American Journal of Hematology 41 :17&183 (1992)
Treatment of Acute Myeloid Leukemia in the Elderly With Low-Dose Cytarabine, Hydroxyurea, and Calcitriol Christopher A. Slapak, Jane F. Desforges, Terry Fogaren, and Kenneth B. Miller Department of Medicine, Division of Hematology-Oncology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts
Twenty-nine patients aged 62-82 years with acute myeloid leukemia (AML) were treated with a 21-day course of continuous infusion cytarabine, oral hydroxyurea, and 1,25dihydroxyvitamin D, (calcitriol). Ten patients had an antecedent myelodysplastic syndrome. Calcitriol was continued as the only postremission therapy. Thirteen patients (45%) obtained a complete remission, and 10 patients (34%) had a partial response for an overall 79% response rate. There were three early deaths. The median remission duration was 9.8 months. Overall median survival was 12 months for all patients and 14 months for responding patients. All responding patients had marked bone marrow hypoplasia. Twenty patients received part or all of their chemotherapy as outpatients. This regimen has acceptable toxicity and can result in prolonged remissions in elderly, high-risk patients with AML. The favorable results may be related to the synergistic effect of hydroxyurea, cytarabine, and calcitriol. o 1992 Wiley-Liss, Inc. Key words: AML, elderly, low-dose cytarabine
INTRODUCTION
Intensive chemotherapy has resulted in high remission induction rates for patients under the age of 65 with acute myeloid leukemia (AML); a substantial proportion of patients have a prolonged disease free survival [I-31. However, 40% of patients with AML are over the age of 65 years. These patients have a significantly worse treatment outcome with median survival often limited to several weeks [4,5]. Many elderly patients have intercurrent medical problems and cannot tolerate the side effects of intensive therapy. Attenuated induction regimens have been used with varying results [2,6]. Low-dose cytarabine given over a prolonged time period has resulted in less acute toxicity than does standard dose combination chemotherapy [7]. Although more patients survived low-dose cytarabine treatment, the complete response rate was decreased compared with standard induction regimens [8]. Cytarabine and hydroxyurea exhibit in vitro cytotoxic synergy through biochemical and cell cycle effects [9,10]. This drug combination is effective in selected refractory malignancies [ 1I]. Additional studies with human myeloid leukemia cell lines have shown calcitriol (1,25-dihydroxyvitamin D3)to display in vitro synergy with both cytarabine and hydroxyurea [ 121. Furthermore, 0 1992 Wiley-Liss, Inc.
calcitriol alone has been reported to promote differentiation of several leukemia cell lines [13,14] and normal bone marrow cells [ 151. Based on these pharmacologic data and the lack of accepted standard therapy for AML in the elderly, we initiated a trial for the treatment of patients with AML over the age of 65 years. We now describe the results of our first 29 consecutive patients treated with continuous infusion cytarabine in conjunction with oral hydroxyurea and calcitriol. METHODS Patient Selection
Twenty-eight patients 65 years of age or older and one aged 62 with secondary AML were treated on study. All patients were treated after obtaining informed consent according to an IRB approved protocol. AML was diagnosed in all patients and classified according to the
Received for publication November 18, 1991; accepted March 10, 1992. Address reprint requests to Dr. Kenneth B. Miller, New England Medical Center, 750 Washington Street, #245, Boston, MA 021 1 1 ,
Treatment of AML in the Elderly
French-American-British (FAB) criteria [ 161. Patients with a secondary leukemia were eligible to participate in this study. Secondary leukemia was defined as leukemia evolving from a known prior myelodysplastic syndrome or resulting from prior chemotherapy. Patients in blast crisis of chronic myelogenous leukemia were not eligible. Patients with a total blast count of greater than 50 X 109/L were given hydroxyurea alone to lower the blast count to 1.0 X 109/L, and a platelet count >50 X 109/L had to be maintained without transfusion support for at least two months. Patients with a prior myelodysplastic syndrome who transformed into AML were considered to have a partial response if they reverted back to their prior myelodysplastic syndrome. This response needed to be maintained for more than 2 months. Resistant disease was defined as a failure to eradicate the leukemia in the day 28 bone marrow. Early death was defined as mortality from any cause occurring within 60 days of the initiation of chemotherapy. The percentage cytoreduction was defined as the ratio of the cellularity of the pretreatment bone marrow biopsy to the day 28 bone marrow biopsy. RESULTS Patient Population
Twenty-nine patients were entered onto the study. All patients completed a 2 1-day course of induction therapy with cytarabine, hydroxyurea, and calcitriol. The age, sex, and FAB type are described in Table I. The mean age was 73, with a range of 62-82 years. Ten of the 29 patients had progressed from a prior myelodysplastic synEvaluation of Response drome and thus had secondary leukemia. Twenty of the Bone marrow aspirates and biopsies were performed 29 (69%) received part of their regimen as outpatients. on day 28 and upon recovery of an ANC of >1.5 X lo9/ Three patients (10%) received their entire 21-day inducL. The bone marrow aspirates and biopsies were evalu- tion therapy as outpatients and were admitted only for ated prospectively without knowledge of the clinical placement of the intravenous access device and the initiaevents. Complete remission was defined by the usual tion of treatment. criteria: a normocellular bone marrow with normal myeloid and erythroid maturation and less than 5% blast forms. In addition, a complete remission required a he- Response to Therapy Patients were analyzed according to the criteria defined matocrit of >30 vol%, an ANC of >1.5 X 109/L, and a above. Table I1 details the response to inducti0.n therapy. platelet count >loo x i o 9 / ~ .
