Evolving characteristics and outcome of secondary acute promyelocytic leukemia (APL): A prospective analysis by the French-Belgian-Swiss APL group
The following are members of the French-Belgian-Swiss Acute Promyelocytic Leukemia Group: Jean-Yves Cahn (Department of Hematology, Grenoble University Hospital, Grenoble, France), Eric Deconinck (Department of Hematology, Besancon University Hospital, Besancon, France), Jacques Delaunay (Department of Hematology, Nantes University Hospital, Nantes, France), Denis Guyotat (Department of Hematology, Institut de Cancérologie de la Loire, Saint Priest en Jarez, France), Norbert Ifrah (Department of Hematology, Angers University Hospital, Angers, France), Cécile Pautas (Department of Hematology, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris 12, Créteil, France), Bruno Quesnel (Department of Hematology, Lille University Hospital, Lille, France), Aspasia Stamatoullas (Department of Hematology, Centre Becquerel, Rouen, France), and Norbert Vey (Department of Hematology, Institut Paoli Calmette, Marseille, France).
Abstract
BACKGROUND
Reports of patients with secondary acute promyelocytic leukemia (APL) have increased in recent years, particularly for those who received treatment with mitoxantrone, and retrospective studies have suggested that their characteristics and outcomes were similar to those of patients with de novo APL.
METHODS
The authors investigated patients with de novo and secondary APL who were included in the ongoing APL-2006 trial. Patients with secondary APL who were included in that trial also were compared with a previous retrospective cohort of patients with secondary APL.
RESULTS
In the APL-2006 trial, 42 of 280 patients (15%) had secondary APL. Compared with the retrospective cohort, patients with secondary APL in the APL-2006 trial had a lower incidence of prior breast carcinoma (35.7% vs 57%; P = .03) and a higher incidence of prior prostate carcinoma (26.2% vs 4.7%; P < .001). Treatment of the primary tumor in the APL-2006 trial less frequently included combined radiochemotherapy (28.6% vs 47.2%; P = .044) and no mitoxantrone (0% vs 46.7%; P = .016) but more frequently included anthracyclines (53.3% vs 38.3%; P = .015). In the APL-2006 trial, patients who had secondary APL, compared with those who had de novo APL, were older (mean, 60.2 years vs 48.7 years, respectively; P < .0001) but had a similar complete response rate (97.6% vs 90.3%, respectively), cumulative incidence of relapse (0% vs 1.8%, respectively), and overall survival (92.3% vs 90.9%, respectively) at 18 months.
CONCLUSIONS
Although the incidence of secondary APL appears to be stable over time, evolving strategies for the treatment of primary cancers have reduced its occurrence among breast cancer patients but have increased its incidence among patients with prostate cancer. The current results confirm prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL. Cancer 2015;121:2393–2399. © 2015 American Cancer Society.
INTRODUCTION
Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia (AML) and represents approximately 10% of adult AMLs. It is characterized by the t(15;17) translocation, which leads to a specific promyelocytic leukemia (PML)-retinoic acid receptor-α (PML-RARα) rearrangement and a specific coagulopathy.1 It is a curable disease in most patients because it is responsive to all-trans retinoic acid (ATRA) therapy combined with chemotherapy and, more recently, arsenic derivatives.2
APL generally occurs de novo, without a known cause. However, secondary APL that emerges after chemotherapy and/or radiotherapy for neoplastic or non-neoplastic disorders has been increasingly described, including in our group's experience,3 and represented from 10% to 20% of all patients with APL in a recent series.
