Therapy-Related Acute Promyelocytic Leukemia: A Report on 16 Cases By Laurence Detourmignies, Sylvie Castaigne, Anne Marie Stoppa, Jean Luc Harousseau, Alain Sadoun, Maud Janvier, Jean Loup Demory, Miguel Sonz, Roland Berger, Francis Bauters, Christine Chomienne, and Pierre Fenaux Purpose: To analyze the type of prior tumor and treatment in therapy-related acute promyelocytic leukemia (tAPL) that occurs after chemotherapy and/or radiotherapy (RT), and the hematologic characteristics and outcome of tAPL. Patientsand Methods: Sixteen patients with tAPL who were gathered during a 10-year period (1982 to 1991) in seven hematologic centers were analyzed retrospectively. Results: There were 13 women and three men. The median age was 46 years (range, 12 to 82). Prior tumor was breast carcinoma in 10 cases, another solid tumor in three cases, and lymphoma in three cases. Two patients had received RT alone, and 14 had received chemotherapy (with RT in 11 cases). Prior chemotherapeutic agents generally included a combination of cyclophosphamide (used for limited periods), fluorouracil (5-FU), vinca alkaloids, and doxorubicin, mitoxantrone, or etoposide (VP1 6). By contrast, alkylating agents other than cyclophosphamide had been used in only two patients. Median interval between onset of treatment for the prior tumor and diagnosis of APL was 25 months. No patient had a known preleukemic phase. Hematologic and cytogenetic charac-

teristics of the cases of tAPL were identical to those of the usual de novo APL, which included the presence of t(15; 17) in nine of the 10 patients tested. Two patients had early death. Seven patients were treated with intensive chemotherapy, and six achieved complete remission (CR). Three of them subsequently relapsed. Seven patients were treated with all-trans-retinoic acid (ATRA), and four achieved CR through the differentiation of blasts into mature granulocytes. None has relapsed so far. Conclusions: Our findings suggest that tAPL is not exceptional, and usually has several features in common with other types of therapy-related AML with specific karyotype (ie, t(8;21), t(9;1 1), inv(16)): solid tumor rather than hematologic malignancy as primary tumor, short interval of development, absence of known preleukemic phase, prior chemotherapy with a combination of several drugs that often included an agent that targets topoisomerase II (doxorubicin or mitoxantrone, but less often VP16). Hematologic characteristics and response to therapy (intensive chemotherapy or ATRA) in tAPL do not seem to differ from those of de novo APL. J Clin Oncol 10:1430-1435. © 1992 by American Society of Clinical Oncology.

T

Alkylating agents are the most frequent etiologic factors of tAML, but in the case of tAML with chro-

HERAPY-RELATED acute myeloid leukemias (tAMLs) that occur after chemotherapy and/or radiotherapy (RT) for malignant (or nonmalignant) disorders are usually preceded by a preleukemic phase, are associated with often complex,rearrangements that involve chromosomes 5 and/or 7, and carry a poor prognosis.1, 2 Approximately 10% of tAML, however, are associated with cytogenetic rearrangements specific for de novo AML, ie, t(8;21), balanced translocations between 11q23 and another chromosome, inv(16), or t(15;17). This subset of tAML usually is characterized by

a solid tumor as primary cancer (rather than hematologic malignancy), an absence of preleukemic phase, and a similar response to chemotherapy as in de novo AML with the same cytogenetic findings.3-5

From the Departmentsof Hematology of Centres Hospitals Universitaires (CHU) of Lille, ParisSt Louis, Marseille, Nantes, Poitiers, St Cloud, France, and the Department of Hematology of Valencia, Spain. Submitted March 30, 1992; acceptedMay 28, 1992. Address reprint requests to Pierre Fenaux, MD, PhD, Service des Maladiesdu Sang, C.H.U., 1,place de Verdun 59037, Lille, France. © 1992 by American Society of Clinical Oncology. 0732-183X/92/1009-0010$3.00/0

1430

mosome rearrangements

specific of de novo AML,

Pedersen-Bjergaard et al 6,7 showed that the epipodophyl-

lotoxins etoposide (VP 16) and teniposide, and anthracyclines and their derivatives, rather than alkylating drugs seemed to be causative agents. The epipodophyllotoxins

and anthracyclines, and their derivatives, unlike alkylat-

ing agents, do not bind covalently to DNA. Anthracyclines, but not epipodophyllotoxins, intercalate DNA. However, both groups of agents target DNA-topoi-

somerase II by interfering with the breakage-reunion reaction of DNA-topoisomerase II, and by stabilizing the cleaved complex formed between the enzyme and DNA.8 Most of the cases of tAML with specific karyotype reported so far had balanced translocations that involved 11q23 or, less often, 21q22. 7 11 Few cases of therapy-related acute promyelocytic leukemia (tAPL)

have been reported,12 and the impact of specific types of drugs on the pathogenesis of tAPL remains unknown. During the past 10 years, we were able to gather 16 cases of tAPL in seven hematologic centers. This allowed us to analyze the type of prior tumor and of prior therapy in