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TABLE II. Results of Induction
All patients N = 29 Complete response Partial response No response Hypoplastic death Resistant disease De novo ANLL N = 19 Complete response Partial response No responseihypoplastic death Secondary leukemia N Complete response Partial response No response
=
No. of Patients
Percentage
13 10 6 2 4
45 34 21 I 14
12 2
63
5
26
II
10 10
80 10
The development of treatment-related thrombocytopenia was independent of the pretreatment platelet count. All patients experienced severe neutropenia (1.O x i o 9 / ~ was 44 days (range: 38-65 days) in the responding patients. Of the 20 patients who received part of their treatment as outpatients, 15 were subsequently readmitted for evaluation of fever and neutropenia. Two patients developed asymptomatic hypercalcemia (1 1.2 mg/dl and 11.5 mg/dl) but did not require treatment. In one patient, the calcitriol was held until the calcium normalized and was then restarted without recurrent hypercalcemia. Five patients had mild, grade l , symptomatic mucositis. No patient developed alopecia. No patient experienced significant nausea or vomiting while receiving the induction regimen.
All patients entered on study were evaluable, and no Cytoreductive Effect Bone marrow aspirates and biopsies were obtained on patient was removed from the study prior to completing the 21-day course. Thirteen of 29 patients attained a day 28, 1 week after completing cytarabine. Two patients complete response (45%), 10 patients had a partial re- had inadequate samples for evaluation. With the 27 evalsponse (34%), and 6 patients did not respond to therapy. uable bone marrows, there appeared to be a correlation Two patients died while hypoplastic and 4 had resistant between cytoreductive effect of the induction regimen disease. In the 19 patients with de novo AML, 14 re- and the response to therapy. All responding patients demsponded (74%), with 12 (63%) exhibiting complete re- onstrated greater than 50% reduction or bone marrow sponses and 2 (11%) partial responses. Five patients cellularity in their day 28 bone marrow compared to (26%) failed to respond. Of the 10 patients in the second- pretreatment. In addition, all patients who did not experiary leukemia group, there were 8 partial responses, 1 ence at least a 50% reduction of the bone marrow cellucomplete response (90% overall response rate; 80% PR larity by day 28 ultimately did not respond to treatment. and 10% CR). All patients with a partial response re- The mean percent cytoreduction between those who responded and those who did not was 67% versus 22% turned to their prior myelodysplastic syndrome. Nine patients received a second cycle of induction ( P < 0.05). By contrast, there was no correlation bechemotherapy at the time of relapse. Five patients tween the duration of response and the percentage cytoreachieved a second CR with a median remission duration duction in the day 28 bone marrow (R = 0.30). Moreof 4 months (range: 3-9 months). One patient achieved a over, there was no difference in the percent of PR of 4 months’ duration, and 3 patients did not respond. cytoreduction between partial responders and complete responders (64% vs. 77%, respectively, P = NS). No patient received a third cycle of chemotherapy. Survival Analysis
The median survival was 12.0 months, with a range of 1.5 months to 24+ months (Fig. 1). The longest complete response to date is 24 months. The projected survival at 24 months is 18% for all patients. The duration of response for the first course is presented in Figure 2. The median duration of response was 9.8 months, with a range of 1.5-20 months. There were 3 early deaths in the 29 patients. Two patients died of sepsis, while hypoplastic and one patient in complete remission died of an acute myocardial infarction. Toxicity All patients developed severe thrombocytopenia and granulocytopenia. Twenty patients were platelet transfusion dependent during the entire course of chemotherapy.
DISCUSSION
Several studies have documented age to be of major prognostic significance in patients with AML [ 1,3,17,18]. Intensive chemotherapy treatment regimens administered to elderly patients have resulted in widely varying complete response rates. These results reflect differences in defining the elderly population (50, 60, 65, or 70 years) and differences in excluding patients with antecedent myelodysplastic syndromes. Most studies, however, have reported complete remission induction rates of 3 0 4 0 % for patients over the age of 60 years [6,19-2 11. The same studies document early deaths or death during induction in 40-60% of patients. Mean survival, when reported, was usually short, limited to several weeks or months. Many studies exclude patients with antecedent myelodys-
Treatment of AML in the Elderly
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P
E
C
E N
60
A T I
401 I
S
01
0
I
I
5
10
I
I
15
20
25
MONTHS Fig. 1. Actuarial survival for patients treated with cytarabine, hydroxyurea, and calcitriol.
