RISK OF THERAPY-RELATED LEUKAEMIA AND PRELEUKAEMIA AFTER HODGKIN'S DISEASE

83

Occasional

Survey

RISK OF THERAPY-RELATED LEUKAEMIA AND PRELEUKAEMIA AFTER HODGKIN’S DISEASE Relation to Age, Cumulative Dose of Alkylating Agents, and Time from Chemotherapy

JENS PEDERSEN-BJERGAARD SEVERIN OLESEN LARSEN JAN STRUCK HEINE H. HANSEN

LENA SPECHT JENS ERSBØLL MOGENS M. HANSEN NIS I. NISSEN

Departments of Internal Medicine and Haematology and Medical Oncology ONB, Finsen Institute-Rigshospitalet; and Department of Biostatistics, Serum Institute, Copenhagen, Denmark

patients treated intensively for Hodgkin’s disease were followed for up to 15 years to evaluate the risk of therapy-related acute non-lymphocytic leukaemia (t-ANLL) and preleukaemia. Only two independent factors, patient age and cumulative dose of alkylating agents, were related to the risk of t-ANLL. The hazard rate of t-ANLL was roughly proportional to the square of patient age and to the total cumulative dose of alkylating agents. In 320 patients treated with alkylating agents the cumulative risk of t-ANLL increased steadily from 1 year after the start of treatment and reached 13.0% (SE 3.0) at 10 years after which time there were no further cases. Calculated from cessation of therapy with alkylating agents, however, the cumulative risk curve increased steeply during the first 1-2 years then gradually levelled out and no new cases were observed beyond 7 years. With a 15-year follow-up the general risk of solid tumours Summary

was not

391

increased. INTRODUCTION

or THERAPY-RELATED secondary acute nonlymphocytic leukaemia (t-ANLL) and its preleukaemic stages with refractory cytopenia and clonal cytogenetic abnormalities of the bone marrow have proved to be the most serious long-term complication of current treatment for Hodgkin’s disease.l-13 Chemotherapy, including alkylating agents, has been regarded as the predominant risk factor.14 Although intensive treatment with alkylating agents (either as long-term treatment,4.5 or retreatment after relapse5-7.lO) results in a high risk of t-ANLL, a direct alkylating agent dose-response relation in leukaemogenesis has never been demonstrated in Hodgkin’s disease. By contrast, treatment with other cytostatic agentsll or high voltage radiotherapy’-’," seems of only minor or no importance for the risk of t-ANLL. In many other tumour types, such as non-Hodgkin

lymphomas,tS.16 multiple myeloma,17-19 polycythaemia very, 20 chronic lymphocytic leukaemia,21 ovarian carcinoma,22-25 lung cancer, 26-28 gastrointestinal cancer, 29 breast cancer,30 and testicular cancer,3’ the findings in Hodgkin’s disease have been replicated many times, implicating almost all alkylating agents in general clinical use today as leukaemogenic. Some workers claim that cyclophosphamide is less leukaemogenic than busulphan 26 and melphalan ’111-25 respectively. These differences, however, have been based on only a few leukaemic cases, and non-equivalence of dosage or variations in follow-up procedures in the patient cohorts may account for the

results. Our own experience5,16 and that of other workers suggests that there are no major differences in leukaemogenic effect between the various alkylating agents. In most investigations of Hodgkin’s disease and of other tumour types the cumulative risk of leukaemia increased by about 03-1 % annually from 1 or 2 years after diagnosis and initiation of treatment and up to 6 to 12 years after. A substantially higher risk oft-ANLL has been demonstrated in patients with multiple myeloma17 and small-cell lung cancer 2728 treated with combinations including two alkylating agents. The duration of t-ANLL risk has been discussed briefly but never analysed in detail. Age over 40 years was a risk factor for t-ANLL in some studies of Hodgkin’s disease 17,10,11 but not in others,9,12 nor was it a risk factor in some other types of tumour. 29.30 A moderately increased risk of non-Hodgkin lymphomas ’32--34 solid tumours of various types,4,6,,9.10.13 or specific types such as lung cancer35,36 and melanoma 37 has also been reported in patients treated for Hodgkin’s disease. Other series have not shown such increased risks.2,5** This investigation includes new data and updated findings in a cohort of patients treated intensively for Hodgkin’s disease, for whom the risk oft-ANLL has been described before.5 The time for start as well as for cessation of chemotherapy with alkylating agents and the total cumulative dose of each alkylating agent have now been recorded for the individuals. The study was undertaken to examine the possible relation between dose of alkylating agents and the risk of t-ANLL; to establish how much age contributes to the risk of t-ANLL; to examine how long after the start and, more important, after the cessation of therapy with alkylating agents the patients are at risk of t-ANLL; whether there is a generally increased risk of solid tumours; and to compare the risk oft-ANLL in Hodgkin’s disease with the risk in non-Hodgkin’s lymphomas, ovarian cancer, and small-cell lung cancer. PATIENTS AND METHODS

