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Acute leukemia as a secondary malignancy in children and adolescents: Current findings and issues†
Version of Record online: 15 DEC 2008
Copyright © 2008 American Cancer Society
Volume 115, Issue 1, pages 23–35, 1 January 2009
How to Cite
Hijiya, N., Ness, K. K., Ribeiro, R. C. and Hudson, M. M. (2009), Acute leukemia as a secondary malignancy in children and adolescents: Current findings and issues. Cancer, 115: 23–35. doi: 10.1002/cncr.23988
We thank Sharon Naron for expert editorial review.
- Issue online: 29 DEC 2008
- Version of Record online: 15 DEC 2008
- Manuscript Accepted: 1 AUG 2008
- Manuscript Revised: 29 JUL 2008
- Manuscript Received: 13 MAY 2008
- secondary leukemia;
- cancer survivor;
- alkylating agents;
- acute myeloid leukemia;
- myelodysplastic syndrome;
- acute lymphoblastic leukemia
Secondary acute leukemia is a devastating complication in children and adolescents who have been treated for cancer. Secondary acute lymphoblastic leukemia (s-ALL) was rarely reported previously but can be distinguished today from recurrent primary ALL by comparison of immunoglobulin and T-cell receptor rearrangement. Secondary acute myeloid leukemia (s-AML) is much more common, and some cases actually may be second primary cancers. Treatment-related and host-related characteristics and their interactions have been identified as risk factors for s-AML. The most widely recognized treatment-related risk factors are alkylating agents and topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines). The magnitude of the risk associated with these factors depends on several variables, including the administration schedule, concomitant medications, and host factors. A high cumulative dose of alkylating agents is well known to predispose to s-AML. The prevalence of alkylator-associated s-AML has diminished among pediatric oncology patients with the reduction of cumulative alkylator dose and limited use of the more leukemogenic alkylators. The best-documented topoisomerase II inhibitor-associated s-AML is s-AML associated with epipodophyllotoxins. The risk of s-AML in these cases is influenced by the schedule of drug administration and by interaction with other antineoplastic agents but is not consistently found to be related to cumulative dose. The unpredictable risk of s-AML after epipodophyllotoxin therapy may discourage the use of these agents, even in patients at a high risk of disease recurrence, although the benefit of recurrence prevention may outweigh the risk of s-AML. Studies in survivors of adult cancers suggest that, contrary to previous beliefs, the outcome of s-AML is not necessarily worse than that of de novo AML when adjusted for cytogenetic features. More studies are needed to confirm this finding in the pediatric patient population. Cancer 2009. © 2008 American Cancer Society.
The sequelae of cancer treatment are of increasing concern as contemporary therapy increases the survival of patients with pediatric malignancies. The development of a second cancer is among the most devastating and potentially life-threatening sequelae of childhood cancer. A second cancer may be of any histologic subtype, from benign, low-grade tumors to high-grade malignancies, such as acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL). There is compelling evidence that specific therapies are etiologic agents of secondary leukemogenesis. 1-4 In some cases, host factors also may contribute.5, 6 Here, we review current knowledge regarding the incidence of second hematologic malignancies and risk factors for their development in children and adolescents who were treated previously for cancer. When information was not available from pediatric studies, we included data derived from adult cancer patients. In addition, we provide a novel mortality-based analysis of the risk-benefit ratio of epipodophyllotoxin administration in patients with ALL by comparing the risk of death from ALL recurrence to the risk of death from secondary AML (s-AML).
