Radiotherapy- and chemotherapy-induced myelodysplasia and acute myeloid leukemia. A review

Leukemia Research Vol. 16, No. 1, pp. 61~5, 1992.

0145-2126/92 $5.00 + .00 Pergamon Press pie

Printed in Great Britain.

R A D I O T H E R A P Y - AND C H E M O T H E R A P Y - I N D U C E D MYELODYSPLASIA AND ACUTE MYELOID LEUKEMIA. A REVIEW* JENS PEDERSEN-BJERGAARD

Rigshospitalet, Department of Internal Medicine and Hematology L 4132, 9 Blegdamsvej, DK-2100 Copenhagen O, Denmark Abstraet--A highly increased risk of myelodysplasia (MDS) and acute myeloid leukemia (AML) has been demonstrated following therapy with alkylating agents. The risk increases with cumulative dose and with the age of the patient. Most cases of MDS and AML following therapy with alkylating agents present chromosome aberrations, primarily loss of whole chromosomes No. 5 and/or No. 7 or various parts of the long arms of these chromosomes. The risk of MDS and AML following high-voltage radiotherapy is much lower. Recently an increased risk of AML has been demonstrated following therapy with the epipodophyllotoxins etoposide and teniposide. These leukemias typically present without preceding MDS and often show balanced aberrations of chromosome bands 1lq23 and 21q22.

Key words: Acute myeloid leukemia, myelodysplasia, alkylating agents, radiotherapy, epipodophyllotoxins, chromosome aberrations.

INTRODUCTION

TABLE 1.

ACUTE myeloid leukemia, most often presenting as MDS with refractory cytopenia, has become the most feared long-term complication of cancer therapy. The risk of therapy-related MDS and A M L (t-MDS and t-AML), the clinical feature of the disease, the characteristic chromosome aberrations and the poor results of intensive antileukemic chemotherapy have been reported on in numerous publications and extensively reviewed recently [1, 2]. The risk of tMDS and t-AML has primarily been related to therapy with alkylating agents, but quite recently also to therapy with etoposide and teniposide. Highvoltage radiotherapy, if not delivered as hemi- or whole-body irradiation, seems to play a less important role for development of t-MDS and t-AML.

ALKYLATING AGENTS DEMONSTRATED AS LEUKEMOGENIC IN VARIOUS TYPES OF PRIMARY TUMOR

Alkylating agent Mechlorethamine Cyclophosphamide

Melphalan Chlorambucil Prednimustine Busulfan Dihydroxybusulfan Carmustine Lomustine

R O L E OF A L K Y L A T I N G AGENTS In numerous well-defined cohort studies a highly increased risk of t-MDS and t-AML has been related to therapy with alkylating agents, and almost all of those in clinical use today have been shown to be leukemogenic [3-18] (Table 1). Most studies appear

Semustine

Primary disease/Ref. No. Hodgkin's disease [3--6] Hodgkin's disease Non-Hodgkin lymphomas [7, 8] Multiple myeloma [10, 11] Ovarian cancer [13] Lung cancer [15] Multiple myeloma [10, 11] Ovarian cancer [13] Breast cancer [16] Hodgkin's disease [4] Polycythemia vera [9] Ovarian cancer Breast cancer [17] Lung cancer [14] Ovarian cancer [12] Hodgkin's disease [4] Multiple myeloma [10] Hodgkin's disease [4] Multiple myeloma [11] Lung cancer [15] Gastro-intestinal cancer [18]

to show that apart from polycythemia vera, the general type of the primary disease, the histological subtype and the clinical stage are unimportant for the risk of t-MDS and t-AML. Age, however, at least in patients with Hodgkin's disease, seems to play an important role, as the risk of t-MDS and t-AML

*Presented at a joint meeting between the European School of Haematology and the Haematology Collaborating Group of Sweden, 22-24 April 1991, at the Karolinska Hospital, Stockholm, Sweden. 61

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J. PEDERSEN-BJERGAARD

TABLE2. STUDIES OF THE RISK OF t-MDS

Author

Year

AND

t-AML FOLLOWING TREATMENT WITH ALKYLATING AGENTS

Primary tumor

Coleman et al. [3] Pedersen-Bjergaard & Larsen [4]

1977 Hodgkin 1982 Hodgkin

Blayney et al. [5] Tucker et al. [6]

1987 Hodgkin 1988 Hodgkin

Greene et al. [7]

1983 Non-Hodgkin

Pedersen-Bjergaard et al. I8] Berk et al. [9] Bergsagel et al. [10]

1985 Non-Hodgkin 1981 Polycythemia 1979 Myeloma

Cuzick et al. [11] Pedersen-Bjergaard et al. [12] Greene et al. [13] Stott et al. [14] Pedersen-Bjergaard et al. [15]