Patients and Previous

Therapy

From January, 1970, to January, 1981, 391 patients with previously untreated Hodgkin’s disease were referred to our department. The disease was classified histopathologically according to Lukes and coworkers’ criteria. The stage of the disease was established clinically in all patients and pathologically with laparotomy and splenectomy in 200, according to the Ann Arbor criteria.39 Patients with stage I or II disease were treated with total nodal irradiation or mantle-field irradiation followed by six cycles of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone).5 Those with stage III or IV disease were treated with MOPP or equivalent combinations replacing mechlorethamine with carmustine or lomustine and/or vincristine with vinblastine. In some patients with stage III or IV disease this regimen was followed by 2-3 years of maintenance chemotherapy with daily chlorambucil to prevent recurrence.5 At relapse the same types of combination chemotherapy or regimens including doxorubicin, sterecyt, or cyclophosphamide were administered. A total of 320 patients received alkylating agents. All patients were followed closely to death or termination of this analysis in September, 1986. Patients treated with alkylating agents for three other malignant diseases were used for comparison of the risks of t-ANLL in Hodgkin’s disease. A total of 498 patients with non-Hodgkin lymphomas had received alkylating agents, mainly cyclophosphamide;lb 553 patients with ovarian cancer had received dihydroxybusulphan, in most cases for 1-3 years;23 and 796 patients with small-cell lung cancer had received a combination of cyclophosphamide, lomustine, etoposide, vincristine, and in some cases additional doxorubicin and methotrexate for periods up to 18 months if they were alive and in remission.28

84 TABLE I-COX REGRESSION ANALYSIS OF RISK FACTORS FOR t-ANLL IN HODGKIN’S DISEASE TREATED WITH

ALKYLATING AGENTS -

--

-

I

characteristic cytogenetically abnormal clone. The preleukaemic stages, like overt t-ANLL, are almost inevitably fatal and usually have a short survival. Such cases were therefore included with overt t-ANLL in the statistical calculations.

Statistical Methods

*All factors are evaluated in models composed of loge dose and loge age. If age in months is used instead of log age almost identical results are obtained. Lymphocytic depletion not evaluated because of the small no of patients with that histology (13 cases).

Follow-up Procedure and Investigations After treatment, all patients with the four types of primary followed closely for relapse or development of t-ANLL or preleukaemia by routine investigations including haemoglobin and leukocyte and platelet counts at least twice a year. For the patients in whom refractory cytopenia developed or there were other findings arousing suspicion of t-ANLL, cytogenetic investigations of the bone marrow were done in addition to the cell counts described before .4"2 This procedure even allows detection of early preleukaemic cases without diagnostic cytological abnormalities in the blood or the bone marrow but with a tumour were