AML As a Secondary Malignancy
‘Secondary’ AML or ‘second de novo’ AML? The terms ‘secondary AML’ and ‘treatment-related AML’ often are used interchangeably to describe AML for which previous cytotoxic therapy is considered to have contributed to its etiology. This designation includes cases of MDS and chronic myeloproliferative disorder. 7 However, some investigators have reported cases of AML occurring as a second cancer that cannot be attributed to previous cancer chemotherapy or radiation. Examples include AML as a second cancer in patients whose sole therapy was surgical resection of the primary cancer.8, 9 It is now hypothesized that these cases are ‘second de novo’ cancers, because leukemogenesis is likely to reflect a genetic predisposition to multiple primary cancers, as opposed to genotoxicity caused by chemotherapy or radiotherapy. This hypothesis is supported by the high incidence of AML and other cancers in patients with specific genetic disorders such as Down syndrome10 and Fanconi anemia.11 The incidence of cancer also is significantly higher in first-degree relatives of patients with s-AML than in those of patients with de novo AML.8
Although the prognosis of s-AML often is considered to be less favorable than that of de novo AML, a similarly favorable prognosis is reported for de novo and secondary acute promyelocytic leukemia (APL). 9, 12 However, because a significant proportion of ‘secondary’ APL seems to be unrelated to prior therapies8, 9 and because of the clinical similarity of de novo APL and APL that develop after other tumors, some cases of ‘secondary’ APL are considered second primary malignancies.12
The combinations of cytotoxic and biologic agents and modalities used to treat pediatric cancer hinder elucidation of the factors that contribute to s-AML (Table 1). Moreover, unknown host factors may confound the calculated risk estimates and compromise their predictive accuracy. Nevertheless, compelling data indicate that treatment with alkylating agents and topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines) increases the probability of s-AML.
|Topoisomerase II inhibitors||Pui 1991, 3 Pui & Relling 200095|
|Alkylating agents||Davies 2001 4|
|Dexrazoxane||Tebbi 2007 44|
|Azathioprine||Offman 2004 50|
|G-CSF||Le Deley 2007, 39 Relling 2003,46 Hershman 200747|
|Radiotherapy||Travis 2006 96|
|Predisposing genetic abnormalities||Bogni 2006 97|
|Original cancer||Le Deley 2003 24 and Felix 199898|
Alkylating agent-related s-AML often is preceded by MDS with losses or deletions of chromosome 5 or 7 (Table 2). This type of s-AML tends to occur late (typically 5-7 years after therapy); the timing between the onset of MDS and s-AML varies and may be explained by the requirement for subsequent genetic events after the loss of material from chromosome 5 or 7. 4 The French-American-British (FAB) type is most commonly M1 or M2, in contrast to the myelomonocytic subtypes of epipodophyllotoxin-induced s-AML (Table 2).
|Genetic aberrations||MLL rearrangements (common), AML1-ETO, CBFβ-MYH11, PML-RARα||PML-RARα, AML1-ETO, CBFβ-MYH11, MLL rearrangements (rare)||Monosomy or partial deletions of chromosome 7 and 5 (common)|
|Mean interval between diagnosis of primary malignancy and secondary AML, y||2-3||2-3||5-7|
|Common presentation||Acute onset; AML M4, M5; APL||Acute onset; AML M4, M5; APL||Protracted onset usually AML M1, M2 preceded by MDS|
|Additional risk factors||See Table 3||High cumulative dosage, concomitant use of alkylating agents||High cumulative dosage, young age, concomitant use of epipodophyllotoxins|
During the early 1970s, several groups reported an excess risk of s-AML in adults and children with Hodgkin lymphoma who received combined mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy or similar alkylating agent regimens. 13-15 The Late Effects Study Group observed that survivors of Hodgkin lymphoma who had been treated with alkylating agents at age ≤16 years had a relative risk of leukemia that was nearly 80 times that of population controls (standardized incidence ratio [SIR] of 78.8; 95% confidence interval [95% CI], 56.6-123.2). The relative risk of s-AML in this group was 321.3 (95% CI, 207.5-467.1).16 German and Austrian investigators subsequently observed a decline in the SIR to 122 (95% CI, 36-254) after the introduction of protocols with lower cumulative doses of alkylating agents that substituted cyclophosphamide for the more leukemogenic mechlorethamine.17 The use of combined doxorubicin, bleomycin, vinblastine, and dacarbazine instead of MOPP also significantly reduced the risk of s-AML.18