In reported series, secondary APL generally occurred relatively early after a primary tumor (within 3 years), predominantly among patients with breast carcinoma who received chemotherapy based on topoisomerase II inhibitors (anthracyclines or mitoxantrone more often than etoposide) combined with alkylating agents, with or without radiotherapy.3, 4 Secondary APL has been reported more recently after mitoxantrone treatment for multiple sclerosis.5 In patients who develop secondary APL after mitoxantrone therapy, PML breakpoints appear tightly clustered in an 8–base-pair region within intron 6, suggesting that the drug is directly involved in mediating breaks of double-stranded DNA.6 Finally, hematologic characteristics and outcomes of secondary APL are considered to be similar to those of de novo APL.7
Conversely, those secondary APL series were published some years ago (Table 1).13, 7, 10, 14 Changes in the use of antineoplastic agents, including a considerable reduction in the use of mitoxantrone and, to a lesser extent, anthracyclines for the treatment of breast carcinoma, have been made in recent years with the objective of reducing the incidence of secondary AML (particularly secondary APL), and those changes could have an impact on the incidence and etiology of secondary APL. In addition, data supporting similar features and outcomes between patients with secondary APL and de novo APL all were retrospective and were obtained using historic controls. We took advantage of our current multicenter APL-2006 trial, which includes both de novo APL and secondary APL, to investigate whether the occurrence of secondary APL has been influenced by recent changes in the treatment of cancers and to prospectively compare the characteristics and outcomes of patients with secondary APL with those of patients with de novo APL.
| Study | Randomized | No./Total No. With sAPL (%) | sAPL: CR Rate, % | sAPL: EFS Rate, % | sAPL: OS Rate, % |
|---|---|---|---|---|---|
| Elliott 20128 | No | 11/53 (20.7)a | 64/93a | ND | 51/84a |
| Dayyani 20119 | No | 29/301 (9.6)a | 89/94 (70/76)a, b | ND | 65/65a |
| Beaumont 20033 | No | 106 (100) | 87 | ND | 59 |
| Pulsoni 20027 | No | 31/641 (4.8)a | 97 vs 93a | 65 vs 68a | 85/78a |
| Andersen 200210 | No | 41/89 (46)c | 69/85 | ND | 29/29 |
| Pagano 200111 | No | 19 (100) | 90 | ||
| Pollicardo 199612 | No | 14/113 (12.4)a | 79 vs 69 | 57/54 | 37/35 |
| Kantarjian 198613 | No | 1 (ND) | ND | ND | ND |
- Abbreviations: CR, complete response; EFS event-free survival; NA, not available; ND, not determined; OS, overall survival; sAPL, secondary acute promyelocytic leukemia.
- a Results are from a comparison between sAPL and APL.
- b Results are from a comparison between all-trans retinoic acid/arsenic trioxide versus all-trans retinoic acid/chemotherapy.
- c Results are from a comparison between sAPL and secondary acute myeloid leukemia.
MATERIALS AND METHODS
Patients
In our ongoing APL-2006 trial, which started in December 2006, patients with confirmed APL received induction and consolidation treatment combining ATRA and anthracycline-based chemotherapy with or without arsenic trioxide (ATO) followed by maintenance treatment with continuous low-dose chemotherapy and intermittent ATRA, a design largely derived from our previous trials15 but with replacement of daunorubicin by idarubicin. Treatment was stratified on age and baseline white blood cell (WBC) counts, as illustrated in Figure 1.
(A-C) This is a flow chart of the French-Belgian-Swiss Acute Promyelocytic Leukemia (APL) Group APL-2006 trial. (A) Patients were stratified according to age and white blood cell (WBC) count. Patients aged ≤70 years who had WBC counts ≤10 g/liter were randomized to receive either cytosine arabinoside (ARAC), arsenic trioxide (ATO), or all-trans retinoic acid (ATRA) in association with idarubicin (IDA) for consolidation treatment. (B) Patients aged ≤70 years who had WBC counts >10 g/liter were randomized to receive either ARAC or ATO. (C) Elderly patients aged >70 years received consolidation and maintenance, including ATO. Patients who had WBC counts >10 g/liter received intrathecal (IT) chemotherapy. 6-MP, 6-mercaptopurine; CR, complete response; D, day; DXM, dexamethasone; h, hours; MTX, methotrexate.