For patients with Hodgkin’s disease theindependent contributions to the risk of t-ANLL of pretreatment indices such as age, sex, histology, and stage of Hodgkin’s disease, and of types and intensity of treatment were evaluated by the Cox proportional hazards model43 with the BMDP program.44 All recorded factors (table i) were included in the multivariate analysis initially, and a step-down procedure was adopted by removal of the least significant factor and repetition of the analysis until only those factors that had significant prognostic influence (p < 0’05) were retained. For each factor a regression coefficient was estimated. A positive value indicates that the hazard of t-ANLL increases with a rising score value for the specific factor. The cumulative dose of all alkylating agents received by each of 320 patients with Hodgkin’s disease was summarised and expressed per square metre. For comparison, 1 mg mechlorethamine was regarded as equivalent to 6-3 mg lomustine, 67 mg carmustine, 100 mg cyclophosphamide, 7 mg chlorambucil, and 45 mg sterecyt, according to results from phase-I studies of these drugs and their dosage in regimens alternative to MOPP. 45 The cumulative risk of t-ANLL from the start of therapy with the first administered alkylating agent as well as from the cessation of therapy with the last administered alkylating agent, and of solid tumours from the start of first treatment of any type, was estimated by the Kaplan-Meier method,46 differences being evaluated by the log-rank test.47 In addition, the relative risk of solid tumours in Hodgkin’s disease was determined by comparison of the observed number with the expected number of cases based on the age-specific and sex-specific incidence of solid tumours in the general Danish population,48 allowance being made for increasing age during the

study.

TABLE II-SECONDARY SOLID TUMOURS IN PATIENTS TREATED FOR HODGKIN’S DISEASE

male, F female, MC mixed cellularity, LP

lymphocytic predominance, NS nodular sclerosis, MVPP mechlorethamine + vinblastine + procarbazine prednisone, vinblastine, CVPP lomustine + vinblastine + procarbazine + prednisone, Clb chlorambucil, BOPP carmustine + vincristine + procarbazine + prednisone, COPP = lomustine + vincristine + procarbazine + prednisone, MOPP = mechlorethamine + vincristine + procarbazine + prednisone, CR = complete remission, PR = partial remission, + = yes, - = no, LD=lymphocytic depletion, TNI = total nodal irradiation M

=

=

+

(1 rad = 0.01 Gy).

=

Vlb

=

=

=

=

=

=

=

85 RESULTS

general Disease

t-ANLL and Solid Tumours Observed in

Hodgkin’s Overt t-ANLL or preleukaemia with severe refractory cytopenia and clonal chromosome abnormalities, including loss of the whole chromosome no 5 or no 7 or the long arm of one of these chromosomes, developed in 20 of the 391 patients treated for Hodgkin’s disease. A total of 14 solid tumours developed in 11 patients (table II). All the leukaemias arose in patients who had been treated with alkylating agents, whereas solid tumours developed after all types of therapy. There were 4 cases of lung cancer and no cases of non-Hodgkin lymphomas.

Danish

population (fig 1) ;

the

courses were

very

similar. Cumulative Risk of t-ANLL Hodgkin’s Disease

after Alkylating Agents in

Since the risk of t-ANLL was related only to treatment with alkylating agents, the cumulative risk of leukaemia was estimated for the 320 patients treated with alkylating agents and was evaluated from the start of chemotherapy. As shown in fig 2 the risk increased steadily from 1 year up to 10

Risk of t-ANLL Related to Pretreatment Indices and Therapy for Hodgkin’s Disease Table I shows the results of the Cox regression analysis of the effect of various pretreatment indices and of therapy on the risk of t-ANLL and preleukaemia based on the time from the start of treatment. Patient age and cumulative dose of alkylating agents were significant and independent risk factors. The regression coefficients for logage of 1-939 (SE 0-622) and for log,dose of 0.685 (SE 0-217) indicate that the risk of t-ANLL is most probably proportional to the square of age and directly proportional to the cumulative dose of alkylating agents. Sex, stage, and histology of Hodgkin’s disease were not significant risk factors, nor was radiotherapy when given in addition to chemotherapy as compared to chemotherapy alone. There were no cases of t-ANLL after radiotherapy alone. When patients had been treated with more than one alkylating agent there was no evidence that the effect was potentiated. Taking into consideration the cumulative dose of alkylating agents and the time of observation, we evaluated the relation between age and risk of t-ANLL for 20-year age groups of patients with Hodgkin’s disease and compared this relation with the age-related risk of acute non-lymphocytic leukaemia in the

Fig 2-Cumulative risk of t-ANLL and preleukaemia up to fifteen years after start of treatment with alkylating agents in Hodgkin’s disease.

