECY protocol. Therefore, we suggest that the use of rhugm-csf in post-remission programs should be included in future studies. Introduction Although the main therapeutic goal in the treatment of acute leukemia is to eradicate the leukemia cells with the administration of high dose of antileukemic drugs, there is still considerable controversy regarding optimal therapy. Among the major questions to be addressed: 1) Should induction remission be further intensified? 2) What is the role of early intensification or consolidation? and 3) What candidates, timing and type of stem cell transplantation (SCT) might be effective? Moreover, major progress in adult acute leukemia (AAL) during the past ten years has been in the area of treatment dealing with post-remission programs. At the present time, approximately 33 to 42% of adult patients with adult acute myeloid leukemia (AML) have a likelihood of prolonged remission, compared to 25 to 41% of those patients with acute lymphoblastic leukemia (ALL) [ The toxic deaths and prolonged periods of myelosuppression that accompany the use of intensive post-remission regimens limit the widespread application of this approach. However, the availability of colony-stimulating factors (CSFs), which enhance the proliferation and differentiation of hematopoietic progenitor cells, has made it possible to include them in the treatment of leukopenia along with such therapeutic measures as chemotherapy, irradiation, SCT and more recently for peripheral blood stem STEM CELLS 1995;13:

2 113 rhugm-csf after High-Dose Chemotherapy in Post-Remission Acute Leukemia Table I. Acute myeloid leukemia* n = TADOP P n Age (years) ~ f Sex (malelfemale) /1 Fab Subgroups M M M M M M *INNSZ experience cells mobilization and autologous transplants. In acute leukemia the use of recombinant human granulocyte-macrophage (rhugm)-csf allows dose-intensive therapy with less toxicity due to earlier neutrophil recovery [ In this concise review we analyze some recent advances in the treatment of adult acute leukemia and the use of rhugm-csf. Acute Myeloid Leukemia For acute myeloid leukemia (AML) there is general agreement that complete remission (CR) rates of 6-85% are obtained in patients 4 years old [ with the combination of cytarabine (ha-c) and daunorubicin administered over 7 and 3 days, respectively ( regimen). In a group of 66 patients treated in our institution from 1985 to 1992 with classical (n = 35) and thioguanine, Ara-C, daunorubicin, vincristine and prednisone (TADOP) (n = 3 1) with comparable clinical and laboratory features (Table I), the CR rate was higher (66%) when compared to TADOP (39%) (p <.5). The days and number of cycles required for CR achievement were also significantly fewer (p <.1) for versus TADOP, (Table 11). The disease-free survival (DFS) after 36 months showed no statistical difference (SD). However, virtually all TADOP treated cases had relapsed by 35 months, and 15% of those treated with remained in the first CR (CR-1) after four years (Table III, Fig. 1). Our data support the fact that the is the standard induction regimen, and the addition of other drugs does not clearly improve results [14, 17-22]. Once CR has been achieved, most patients can be expected to remain in CR from 9 to 16 months, and although the finding is hard to reproduce, from 2 to 4% of patients in some series remain in CR for two years or more [12, 21-23]. Therefore it is clear that new treatment strategies are mandatory. Today most centers focus the treatment in Table 11. Acute myeloid leukemia, mean clinical and laboratory features* Gingivitis (a) Hepatomegaly (a) Splenomegaly (%) Node enlargement (%) Peripheral blood blast (%) Bone marrow blast (%) Hemoglobin values (gldl) White blood cells (19/L) Platelets TADOP P *INNSZ experience