1987 Myeloma 1980 Ovarian cancer 1986 Ovarian cancer 1977 Lung cancer 1985 Lung cancer

Fisher et al. [16] Anderssonetal. [17]

1985 Breast cancer 1990 Breast cancer

Boice et al. [18]

1983

Type of therapy MOPP, X-rays MOPP, CVPP, BOPP, Chl, X-rays MOPP, X-rays MOPP, PAVe, ABVD, VBM, X-rays COP, MOPP, BACOP, Chl, Bu, X-rays COP, X-rays Chl Me, Ctx, BCNU Me, Ctx, CCNU DHB, X-rays Me, Ctx, X-rays Bu CCNU+Ctx +Etop Me Pre+Mit

Gastro-intestinal Se cancer

No. of t-MDS+ t-AML/ No. patients treated

Relative risk of t-MDS + t-AML

Cumulative risk of t-MDS+t-AML

8/680 17/391

NS 167

2.0% at 7 years 9.9% at 9 years

12/192 28/1507

95.7 10% at 10 years RT : 11 3.3% at 10 years RT+CT: 117 CT : 130 105 7.9% at 10 years

9/517 9/602 16/141 14/364

76 NS 214

12/648 7/553 33/1718 4/243 6/796

NS 175 93 NS 77

34/5299 5/71

NS 339

14/2067

9.9

6.3% at 7 years >20% at 8 years 17.4% at 50 months 10% at 8 years 7.6% at 5 years 8.5% at 10 years 5.8% at 5 years 14.0% at 4 years 1.7% at 10 years 25.4% at 37 months 4.0% at 6 years

Abbreviations used are: M O P P , (mechlorethamine + vincristine + procarbazine + prednisone); CVPP, (lomustine + vinblastine + procarbazine + prednisone); B O P P , (carmustine + vincristine + procarbazine + prednisone); Chl, (chlorambucil); PAVe, (procarbazine + melphalan + vinblastine); A B V D , (doxorubicin + bleomycin + vinblastine + dacarbazide); V B M , (vinblastine + bleomycin + methotrexate); COP, (cyclophosphamide + vincristine + prednisone); B A C O P , (bleomycin + doxorubicin + cyclophosphamide + vincristine + prednisone); Bu, (busulfan); Me, (melphalan); BCNU, (carmustine); CCNU, (lomustine); D H B , (dihydroxybusulfan); Etop, (etoposide); Mit, (mitoxantrone); Se, (semustine); NS, (not specified); RT, (radiotherapy); C T (chemotherapy).

increases with increasing age like the risk of de n o v o A M L in the general population [6, 19]. The risk of t-MDS and t-AML varies from study to study, but has in several studies been shown to increase with the dose of alkylating agents. In a recent study of patients with Hodgkin's disease [19], the risk was found approximately proportional to the cumulative dose of alkylating agents administered. The relative risk of t-AML (ratio between the observed number of A M L cases and the number of de n o v o A M L cases expected) is in many studies in the order of 100-300 [3-18] (Table 2). In the same studies the cumulative risk of leukemic complications increases by 1/4-1% per year from 1 to 2 years to at least 6--8,years from start of therapy. The risk of leukemia seems to stop to increase 8-10 years from start of chemotherapy [5, 6], but more important, the risk of

new cases levels out 6-8 years from cessation of chemotherapy with alkylating agents [19]. Actuarial risk estimates determining the cumulative risk (in %) should be strongly preferred to estimates of the relative risk, which involve severe methodologic problems and difficulties in their clinical application. Only few studies have directly compared the risk of t-MDS and t-AML following treatment with the various alkylating agents. Some studies, however, have indicated that cyclophosphamide could be less leukemogenic than melphalan [11, 13]. R O L E OF O T H E R CYTOSTATIC D R U G S Previously, other drugs than the alkylating agents have not been firmly established as leukemogenic in man. Quite recently, however, the epipodophyllo-

63

Radiotherapy-and;~hemotherapy-inducedmyelodysplasia TABLE 3. STUDIES OF THE RISK OF t - M D S AND t - A M L FOLLOWING TREATMENT WITH THE EPIPODOPHYLLOTOXINS

Authors

Year

Primary tumor

Typeof therapy

Ratain et al. [20] 1987 Lung cancer Etop+Cis+Vds Pedersen-Bjergaard et al. [21] 1991 Germ-cell tumors Etop+Cis+Bleo Ingram et al. [22] 1987 Non-Hodgkin Tenip+Dox+ Ctx+others Pui et al. [23] 1989 Acute lymphoid Tenip+Dox+ leukemia Ctx+others

No. of t-MDS +t-AML/ Relative risk Cumulative risk No. patients oft-MDS+ oft-MDS+ treated t-AML t-AML 4/119 5/212 6/261