Methods
First, we compared patients who had secondary APL and were included in the trial before March 2009 in the APL-2006 trial with our last published cohort of 106 patients who had therapy-related APL diagnosed between 1982 and 2001 in 45 French, Spanish, and Belgian centers.3 APL was considered secondary if it occurred after a primary malignancy, irrespective of the treatment administered for that malignancy, or after a non-neoplastic disorder treated by chemotherapy, radiotherapy, or immunosuppressive drugs. Comparisons were made based on etiologic factors, including the type of primary cancer (or nonmalignant disorder) and its treatment (chemotherapeutic agents and their cumulative dose, radiotherapy, hormone therapy, and surgery), the interval between treatment of the primary disease, and the occurrence of secondary APL. Next, we prospectively compared the baseline characteristics and outcomes of 42 patients who had secondary APL with those of 238 patients who had de novo APL and were included in the APL-2006 trial before March 2009 and followed until the reference date of January 1, 2014 (closing date of our analysis).
For statistical analyses, the SAS statistical software package (SAS Institute Inc, Cary, NC) was used. Mean ± standard deviation and median (interquartile range) values were used to describe the distribution of variables. Proportions were compared using the chi-square test or the Fisher exact test. Student t tests and analyses of variance were used to compare means between independent groups (≥2) when the variable of interest had a normal distribution; in other cases, the Mann-Whitney U test and the Kruskal-Wallis test, respectively, were used. Throughout these analyses, 2-tailed P values < .05 were considered statistically significant.
RESULTS
Incidence of Secondary APL in the APL-2006 Trial
Between November 2006 and March 2009, 280 patients were enrolled in the APL-2006 trial, including 42 (15%) with secondary APL, compared with 22% in our previous cohort, although that cohort was retrospective (P = .12).
Characteristics of the Primary Disease and its Treatment
The primary disease was neoplastic in all patients (Table 2), including 6 patients who had 2 cancers before secondary APL, and consisted of breast carcinoma in 15 patients (35.7%), prostate carcinoma in 11 patients (26.2%), various other solid tumors in 19 patients (45.2%), and lymphoma in 3 patients (7.1%). Compared with our historic cohort, patients who were included in the APL-2006 trial had significantly fewer primary breast carcinomas (35.7% vs 57%; P = .03) and more primary prostate carcinomas (26.2% vs 4.7%; P < .001), whereas the incidence of other cancers did not differ significantly between the 2 cohorts.
| No. of Patients/Total No. (%) | |||
|---|---|---|---|
| Malignancy | Current Series: APL-2006 Trial Patients, N = 42 | Beaumont 2003,3 N = 106 | P |
| Breast cancer | 15/42 (35.7) | 60/106 (57) | .03 |
| Prostate cancer | 11/42 (26.2) | 5/106 (4.7) | <.001 |
| Others solid tumors | 19/42 (45.2) | 20/106 (18.8) | NS |
| Lymphoma | 3/42 (7.1) | 17/106 (16) | NS |
| Myeloid disorders | 0/0 (0) | 2/106 (1.8) | NS |
- Abbreviations: APL, acute promyelocytic leukemia; NS, nonsignificant.
In the patients with secondary APL who were included in the APL-2006 trial, treatment of the primary neoplasm had been chemotherapy alone in 9 patients (21.4%), radiotherapy alone in 17 patients (40.5%), and chemotherapy plus radiotherapy in 12 patients (28.6%) (Table 3). Chemotherapy (n = 21) had included at least 1 alkylating agent in 19 patients (90.5%) and at least 1 topoisomerase II inhibitor in 13 patients (61.9%), but none of the patients had received mitoxantrone. Hormone therapy was received by 18 patients (11 with breast cancer and 7 with prostate cancer), including 7 (39%) who received antiestrogens, 7 (39%) who received aromatase inhibitors, 4 (22%) who received gonadotropin-releasing hormone analogues, and 4 (22%) who received antiandrogens. Hormone therapy had been received alone by 2 patients with prostate cancer (4.8%), had been combined with radiotherapy in 9 patients (21.4%), and had been combined with radiochemotherapy in 7 patients (16.7%). Finally, in 3 patients, the primary neoplasm (breast carcinoma in all 3) had been treated with surgery alone without chemotherapy, radiotherapy, or hormone therapy.