Unlike s-AML associated with topoisomerase II inhibitors, alkylating agent-related s-AML 4, 19 appears to be dependent on the dose, but not the schedule, of administration.4 Moreover, some alkylating agents are more leukemogenic than others.17 For example, mechlorethamine is more leukemogenic than cyclophosphamide.17 Host factors also appear to play a crucial role in the development of alkylating agent-induced s-AML.4 For example, a high incidence of second malignancies, including s-AML, has been reported in individuals with neurofibromatosis 1 (Nf1) who develop a first cancer. The increased susceptibility to s-AML in patients with Nf1 who were treated previously with alkylating agents was verified in Nf1 knockout mice.20 Patients with other genetic syndromes, such as Fanconi anemia, also exhibit susceptibility to alkylating agent-induced s-AML and MDS,4 as do individuals with genetic polymorphisms that affect glutathione transferase theta 1 activity.21
Epipodophyllotoxin-induced s-AML was described first in the late 1980s 22-24 and, since then, has been the characteristic model of s-AML. This type of s-AML is usually of the FAB M4 or M5 subtype, although other subtypes have been reported (Table 2).23 Unlike alkylating agent-related s-AML, which occurs relatively late and often has a preleukemic phase, epipodophyllotoxin-related s-AML commonly presents as overt AML after a brief (usually 2-3 year) latency period (Table 2). The risk varies as a function of the schedule, the cumulative total dose, concomitant administration of other chemotherapeutic or supportive drug regimens, and the genetic makeup of the host. Table 3 summarizes the risk factors that have been documented.
|Frequency of administration||Hijiya 2007, 1 Pui 1991,2 Smith 199926||Weekly or twice-weekly schedule causes greater risk than every-other-week schedule; administration for 5 consecutive d causes less risk than intermittent schedule|
|Prolonged administration of low dose||Hijiya 2004 29||May reduce risk|
|Cumulative dose||Pui 1991, 2 Smith 1999,26 Pedersen-Bjergaard 199335||Available data are inconsistent|
|Asparaginase||Pui 1995, 31 Amylon 199932|
|Antimetabolites||Pui 1991, 2 Winick 199322|
|Alkylating agents||Kushner 1998 36|
|G-CSF||Bhatia 2007, 19 Le Deley 2007,39 Relling 2003,46 Hershman 2007,47 Patt 200748||Available data are inconsistent|
|Primary tumor||Le Deley 2003, 24 Felix 199898|
|Host factors||Bogni 2006 97||Polymorphism of CYP3A, GST1 TPMT genes|
Cumulative dose and schedule of epipodophyllotoxins
Data concerning the impact of cumulative epipodophyllotoxin dose on the risk of s-AML are contradictory. Some groups 24, 25 have observed a significant excess risk of s-AML in patients who were treated with higher cumulative etoposide doses, although no specific threshold has been shown to be necessary for induction of leukemogenesis. Ratain et al25 observed that a median cumulative etoposide dose of 6795 mg/m2 was more leukemogenic than a 3025 mg/m2 dose in adults with advanced nonsmall cell lung cancer. Le Deley et al24 reported a 7-fold (95% CI, 2.6-19-fold) greater risk of s-AML in children who were treated for solid tumors who received between 1200 and 6000 mg/m2 of epipodophyllotoxins or >170 mg/m2 of anthracyclines than in those who received lower doses or none of these drugs. However, these dose relations have not been confirmed by other investigators.2, 26