100
P E
C
-
80-
E N
60-
0 F P A
40-
T I N T
20-
S
0 0
I
I
I
I
5
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20
25
MONTHS Fig. 2. Actuarial remission duration for patients treated with cytarabine, hydroxyurea, and calcitriol.
plastic syndromes, a recognized poor prognostic factor [22,23]. Cytarabine at low doses has been administered to elderly and high-risk patients with AML with reported complete response rates of 30-50% [7,24]. A randomized trial comparing low-dose cytarabine with intensive chemotherapy also noted a 32% CR rate for low-dose therapy [8]. While low-dose cytarabine appears to have significant activity in the treatment of AML and is better tolerated than intensive chemotherapy regimens, it also has been shown to result in shorter remission durations
when compared with standard intensive chemotherapy [6,81. In vitro studies have demonstrated synergistic activity between cytarabine, hydroxyurea, and calcitriol . We initiated a trial of continuous infusion cytarabine with concomitant oral hydroxyurea and calcitriol in an effort to improve the overall response to low-dose cytarabine through biochemical modulation. The results of our study are notable for several reasons. The patients in this study had a mean age of 73 years, with only one patient under the age of 65 years. More-
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over, 34% of the patients treated had a secondary leukemia. The overall complete response rate of 45% compares favorably with reported CR rates for intensive induction regimens in this age group. If patients with antecedent myelodysplastic syndromes are excluded, the resulting CR rate of 63% is comparable to the best reported CR rates for intensive induction regimens in a similar age group. Patients in complete remission were given no postremission therapy with the exception of oral calcitriol. Patients who relapsed more than 6 months after beginning therapy were offered a second course of induction therapy. A large number of these patients (56%) obtained a second complete remission. Overall the median survival was 12 months (with a range of 1.5-24+ months). This survival compares very favorably to other studies using intensive postremission therapy [25]. An important factor in the high overall response rate in this study was the observed low early death rate. Only 10% of the patients treated died during the first 60 days. Although this regimen did result in bone marrow hypoplasia with marked granulocytopenia and thrombocytopenia, there were few life-threatening or serious infectious complications and many patients received part or all of their induction regimen as outpatients. The minimal gastrointestinal toxicity and mucositis may have allowed these high-risk patients to tolerate a period of neutropenia with fewer life-threatening complications. Low-dose cytarabine can induce leukemia cell differentiation in vitro [26,27]. Our results, however, suggest that a cytotoxic effect is needed for a response to this regimen, which may well be related to the previously described synergy between cytarabine, hydroxyurea, and calcitriol. For biologic activity, cytarabine is phosphorylated intracellularly to the triphosphate, ara-CTP. This metabolite exerts its cytotoxic effect through inhibition of DNA polymerase [28,29] or through its action as a chain terminator [30,3 11. Deoxycytidine is the natural substrate for this phosphorylation step and is a competitive inhibitor of cytarabine. Elevated intracellular pools of phosphorylated deoxycytidine (dCTP) have been implicated in cytarabine resistance 1321. Hydroxyurea is an inhibitor of ribonucleotide reductase and leads to depletion of intracellular dCTP by inhibiting de novo synthesis of deoxycytidine [33]. This dCTP depletion appears to be the mechanism underlying the in vitro synergistic cytotoxicity of hydroxyurea with cytarabine. The observed cytoreductive effect of this regimen supports that these agents may also be synergistic in vivo. As opposed to other studies that evaluated cytarabine alone, the patients treated with this combination developed severe granulocytopenia and thrombocytopenia. The augmented cytotoxic effect may reflect potentiation of cytarabine cytotoxicity by hydroxyurea or may simply be additive.