Kaplan-Meier estunate. Shaded area SE. =

years from the start of treatment, after which time there were no further cases of t-ANLL. The risk of t-ANLL at 5 years was 3-9% (SE 1-3) and at 10 years was 13.0% (3-0). When

calculated the risk of t-ANLL from the cessation of therapy with last administered alkylating agent, a quite different curve was seen (fig 3): the risk increased steeply during the first year or two, after which the risk of new cases decreased strikingly, with no new cases observed beyond seven years after cessation of chemotherapy with alkylating agents. we

Cumulative Risk Disease

of t-ANLL in Subgroups with Hodgkin’s

The cumulative risk of t-ANLL and preleukaemia was evaluated separately in patients aged under 40 and 40 or more and in those who had received a low, an intermediate, or a high cumulative dose of alkylating agents, equivalent to up to six 4-week cycles of MOPP, seven to twelve 4-week cycles, and more than twelve 4-week cycles. Fig 4 shows the

U

YU

LV

UU

uu

YEARS OF AGE

Fig 1-Relation between age and risk oft-ANLL in Hodgkin’s disease (-)and age and risk of acute non-lymphocytic leukaemia in the general population (- - - - -). n 107 and x

Risk of t-ANLL estimated

as

risk of de-novo leukaemia

L(d x t) estimated as number of cases of acute non-lymphotic leukaemia per 100 000 person-years of observation; n = number of t-ANLLs in 20-year age groups; d=cumulative dose of alkylanng agents in units (equivalent to 1 mg cyclophosphamide), and t = time of observation in months.

Fig 3--Cumulative risk oft-ANLL and preleukaemia up to thirteen years after cessation of therapy with alkylating agents in Hodgkin’s disease. Kaplan-Meier estimate. Shaded area SE. =

86

Fig 5-Cumulative risk of t-ANLL and preleukaemia from start of treatment with alkylating agents in four different diseases. Patients with Hodgkin’s disease have been divided into those who received low or an intermediate/high dose of alkylating agents. Kaplan-Meier estimates. a

Fig 4-Cumulative risk of t-ANLL and preleukaemia from start of treatment with alkylating agents in patients with Hodgkin’s disease aged under 40 and 40 or more, and iri patients treated with a low, an intermediate, and a high cumulative dose of alkylating

agents. Kaplan-Meier estimates.

(risk at 43 months was 14-0% [6-9]). Note the steeply increasing risk curves running almost parallel for the last two groups of patients (fig 5).

mide

Risk strong influence of age and of the cumulative dose of alkylating agents on the risk of t-ANLL. Thus, in patients under 40 years the 10-year risk of t-ANLL was 5-6% (SE 2-4) whereas in patients 40 years or more the risk was 30-9% (8-7). The cumulative 10-year risk of t-ANLL was 6-4% (2-3) for patients treated with a low cumulative dose of alkylating agents, was 11-3% (4-8) for an intermediate dose, and was 37-5% (11-6) for a high dose (fig 4).

of Solid

Tumours in

Hodgkin’s Disease Solid tumours developed 16-125 months from diagnosis and start of treatment. Since they occurred after all types of therapy, risks were calculated from initiation of the first administered treatment and were based on the whole cohort of 391 patients with Hodgkin’s disease. In this cohort 10-7 solid tumours would be expected a total observation The number of tumours of 2732 period patient-years. observed (14 in 11 patients) indicates that the general risk is not significantly greater than that for the general Danish population (p 0-19). The cumulative risk of a solid tumour steadily increased from 16 months after the start of treatment, rising to 5-2% (1-7) at 123 months. 3 patients had double tumours (table II), 1 of whom also had a persistent cytogenetically abnormal clone in the bone marrow with a missing chromosome no 7; the patient is no longer included in the preleukaemic group since her cytopenia ceased, and she died because of the solid tumours.

during

=

Cumulative Risk of t-ANLL in Four

Different Diseases

The cumulative. risk of t-ANLL and preleukaemia was compared in four different types of tumours, patients with Hodgkin’s disease being divided into those treated with up to six cycles of MOPP or equivalent combinations and those treated with higher cumulative doses of alkylating agents (fig 5). In Hodgkin’s disease treated with up to six cycles of MOPP the 9-year risk of t-ANLL was 6-4% (2-3), in patients with ovarian cancer treated with dihydroxybusulphan it was 7-1% (1-9), and in non-Hodgkin lymphomas treated with cyclophosphamide it was 8-0% (3-3). The risk was substantially raised in Hodgkin’s disease treated with higher cumulative doses of alkylating agents (10-year risk was 24-6% [6-8]) and in small-cell lung cancer treated very intensively with lomustine and cyclophospha-

.