The findings of several studies suggest that the schedule of administration of epipodophyllotoxins is more important than the cumulative dose. 1, 2 St. Jude investigators compared frequent, intermittent (once or twice weekly) administration of etoposide with other schedules (during induction therapy only or every other week) in children with ALL. The frequent, intermittent schedule was associated with a greater risk of s-AML (6-year cumulative incidence [standard error], 8.3% [3%] for the weekly schedule and 7.1% [2.8%] for the twice-weekly schedule) than the other schedules (0%-2% [1.2%] for induction only or every other week; P = .02).1, 2 A review by Cancer Therapy Evaluation Program investigators also determined that the likelihood of s-AML after treatment with epipodophyllotoxins is not dose-dependent. The 6-year cumulative incidence of s-AML in groups that received low (<1.5 g/m2), moderate (1.5-2.99 g/m2), and higher (≥3 g/m2) cumulative doses of etoposide was 3.3%, (95% upper confidence limit, 5.9%), 0.7% (1.6%), and 2.2% (4.6%), respectively. The authors also noted that patients with solid tumors had a lower frequency of s-AML than those with leukemia, which they attributed to the different dosing schedules of epipodophyllotoxins.26 In regimens for solid tumors, etoposide commonly is administered for 5 consecutive days, whereas intermittent dosing schedules are used in treating leukemia. These investigators speculated that mutant cells that had undergone leukemogenic recombination did not survive the more protracted schedule.26 It is also plausible that the hematopoietic cells of patients with leukemia are more vulnerable to genotoxic events that predispose to s-AML. Indeed, patients who are treated for certain solid tumors (eg, retinoblastoma) appear to be less susceptible to s-AML than patients with other tumors despite the use of epipodophyllotoxins.24, 27 Regimens for recurrent tumors and for palliative care often call for continuous administration of low-dose etoposide.28, 29 Although the limited survival of this patient population obscures the true incidence of s-AML, this approach appears to confer a low risk of s-AML.29 Consistent with this observation are the results of in vitro studies demonstrating a greater ratio of cytotoxicity to genetic recombination after prolonged exposure to etoposide than after brief exposure.30
Concomitant chemotherapy agents
The results of a few studies published to date suggest that asparaginase administration enhances the risk of epipodophyllotoxin-induced s-AML. 31, 32 The precise mechanism is not known, but Relling speculated that the lower protein levels generated by asparaginase decrease the synthesis of some proteins involved in protection from etoposide-induced recombinogenesis.33 If this premise is correct, then the high incidence of s-AML in the Pediatric Oncology Group (POG) 8704 study may be explained by chronic exposure to high-dose asparaginase (25,000 IU/m2) administered weekly for 20 weeks.32 Likewise, St. Jude investigators postulated that asparaginase exposure immediately before epipodophyllotoxin administration accounted for the increased incidence of s-AML.31 In that study, asparaginase was given every 4 weeks, which most likely resulted in consistent suppression of the plasma protein level. The combination of epipodophyllotoxins and alkylating agents (eg, cisplatin)25, 34-36 or antimetabolites (eg, mercaptopurine or methotrexate)2, 22 also has been associated with an increased incidence of s-AML.
Anthracyclines and mitoxantrone
The administration of topoisomerase II inhibitors other than epipodophyllotoxins also is associated with an increased risk of s-AML; these agents include anthracyclines and anthracenediones (mitoxantrone). Their impact tends to be underrated because of the substantial risk associated with epipodophyllotoxins, but their potential leukemogenic activity should be considered. In fact, it appears that only 5 of the 24 patients who were treated on the Children's Cancer Group (CCG) 2891 study who later had s-AML 37 received epipodophyllotoxins. Most of those patients had received anthracyclines and/or cyclophosphamide. A St. Jude series identified 4 patients with s-AML that involving 11q23 and 21q23 abnormalities34 among those whose prior therapy included doxorubicin, cyclophosphamide, and radiation therapy but not epipodophyllotoxins.