Calcitriol is an important hematopoietic regulatory hormone which is capable of inducing terminal differentiation in normal and abnormal states [13-15,34,35]. Calcitriol appears to act through a 1,25-(OH),D3-specific intracellular receptor expressed during the cell cycle [36]. Cytarabine and hydroxyurea, both inhibitors of DNA synthesis, potentiate the differentiating effects of calcitriol [37]. In addition, calcitriol potentiates the in vitro cytotoxicity of both cytarabine and hydroxyurea [ 121. These effects may, in part, account for the added cytotoxicity of our regimen. In the myelodysplastic syndromes, calcitriol has been shown to delay the progression to acute leukemia and prolong leukemia-free survival [38]. However, the role of calcitriol in this regimen is unclear. The long duration of the unmaintained responses may reflect the combined therapy with cytarabine and hydroxyurea alone. The overall high response rate, relatively long unmaintained remissions, and acceptable toxicity with low early death rate are sufficiently encouraging to warrant further study of this regimen in elderly and high-risk patients with de novo and secondary AML. ACKNOWLEDGMENT
This work was supported by P.H.S. Fellowship F32CA08774 to C.A.S. REFERENCES I . Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, Preisler HD, Nawabi IW, Prager D, Carey RW, Cooper MR, Haurani F, Hutchison JL, Silver RT, Falkson G, Wiemik P, Hoagland HC, Bloomfield CD, James GW, Gottlieb A, Ramanan SV, Blom J, Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan SK: Treatment of acute myelocytic leukemia: A study by Cancer andLeukemiaGroup B. BloodS8:1203, 1981. 2. Yates J, Glidewell 0, Wiemik P, Cooper MR, Steinberg D, Dosik H, Levy R, Hoagland C, Henry P, Gottlieb A, Cornell C, Berenberg J , Hutchison JL, Raich P, Nissen N, Ellison RR, Frelick R, James GW, Falkson G, Silver RT, Haurani F, Green M, Henderson E, Leone L, Holland JF: Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: A CALGB study. Blood 60:454, 1982. 3 . Rees JKH, Gray RG. Swirsky D, Hayhoe FGJ: Principal results of the Medical Research Council’s 8th acute myeloid leukaemia trial. Lancet 2:1236, 1986. 4. Champlin RE, Gajewski JL, Golde DW: Treatment of acute myelogenous leukemia in the elderly. Semin Oncol 16:51, 1989. 5 . Whitely R, Hannah P, and Holmes, F Survival in acute leukemia in elderly patients: No improvement in the 1980s. J Am Geriatr Soc 38:527, 1990. 6. Kahn SB, Begg CB, Mazza JJ, Bennett JM, Bonner H, Glick JH: Full dose versus attenuated dose daunorubicin, cytosine arabinoside, and 6-thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol2:865, 1984. 7. Tilly H, Castaigne S , Bordessoule D, Sigaux F, Daniel M, Monconduit M, Degos L: Low-dose cytosine arabinoside treatment for acute nonlymphocytic leukemia in elderly patients. Cancer 55: 1633, 1985.
Treatment of AML in the Elderly 8. Tilly H, Castaigne S, Bordessoule D, Casassus P, Le Prise P, Tertian G, Desablens B, Henry-Amar M, Degos L: Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 8:272, 1990. 9. Rauscher F, Cadman E: Biochemical and cytokinetic modulation of L1210 and HL-60 cells by hydroxyurea and effect on I-p-o-ambinofuranosylcytosine metabolism and cytotoxicity. Cancer Res 43:2688, 1983. 10. Tanaka M, Kimura K, and Yoshida S: Mechanism of synergistic cell killing by hydroxyurea and cytosine arabinoside. Jpn J Cancer Res 76729, 1985. I 1 . Schilsky RL, Williams SF, Ultmann JE, Watson S: Sequential hydroxyurea-cytarabine chemotherapy for refractory Non-Hodgkin’s lymphoma. J Clin Oncol5:419, 1987. 12. Studzinski GP, Bhandal AK, and Breivi, Z S : Potentiation by 1.25dihydroxyvitamin D, of cytotoxicity to HL-60 cells produced by cytarabine and hydroxyurea. JNCI 76:641, 1986. 13. Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, Yarnazaki T, Yoshiki S, Suda T: Differentiation of mouse myeloid leukemia cells induced by 1,25 dihydroxyvitamin D,. Proc Natl Acad Sci USA 78:4990, 1981. 14. Mangelsdorf DJ, Koeffler HP, Donaldson CA, Pike JW, Haussler MR: 1,25-dihydroxyvitamin D,-induced differentiation in a human promyelocytic leukemia cell line (HL-60): Receptor-mediated maturation to macrophage like cells. J Cell Biol98:391, 1984. 15. Koeffler HP, Amatruda T, Ikekawa N, Kobayashi Y , DeLuca H F Induction of macrophage differentiation of human normal and leukemic myeloid stem cells by 1,25-dihydroxyvitamin D, and its fluorinated analogues. Cancer Res 44:5624, 1984. 16. Bennett JM, Catovsky D, Daniel MT, Flandrin G , Galton DAG, Gralnick HR, Sultan C: Proposals for the classification of the acute leukaemias. Br J Haematol 33:451, 1976. 17. Weinstein HJ, Mayer RJ, Rosenthal DS, Coral FS, Camitta BM, Gelber RD: Chemotherapy for acute myelogenous leukemia in children and adults: VAPA update. Blood 62:315, 1983. 18. Toronto Leukemia Study Group: Results of chemotherapy for unselected patients with acute myeloblastic leukemia: Effect of exclusions on interpretation of results. Lancet 1:768, 1986. 19. Lazarus HM, Vogler WR, Bums CP, Winton EF: High dose cytosine arabinoside and daunorubicin as primary therapy in elderly patients with acute myelogenous leukemia: A Phase 1-11 study of the Southeastern Cancer Study Group. Cancer 63:1055, 1989. 20. Walters RS, Kantarjian HM, Keating MJ, Estey EH, McCredie KB, Freireich EJ: Intensive treatment of acute leukemia in adults 70 years of age and older. Cancer 60:149, 1987. 21. Preisler HD, Raza A, Barcos M, Azarnia N, Larson R, Walker I , Browman M, Grunwald H, D’Arrigo P, Doeblin T, Bloom M, Stein A, Logue G, Goldberg J , Kirshner J, Gottlieb A, Bennett J: High-dose cytosine arabinoside as the initial treatment of poor-risk patients with acute nonlymphocytic leukemia: A Leukemia Intergroup study. J Clin Oncol5:75, 1987. 22. Keating MJ, Smith TL, Gehan EA, McCredie KB, Bodey GP, Freireich EJ: A prognostic factor analysis for use in development of predictive models for response in adult acute leukemia. Cancer 50:457, 1982.
