Acute nonlymphocytic leukemia after treatment for Hodgkin's disease

Acute Nonlymphocytic Leukemia after Treatment for Hodgkin’s Disease

ALAN C. AISENBERG, M.D., Ph.D. Boston, Massachusetts

Eight cases of acute nonlymphocytic leukemia and one case of complicating non-Hodgkin’s lymphoma were seen over a 15-year period in 408 patients treated for Hodgkin% disease (actuarial risk of acute nonlymphocytic leukemia of 4.9 percent at 12 years). Two cases of leukemia occurred 11 years after diagnosis of Hodgkin’s disease. All nine complications were observed in the 220 patients who received MOPP combination therapy (9.1 percent risk of acute nontymphocytic leukemia at 12 years) either with (n = 8) or without (n = 1) radiation therapy. Patients treated with MOPP with pathologic stage IV disease (37.2 percent risk of acute nonlymphocytic leukemia at 12 years) or over the age of 40 years (33.1 percent risk), and those with failure of MOPP treatment (18.0 percent risk) were in particular jeopardy. If MOPP treatment had been restricted to patients who were under the age of 40 years and with stages I, II, and III disease, it would have been possible to use the drug combination in two thirds of those who had been so treated while elimtnating all but one case of leukemia. Furthermore, leukemia was not observed in 78 patients treated with six cycles of MOPP and less than total nodal irradiation. A final decision concerning optimal management of Hodgkin’s disease will require definition of the leukemia incidence curve in the second decade afler MOPP treatment, and acquisition of additional knowledge of the long-term efficacy and toxicity of alternate treatment regimens. The alarming incidence of acute nonlymphocytic leukemia after the treatment of Hodgkin’s disease with the MOPP (nitrogen mustard, Oncovin, prednisone, and procarbazine) combination, with and without irradiation [l-9], has led some clinics to propose the use of alternative drug regimens [lo]. Reported herein is the experience with this complication over a K-year period at Massachusetts General Hospital. As a result of these findings, MOPP treatment has been retained for the definitive chemotherapy of patients who are under the age of 40 years and with stages I, II, and III disease, pending further demonstration of the efficacy and toxicity of alternate drug programs. PATIENTS AND METHODS

From the Hematology-Oncology Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Research support was provided by Public Health Service Grant CA 30020-02, awarded by the National Cancer Institute, Department of Health and Human Services. Requests for reprints should be addressed to Dr. Alan Aisenberg, Massachusetts General Hospital, Boston, Massachusetts 02114. Manuscript accepted February 3, 1983.

This report is based on 408 consecutive patients aged 65 years or less whose biopsy findings of Hodgkin’s disease were reviewed at the Massachusetts General Hospital and who received their primary treatment here. Patients first seen between July 1, 1967, and June 30, 1981, were included in this analysis, and were followed to June 30, 1982. Thus, the period of observation ranged from one to 15 years (median seven and a half years). The risk of acute nonlymphocytic leukemia was calculated by the actuarial method of Mantel [ Ill. Except for the single complicating non-Hodgkin’s lymphoma, this report does not consider second solid neoplasms.

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A’=‘_?

!_‘?u’L
TPCATMEh

IT =c)P

TABLE I Acute! Wonlymphocytic --_-__._-._-__-

Palienl Number ----.--.---__

Age (yr) & Sex

1 2 3 4 5 6 7 8 9”

21, 41, 41, 26, 51, 25, 29, 44, 42,

F M M F F M M F M

L10DGKlN’S DISEASE-AISENBERG

Leukemia

and Second Lymphomas’

after Diagnosis of Hodgkin’s Disease

Treatment

Pathologic Stage

Radiationt

IIB IllA, IllB IVA IVB IVB IVB IVB IIIB

MOPPS

Yes Yes Yes Yes Yes Yes No Yes Yes

CCNU

9 6 6 6 12 6 12 12 6

No No No Yes No Yes No No No

Hodgkin’s Disease Recurrence after MOPP Yes Yes No Yes Yes Yes No Yes No

Hodgkin’s Disease at Time of Leukemia No No No No No Yes No No No

Years to Leukemia 3.5 3.5 6.5 4.5 4.5 11 6 11 6

Diffuse histiocytic lymphoma, undifferentiated non-Burkitt subtype. t Patients 1 and 9 received extended-field irradiation; Patients 2 and 3 received total nodal irradiation; Patients 4, 6, and 8 received mantle irradiation; and Patient 5 received total abdominal irradiation. t Number of cycles. MOPP was the initial treatment in all but Patient 1, in whom it was given for relapse 18 months before the development of leukemia. l