The clinical and cytogenetic features of anthracycline-related s-AML resemble those of epipodophyllotoxin-related s-AML (Table 2), but other chromosomal abnormalities have been reported. A large study of adults with APL treated with all-trans retinoic acid and anthracycline monochemotherapy identified cytogenetic abnormalities involving chromosomes 5 and 7 that are characteristic of alkylating agent-associated s-AML. 38 The role of the dosing schedule or cumulative dose of anthracyclines in the development of s-AML has not been established.19, 34
Several studies of adults with cancer have demonstrated an excess risk of s-AML related to anthracenedione therapy. In a large case-control study of patients with breast cancer, those who received an anthracenedione-based regimen that featured mitoxantrone had a much higher risk of s-AML than those who received an anthracycline-based regimen. 39 This finding has been confirmed by other groups.40-42 Adults who developed s-AML after receiving mitoxantrone-based chemotherapy for acute leukemia had cytogenetic abnormalities most frequently involving chromosomes 7q, 20q, 1q, and 13q, but not the 11q23 abnormalities typically associated with topoisomerase-II inhibitors.43
Several nonchemotherapeutic agents also may contribute to the development of s-AML, either independently or through interaction with cytotoxic antineoplastic agents. POG studies 9426 and 9425 evaluated the impact of the cardioprotectant dexrazoxane on the outcomes of children with Hodgkin lymphoma who received standard chemotherapy (doxorubicin, bleomycin, vincristine, and etoposide with or without prednisone and cyclophosphamide) and low-dose radiation. Participants were assigned randomly to receive either dexrazoxane or no cardioprotectant before anthracycline. 44 Six of 8 patients who developed s-AML and 2 patients who developed secondary solid tumors were in the dexrazoxane arm. The 4-year cumulative incidence of s-AML was 2.55% ± 1% with dexrazoxane and 0.85% ± 0.6% in the nondexrazoxane group (P = .160). The SIR for s-AML was 613.6 (95% CI, 225.2-1335.6) among patients who received dexrazoxane (n = 239) and 202.4 (95% CI, 24.5-731.0) among those who did not receive dexrazoxane (n = 239; P = .099). The investigators speculated that dexrazoxane, which is a topoisomerase II inhibitor with a mechanism distinct from that of either epipodophyllotoxins or anthracyclines, may have had a synergistic adverse effect on DNA repair when combined with etoposide. It is noteworthy that most patients with s-AML in that study did not exhibit the typical 11q23 translocation but had other cytogenetic abnormalities (including monosomy 7 and trisomy 8) usually associated with alkylating agent-induced s-AML. Similar results were not reported in a study of high-risk ALL in children at Dana-Farber Cancer Institute. With a median follow-up of 6.2 years, only 1 patient developed a second cancer (melanoma), and that patient did not receive dexrazoxane; the incidence of second malignancy did not differ statistically between the groups that did (n = 105) and did not (n = 100) receive dexrazoxane (P = .66).45
Granulocyte–colony-stimulating factor (G-CSF) also may increase the incidence of s-AML, although reports have not been consistent. Relling et al observed an increased risk of s-AML in pediatric patients with ALL who received G-CSF plus a regimen that included alkylating agents, anthracyclines, and epipodophyllotoxins. 46 Conversely, Bhatia et al reported no association between G-CSF administration and s-AML in a group of children with Ewing sarcoma who received doxorubicin, vincristine, cyclophosphamide, and dactinomycin (Regimen A) or those 4 drugs alternating with etoposide and ifosfamide (Regimen B).19 In adults, a few studies associated G-CSF with an increased risk of s-AML in patients who had breast cancer,39, 47 but that finding was not replicated in a study of patients who were older (median age, 75.6 years; range, 66-104 years) at the time of breast cancer diagnosis.48 Therefore, it is not clear whether G-CSF treatment induces s-AML, and it is not clear whether G-CSF enhances leukemogenesis associated with alkylating agents or topoisomerase II inhibitors.49
Immunosuppression associated with solid organ transplantation is a well known risk factor for lymphoma, but myeloid leukemia has been reported only rarely in transplantation recipients. Offman et al examined data from 170,000 recipients of solid organ transplantation at >300 centers participating in the Collaborative Transplant Study. 50 The relative risk of s-AML in transplantation recipients versus age-matched, sex-matched, and geographically matched controls was 5.5 (95% CI, 4.0-7.7; P < .0001) for heart/lung recipients and 2.1 (95% CI, 1.6-2.7; P < .0001) for kidney recipients. In that study, the incidence of s-AML was significantly higher in patients who received 2 to 3 mg/kg per day of azathioprine than in patients who received <1 mg/kg per day (P = .031).