3 Hurtado et al. 114 Table 111. Acute myeloid leukemia, treatment results* 7+3 CR (%) 66 Days required for CR achievment (%) 33.2 i 14.8 Cycles required for CR achievment (%) 1.3 Induction remission deaths (%) 2 Resistant disease (%) 14 Relapses 28 Mean follow-up (range 1-49)** 36 month DFS (%) 15 TADOP f (range 1-36)** *INNSZ experience **Indicates range in months of patient follow-up since time of last CR case (one month) to last live patient (49 months) of the and 36 months of the TADOP group. P post-remission programs on eradication of residual leukemia cells and thus prevention of recurrence of leukemia and prolonging disease-free survival. Early intensification chemotherapy (EICH) and consolidation (Conso) are examples of such programs: EICH involves the use of high-dose chemotherapy with drugs that the patient has not previously received, and it is indicated within a few months of achievement of remission. Conso therapy refers to the use of one or more cycles of chemotherapy given immediately following remission and usually uses the same drugs employed to induce remission [ The use of high-dose cytarabine (HIDAC) given alone or in combination with other drugs has I-. Fig. 1. de novo (dn) AML. DFS INNSZ experience W A TADOP. been the most popular regimen investigated as consolidation in newly diagnosed acute leukemia. Such regimens are used after CR has demonstrated that 3 to 62% of AML patients in CR remain in remission two years after diagnosis [ 11. This result suggests that allogeneic SCT in CR-1 AML and ALL should be limited to patients with adverse prognostic factors and histocompatible donors [ In the treatment of myelosuppression one of the most important contributions has been the introduction of CSFs, which have modified patient morbidity and mortality and thus permitted the use of dose intensification in certain hemato-oncological diseases [29, 31. Several studies have evaluated or are examining the ability of growth factors to modify the hematopoietic toxicity of chemotherapy programs that vary according to their marrow ablative potential. The common feature of high-dose chemotherapy is that the granulocytemacrophage precursors are almost totally depleted for several days following the administration of such therapy, which creates an inevitable risk of severe absolute neutropenia. Although it has been reported that the use of CSFs modifies the hematopoietic toxicity of intensive chemotherapy programs, the majority of the findings are from autologous SCT transplants using bone marrow and peripheral blood. Gulati [31] has pointed out that the true clinical benefit of the CSFs and or SCT support will be derived from the results of future randomized clinical trials that address the benefit of dose intensification with less infectious complications with the use of CSFs without STC rescue, and-most important-prolonged survival of the patients with improved quality of life [

4 115 rhugm-csf after High-Dose Chemotherapy in Post-Remission Acute Leukemia The use of rhugm-csf in AML has been mainly in the treatment of neutropenia [35-381, and more recently in prior induction chemotherapy, since learning that GM-CSF induces an increase in leukemic S phase cells and also increases the leukemic clonogenic cell-kill by Ara-C [ In a clinical setting, Bettelheirn administered rhugm-csf 24 or 48 hours prior to induction, and 15 of 18 patients achieved CR. Similar results were obtained by Biichner et al. [ The study of Estey et al. in 1992 achieved a lower CR rate and shorter survival with the use of rhugm-csf to sensitize leukemic blast cells to cytotoxic chemotherapy. Although 68% of patients were in CR at 2.5 years in the GM-CSF group, these authors suggested exercising caution before introducing this treatment into widespread practice [43]. However, other studies have not confirmed these results [4,42]. The efficacy of rhugm-csf for induction remission has also been studied by Biichner et al., who reported that absolute neutrophil count recovery (ANCR) occurred in a median of one week (shorter than controls), and early deaths fell from 39 to 14%. These results were confirmed by the Eastern Cooperative Group (ECOG) in a randomized, placebo-controlled trial in patients between 55-7 years with newly diagnosed AML [4 1,441. The use of HIDAC as post-remission consolidation alone or combined with anthracyclines has confirmed that it is the most significant factor related to prolonged DFS, since the description by Wolfs et al. in 1989 that the global DFS was 49%, but it was 83% and 5% for patients less than 25 and 45 years of age respectively after 3.5 years of follow-up [45]. Myelosuppression had a median duration of three weeks, and 5% of patients died due