Disease cation

was staged according

[ 121, and biopsy specimens

to the Ann Arbor

Classifi-

were subclassified

system

of Lukes et al [ 131. Lymphangiography

carried

out, and patients

with symptoms

were

by the

was routinely subjected

to

Since January 1, 1969, staging laparotomy and splenectomy have been widely employed at this institution, and were performed in 275 of the 408 patients in the present series. The staging studies indicated 233 patients with stages I and II, 77 with stage IIIA, 73 with stage 1118,and 25 with stage IV disease. Irradiation (3,500 to 4,100 rads) was standard treatment for patients with stages I and II disease, and the MOPP combination treatment was used as the initial treatment for the great majority of patients with stages Ill and IV disease. In addition, almost all patients with stage IIIA disease and apbone marrow

biopsy.

proximately one third of those with stage IIIB disease received adjuvant irradiation after the completion of chemotherapy. Radiation therapy, both as primary and adjuvant treatment, was usually administered to extended fields, but 38 patients, primarily from the early years of the study, received total nodal irradiation. Patients who had a relapse after irradiation were treated with the MOPP combination after January 1, 1969, whereas those who failed to respond to MOPP therapy have received other fourdrug regimens: ABVD (Adriamycin bleomycin, vinblastine, and DTIC) or CVPP (CCNU, vinblastine, prednisone, and procarbazine), since these have become available [ 14, IS]. Further details about the diagnostic work-up and treatment can be obtained from an earlier publication [ 161. RESULTS

TABLE II

Incidence* of Acute Nonlymphocytic Leukemia afler Treatment for Hodgkin’s Disease

Group All patients (n = 406) Radiation only (n = 186) MOPP f radiation (n = 220) Stages I, II, and Ill (n = 188) Pathologic stage IV (n = 24) Less than age 40 years (n = 173) Greater than age 40 years (n = 47) No recurrence after MOPP (n = 138) Recurrence after MOPP (n = 82)

Percent

Leukemia Number 6

4.9

0.0

0

9.1 2.6

8 3

37.2

5

5.4

4

p = 0.0006

p = 0.012 33.1

4I

2.8

2

18.0

6I

p = 0.020

Expressed as the percent leukemia at 12 years by actuarial calculation. l

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Eight patients with acute nonlymphocytic leukemia and one with a non-Hodgkin’s lymphoma (diffuse histiocytic lymphoma of the undifferentiated non-Burkitt subtype [ 17,181) were observed over a 1%year period (Table I). All nine patients had received MOPP chemotherapy. Of the eight patients with acute nonlymphocytic leukemia, seven had also undergone irradiation (total nodal irradiation in two), six had experienced a relapse after MOPP treatment, five had pathologic stage IV disease at presentation, four received more than the usual six cycles of MOPP therapy, four were above age 40, and two received CCNU treatment subsequent to MOPP treatment. No patient with acute nonlymphocytic leukemia was observed in 188 patients treated with irradiation alone or, more significantly, in 78 patients whose treatment was limited to six cycles of MOPP therapy plus extended-field irradiation. In this series, leukemia was not observed within the first three years after diagnosis of Hodgkin’s disease, but two cases were observed after 11 years. If the time

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ACUTE LEUKEMIA AFTER TREATMENT FOR HODGKIN’S DISEASE-AISENBERG

30

ALL CASES MOPPCASES

H 0-0

O-O STAGES I, II and III o-0

t

i

Z!

t

1

;

p-o-o..*.i i

,a Figure 1. Cumulative actuarially calculated incidence of acute nonlymphocytic leukemia after treatment of Hodgkin’s disease. Only MOPP-treated patients are plotted in B, C, and D.

STAGE

u=

2

6

4

8

io

12

2

4

6

8

i0

12

YEAh’S FROM D/AGNOS/S

elapsed from the diagnosis of Hodgkin’s disease to the onset of leukemia (last column of Table I) is divided into three-year periods, the actuarial risk of acute nonlymphocytic leukemia developing in MOPP-treated patients during successive intervals is 0 percent, 2.5 percent, 1.7 percent, and 4.9 percent: that is, approximately 1 percent per year for the fourth through the 12th years. Table II and Figure 1 present actuarial risks for the development of acute nonlymphocytic leukemia in our population. The risk at 12 years was 4.9 percent for all patients, and 9.1 percent for those treated with MOPP (with or without irradiation) (Figure 1A). In this population, patients who presented with pathologic stage IV disease had a much higher risk for the development of leukemia than did those with stages I, II, and Ill disease (37.2 percent risk at 12 years in the former and 2.6 percent in the latter) (Table II, Figure IB). Similar lowrisk rates were seen for patients with stages I and II disease in whom MOPP treatment was used predominantly because of irradiation failure (one case of leukemia in 65 patients), and those with stage IIIA disease (one case of leukemia in 66 patients) and stage IIIB disease (one case of leukemia in 59 patients) in whom