Hematopoietic stem cell transplantation
Various second malignancies have been reported in recipients of hematopoietic stem cell transplantation. Oncogenesis in these patients most likely is multifactorial. 51, 52 Several studies have observed a higher incidence of s-AML in patients with lymphoma who underwent autologous hematopoietic cell transplantation than in those who received conventional chemotherapy.53-55 Pretransplantation therapy is likely an important contributor to leukemogenesis; preparative conditioning chemotherapy and total body irradiation for autologous transplantation also are contributors along with polymorphisms that govern drug metabolism and DNA repair during the extensive cellular proliferation associated with engraftment.52 S-AML in transplantation survivors usually exhibits features of alkylating agent-associated disease,55 although it is not clear whether alkylating agents or other factors play a causative role.54
Certain host factors contribute to susceptibility to s-AML. Several studies have demonstrated that specific polymorphisms of detoxification enzymes play an important role in secondary oncogenesis. Polymorphisms that reduce the enzymatic activity of thiopurine methyltransferase, 56 a variant of cytochrome P450, family 3, subfamily A that affects production of a DNA-damaging metabolite of epipodophyllotoxin,57 and polymorphisms in glutathione S-transferase P158 and nicotinamide adenine dinucleotide phosphate(H):quinine oxidoreductase (NQO1)59 also are associated with increased risk of s-AML after chemotherapy. Increased susceptibility to s-AML also has been linked to polymorphisms of DNA repair genes.60, 61 Emerging genome-wide approaches, such as gene expression profiling62 and single-nucleotide polymorphism arrays,63 are being used to understand the pathogenesis of s-AML and identify patients at risk. Further studies are needed to confirm the predictive value of these methods.
A higher incidence of s-AML has been observed in association with certain primary malignancies. For example, breast cancer often precedes acute promyelocytic leukemia (APL). 64 Le Deley et al also reported a high incidence of s-AML after pediatric Hodgkin lymphoma or osteosarcoma.24 However, various confounding factors may affect the interpretation of those findings. For instance, Smith et al hypothesized that the incidence of s-AML was lower in pediatric patients with solid tumors than in those with ALL because of the different dosing schedule of epipodophyllotoxins.26 Nonocular secondary solid tumors are common in patients with retinoblastoma, but s-AML is rare in this population despite the common use of alkylating agents and topoisomerase II inhibitors.27 This may be because the genotype that results in the retinoblastoma phenotype does not include hematopoietic stem cell abnormalities.65
Treatment and Outcome of Secondary AML
The prognosis of s-AML is generally considered to be poorer than that of de novo AML. 66 The disease tends to be refractory to chemotherapy, and patients' tolerance of treatment generally is reduced because of prior therapies. For these reasons, clinicians have been reluctant to use curative (ie, highly intensive) therapies. Furthermore, the survival rates of patients with s-AML are difficult to predict, because they often are affected by recurrence of the primary cancer. The outcome of treatment has been reported only for small series of pediatric patients with s-AML.67-69 Twenty-four patients with s-AML who were treated on the CCG 2891 study had lower rates of remission induction, survival, and event-free survival than patients with de novo AML.37 In that study, outcomes were better among patients (including patients with s-AML) who were assigned randomly to receive intensively timed induction therapy than among those who received standard-timed induction.