Journalof Clinical Oncology, Vol 10, No 9 (September), 1992: pp 1430-1435

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1431

THERAPY-RELATED ACUTE PROMYELOCYTIC LEUKEMIA

those patients, and the hematologic characteristics and therapeutic outcome of tAPL. PATIENTS AND METHODS Between 1982 and 1991, the seven hematologic centers that participated in this study diagnosed 284 cases of APL according to 13 French-American-British (FAB) criteria. ,14In the 16 cases (5.6%) that form the basis of this study, a history of prior cancer that was managed with chemotherapy and/or RT was found. Patient no. 7 45 has been reported previously. , Cytogenetic analysis was made on bone marrow in 11 patients, and mitoses were obtained in 10 patients after short-term culture. Chromosomes were classified after R and G banding, according to 5 the International System for Cytogenetic Nomenclature (ISCN).' Diagnostic criteria for disseminated intravascular coagulation (DIC) included the presence of at least two of the following criteria: fibrinogen less than 1.8 g/L; prothrombin time or factor V less than 60%; and fibrin split products (FSP) more than 40 ýLg/mL in the absence of significant liver disease. In vitro study of differentiation of abnormal promyelocytes with all-trans-retinoic 6 acid (ATRA) was performed as previously reported.' Two of the 16 patients died within 24 hours of the diagnosis. Seven patients were treated with intensive chemotherapy (daunorubicin alone or in combination with cytarabine [Ara-C], or rubidazone (daunorubicin) in combination with Ara-C), and seven patients were treated with ATRA at 45 mg/m 2 /d orally, which was scheduled until a complete remission (CR) was achieved. Patients who achieved CR with intensive chemotherapy or ATRA received various consolidation regimens, based on their age and general condition.

RESULTS

The initial characteristics of the 16 patients are listed in Table 1. There were 13 women and three men. Age at the time of diagnosis of APL ranged from 12 to 82 years (median, 46). Prior tumor included breast carcinoma in 10 patients, non-Hodgkin's lymphoma in two patients, Hodgkin's disease, ovarian carcinoma, brain astrocytoma, and hydatidiform mole in one case each. Two patients (patients no. 15 and 16) were treated by RT alone, three by chemotherapy alone, and 11 by a combination of both. Among chemotherapeutic agents, cyclophosphamide was used in nine patients (always discontinuously for limited periods), fluorouracil (5-FU) in nine patients, vinca alkaloids (vincristine or vindesine) in eight patients, doxorubicin or mitoxantrone in six patients, methotrexate in three patients, VP 16 in three patients, and mitomycin and thiotepa in two patients, whereas other drugs have been used in only one patient. Alkylating agents other than cyclophosphamide were used in only two patients (mechlorethamine and procarbazine in one case, and melphalan in the other case). Eight patients had received at least one agent that targeted topoisomerase II (VP 16, doxorubicin, or mitoxantrone). The interval between onset of

chemotherapy or RT for the first tumor and diagnosis of APL ranged from 9 to 84 months (median, 25) and was 24 months or less in eight patients. No patient had a known preleukemic phase. At the time of diagnosis of APL, no patient had organomegaly. Two patients had leukocytosis (WBC count > 10 x 10 9 /L),