| No./Total No. of Patients (%) | |||
|---|---|---|---|
| Treatment | APL2006 Trial Patients, N = 42 | Beaumont et al, Beaumont 2003,3 N = 106 | P |
| Chemotherapy only | 9/42 (21.4) | 29/106 (27.3) | NS |
| Alkylating agents | 38/42 (90.5) | 91/106 (86) | NS |
| Topoisomerase II inhibitors | 26/42 (61.9) | 82/106 (77) | NS |
| Mitoxantrone | 0/42 (0) | 39/106 (36.4) | < .001 |
| Anthracyclines | 20/42 (47.6) | 40/106 (37.9) | NS |
| VP16 | 6/42 (14.2) | 26/106 (24.1) | NS |
| Radiotherapy only | 17/42 (40.5) | 27/106 (25.4) | .077 |
| Radiochemotherapy | 12/42 (28.6) | 50/106 (47.2) | .044 |
| Hormone therapy | 18/42 (42.9) | 25/106 (23.6) | NS |
| Surgery only | 3/42 (7.1) | Patients excluded | — |
- Abbreviations: APL, acute promyelocytic leukemia; NS, nonsignificant; VP16, etoposide.
Compared with our historic cohort, patients in the APL-2006 trial had received less combined radiotherapy and chemotherapy (28.6% vs 47.2%; P = .044), trended toward more frequent receipt of radiotherapy alone (40.5% vs 25.4%; P = .077), and had not received mitoxantrone (compared with 36.4%; P < .001), whereas there was no significant difference in the receipt of other drugs.
By restricting the analysis to patients who had breast cancer as the primary tumor, patients in the APL-2006 trial were characterized by no receipt of mitoxantrone (0% vs 46.7%; P = .016) and more frequent receipt of anthracyclines (53.3% vs 38.3%; P = .015) (Table 4). For prostate cancer, more patients from the APL-2006 trial cohort had received antiestrogens (0% vs 80%; P = .002).
| No./Total No. of Patients (%) | |||
|---|---|---|---|
| Treatment | APL-2006 Trial Patients. N = 15 | Beaumont 2003,3 N = 60 | P |
| Chemotherapy alone | 0/15 (0) | 4/60 (6.7) | NS |
| Radiotherapy alone | 7/15 (46.7) | 15/60 (25) | NS |
| Chemotherapy and radiotherapy | 8/15 (53.3) | 41/60 (68.3) | NS |
| Alkylating agent | 8/15 (53.3) | 39/60 (86.7) | NS |
| Topoisomerase II inhibitors | 8/15 (53.3) | 26/60 (43.3) | .039 |
| Mitoxantrone | 0/15 (0) | 21/60 (35) | .016 |
| Anthracyclines | 8/15 (53.3) | 23/60 (38.3) | .015 |
| VP16 | 0/15 (0) | 3/60 (5) | NS |
| Hormone therapy | 11/15 (73.3) | 21/60 (35) | .051 |
- Abbreviations: APL, acute promyelocytic leukemia; NS, nonsignificant; VP16, etoposide.
The median interval between diagnoses of the primary tumor and secondary APL was 48 months (range, 6.9-299 months) in the APL-2006 trial cohort compared with 25 months (range, 4-276 months) in our previous secondary APL cohort (P value nonsignificant).
Baseline Hematologic Characteristics and Outcomes of Patients With Secondary APL and De Novo APL Included in the APL-2006 Trial
In the APL-2006 trial, patients with secondary APL were older (mean age, 60.2 years vs 48.7 years in the de novo cohort; P < .0001) and had a higher frequency of breakpoint cluster region 3 (bcr3) breakpoint (35% vs 57.2%; P = .0093) than patients with de novo APL (Table 5). No significant differences were observed for other characteristics, including sex, baseline WBC count, and the proportion with the hypogranular variant of APL.
| Characteristic | Secondary APL | De Novo APL | P |
|---|---|---|---|
| WBC >10 g/L, % | 21.4 | 22.3 | .84 |
| M3 variant, % | 14 | 14 | .81 |
| Age: Mean ± SD, y | 60.2 ± 14.1 | 48.7 ±15.8 | < .0001 |
| Breakpoint for bcr3: No./Total no. (%) | 24/42 (57.2) | 82/236 (35) | .0093 |
| Women: No./Total no. (%) | 20/42 (47.6) | 116/234 (84.8) | .9 |
- Abbreviations: bcr3, breakpoint cluster region 3; SD, standard deviation; WBC, white blood cells.