For a part of the current review, we used data from the Surveillance, Epidemiology and End Results (SEER) cancer registry to compare the outcomes of children with newly diagnosed ALL, AML, and s-AML. 70, 71 Figure 1 shows the 2003 period estimate of 5-year survival by diagnostic category among children aged <20 years at diagnosis. Children with s-AML had a 5-year survival rate (23.7%) that was significantly lower than the rate among children with AML as a first primary cancer (53.2%; 2-sample z-test comparing proportions = 4.34; P < .001; Stata version 10.1).
Investigators in the German Cooperative Groups trials speculated that the comparatively low survival rate of s-AML patients (median age, 57 years; range, 16-82 years) resulted from the predominance of s-AML with unfavorable karyotypes. The presence of s-AML did not result in poor survival with standard intensive chemotherapy. 66, 72 This finding also was supported by the Italian Adult Hematologic Diseases Group study, in which poor survival was correlated with older age, lower performance status, and high comorbidity after onset of s-AML during adulthood.73 More recently, investigators at the Fred Hutchinson Cancer Research Center reported that, after hematopoietic stem cell transplantation, the outcome of pediatric and adult patients with s-AML was comparable to the outcome of patients with de novo AML after adjustment for risk factors.74 However, that study included patients with non-neoplastic primary diseases.74
Larson proposed a management algorithm for adult s-AML that uses performance status (age, comorbidities, primary disease status, and complications of primary therapy) and karyotype. 75 According to the algorithm, patients with s-AML who have a good performance status should be treated in a manner similar to the treatment for patients with de novo AML who have the same cytogenetic abnormalities (ie, chemotherapy alone for favorable cytogenetic features), such as t(15;17), inv(16), and t(8;21); intensive chemotherapy and hematopoietic stem cell transplantation for other karyotypes; and more investigational therapy for unfavorable karyotypes. Supportive care alone may be warranted for those with poor performance status. Further studies are needed to determine whether this approach is applicable to pediatric patients.
When Is the Use of Epipodophyllotoxins Justified?
Epipodophyllotoxins still are used commonly to treat various solid tumors, Hodgkin lymphoma, and de novo AML in children. However, they have been eliminated from most frontline therapies for ALL. 76 Although clinicians are reluctant to use epipodophyllotoxins, nearly all standard ALL regimens include anthracyclines and cyclophosphamide, which also are common causes of s-AML. Moreover, to the best of our knowledge, the contribution of epipodophyllotoxins to the overall success of frontline ALL therapies has not been established to date. Large clinical trials77, 78 have demonstrated that the majority of cases of pediatric ALL can be cured with regimens that do not include epipodophyllotoxins. A few frontline regimens for very high-risk ALL78 have included epipodophyllotoxins but did not establish their efficacy. It is possible that specific groups of patients with high-risk disease features could benefit from these agents. In a preliminary exploration of this possibility, we used existing data to compare the relative risk of recurrence of ALL with that of s-AML in children with ALL.
Figure 2 summarizes and estimates the proportions of potential outcomes of children within 5 years after diagnosis of ALL. Estimated proportions are either means calculated from reports of contemporary trials 79-89 or were derived from SEER data (survival after secondary AML).90 These estimates indicate that the proportion of children who had a first remission but died because of disease recurrence was approximately 0.13 (0.24*0.54). The proportion of children who had a first remission but died because of s-AML was estimated at 0.01 (0.016*0.763). The 12% (95% CI, 5.1%-18.9%) difference between these 2 proportions is substantial and significant (P = .001).
Because many other host-related and treatment-related factors may influence survival, we cannot identify the specific contributions of epipodophyllotoxins to the total risk of death from s-AML. However, although we acknowledge the confounding survival factors and differences between risk groups in published trials, we can use recurrence-related and s-AML-related death rates to estimate the minimum event-free survival rate at which the risk of death from s-AML is less than the risk of death from recurrence. At this point, clinicians considering the risks and benefits of treatment for an individual patient may wish to explore the role of epipodophyllotoxins administered on an appropriate dose schedule to reduce the risk of recurrence. By using the highest reported incidence of epipodophyllotoxin-related s-AML (0.083) 1 and the survival estimates from Figure 2, we estimate that the risk of death from s-AML exceeds the risk of death from recurrence in a child with newly diagnosed ALL when the probability of recurrence is ≥0.117.