MOPP treatment was employed as primary treatment, usually followed by irradiation. In addition to patients with pathologic stage IV disease, a markedly increased risk of leukemia was noted in patients above the age of 40 years treated with the MOPP combination (33.1 percent at 12 years compared with 5.4 percent for younger patients) (Table II, Figure IC). Table II and Figure 1D also reveal that patients with relapse after MOPP treatment are at increased risk for the development of acute nonlymphocytic leukemia (actuarial risk of 18.0 percent at 12 years for those who have relapse and 2.8 percent for those who do not). Calculated from the time of MOPP treatment rather than the time of diagnosis, the incidence of leukemia at 12 years is 25.2 percent for those with failure of MOPP treatment. COMMENTS Even when large series of patients are followed for extended periods of time, it is difficult to arrive at statistically reliable figures for the risk of the development of leukemia after treatment for Hodgkin’s disease. Nonetheless, the actuarially derived figure of 9.1 per-

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ACL’Y

~YvhlrlA

AFTEQ

I

TREATMENT

=OP

HODGKIN’S

I

I

I

I

I

2

4

6

8

40

DISEASE-A’SENBEPG

1 12

YEARS FROM DIAGtWSfS L-

Figure 2. Cumulative actuarially calculated incidence of acute nonlymphocytic leukemia after treatment of Hodgkin’s disease with the MOPP combination and irradiation. 0 = present study; 0 = figures from the recent literature [ 3-5, 7, 91; see text for details.

cent acute nonlymphocytic leukemia 12 years after combined treatment with MOPP and irradiation in the population described herein is in agreement with figures in other recent reports. Plotted in Figure 2 are the results of the present investigation and figures from five earlier studies: 6.5 percent acute nonlymphocytic leukemia eight years after combined treatment from Italy [5], 9.9 percent at nine years from Denmark [9], 6.4 percent at seven years from the Southwest Oncology Group [ 71, 3.9 percent at seven years from Stanford [3], and 5.6 percent at six years from the Cancer and Leukemia Group B [8]. An unsettling feature of this plot is the continuing accumulation of cases of leukemia after more than a decade of observation. In this series, the development of leukemia in two patients 11 years after diagnosis of Hodgkin’s disease reinforces this observation, and similar late cases of leukemia have been observed by others [9]. Such findings suggest that the period of risk for leukemia after treatment for Hodgkin’s disease approaches the 20-year risk period observed in Japanese atomic bomb survivors [ 191, although it should be stressed that most patients with development of leukemia late in the course of Hodgkin’s disease have received secondary chemotherapy for recurrent lymphoma. Although leukemia has been reported in patients with Hodgkin’s disease treated with irradiation alone [2,6,20], there can be little question that the present epidemic of acute nonlymphocytic leukemia is primarily the result of the introduction of combination chemotherapy with MOPP and similar drug regimens [4-g]. Thus, there were no cases of leukemia in 188 patients treated at our hospital with radiation alone, and acute nonlymphocytic leukemia was not seen in a total of 957 patients similarly treated at five other institutions [3-5,7,9]. The added contribution of irradiation to the incidence of leukemia in the present study cannot be