13 had leukopenia (WBC

count < 4 x 109/L), and one had a normal leukocyte count. Four patients had bleeding symptoms. Criteria for DIC were present in 10 patients. Morphologically, all patients had classic APL according the FAB classification, and none had the microgranular variant APL. No myelodysplastic features were present in the bone marrow in any patient. Cytogenetic analysis (successfully performed in 10 patients) showed t(15;17) translocation in nine cases (with additional aberrations in three patients), whereas the remaining patient had normal diploid karyotype (Table 1). Two patients died within 24 hours of the diagnosis. Six of the seven patients who were treated with intensive chemotherapy achieved CR, and one had early death from CNS bleeding. Three of the patients who achieved CR relapsed after 6, 14, and 23 months; one patient (no. 7) died in CR after 5 months, from recurrence of her breast cancer; and the two remaining patients were still in CR after 10 and 12 months, respectively. Seven patients were treated with ATRA. Four achieved CR, and the remaining three patients had an early death from leukostasis (patients no. 9 and 16), and pulmonary bleeding (patient no. 11). In patients no. 9 and 16, leukostasis resulted from rapidly increasing leukocyte counts under treatment with ATRA. In all the seven patients who were treated with ATRA, in vivo signs of differentiation of blasts (in particular the presence of Auer rods in mature granulocytes) were present after the onset of treatment. In vitro differentiation of blasts with ATRA was studied in only two of the seven patients (including one of those who achieved CR and of those who had early death). In both cases, major differentiation of blasts into mature granulocytes was observed. The four patients who achieved CR received consolidation chemotherapy and remained in CR after 38, 9, 7, and 4 months, respectively. DISCUSSION

tAPL seems to be a rare disorder; Rosner and Grfinwald12 found only 19 cases of tAPL among 1,303 published cases of tAML (1.4%). In several large published series of APL, the presence of secondary cases was not mentioned,17- 24 but in three other series of 60,

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1432

DETOURMIGNIES ET AL

Table 1. Characteristics and Outcome of the 16 Patients With Therapy-Related APL Patient No.

Sex/Age (years)

Primary Tumor

Chemotherapy (months)

Patients who received chemotherapy (with or without RT) Cy Non-Hodgkin's 1 F/68 Vindesine (6) lymphoma Thiotepa (2) Breast carcinoma F/70 2 High-dose MTX (8) Non-Hodgkin's M/23 3 lymphoma High-dose Ara-C Hydatidiform mole Carboplatin F/30 4 VP 16 Bleomycin MTX (8) Dox Breast carcinoma 5 F/43 VCR Cy, 5-FU (8) Dox, 5-FU F/68 Breast carcinoma 6 VCR, Cy (4) Vindesine Mitomycin (7) VP 16 (5) Cy, Dox F/42 Breast carcinoma 7 5-FU (4) 8

F/51

Breast carcinoma

9

F/42

Breast carcinoma

10

F/50

Breast carcinoma

11

F/47

Breast carcinoma

12

F/60

Breast carcinoma

13

F/29

Ovarian carcinoma

14

M/45

Hodgkin's disease

Patients who received RT alone Brain astracytomao M/12 15 16

F/82

Breast carcinoma

RT

Interval to APL (months)

Karyotype

Treatment of APL

Results of Treatment

None

Survival < 1 day

ATRA DNR + Ara-C

CR (4+ months) CR (10* months)

ATRA

CR (7+ months)

45,XX,-1 ,18p+, t(15;17)

ATRA

CR (9+ months)

54

ND

None

Survival < 1 day

Chest + axillary

24

46,XX,t(15;17)

DNR Alone

Mitoxantrone VCR Cy, 5-FU (6) Mitoxantrone 5-FU, VCR (6)

Chest + axillary

9

46,XX

DNR + Ara-C

CR (4+ months). Died from breast carcinoma CR (12+ months)

Chest

17

ND

ATRA

Cy, Dox 5-FU (6) Cy, 5-FU MTX (6)

Chest + axillary

72

ND

ATRA

Chest + oxillary

40

No mitoses

ATRA

Cy, 5-FU VCR (7) Thiotepa 5-FU (3) VCR, 5-FU Mitomycin (3) Melphalan (4) VP 16, Cy, 5-FU (12) MOPP (6)

Chest + axillary + pelvis None

15

46,XX,t(15;17)

61

ND

DNR Alone DNR + Ara-C

Mantle field + paroaaortic

84

ND

Rubidazone + Ara-C

CR (23 months) second CR with ATRA (12 months)

None

Brain

26

46,XY,t(15;17)

CR (6 months)

None

Chest

19

46,XX,t(15;17)

Rubidazone + Ara-C ATRA

Mantle field

30

Chest None

23 30

None

24

46,XX,t(1;5), t(15;17)

Chest + axillary

19

Chest + axillary

46,XX,-7,+4, t(15;17) 46,XX,t(15;17) 46,XY,t(15;17)

6

Early death from leukostasis (survival 7 days) CR (38+ months) Early death from pulmonary bleeding (survival 15 days) CR (14 months) Early death from CNS bleeding (survival 6 days)

Early death from leukostasis (survival 10 days)

Abbreviations: Cy, cyclophosphamide; Dox, doxorubicin; MTX, methotrexate; VCR, vincristine; DNR, daunorubicin; Ara-C, cytarabine; ATRA, all-tronsretinoic acid; ND, not done; CR, complete remission.