to infection and/or hemorrhage; 59% of patients experienced severe but nonfatal infectious complications. However, rhugm-csf has not been used in previous studies or even in the most recent reports. Bow et al. reported prolonged DFS with HIDAC Conso in 14 patients; 43% (8 months median follow-up) remained in continued CR-1 after 36 months compared with 15% of those patients included in low dose post-remission chemotherapy ( regimen) and none in the group without Conso. The HIDAC schedule also produced longer periods of neutropenia with high blood product requirement, and all courses were associated with severe neutropenia and thrombocytopenia. Twenty-eight days were required for ANCR.5 x 19/1 and more for 1 x 19/l. Thirty infectious episodes were registered during the four courses of consolidation, and bacterial as well as fungal infections were common. The 28-day recovery of myelosuppression was in the range of 21 to 4 days reported in other series [ The mortality in this study was 5%. The Cancer and Leukemia Group B (CALGB) also studied HIDAC alone as post-remission therapy, and 44% of the patients less than 6 years old remain in CR-1 at three years, with a mortality rate of 5% [53]. The ECOG reported their results in 143 adults with HIDAC plus Amsacrine in 1992; the probability of remaining in CR after a median follow-up of four years was 28% with a 12% risk of toxic death [53]. Adult Acute Lymphoblastic Leukemia (AALL) Post-induction chemotherapy for AALL is also controversial, and information on the use of rhugm-csf is limited [54]. The use of HIDAC alone or in combination with other drugs is summarized in the excellent review by Hoeltzer and the annotation of Rohatiner and Lister [2-31. To our knowledge, there is one study-reported by Brown et a1.-using high doses of etoposide and cyclophosphamide to induce remission in resistant AALL with a 28% CR rate. The ANCR occurred on median day 27 (range 19 to 58). There were toxic deaths in 17% of patients between 8 and 45 days after treatment as a result of infection [55]. In another interesting recent study reported by Wernly et al., six (9.5%) toxic deaths were registered with the intensive inductionlconsolidation therapy protocol without maintenance in AALL. CSFs were not used [56]. CECY Protocol Despite the encouraging results obtained with HIDAC alone or in combination with other drugs in post-remission therapy for newly diagnosed AML and AALL, it is clear that mortality (5 to 17%) and morbidity due to infection limit the widespread use of such programs. Because of the additional economic limitations of

5 Hurtado et al. 116 Table IV. Acute myeloid leukemia, patient characteristics* Mean age (range) Malelfemale Fab subgroups M- 1 M-2 M-3 M-4 M-5 M-6 M-7 RAEBt * 1992 study (range 15-52) (range 15-55) 12/ SCT for our patients, we decided to evaluate in a prospective, single institution study the use of combination etoposide-cyclophosphamide (CECY) as consolidation in acute leukemias. The theoretical basis was that such drugs might act against residual cells resistant to the induction drugs used, and that such a drug combination had been effective in the treatment of resistant or relapsed leukemia [55]. The main objective of this study was to assess the effect of such treatment in prolonging CR duration. The second objective addressed the efficacy of rhugm-csf in enhancing earlier neutrophil recovery and therefore reducing the morbidity and mortality due to infection. The decision to use rhugm-csf was that it might potentiate the effect of monocyte function and could be important in the defense against fungal infections that accompany the use of consolidation therapy for AML [46,57]. From 1992 to July, 1994, 51 patients with AAL were included in the CECY protocol. The patients were those who had achieved CR after standard induction conventional chemotherapy regimens, including the regimen for AML and the HOP regimen for AALL [58]. Vincristine sulfate was administered intravenously (i.v.) at a dose of 1.4 mg/m2 weekly for six weeks; 4 mg/m2 i.v. doxorubicin was given on days 1 to 3 with an equal single dose in week 4. If infiltration persisted, we added the same dose of doxorubicin. Oral prednisone (6 mg/m2) was given daily during the six weeks. The