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assessed since too few patients were treated here with chemotherapy alone. However, several reports that critically examine this point 17-91 suggest that adjuvant irradiation does not play an important role in these cases of acute nonlymphocytic leukemia. The central role of cytotoxic chemotherapy, alkylating agents in particular, is reinforced by the experience with acute nonlymphocytic leukemia after cytotoxic treatment of multiple myeloma [21], ovarian carcinoma [22], and other disorders [ 231. The present study also confirms advancing age as an important risk factor in the acute leukemia seen in patients treated for Hodgkin’s disease. In this series, the actuarial figure of 33.1 percent acute nonlymphocytic leukemia 12 years after treatment of patients more than 40 years of age is quite similar to the Southwestern Oncology Group incidence of 32.5 percent at seven years [7] and the Danish experience of 39.5 percent at nine years [9]. In the present analysis, patients with Hodgkin’s disease with pathologic stage IV disease and those with relapse after MOPP chemotherapy treatment were also at very high risk for the development of leukemia. Other clinics have noted the increased incidence of acute nonlymphocytic leukemia after relapse [ 1,3]. The actual incidence of leukemia in both these circumstances is seriously underestimated by the actuarial figures, since many of these patients do not survive long enough after the diagnosis of Hodgkin’s disease for acute nonlymphocytic leukemia to develop. Although it is possible that the increased incidence of leukemia in these circumstances reflects some biologic characteristic of the aggressive underlying lymphoma, it is far more plausible that the high incidence of acute nonlymphocytic leukemia is a consequence of the additional leukemogenic drug administered to patients who present with stage IV disease or who have failure of MOPP treatment [2,6]. In this connection, it should be noted (Table I) that four of the cases of acute nonlymphocytic leukemia observed in the present series developed in the minor fraction of patients treated with MOPP who received nine or 12 cycles of MOPP therapy rather than the conventional six. Thus, major factors in the incidence of acute nonlymphocytic leukemia are the strength of the leukemogenic stimulus (amount of cytotoxic drug) and the susceptibility of the host (age). From the present study and the work of earlier investigators, it is possible to define the profile of patients with Hodgkin’s disease in whom it is likely that acute nonlymphocytic leukemia will develop. At disease presentation, these patients are apt to be above age 40 or have pathologic stage IV disease. They will receive MOPP treatment or a similar drug regimen containing alkylating agents, perhaps receiving more than six cy-

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cles. After chemotherapy, disease will probably relapse, but either it will be cured by additional treatment, or survival will be long enough for acute nonlymphocytic leukemia to develop. The greater the chance (at presentation) of failure of MOPP treatment, the greater the risk of leukemia. How is this epidemic of acute nonlymphocytic leukemia to be controlled? The more radical proposal advocated by some [lo] would replace MOPP with ABVD, a combination that has not been associated, so far, with a significant incidence of leukemia. At Massachusetts General Hospital, we are reluctant to follow this lead for two reasons. First, it seems early to be certain of the risks of the ABVD program, that is, a sufficient number of patients have not been observed long enough to allow a clear perception of the leukemogenic potential and other toxicity, particularly cardiac [24], of this drug regimen. Second, more time is also needed to assess the durability of ABVD responses. At this institution, a less radical approach is preferred, which would employ the less leukemogenic drug combinations (ABVD) in place of MOPP treatment in those patients with the highest risk for the development of acute nonlymphocytic leukemia. It is encouraging that in the present study, the risk was confined largely to certain clinical groups, that is, those MOPP-treated patients who were above the age of 40 or had pathologic stage IV disease at the time of diagnosis. Thus, seven of eight cases of acute nonlymphocytic leukemia (and the single secondary lymphoma) were restricted to the 71 patients in the two latter groups, whereas only a single case of leukemia was observed among 149 persons under the age of 40 with stages I, II, and III disease. Restricting MOPP treatment to such younger

patients with stages I, II, and Ill disease would have eliminated all but one case of leukemia. The absence, so far, of leukemia in 78 patients treated by six cycles of MOPP and less than total nodal irradiation is particularly encouraging. The approach advocated here posits the continued need of staging laparotomy to accurately assess the extent of disease. An evolutionary approach seems less likely to jeopardize the magnificent strides in control of Hodgkin’s disease that have followed the introduction of MOPP chemotherapy [25]. At the present time, deaths from Hodgkin’s disease and from unrelated causes still exceed deaths from acute nonlymphocytic leukemia both in our own and in other series [9]. Thus, the eight deaths from acute nonlymphocytic leukemia in our clinic must be viewed against three deaths from automobile accidents in the same patient population. A final decision about optimal management of Hodgkin’s disease cannot be made at this time. It requires definition of the leukemia incidence curve in the second decade after MOPP treatment and accurate knowledge of the efficacy and toxicity of alternate regimens such as ABVD. Finally, the long-term risks of treatment-induced solid tumors, both second lymphomas [ 17,231 and epithelial neoplasms [ 1,8], and the cardiac complications of mantle irradiation [26] must be established. ACKNOWLEDGMENT I am grateful to Dr. Daniel Dosoretz, who supplied the statistical analysis, and to Drs. Robert Carey, Zareh Demirjian, Leonard Ellman, Sheldon Kaufman, Allan Sandler, W. Davies Sohier, Jr., and John Truman, whose patients have been included in this study.

REFERENCES 1.

2.

3.

4.

5.

6.