DISCUSSION

Our results accord with the many reports that t-ANLL is serious rather frequent complication of chemotherapy with alkylating agents.1-31 The cumulative risk of 13-0% at 10 years in Hodgkin’s disease treated with alkylating agents is higher than has been reported by others.l-4,6-13 This high rate undoubtedly reflects three circumstances. The first is

a

87

diagnostic procedures we used with cytogenetic screening allowing all preleukaemic cases to be included. The second is the high cumulative dose of alkylating agents used, particularly the maintenance chemotherapy with chlorambucil previously administered to 74 patients after MOPP or equivalent combinations. The third is the high proportion of elderly patients with Hodgkin’s disease who received intensive therapy with alkylating agents. The Cox regression analysis confirmed that age at diagnosis is a significant and independent risk factor for the

t-ANLL in Hodgkin’s disease. The

exact extent to

which

age raises the risk of t-ANLL has not been estimated before in such detail. The results, however, were compatible with a hazard rate of t-ANLL almost directly proportional to the square of age-a relation very similar to that between age and risk of acute non-lymphocytic leukaemia de novo in the general Danish population (fig 1). The risk of t-ANLL rises so much with age (fig 4) that we

increasing

advise caution in the intensive treatment of older patients with alkylating agents. The cumulative dose of alkylating agents was also an independent and important risk factor for t-ANLL. The Cox model suggested a hazard rate of t-ANLL roughly proportional to the cumulative dose. Although it has not been proven that equitoxic doses of alkylating agents are equally leukaemogenic, this assumption is reasonable from the previous reports. Furthermore, it is important that cyclophosphamide, the only alkylating agent claimed to be less leukaemogenic than the others ’1125-16 contributed little to the total burden of alkylating agents, since it was administered to only 26 patients with Hodgkin’s disease, mainly in the terminal phase. Finally, the association between cumulative dose of alkylating agents and risk of t-ANLL was so strong that the dosage impact probably outweighs any possible difference in the degree to which equitoxic doses of alkylating agents are leukaemogenic. Our results for Hodgkin’s disease thus seem to support a few reports of other tumour types indicating a relation between alkylating agent dose and risk of t - ANLL. 16,20,25,49 The effect of the cumulative dose of alkylating agents on the risk of t-ANLL (fig 4) seems to explain the striking differences in risk between patients treated for three different types of tumour with modest doses of alkylating agent and patients treated with high doses for small cell lung cancer and Hodgkin’s disease (fig 5). The high risks must sound a warning against the use of two alkylating agents in combination and if possible against retreatment with alkylating agents-eg, in patients with Hodgkin’s disease in

relapse.

,

Like all previous studies from our institution5,16,23 our present investigation did not disclose any detectable risk of t-ANLL after high-voltage radiotherapy, whether administered as the sole type of therapy or combined with chemotherapy (table I). We have not excluded the possibility that high-voltage radiotherapy is leukaemogenic, but the risk seems negligible compared with that of

chemotherapy. So far there has been little published about the duration of risk of t-ANLL after exposure to alkylating agents, and many investigations have demonstrated a cumulative risk increasing for at least 8-12 years from the start of treatment. Such cumulative risk curves usually include patients treated continuously over long periods as well as patients retreated with alkylating agents for relapse during the period of observation. Our results (fig 3) indicate that the risk of t-ANLL after the cessation of therapy with alkylating agents