The complete response (CR) rate was 97.6% (41 of 42 patients) in patients with secondary APL and 90.3% (215 of 238 patients) in those with de novo APL (P = .14) (Table 6). With a median follow-up of 58.5 months, the 18-month cumulative incidence of relapse and overall survival were 0% versus 1.8% (P = .55) and 92.9% versus 90.9% (P = .51), respectively, in patients with secondary APL and de novo APL, respectively.
| Outcome | Secondary APL | De Novo APL | P |
|---|---|---|---|
| CR: No./Total no. (%) | 41/42 (97.6) | 215/238 (90.3) | .14 |
| Cumulative incidence of relapse at 18 mo, % | 0 | 1.8 | .55 |
| Overall survival at 18 mo, % | 92.9 | 90.9 | .51 |
| Deaths in CR: No./Total no. (% CR) | 6/41 (14.6) | 16/215 (7.4) | .13 |
- Abbreviation: CR, complete response.
DISCUSSION
Although secondary APL was considered rare 20 years ago (1 in 60 patients were published before 1986 by The University of Texas MD Anderson Cancer Center, 4.8% of APLs were diagnosed by the Italian Adult Hematologic Malignancy Group between 1982 and 1991, and 5% of APLs were diagnosed in our experience between 1984 and 1993),3, 7, 13 more recent data indicate an increasing incidence: 22% between 1994 and 2000 in our experience and 12% after 1986 in The University of Texas MD Anderson Cancer Center experience.3, 12, 13, 16 The incidence of 15% secondary APLs in the APL-2006 trial is a little lower than that reported in our previous retrospective experience but may have been underestimated, because some patients with APL may not have been included in the APL-2006 trial, especially those who had active tumors or who had already received high cumulative doses of anthracyclines. Conversely, during the period of accrual in the APL-2006 trial, a thorough analysis of all APLs diagnosed in the 17 largest participating centers was made. We observed that 68.7% of patients had been included in the APL trial, whereas 31.3% had not been included for a variety of reasons (mainly older age and direct admission to the hospital's intensive care unit),17 The proportion of secondary APL was 15% in patients who were included in the APL0200 6 trial and 8.8% in those who were not included.
Although comparison between the current prospective study and our previous retrospective experience of secondary APL may have some limitations, we observed that, compared with the former series, patients with secondary APL who were included in the APL-2006 trial were characterized by a significantly lower incidence of breast carcinoma (35.7% vs 57%) and a higher incidence of prostate carcinoma (26.2% vs 4.7%) as the primary tumor. For APL that occurred after breast cancer, previous receipt of mitoxantrone was an important etiologic factor.4 The disappearance of mitoxantrone from breast carcinoma chemotherapy protocols over the last decade in France probably accounts for the reduced proportion of secondary APLs occurring after breast cancer observed in the current series. Still, breast carcinoma remained the first primary cancer in the current series. In part, this may have been because anthracycline-based chemotherapy, which had replaced mitoxantrone-based chemotherapy in breast carcinoma (until it was largely replaced more recently by taxane-based protocols), also has been associated with an increased risk of secondary AML, particularly secondary APL, especially when anthracyclines are combined with cyclophosphamide and radiotherapy.18 Also, 7 of the 15 patients with breast carcinoma had received radiotherapy alone, which, although this is disputed, may be associated with a higher risk of secondary AML among patients with breast cancer.19 Regarding hormone therapy for breast carcinoma, a higher risk of AML has been reported for patients receiving tamoxifen, but only in univariate analysis.4 Finally, patients with breast cancer may be predisposed to developing AML, as reported in patients with breast carcinoma who underwent surgery alone and in patients with a family history of breast cancer.20, 21 Such a predisposition may account for the 3 patients in the current series who developed APL after undergoing surgery alone for breast carcinoma.