Canellos GP, DeVita VT, Arseneau JC, Whang-Peng J, Johnson REC: Second malignancies complicating Hodgkin’s disease. Lancet 1975; I: 947-949. Cadman EC, Capizzi RL, Bertino JR: Acute nonlymphocytic leukemia: a delayed complication of Hodgkin’s disease therapy: analysis of 109 cases. Cancer 1977; 40: 12801296. Coleman CN, Williams CJ, Flint A, Glatstein EJ, Rosenberg SA, Kaplan HS: Hematologic neoplasia in patients treated for Hodgkin’s disease. N Engl J Med 1977; 297: 12491252. Baccarani M, Bosi A, Papa G: Second malignancy in patients treated for Hodgkin’s disease. Cancer 1980; 46: 17351740. Valagussa P, Santoro A, Kenda R, et al: Second malignancies in Hodgkin’s disease: a complication of certain forms of treatment. Br Med J 1980: 280: 218-219. Grunwald HW, Rosner F: Acute myeloid leukemia following treatment of Hodgkin’s disease. Cancer 1982; 50: 676683.

7.

8.

9.

10.

11.

12.

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Coltman CA Jr, Dixon DO Second malignancies complicating Hodgkin’s disease. A Southwest Oncology Group ten year follow-up. Cancer Treat Rep 1982: 86: 1023-1033. Glicksman AS, Pajak TF, Gottlieb A, Nissan N, Stutzman L, Cooper MR: Second malignant neoplasms in patients successfully treated for Hodgkin’s disease: A Cancer and Leukemia Group B study. Cancer Treat Rep 1982; 66: 1035-1044. Pedersen-Bjergaard J, Larsen SO: Incidence of acute nonlymphocytic leukemia, preleukemia and acute myeloproliferative syndrome up to 10 years after treatment of Hodgkin’s disease. N Engl J Med 1982; 307: 965-971, Valagussa P, Santoro A, Fossati Bellani F, Franchi F, Banti A, Bonadonna G: Absence of treatment-induced neoplasms after ABVD in Hodgkin’s disease. Blood 1982; 59: 488494. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163-170. Carbone PP, Kaplan HS, Musshof K, Smithers DW, Tubiana

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ACUTE

13. 14.

15.

16. 17.

16.

19.

454

LEUKEMIA

Al-TW

THtAlMtNl

I-WI-I

HOUtiKIN’S

LJlStASt-AIStNt(tKti

M: Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 1971; 31: 1660-1661. Lukes RJ, Craver LF, Hall TC, et al: Report of the Nomenclature Committee. Cancer Res 1966; 26: 1311. Longo DL, Young RC, DeVita VT Jr: Chemotherapy of Hodgkin’s disease: the remaining challenges. Cancer Treat Rep 1962; 66: 925-936. Bonadonna G, Santoro A: Evolution of the treatment strategy of Hodgkin’s disease. Adv Cancer Res 1962; 36: 257293. Aisenberg AC, Linggood RM, Lew RA: The changing face of Hodgkin’s disease. Am J Med 1979; 67: 921-926. Krikorian JG, Burke JS, Rosenberg SA, Kaplan HS: Occurrence of non-Hodgkin’s lymphoma after therapy for Hodgkin’s disease. N Engl J Med 1979; 300: 452-456. Rosenberg SA, Berard CW, Brown BW Jr, et al: National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas. Summary and description of a working formulation for clinical usage. Cancer 1962; 49: 2112-2135. Lilienfeld AM: Epidemiological studies of the leukemogenic effects of radiation. Yale J Biol Med 1966; 39: 143.

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20.

21.

22.

23. 24. 25.

26.

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Ezdinli EZ, Sokal JE, Aungst CW, et al: Myeloid leukemia in Hodgkin’s disease: chromosomal abnormalities. Ann Intern Med 1969; 71: 1097-1104. Rosner F, Grunwald H: Multiple myeloma terminating in acute leukemia: report of 12 cases and review of the literature. Am J Med 1974; 57: 927-939. Greene MH, Bate JD Jr, Greer BE, Blessing JA, Dembo AM: Acute nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer: a study of five randomized clinical trials. N Engl J Med 1962; 307: 1416-1421. Kyle RA: Second malignancies associated with chemotherapeutic agents. Semin Oncol 1962; 9: 131-142. VonHoff DD, Rosencweig M, Piccart M: The cardiotoxicity of anticancer agents. Semin Oncol 1962; 9: 23-33. DeVita VT, Serpick AA, Carbone PP: Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 1970; 73: 661-695. Applefeld M, Slawson RG, Spicer KM Singleton RT, Wesley MN, Wiernik PH: Long-term cardiovascular evaluation of patients with Hodgkin’s disease treated by thoracic mantle radiation therapy. Cancer Treat Rep 1962; 66: 10031013.