is high during the first 2 years, decreases over the following 2-4 years and levels out after 6-8 years. This finding is important and corresponds to observations in radiationinduced leukaemia-for instance, in survivors from the atomic bombing of Japan. 50 We found no increased general risk of solid tumours, and the observed cases arose continuously from 16 to 125 months after the start of treatment-ie, at random. No cases of secondary non-Hodgkin lymphoma were seen. With allowance for the great number of cases of t-ANLL recorded, the results suggest that non-Hodgkin lymphomas and solid tumours in general are not related to intensive chemotherapy with alkylating agents. The haemangioendotheliosarcoma and the squamous cell carcinoma of the skin observed in cases 9 and 11, however, are probably induced by radiotherapy as also could be the two lung cancers (cases 2 and 3) observed within the irradiated field (table II). The observation of double solid tumours in 3 patients (table I I) could indicate that in Hodgkin’s disease, as in other tumour types, there is a slightly increased risk of other types of malignancy developing spontaneously. Besides being a clinical problem t-ANLL is an important biological phenomenon. Although all alkylating agents are mutagenic and carcinogenic in animals, they do not seem to induce a wide spectrum of malignant tumours in man. The fact that they induce predominantly a distinct cytogenetic subtype of an uncommon malignancy such as acute non-lymphocytic leukaemia42,51 may indicate that chemical carcinogenesis in man is a much more specific process than generally recognised. We have found that the risk of t-ANLL is directly proportional to the cumulative dose of alkylating agents and to the square of age as is acute non-lymphocytic leukaemia de-novo; these findings are compatible with there being at least two separate agedependent steps in leukaemogenesis. One of these steps, or a third age-independent step, could be highly facilitated by exposure to alkylating agents. We thank Mr H. Cowan for linguistic correction and Mrs H. Christiansen, Mrs E. Resdal, and Mrs J. Steuch for technical assistance in preparation of the script. This work was supported by grants from Danish Medical Research Council and the Danish Cancer Society.

Correspondence should be addressed to J. P.-B., Department of Internal Medicine and Haematology, the Finsen Institute-Rigshospitalet, Strandboulevarden 49, DK 2100 Copenhagen 0, Denmark. REFERENCES

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Public Health MATERNAL RUBELLA AT ST THOMAS’ HOSPITAL IN 1978 AND 1986: SUPPORT FOR AUGMENTING THE RUBELLA VACCINATION PROGRAMME

JENNIFER M. BEST DOROTHEA A. BAKER

JAN M. WELCH J. E. BANATVALA

Department of Virology, St Thomas’ Campus, United Medical and Dental Schools of Guy’s and St Thomas’s Hospitals, London SE1 7EH

Summary

The effects of the rubella epidemics in 1978 and 1986 among patients attending antenatal clinics at St Thomas’ Hospital were compared. Although many pregnant women who had been exposed to rubella-like illnesses were investigated in both 1978 (269) and 1986 (160), the number of cases of maternal rubella was substantially lower in 1986 (1) than in 1978 (17). Rubella vaccination of 11-14-year-old girls was introduced in the United Kingdom in 1970, but 10% of our patients were susceptible and only 36% gave a definite history of vaccination. Despite the smaller number of maternal rubella cases, substantial resources were expended on assessing patients who had been exposed to or who presented with rubella-like illnesses. In 1978 an intensification of the selective rubella vaccination campaign was recommended, but experience in the 1986 epidemic supports the view that the programme should be augmented by vaccination of preschool children with a combined measles, mumps, and rubella vaccine, with a view to rubella eradication. INTRODUCTION

IN 1970, the United Kingdom adopted a selective policy for rubella vaccination, in which rubella vaccine was offered initially to schoolgirls aged 11-14 years.1 Vaccination was later extended to rubella-susceptible adult -women, including those attending antenatal clinics, who were offered rubella vaccine post partum.2 This policy was not expected to reduce congenital rubella substantially until the 1990s, when all women of childbearing age should have been offered vaccination at school. It is encouraging that uptake of rubella vaccine among schoolgirls in the UK is now 86%, and the proportion of rubella-susceptible women attending antenatal clinics in some parts of the country3 has fallen to less than 3%. The selective vaccination policy does not aim to interrupt virus transmission in the community. Outbreaks of rubella will therefore occur, and rubellasusceptible people will be infected, including some pregnant women.

In 1978, we described the impact of a rubella epidemic among patients attending the antenatal clinic at St Thomas’

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nonlymphocytic