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23. Michels SD, McKenna RW, Arthur DC, Brunning RD: Therapyrelated acute myeloid leukemia and myelodysplasic syndrome: A clinical and morphological study of 65 cases. Blood 65: 1364, 1985. 24. Cheson BD, Jasperse DM, Simon R, Friedman MA: A critical appraisal of low-dose cytosine arabinoside in patients with acute nonlymphocytic leukemia and myelodysplastic syndromes. J Clin Oncol 4:1857, 1986. 25. Walters RS, Kantarjian HM, Keating MJ, et al: Inlensive treatment of acute leukemia in adults 70 years of age and older. Cancer 60:149, 1987. 26. Griffin J , Munroe D, Major P, Kufe D: Induction of differentiation of human myeloid leukemia cells by inhibitors of DNA synthesis. Exp Hematol 10:774, 1982. 27. Luisi-DeLuca C, Mitchell T, Spriggs D, Kufe DW,: Induction of terminal differentiation in human K562 erythroleukemia cells by arabinofuranosylcytosine. J Clin Invest 74:821, 1984. 28. Furth JJ, Cohen SS: Inhibition of mammalian DNA polymerase by the 5’-triphosphate of 1 -P-o-arabinofuranosylcytosine and the 5’-triphosphate of 9-P-o-arabinofuranosyladenine. Cancer Res 28:2061, 1968. 29. Townsend AJ, Cheng YC: Sequence-specific effects of ara-5-aza-CTP and ara-CTP on DNA synthesis by purified human DNA polymerases in vitro: Visualization of chain elongation on a defined template. Mol Pharmacol32:330, 1987. 30. Kufe DW, Major PP, Egan EM, Beardsley GP: Correlation of cytotoxicity with incorporation of ara-C into DNA. J Biol Chem 255:8997, 1980. 31. Fram RJ, Egan EM, Kufe DW: Accumulation of leukemic cell DNA strand breaks with adriamycin and cytosine arabinoside Leuk Res 7:243, 1983. 32. de Saint Vincent BR, Buttin G: Studies on 1-P-o-arabinofuranosyl cytosine-resistant mutants of Chinese hamster fibroblasts. 111. Joint resistance to arabinofuranosyl cytosine and to excess thymidine-a semidominant manifestation of deoxycytidine triphosphate pool expansion. Somatic Cell Genet 5:67, 1979. 33. Kubota M. Takimoto T, Tanizawa A, Akiyama Y, Mikawa H: Differmetabolism by ential modulation of l-~-o-arabinofuranosy~cytosine hydroxyurea in human leukemia cell lines. Biochem Pharmacol 37:1745, 1988. 34. Manolagas SC, Deftos LJ: The vitamin D endocrine system and the hematolymphopoietic tissue. Ann Intern Med 100:144, 1984. 35. Koeffler HP, Hirji K, Itri L, and the Southern California Leukemia Group: 1,25-dihydroxyvitamin D,: In vivo and in vitro effects on human preleukemic and leukemic cells. Cancer Treat Rep 69: 1399, 1985. 36. Kizaki M, Norman AW, Bishop JE, Lin C, Karmakar A, Koeffler H P I ,25-Dihydroxyvitamin D, receptor RNA: Expression in hematopoietic cells. Blood 77:1238, 1991. 37. Ishikura H, Okazaki T, Mochizuki T, Izumi Y, Tashima M, Sawada H , Uchino H: Effect of antimetabolites and thymidine blockage on the induction of differentiation of HL-60 cells by retinoic acid or 1,25dihydroxyvitamin D,. Exp Hematol 13:98 I , 1985. 38. Motomura S, Kanamori H, Maruta A, Kodama F, Ohkubo T: The effect of 1,25-hydroxyvitamin D, for prolongation of leukemic transformation-free survival in myelodysplastic syndromes. Am J Hematol 38:67, 1991.
