The risk of acute leukemia in patients treated for Hodgkin's disease is significantly higher aft [see bined modality programs than after chemotherapy alone and is correlated with the extent of radiotherapy and type and duration of chemotherapy: a case-control study.
OBJECTIVE
Patients treated for Hodgkin's disease have an increased risk of developing subsequent acute leukemia. This co-operative study was conducted to assess the relative risk associated with several candidate factors including age, splenectomy, combined modality therapy and cumulative drug dose including alkylating agents and nitrosurea derivatives.


METHODS
This study evaluated the risk of acute leukemia according to pretreatment variables and therapy modalities among 1659 patients treated for Hodgkin's disease and followed for a median time of 10 years. Both case-control and actuarial risk studies were performed. Median age was 34 years (range: 12-83); 53% of patients were splenectomized. As to the overall therapy, 348 patients (21%) were given radiotherapy (RT) alone, 375 (23%) chemotherapy (CT) alone (including MOPP, MOPP + ABVD or MOPP + ABVD + lomustine); 936 (56%) received both CT and RT, either as primary or salvage treatment.


RESULTS
The overall 15-year actuarial risk of leukemia was 4.2%; the hazard function curve showed two peaks of risk at the 3th and the 8th year from the initiation of therapy and no leukemia beyond the 12th year of follow-up. Risk of leukemia was 0.3% after RT alone, 2.8% after CT alone (2.2% after MOPP; 4.4% after MOPP + ABVD + lomustine), and 5.4% in patients given combined modality therapy (10.2% for RT + MOPP; 15.6% for RT + MOPP + lomustine). No leukemia occurred after ABVD alone and the risk was low (0.6%) when neither mechlorethamine nor lomustine were utilized. Patients who had received extended radiotherapy including abdomen and pelvis in addition to MOPP showed a significantly higher risk of leukemia compared to those given limited RT + MOPP (P = 0.01). Case-control analysis indicated advanced stage, type and duration (> 8 months) of CT and extension of RT as significant risk factors for leukemia. Compared to RT alone, the odds ratio was 5.9 after MOPP + extended RT, and 8 when a lomustine-containing regimen was used, as well. Neither age nor splenectomy were independent risk factors for leukemia; splenectomy was influential only when patients had been given MOPP chemotherapy, as well.


CONCLUSIONS
Both case-control and actuarial analyses indicated that: a) combined modality therapy with MOPP and extensive RT (including abdomen and pelvis), and the use of lomustine added to the leukemogenic risk of MOPP alone; b) programs without mechlorethamine, procarbazine and lomustine were almost devoid of leukemogenic risk.
Brusamolino
E
E
Istituto di Ematologia, Università di Pavia, Italy.
Anselmo
A P
AP
Klersy
C
C
Santoro
M
M
Orlandi
E
E
Pagnucco
G
G
Lunghi
F
F
Maurizi-Enrici
R
R
Baroni
C D
CD
Lazzarino
M
M
Mandelli
F
F
Bernasconi
C
C
D000005:Abdomen / Q000528:radiation effects; D000206:Actuarial Analysis; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D016022:Case-Control Studies; D002423:Cause of Death; D002648:Child; D003131:Combined Modality Therapy / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006689:Hodgkin Disease / Q000150:complications / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D007938:Leukemia / Q000139:chemically induced / Q000453:epidemiology* / Q000209:etiology; D007953:Leukemia, Radiation-Induced / Q000453:epidemiology* / Q000209:etiology; D008130:Lomustine / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008466:Mechlorethamine / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000139:chemically induced / Q000453:epidemiology / Q000209:etiology; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000453:epidemiology* / Q000209:etiology; D016017:Odds Ratio; D010388:Pelvis / Q000528:radiation effects; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects; D011344:Procarbazine / Q000008:administration & dosage / Q000009:adverse effects; D011878:Radiotherapy / Q000009:adverse effects*; D012306:Risk; D013156:Splenectomy / Q000009:adverse effects; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
D018906:Antineoplastic Agents, Alkylating; D011344:Procarbazine; D008466:Mechlorethamine; D014750:Vincristine; D008130:Lomustine; D011241:Prednisone