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1433

THERAPY-RELATED ACUTE PROMYELOCYTIC LEUKEMIA

87, and 119 APL patients, one, five, and five patients, respectively, had tAPL.25-27 tAPL could have been underdiagnosed, however, because some patients with tAPL were excluded from therapeutic trials because they had a contraindication or refused intensive chemotherapy. Furthermore, some clinicians probably felt that APL, which occurs after chemotherapy and/or RT for a prior tumor, was not secondary to this treatment because it was different from usual cases of tAML. In 10 of our 16 patients, the prior tumor was breast carcinoma. Of the 19 previously published cases of tAPL reviewed by Rosner and Grunwald, 12 five occurred after breast carcinoma, and the incidence of tAPL, among tAML, was higher after breast carcinoma (4.3%) than after other cancers (0.8%). Only three patients in our series had a history of prior hematologic malignancy. This was in agreement with previous reports in other tAML with specific karyotype (ie, t(8;21) inv(16) t(9;11)) in which prior solid tumor rather than hematologic malignancy was found. 3 ,5.7 On the other hand, nine of

the 19 cases of tAPL reviewed by Rosner and Griinwald occurred after hematologic malignancies, which included seven cases of Hodgkin's disease. In eight of 16 cases and seven of the 14 previously reported cases of tAPL in which it is available, 12 the interval between onset of chemotherapy or RT for the prior tumor and diagnosis of APL was < 24 months. This was in agreement with the early onset often re34 7 ported in tAML with specific karyotype. A '

Pedersen-Bjergaard et al, while reviewing their experience and published data, found that tAML with cytogenetic rearrangements specific of de novo AML usually occurred after treatment with agents that target topoisomerase II (epipodophyllotoxins and to a lesser extent anthracyclines and derivatives) rather than after the prolonged use of alkylating agents.1''A7 Some of the patients they reported, in fact, had also received cyclophosphamide, but for short periods. This drug, at least if used for short periods, is probably less leukemogenic than other alkylating agents, which include melphalan, mechlorethamine, procarbazine, and chlorambucil. 2 However, most of the cases of tAML with specific karyotypes analyzed by Pedersen-Bjergaard et al had translocations that involved 11q23 or 21q22, and few had a t(15;17) translocation. Of the 19 cases of tAPL reviewed by Rosner and Griinwald,12 detailed analysis was available in 16 cases (Table 2), to which our 16 cases can be added. Of those 32 patients, nine had previously received RT alone, and 23 had received chemotherapy (and RT in 14 cases). Thirteen of 23 had received cyclophosphamide (always

for limited periods), 13 had received vinca alkaloids, 12 had received 5-FU, 11 doxorubicin or mitoxantrone, five methotrexate, and three an epipodophyllotoxin (VP 16). Only five patients had received an alkylating agent other than cyclophosphamide. These results suggest that, as for other tAML with specific karyotype, the prolonged use of alkylating agents has a relatively limited role in the development of tAPL. Although few of the 23 tAPL patients who were treated previously by chemotherapy had received an epipodophyllotoxin, 13 of them had received at least one agent that targets topoisomerase II (VP 16, doxorubicin, or mitoxantrone). Most had also received cyclophosphamide for limited periods, 5-FU, or vinca alkaloids. Each of these drugs, when administered alone, seems to have relatively limited leukemogenic potential, but their association may be leukemogenic, particularly in patients who also received RT. Of the 32 cases of tAPL (including our patients and previously published cases), nine had received RT alone. RT alone is often considered to have limited leukemogenic potential, 2 and one could argue that APL, in those patients, was a coincidental event and was not therapyrelated. However, other studies have suggested that RT alone (without chemotherapy) was associated with an increased risk of AML, especially in breast carcinoma.39 Hematologic and cytogenctic features of our cases and previously reported cases (Table 2) were identical to those found in de novo APL.17 27 The incidence and type of chromosomal abnormalities in addition to t(15;17) in our patients and in previously reported cases of tAPL was not different from that observed in de novo APL.41 Although the number of patients was limited and follow-up was short, response to treatment of tAPL apparently was similar to that observed in de novo APL.17- 24,424, 3 Six of the seven patients we treated with intensive chemotherapy achieved CR; three relapsed. Of the six previously reported patients with tAPL who received intensive chemotherapy, four achieved CR, and two of them subsequently relapsed. Among the seven patients we treated with ATRA, four achieved CR through the differentiation of blasts, but the three other patients also showed in vivo signs of differentiation, which are highly characteristic of APL. 16 In the two patients studied in vitro, differentiation of blasts with ATRA was also demonstrated. The cause of death in two of the three patients who did not achieve CR with ATRA was leukostasis associated with rapidly increasing leukocyte counts. This complication is a relatively frequent side effect of ATRA that can be reversed by 42 adding chemotherapy to ATRA.