Treatment of Acute Myeloid Leukemia in the Elderly With Low-Dose Cytarabine, Hydroxyurea, and Calcitriol Christopher A. Slapak, Jane F. Desforges, Terry Fogaren, and Kenneth B. Miller Department of Medicine, Division of Hematology-Oncology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts
Twenty-nine patients aged 62-82 years with acute myeloid leukemia (AML) were treated with a 21-day course of continuous infusion cytarabine, oral hydroxyurea, and 1,25dihydroxyvitamin D, (calcitriol). Ten patients had an antecedent myelodysplastic syndrome. Calcitriol was continued as the only postremission therapy. Thirteen patients (45%) obtained a complete remission, and 10 patients (34%) had a partial response for an overall 79% response rate. There were three early deaths. The median remission duration was 9.8 months. Overall median survival was 12 months for all patients and 14 months for responding patients. All responding patients had marked bone marrow hypoplasia. Twenty patients received part or all of their chemotherapy as outpatients. This regimen has acceptable toxicity and can result in prolonged remissions in elderly, high-risk patients with AML. The favorable results may be related to the synergistic effect of hydroxyurea, cytarabine, and calcitriol. o 1992 Wiley-Liss, Inc. Key words: AML, elderly, low-dose cytarabine
INTRODUCTION
Intensive chemotherapy has resulted in high remission induction rates for patients under the age of 65 with acute myeloid leukemia (AML); a substantial proportion of patients have a prolonged disease free survival [I-31. However, 40% of patients with AML are over the age of 65 years. These patients have a significantly worse treatment outcome with median survival often limited to several weeks [4,5]. Many elderly patients have intercurrent medical problems and cannot tolerate the side effects of intensive therapy. Attenuated induction regimens have been used with varying results [2,6]. Low-dose cytarabine given over a prolonged time period has resulted in less acute toxicity than does standard dose combination chemotherapy [7]. Although more patients survived low-dose cytarabine treatment, the complete response rate was decreased compared with standard induction regimens [8]. Cytarabine and hydroxyurea exhibit in vitro cytotoxic synergy through biochemical and cell cycle effects [9,10]. This drug combination is effective in selected refractory malignancies [ 1I]. Additional studies with human myeloid leukemia cell lines have shown calcitriol (1,25-dihydroxyvitamin D3)to display in vitro synergy with both cytarabine and hydroxyurea [ 121. Furthermore, 0 1992 Wiley-Liss, Inc.
calcitriol alone has been reported to promote differentiation of several leukemia cell lines [13,14] and normal bone marrow cells [ 151. Based on these pharmacologic data and the lack of accepted standard therapy for AML in the elderly, we initiated a trial for the treatment of patients with AML over the age of 65 years. We now describe the results of our first 29 consecutive patients treated with continuous infusion cytarabine in conjunction with oral hydroxyurea and calcitriol. METHODS Patient Selection
Twenty-eight patients 65 years of age or older and one aged 62 with secondary AML were treated on study. All patients were treated after obtaining informed consent according to an IRB approved protocol. AML was diagnosed in all patients and classified according to the
Received for publication November 18, 1991; accepted March 10, 1992. Address reprint requests to Dr. Kenneth B. Miller, New England Medical Center, 750 Washington Street, #245, Boston, MA 021 1 1 ,
Treatment of AML in the Elderly
French-American-British (FAB) criteria [ 161. Patients with a secondary leukemia were eligible to participate in this study. Secondary leukemia was defined as leukemia evolving from a known prior myelodysplastic syndrome or resulting from prior chemotherapy. Patients in blast crisis of chronic myelogenous leukemia were not eligible. Patients with a total blast count of greater than 50 X 109/L were given hydroxyurea alone to lower the blast count to 1.0 X 109/L, and a platelet count >50 X 109/L had to be maintained without transfusion support for at least two months. Patients with a prior myelodysplastic syndrome who transformed into AML were considered to have a partial response if they reverted back to their prior myelodysplastic syndrome. This response needed to be maintained for more than 2 months. Resistant disease was defined as a failure to eradicate the leukemia in the day 28 bone marrow. Early death was defined as mortality from any cause occurring within 60 days of the initiation of chemotherapy. The percentage cytoreduction was defined as the ratio of the cellularity of the pretreatment bone marrow biopsy to the day 28 bone marrow biopsy. RESULTS Patient Population
Twenty-nine patients were entered onto the study. All patients completed a 2 1-day course of induction therapy with cytarabine, hydroxyurea, and calcitriol. The age, sex, and FAB type are described in Table I. The mean age was 73, with a range of 62-82 years. Ten of the 29 patients had progressed from a prior myelodysplastic synEvaluation of Response drome and thus had secondary leukemia. Twenty of the Bone marrow aspirates and biopsies were performed 29 (69%) received part of their regimen as outpatients. on day 28 and upon recovery of an ANC of >1.5 X lo9/ Three patients (10%) received their entire 21-day inducL. The bone marrow aspirates and biopsies were evalu- tion therapy as outpatients and were admitted only for ated prospectively without knowledge of the clinical placement of the intravenous access device and the initiaevents. Complete remission was defined by the usual tion of treatment. criteria: a normocellular bone marrow with normal myeloid and erythroid maturation and less than 5% blast forms. In addition, a complete remission required a he- Response to Therapy Patients were analyzed according to the criteria defined matocrit of >30 vol%, an ANC of >1.5 X 109/L, and a above. Table I1 details the response to inducti0.n therapy. platelet count >loo x i o 9 / ~ .