CR status was established in agreement with approved criteria [59]. For relapsed or resistant leukemia, the induction regimen consisted of an intermediate dose of Ara-C (1 g/m2 in a three-hour i.v. infusion every 12 h for three days) and etoposide 5 mg/m2 i.v. on days 1 to 3. After CR, patients received CECY as consolidation which consisted of the combination of 1.3 g/m2 etoposide in a 24-h continuous i.v. infusion on days 1 and 2, and 25 mg/kg of cyclophosphamide in 3-min i.v. infusion from days 3 to 6. All patients received 5 pg/kg of rhugm-csf (Sandoz/Schering-Plough, Mexico City) in a 24-h continuous i.v. infusion, given until ANCR reached 115. All patients were in single nurse reverse isolated rooms with standard infection prophylactic drugs, and platelet transfusion supportive measures were given if indicated. Survival was calculated from the first day of therapy to death, and DFS was measured from the first day of therapy to relapse or death; the Kaplan-Meier method was used. For comparison of the recovery days between ANCR and platelets, the Wilcoxon signed rank test was used. DFS and overall survival were compared with a historic well-balanced group of patients who received the same induction regimens but did not received consolidation (n = 115). Among 51 CR responders, 17 were de novo (dn) AML and 23 dnaall; 7 were AML resistant (R); 4 were AALL-R. Acute leukemias dn were evaluable for DFS in comparison with historic controls (AML 23 and AALL 92). The 51 CR cases were evaluable for ANCR after rhugm-csf. The patient demographics and Fab subtypes are shown in

6 ~~ 117 rhugm-csf after High-Dose Chemotherapy in Post-Remission Acute Leukemia Table V. Acute lymphoid leukemia, CECY versus historic group, patient characteristics CECY HOP-1 HOP-2 n Mean age (range) (range 14-47) 25.1 (range 14-66) 24.6 (range 14-46) Male/female 12/11 19/25 28/2 Fab subgroups L L L Tables IV and V. For the whole CECY group ages ranged from years with a mean of 27.5 (standard deviation 11.84). The basic hematologic values before the CECY protocol was started are shown in Table VI, which also describes the maximal myelosuppression values secondary to the high-dose cyclophosphamide-etoposide combination. Neutrophil nadir was reached at a mean of 6.4 days, (range 4-13) and the ANCR (>15) after rhugm-csf was obtained in a mean of 13.7 days (range 6-34). The platelet recovery values were longer (mean 21) when compared to ANCR (p <.1; Wilcoxon signed rank test) (Fig. 2). Although Grade IV myelosuppression occurred in all cases, no toxic deaths were registered during the aplasia period. Because this study is ongoing in terms of a two year follow-up, we consider it early for final evaluation of DFS and survival. However for dnaml at 13 months, 5% of the CECY group have relapsed with no SD compared to historic groups (5% at nine months), and the overall survival (s) was better in the CECY protocol (69% at 22 months compared to 38% in the historic group at the same period) (Figs. 3 and 4). For dnaall, the DFS was 5% at 15 months in the CECY group and identical to the HOP- 1 and 24 months of the HOP-2 historic controls. The s shown had no SD in the CECY group at 22 months (3% CECY versus 45 and 4% of HOP-1 and HOP-2 respectively at 3 months) (Figs. 5 and 6). Our data are difficult to compare with the overall literature information because differences in treatment regimens are the rule. For both AML and AALL, the maintenance chemotherapy programs after Conso vary from one center to another. Some give Conso and observation, while others treat with different maintenance programs. Our policy is in favor of maintenance; and although all patients receive treatment, relapses occur and probably reflect." Table VI. Acute leukemia, CECY protocol, basic hematologic values ~~ ~ Values pre * WBC Neutrophils Platelets Nadir of maximal MS** (days) WBC Neutrophils Platelets *x 19/L; **myelosuppression 6.2 ( ) 3.3 ( ) 32 ( ) 6 (4-13).2 (.1-.5).2 (-.38) 22 (4-86) Fig. 2. CECY Protocol. ANCR and platelet recovery after rhugm-csf. (p <.1 Wilcoxon signed rank test). No SD in the mean days for ANCR between Ir AML and ALL (13.4 f 5.7 versus 9.3 It 4.59, neither for platelet recovery among AML and A ALL (22.9 f 5.6 versus 15.4 f 5.8) respectively.