This result indicates, in theory, that the risk of death from recurrence of ALL exceeds the risk of death from s-AML when the survival rate of ALL is <88.3%. In reality, any pediatric oncologist would hesitate to use epipodophyllotoxins in a patient with an excellent (>80%) chance of survival. Moreover, most clinicians view s-AML as a treatment complication that should be avoided at all costs. Nonetheless, it appears that there is a subset of patients for whom treatment with epipodophyllotoxins may provide a benefit in optimizing disease control. Moreover, factors such as the administration schedule, combination with other agents, and host characteristics can modify the risk of s-AML.
ALL as a Secondary Malignancy
Although clinicians are well aware of s-AML, ALL after primary cancer is considered very rare and usually receives little attention. 91-93 It is not known whether those cases are secondary to the primary cancer or represent a second primary cancer. Herein, we have termed cases of ALL after cancer ‘secondary ALL’ (s-ALL). Only 5% to 10% of all secondary acute leukemias are ALL.93 s-ALL has been reported after primary ALL1, 91 as well as after various other cancers.92, 93
Because cases of s-ALL after primary ALL are rare, the majority of cases have most likely been misdiagnosed as recurrent ALL. In 14 consecutive ALL studies at St. Jude over a 30-year period, only 2 of 2304 patients with primary ALL had a diagnosis of s-ALL. 1 In recent years, molecular detection of immunoglobulin and T-cell receptor rearrangements has facilitated the identification of s-ALL. By using these methods, Zuna et al91 estimated that between 0.5% to 1.5% of 366 cases of ‘recurrent’ ALL actually were s-ALL. The malignant clones in all of those cases differed from those that were present at the time of diagnosis. The duration of first complete remission ranged from 1.7 years to 6.5 years. The authors proposed diagnostic criteria for s-ALL while acknowledging the obstacles to its definitive diagnosis (Table 4). Another recent study94 identified a completely different T-cell receptor gene rearrangement at diagnosis and late ‘recurrence’ of T-ALL in 5 of 16 patients, suggesting the diagnosis of secondary T-cell ALL rather than recurrence. Furthermore, all patients remained in complete remission after retrieval therapy, which is an unusually good outcome for patients with recurrent T-ALL. Our knowledge will increase as more cases of s-ALL are identified using modern technologies.
|A) Essential factor*|
|No relation between ALL clones at diagnosis and at disease recurrence (immunoglobulin/T-cell receptor gene arrangements, fusion genes at DNA level, cytogenetic markers)|
|B) Additional factors|
|1) Significant immunophenotypic shift|
|2) Significant cytogenetic shift|
|3) Gain or loss of a fusion gene|
Numerous studies have confirmed that treatment with topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines) and alkylating agents increases the probability of s-AML. The risk of s-AML is influenced by treatment factors, including the schedule of administration and concomitant medications. The role of host factors, such as polymorphisms of detoxification enzymes and primary tumors, also should be considered. The risks and benefits of using epipodophyllotoxins in frontline pediatric cancer treatment regimens often are unclear. The benefit of epipodophyllotoxins may outweigh the risk of s-AML in some cases of high-risk childhood ALL, although more studies are needed to confirm this possibility. In addition, the probability of s-AML may be reduced by controlling or considering other risk factors, such as concomitantly administered drugs, administration schedule, and host characteristics. Recent studies have demonstrated that the outcome of adults with s-AML does not differ from that of those with de novo AML when data are adjusted for unfavorable cytogenetic findings; therefore, the recommended treatment for adult patients with s-AML is the same as that used for de novo AML in the same cytogenetic risk group. More studies are needed to determine whether the same approach can be applied to pediatric patients. S-ALL has been reported very rarely, but more cases may be identified through modern technologies.
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