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TABLE II. Results of Induction
All patients N = 29 Complete response Partial response No response Hypoplastic death Resistant disease De novo ANLL N = 19 Complete response Partial response No responseihypoplastic death Secondary leukemia N Complete response Partial response No response
=
No. of Patients
Percentage
13 10 6 2 4
45 34 21 I 14
12 2
63
5
26
II
10 10
80 10
The development of treatment-related thrombocytopenia was independent of the pretreatment platelet count. All patients experienced severe neutropenia (1.O x i o 9 / ~ was 44 days (range: 38-65 days) in the responding patients. Of the 20 patients who received part of their treatment as outpatients, 15 were subsequently readmitted for evaluation of fever and neutropenia. Two patients developed asymptomatic hypercalcemia (1 1.2 mg/dl and 11.5 mg/dl) but did not require treatment. In one patient, the calcitriol was held until the calcium normalized and was then restarted without recurrent hypercalcemia. Five patients had mild, grade l , symptomatic mucositis. No patient developed alopecia. No patient experienced significant nausea or vomiting while receiving the induction regimen.
All patients entered on study were evaluable, and no Cytoreductive Effect Bone marrow aspirates and biopsies were obtained on patient was removed from the study prior to completing the 21-day course. Thirteen of 29 patients attained a day 28, 1 week after completing cytarabine. Two patients complete response (45%), 10 patients had a partial re- had inadequate samples for evaluation. With the 27 evalsponse (34%), and 6 patients did not respond to therapy. uable bone marrows, there appeared to be a correlation Two patients died while hypoplastic and 4 had resistant between cytoreductive effect of the induction regimen disease. In the 19 patients with de novo AML, 14 re- and the response to therapy. All responding patients demsponded (74%), with 12 (63%) exhibiting complete re- onstrated greater than 50% reduction or bone marrow sponses and 2 (11%) partial responses. Five patients cellularity in their day 28 bone marrow compared to (26%) failed to respond. Of the 10 patients in the second- pretreatment. In addition, all patients who did not experiary leukemia group, there were 8 partial responses, 1 ence at least a 50% reduction of the bone marrow cellucomplete response (90% overall response rate; 80% PR larity by day 28 ultimately did not respond to treatment. and 10% CR). All patients with a partial response re- The mean percent cytoreduction between those who responded and those who did not was 67% versus 22% turned to their prior myelodysplastic syndrome. Nine patients received a second cycle of induction ( P < 0.05). By contrast, there was no correlation bechemotherapy at the time of relapse. Five patients tween the duration of response and the percentage cytoreachieved a second CR with a median remission duration duction in the day 28 bone marrow (R = 0.30). Moreof 4 months (range: 3-9 months). One patient achieved a over, there was no difference in the percent of PR of 4 months’ duration, and 3 patients did not respond. cytoreduction between partial responders and complete responders (64% vs. 77%, respectively, P = NS). No patient received a third cycle of chemotherapy. Survival Analysis
The median survival was 12.0 months, with a range of 1.5 months to 24+ months (Fig. 1). The longest complete response to date is 24 months. The projected survival at 24 months is 18% for all patients. The duration of response for the first course is presented in Figure 2. The median duration of response was 9.8 months, with a range of 1.5-20 months. There were 3 early deaths in the 29 patients. Two patients died of sepsis, while hypoplastic and one patient in complete remission died of an acute myocardial infarction. Toxicity All patients developed severe thrombocytopenia and granulocytopenia. Twenty patients were platelet transfusion dependent during the entire course of chemotherapy.