NS 308 NS

44% at 2.5 years 4.7% at 5.7 years 7.8%* at 7 years

13/733

NS

4.7% at 6 years

Abbreviations used are: as in Table 2; C/s, (cisplatin); Vds, (vindesine); Tenip, (teniposide); Dox, (doxorubicin); Bleo, (bleomycin). *Two patients with solid tumors included. toxins, etoposide and teniposide, if administered in combination with cisplatin or alkylating agents, have been shown to be leukemogenic. In studies of patients with non-small-cell lung cancer [20] and germ cell tumors [21], etoposide combined with cisplatin resulted in a high risk of t-AML (Table 3). Similarly, treatment with teniposide combined with doxorubicin, cyclophosphamide and other cytostatic agents in children with non-Hodgkin's lymphomas [22] or acute lymphoid leukemia [23] resulted in a high risk of AML (Table 3). A synergistic effect on leukemogenesis between drugs reacting directly with D N A as alkylating agents or cisplatin and drugs targeting at DNA-topoisomerase II as the epipodophyllotoxins has been suggested with a steep dose-response effect [21]. Leukemias following treatment with the epipodophyllotoxins often present with overt leukemia without preceding MDS and show chromosome aberrations diverging from those in t-AML following therapy with alkylating agents (see below). The extent to which other cytostatic drugs than the alkylating agents and the epipodophyllotoxins are leukemogenic remains to be determined. R O L E OF H I G H - V O L T A G E RADIOTHERAPY In one series, when administered as low-dose total or hemi-body irradiation to patients with nonHodgkin's lymphomas, radiotherapy has been shown to result in a high risk of t-AML [7]. In general, however, high-dose high-voltage radiotherapy has in some studies not resulted in any detectable risk of tMDS or t-AML [4, 8, 12, 13], in other studies in a low risk [6, 16] with an estimated relative risk in the range of only 2-10. This somewhat surprising finding has been related to cell kill rather than leukemic transformation of the hematopoietic stem cell within the field of irradiation [24]. A few studies have suggested

a synergistic leukemogenic effect between radiotherapy and combination chemotherapy including alkylating agents. Such an effect has not been observed in other studies, for instance in a study of Hodgkin's disease in which also patient age and cumulative dose of alkylating agents were included in a multi-regression analysis [19]. CYTOGENETIC STUDIES Following therapy with alkylating agents most patients with t-MDS and t-AML (80-90%) present clonal chromosome aberrations in the bone marrow, primarily loss of whole chromosomes No. 5 and/or No. 7 or various parts of the long arms of these chromosomes [25-27] (Fig. 1). The aberrations are present in the bone marrow in the early stages of the disease and are of major diagnostic importance. Other characteristic aberrations include loss of a whole chromosome No. 18 and rearrangement of the short arm of chromosome No. 17. Quite recently, also balanced rearrangements of chromosome bands 11q23 and 21q22 have been observed and related to previous therapy with the epipodophyllotoxins [20, 21, 23]. Most of the patients with these aberrations shown in Fig. 1 had previously been treated with the epipodophyllotoxins or with other drugs targeting at DNA-topoisomerase II. In patients with t-MDS the number of chromosome aberrations (degree of aneuploidy) has been shown to be an independent prognostic factor [27]. PROGNOSTIC FACTORS AND T H E R A P Y The most important prognostic factor in t-MDS and t-AML is the remission status of the primary tumor [27]. Thus, patients with an active primary malignancy generally have a very poor prognosis, as they often die in the early stage of MDS due to infections or hemorrhage. Other prognostic para-

64

J. PEDERSEN-BJERGAARD CHROMOSOME NUMBER

1 2 3 4 5 6 7 8 9 10111213141516

.

•

__

171819202122X

"u

Y

't

O,,N L

4.

Loss

5.

NUMERICAL ABERRATIONS

6.

7. SHORT ARM LONG ARM

8.

STRUCTURAL ABERRATIONS 1 2 3 4 5 6 7 8 9 10111213141516171819202122X

Y

CHROMOSOME NUMBER

FIG. 1. Chromosome aberrations consistently present in all abnormal mitoses at diagnosis of t-MDS and t-AML in 91 consecutive patients. Thirteen cases presented a normal karyotype. Each box represents one case. • (gain), [ ] (loss), × (balanced translocation), [ ] (unbalanced translocation or deletion). (From Pedersen-Bjergaard et al. (1990) Blood 76, 1083-1091; by permission.)

meters include thrombocyte counts at diagnosis and, for patients with t-MDS, the hemoglobin concentration and the percentage of blasts in the bone marrow in addition to the number of chromosome aberrations already discussed. The results of intensive antileukemic chemotherapy of t-MDS and t - A M L are generally poor except for patients presenting without MDS and with normal chromosomes No. 5 and No. 7 [26, 27]. Allogeneic bone marrow transplantation seems to offer a new approach to treatment of the younger group of this poor type of patient [28].

9.

10.

11.

12.

13.

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