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1434

DETOURMIGNIES ET AL Table 2. Previous Cases of Therapy-Related Acute Promyelocytic Leukemia: Sixteen Cases Reported in Detail Patient No.

Authors

Sex/Age (years)

Primary Tumor

Previous Treatment

Patients who received chemotherapy (with or without RT) Kantarjian et aP 1 F/23 Breast carcinoma Cy, Dox, 5-FU

Interval to APL (months)

Treatment of APL

Karyotype

NR

46XX t1 5; 17)

Results of Treatments

CR (32 months)

Whang-Peng et al2a Michels et a129

2

M/63

Fibrohistiocytoma

Dox, Cy

39

46XY t(15;17)

Amsa Aro-C VCR Prednisone NR

3

M/66

Chlorambucil

32

46XY t(15;17)

NR

Survival NR

Papa at aP0 2 Rosner et a13

4 5 6

F/45 F/67 F/54

Chronic lymphocytic leukemia Hodgkin's disease Breast carcinoma Breast carcinoma

24 48 96

46XX ND ND

NR Ara-C thioguanine 0

Survival 1 month Survival 1 month Survival 2 weeks

Konakura et a1 l

7

M/43

ABVD + RT Cy, 5-FU,MTX Dox, 5-FU, Thiotepa VCR CHOP Bleo + RT

10

ND

8 9

M/33 M/34

30 6

NR ND

DNR, Ara-C 6MP, Prednisone NR Dox + Ara-C

CR (19+ months)

Auclerc et aP13 Rosenstrauch et a13 Patients who received 33 Le Beau et aP

Non-Hodgkin's lymphoma Hodgkin's disease MOPP x 6 Hodgkin's disease MOPP x 5

Lung carcinoma

56

46XY,-21,-21,+8

DNR + Ara-C

CR (9 months)

0 6MP Dox, VCR Prednisone, Ara-C

Survival 1 day Survival 2 months CR (61' months)

Cy, MTX, 5-FU + RT

3

RT alone 10 M/63

RT alone (chest +

11 12 13

M/26 M/28 F/28

Amadon 30 et a1 Le Beau et a133

14

N/R

15

F/47

Bennett et o34

16

F/54

Kantarjion et aP

Survival NR Early death

t(15;17) + der

liver)

Newman et aPl3

Survival 1 month

15 226 NR

21 ND ND 46XX t(15;17)

Hodgkin's disease Hodgkin's disease Papillary thyroid carcinoma Hodgkin's disease

RT alone (4 sites) RTalone (12 sites) RT alone RTalone

16

t(15;17)

Endometrium carcinoma Breast carcinoma

RT alone

23

46XX t(15;17)

Dox + Ara-C

Early death

RT alone

2

NR

NR

Survival NR

Abbreviations: Cy, cyclosphosphamide; Dox, doxorubicin; DNR, daunorubicin; RT, radiotherapy; MTX, methotrexote; VCR, vincristine; 6MP, mercaptopurine; Bleoo, bleomycin; NR, not reported; CR, complete remission; ABVD, doxorubicin, bleomycin, vinblastine, and docarbazine; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone.

Our findings suggest that tAPL may not be exceptional. In our experience, tAPL usually occurs after a solid tumor (especially breast carcinoma) is treated by a combination of antineoplastic drugs often including an agent that targets topoisomerase II. Hematologic characteristics and response to treatment (chemotherapy or ATRA) seem to be identical in tAPL and de novo APL. Molecular mechanisms that connect agents that target topoisomerase II and tAML with translocations specific to de novo AML, especially t(15;17), remain unknown. However, sister chromatid exchange has been suggested to reflect directly the cytotoxic effet of epipodophyllotoxins" and Pedersen-Bjergaard and Philip7 hypothesized that other chromosome abnormalities that occur without apparent loss of chromosome material, such as reciprocal translocations, could perhaps also be induced by agents that impair the activity of topoisomerase-I1.

ACKNOWLEDGMENT We are indebted to Dr J. Pedersen-Bjergaard for his helpful advice in this work.

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