7 Hurtado et al as OA MONTHS Fig. 3. AML DFS; CECY Protocol + versus Historic group * without conso n = 23; plus CECY n = 17. Mean follow-up in months (19 and 12.4 respectively) (update August 1994). Fig. 5. dn AALL DFS CECY versus Historic groups. MEAN FOLLOW UP (MONTHS) * HOP-1; n = CECY; n = the emergence of a chemotherapy resistant leukemic cell population as demonstrated by an.8 1k increased expression of P-glycoprotein in leukemia patients at relapse [6]. Whether the a loa 18 2 P MOKRlS Mom Fig. 4. dn AML overall survival CECY versus Historic groups. MEAN FOLLOW UP (MONTHS) n = 23 * CECY; n = Fig. 6. dn AALL overall survival CECY versus Historic groups. MEAN FOLLOW UP (MONTHS) A - HOP-1; n = HOP-2; n = * CECY; n = 23 18

8 119 rhugm-csf after High-Dose Chemotherapy in Post-Remission Acute Leukemia Table VII. Toxicity Myleosuppression Fever of unknown origin (FUO) Fever secondary to infection Skin rash 4 Allergic I Stomatitis 1 Vomiting 2 Infection I I1 111 IV V % use of Resistant Modifiers [ added to post-remission programs will improve the response is an interesting issue that future studies will address. The absence of toxic deaths in our study is the most important difference compared to other post-remission chemotherapy programs. All 5 1 cases that received the CECY protocol plus rhugm-csf developed Grade IV myelosuppression, and during the aplasia period two cases of severe infection were registered, one of gastroenteritis with sepsis and the other of bacteremia due to central catheter colonization. Both cases responded well to antimicrobial therapy. Although fever of unknown origin (FUO; Grade 111) was seen in 15.6% of the cases, it was hard to attribute it to the use of rhugm-csf, because FUO also occurs in virtually all severe neutropenic patients. All other toxic events were mild and tolerable (Table VII). Our data support the fact that rhugm- CSF after CECY protocol was effective for ANCR in a mean of 13 days, and there was no effect on platelets. There was a SD in the ANCR for resistant or relapsed patients with a mean of 17 versus 13 days for the newly diagnosed cases; this effect could be due to low bone marrow reserve in these previously heavily treated patients. Post-remission consolidation has shown promise for improving the DFS in adult acute leukemia. The reduction of the days required for ANCR is important because of the reduction of morbimortality associated with highdose chemotherapy regimens. The use of rhugm-csf without SCT is one such support alternative that should be included in light of our encouraging results. Acknowledgments Supported in part by Fundacion Miguel Aleman, Mexico City, Mexico. rhugm-csf (Leucomax was kindly donated by Sandoz- Schering Plough, Mexico City.) To Oscar Bolafios for his assistance in the preparation of the manuscript. References 1 Stone R, Mayer RJ. Treatment of newly diagnosed adult with de novo acute myeloid leukemia. In: Bloomfield CD, Herzig GP, eds. Hematology/Oncology Clinics of North America. Philadelphia, PA: W.B. Saunders Company, 1993;7: Hoeltzer D. Treatment of acute lymphoblastic leukemia. Semin Hematol 1994;31 : Rohatiner U S, Lister TA. The challenge of acute lymphoblastic leukaemia in adults. Br J Haematol 1993 $ Buchner T. Hematopoietic growth factors in cancer treatment. Stem Cells 1994;12: Baranov AE, Selidovkin GD, Buturini A et al. Hematopoietic recovery after 1-Gy acute total body radiation. Blood 1994, Hurtado-Monroy R, Lopez Karpovitch X, Alanis A. Recombinant human granulocyte/monocyte colony-stimulating factor (rhugm-csf) for the treatment of bone marrow (BM) aplasia in accidentally irradiated (6 Co) patients (pts). Report of three cases. Blood 1989;74(suppl 1):16a. 7 Bishop MR, Anderson JR, Jackson JD et al. High dose therapy and peripheral blood progenitor cell transplantation: effects of recombinant human granulocyte-macrophage colony stimulating factor on the autograft. Blood 1994;83:

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