An important finding for the patients with secondary APL who were included in the APL-2006 trial was the high rate of prostate cancer (26.2%) as primary tumor compared with 2% to 5% in previous studies.3, 7, 22 Four of the 11 patients with prostate cancer in the APL-2006 trial had received radiotherapy alone, 8 had received hormone therapy with gonadotropin-releasing hormone and/or antiandrogens alone, and 5 patients had received both treatments. Radiotherapy alone in prostate carcinoma may be a risk factor for secondary AML,23 although this remains disputed; however, to our knowledge, hormone therapy in prostate carcinoma has not been linked to an increased risk of AML. Another difference in our current series of secondary APL was the relatively low incidence of previous lymphoma (7%) compared with our previous experience and other studies (range, 17.6%-23%).7, 10, 14
Although, in the current secondary APL series, we observed a trend toward lower receipt of previous chemotherapy and combined chemotherapy and radiotherapy and greater receipt of radiotherapy alone and hormone therapy alone (probably reflecting the tendency to de-escalate cancer treatment intensity in recent years), those measures may not be able to prevent the occurrence of secondary AML (or at least of secondary APL). Conversely, as mentioned above, 9.5% of patients in the current series had not received any chemotherapy or radiotherapy for their primary tumor, pointing to a possible genetic predisposition to develop secondary APL in those patients.7, 12, 20
In previously published secondary APL series, a higher proportion of women was reported,3, 7 and the patients who had secondary APL were older compared with those who had de novo APL, although no other differences were observed between de novo and secondary APL with regard to APL morphologic subsets, WBC count, or type of PML/RARα fusion. Our study, the first prospective comparison to our knowledge between patients with secondary APL and de novo APL, confirmed the older age of those with secondary APL but demonstrated no significant difference between the sexes. We also reported a higher incidence of bcr3 breakpoints in secondary APL (54%) compared with our previous study (35%) and the Italian Adult Hematologic Malignancy Group experience (29%).3, 7 However, this higher incidence of bcr3 breakpoints was not associated with the tendencies to develop more of the microgranular variant of APL (M3v) or more of the hyperleukocytosis reported for patients with de novo APL.24
In previously retrospective series of patients with secondary APL, the outcome generally was similar to that of patients with de novo APL in terms of complete remission, event-free survival, and overall survival except in 1 study,8 in which the CR and survival rates were significantly lower in patients who had secondary APL compared with those who had de novo APL (Table 1). Our prospective study confirms that patients who have secondary APL respond equally well to therapy as patients who have de novo APL with an acceptable toxicity profile regarding adverse events, duration of aplasia, and days in hospital. The outcome of secondary APL appears to be similar to that of de novo APL, with a high proportion of potentially cured patients. One limitation of the current study is the relatively limited follow-up (median, 18 months) in the APL-2006 trial, because more late relapses may occur in patients with secondary APL. Although longer follow-up will be required to confirm our results, published experience in patients who had secondary APL treated with ATRA and chemotherapy reported that only 7.6% of the relapses occurred beyond 18 months.3
Overall, our findings suggest that the efforts made to reduce the risk of secondary APL, especially by avoiding the use of mitoxantrone in breast carcinoma, have changed the types of primary tumors and their treatment in recently diagnosed patients with secondary APL, but they may not have reduced the incidence of secondary APL. It seems reasonable to suspect that the same phenomenon may occur in other types of secondary AML, in which the frequency does not seem to diminish but etiologic factors appear to evolve over the years (for example, an increasing frequency of AML secondary to purine analogs).25 Our study also confirms prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL; however, a longer median follow-up will be necessary to confirm that secondary APLs are not associated with more frequent relapses.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