DISCUSSION
Several studies have documented age to be of major prognostic significance in patients with AML [ 1,3,17,18]. Intensive chemotherapy treatment regimens administered to elderly patients have resulted in widely varying complete response rates. These results reflect differences in defining the elderly population (50, 60, 65, or 70 years) and differences in excluding patients with antecedent myelodysplastic syndromes. Most studies, however, have reported complete remission induction rates of 3 0 4 0 % for patients over the age of 60 years [6,19-2 11. The same studies document early deaths or death during induction in 40-60% of patients. Mean survival, when reported, was usually short, limited to several weeks or months. Many studies exclude patients with antecedent myelodys-
Treatment of AML in the Elderly
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plastic syndromes, a recognized poor prognostic factor [22,23]. Cytarabine at low doses has been administered to elderly and high-risk patients with AML with reported complete response rates of 30-50% [7,24]. A randomized trial comparing low-dose cytarabine with intensive chemotherapy also noted a 32% CR rate for low-dose therapy [8]. While low-dose cytarabine appears to have significant activity in the treatment of AML and is better tolerated than intensive chemotherapy regimens, it also has been shown to result in shorter remission durations
when compared with standard intensive chemotherapy [6,81. In vitro studies have demonstrated synergistic activity between cytarabine, hydroxyurea, and calcitriol . We initiated a trial of continuous infusion cytarabine with concomitant oral hydroxyurea and calcitriol in an effort to improve the overall response to low-dose cytarabine through biochemical modulation. The results of our study are notable for several reasons. The patients in this study had a mean age of 73 years, with only one patient under the age of 65 years. More-
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over, 34% of the patients treated had a secondary leukemia. The overall complete response rate of 45% compares favorably with reported CR rates for intensive induction regimens in this age group. If patients with antecedent myelodysplastic syndromes are excluded, the resulting CR rate of 63% is comparable to the best reported CR rates for intensive induction regimens in a similar age group. Patients in complete remission were given no postremission therapy with the exception of oral calcitriol. Patients who relapsed more than 6 months after beginning therapy were offered a second course of induction therapy. A large number of these patients (56%) obtained a second complete remission. Overall the median survival was 12 months (with a range of 1.5-24+ months). This survival compares very favorably to other studies using intensive postremission therapy [25]. An important factor in the high overall response rate in this study was the observed low early death rate. Only 10% of the patients treated died during the first 60 days. Although this regimen did result in bone marrow hypoplasia with marked granulocytopenia and thrombocytopenia, there were few life-threatening or serious infectious complications and many patients received part or all of their induction regimen as outpatients. The minimal gastrointestinal toxicity and mucositis may have allowed these high-risk patients to tolerate a period of neutropenia with fewer life-threatening complications. Low-dose cytarabine can induce leukemia cell differentiation in vitro [26,27]. Our results, however, suggest that a cytotoxic effect is needed for a response to this regimen, which may well be related to the previously described synergy between cytarabine, hydroxyurea, and calcitriol. For biologic activity, cytarabine is phosphorylated intracellularly to the triphosphate, ara-CTP. This metabolite exerts its cytotoxic effect through inhibition of DNA polymerase [28,29] or through its action as a chain terminator [30,3 11. Deoxycytidine is the natural substrate for this phosphorylation step and is a competitive inhibitor of cytarabine. Elevated intracellular pools of phosphorylated deoxycytidine (dCTP) have been implicated in cytarabine resistance 1321. Hydroxyurea is an inhibitor of ribonucleotide reductase and leads to depletion of intracellular dCTP by inhibiting de novo synthesis of deoxycytidine [33]. This dCTP depletion appears to be the mechanism underlying the in vitro synergistic cytotoxicity of hydroxyurea with cytarabine. The observed cytoreductive effect of this regimen supports that these agents may also be synergistic in vivo. As opposed to other studies that evaluated cytarabine alone, the patients treated with this combination developed severe granulocytopenia and thrombocytopenia. The augmented cytotoxic effect may reflect potentiation of cytarabine cytotoxicity by hydroxyurea or may simply be additive.
Calcitriol is an important hematopoietic regulatory hormone which is capable of inducing terminal differentiation in normal and abnormal states [13-15,34,35]. Calcitriol appears to act through a 1,25-(OH),D3-specific intracellular receptor expressed during the cell cycle [36]. Cytarabine and hydroxyurea, both inhibitors of DNA synthesis, potentiate the differentiating effects of calcitriol [37]. In addition, calcitriol potentiates the in vitro cytotoxicity of both cytarabine and hydroxyurea [ 121. These effects may, in part, account for the added cytotoxicity of our regimen. In the myelodysplastic syndromes, calcitriol has been shown to delay the progression to acute leukemia and prolong leukemia-free survival [38]. However, the role of calcitriol in this regimen is unclear. The long duration of the unmaintained responses may reflect the combined therapy with cytarabine and hydroxyurea alone. The overall high response rate, relatively long unmaintained remissions, and acceptable toxicity with low early death rate are sufficiently encouraging to warrant further study of this regimen in elderly and high-risk patients with de novo and secondary AML. ACKNOWLEDGMENT
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