Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2020 Aug 1.
Published in final edited form as: Pediatr Blood Cancer. 2019 Mar 25;66(8):e27700. doi: 10.1002/pbc.27700

Development of acute lymphoblastic leukemia following treatment for acute myeloid leukemia in children with Down syndrome: A case report and retrospective review of Children’s Oncology Group acute myeloid leukemia trials

Brianna R Murphy 1, Michael Roth 1, E Anders Kolb 2, Todd Alonzo 3, Robert Gerbing 4, Robert J Wells 1
PMCID: PMC6941434  NIHMSID: NIHMS1063359  PMID: 30908863

Abstract

Children with Down syndrome have 150-fold increased risk of developing acute myeloid leukemia (AML) and 20-fold increased risk of developing acute lymphoblastic leukemia (ALL). Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. We describe a patient with Down syndrome who developed ALL six years after being diagnosed with AML. We performed a literature review and Children’s Oncology Group query and discovered eight published cases and five cases of ALL following AML in pediatric patients with Down syndrome, as well as six cases of ALL following AML in non-Down syndrome patients. There was a similar cumulative incidence of ALL after treatment for AML in the Down syndrome and non-Down syndrome populations. Overall survival in patients with Down syndrome who developed ALL after treatment for AML was comparable to overall survival for Down syndrome patients with de novo ALL with an average follow up of seven years after ALL diagnosis. Clinical data collected was used to discuss whether this phenomenon represents a secondary leukemia, second primary cancer, or mixed lineage leukemia.

Keywords: Down syndrome, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia

Background

Children with Down syndrome have a 150-fold increased risk of developing acute myeloid leukemia (AML) in the first five years of life [1]. Their typical presentation differs from non-Down syndrome patients in that they are younger and usually have preceding transient myeloproliferative disorder and, most notably, their survival is superior to non-Down syndrome AML patients [1]. Patients with Down syndrome also have a 20-fold increased risk of developing acute lymphoblastic leukemia (ALL), typically of B-cell lineage [2 3]. While children with Down syndrome tend to experience more therapy related toxicities and sequelae, they have similar overall survival when compared to non-Down syndrome patients with ALL [4]. Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. To date, there have been only eight published cases describing ALL developing in survivors of AML with Down syndrome [5–7].

Methods

We describe a child with Down syndrome who initially presented to M.D. Anderson with a diagnosis of AML and successfully completed therapy but was found, on routine follow up, to have ALL six years after initial AML diagnosis. We electronically searched journals in PubMed for any articles containing the key words ‘two primary leukemias’ or ‘ALL following AML’. This search yielded 26,484 articles, many were reports of AML following ALL. Searches were further refined with the terms ‘pediatric’ and ‘Down syndrome’ or ‘trisomy 21’ to yield 3,666 articles. Titles and abstracts were reviewed to filter relevant articles. We included any cases of ALL in patients who previously were diagnosed with AML, this resulted in three articles: two case reports/case series from Japan and Norway and one outcome report from the Dutch Nordic group.

Internal review Board approval was obtained (PA17–0899) and a retrospective query of all COG/CCG/POG AML clinical trials from the years 1972–2011 was performed to search for cases of a diagnosis of ALL reported in these patients. This query included any patient with Down syndrome treated through these CCG, POG, or COG protocols with the diagnosis of AML. Outcomes of AML trials were reviewed and phenotype and genotype information for patients who developed ALL were requested from the Children’s Oncology Group. Inclusion criteria were all pediatric patients less than 18 years of age, enrolled on COG/POG/CCG AML protocols from 1972 to 2011. Exclusion criteria were any patients currently in treatment for AML and patients with a diagnosis other than AML. In addition, patients diagnosed with acute promyelocytic leukemia and juvenile monomyelocytic leukemia were excluded. We also reviewed the treatment protocols for the included queried studies to compare therapy doses, duration, and frequency available through the COG website (See figure 1). A similar query for all patients 0–18 years diagnosed with AML without Down syndrome and enrolled on CCG/POG/COG AML studies who developed ALL was done during the same time period.

Figure 1:

Figure 1:

Open in a new tab

AML protocols from COG/POG/CCG from 1979 to 2011 were considered. Prior to 1979 patients were not differentiated as having Down syndrome or not having Down syndrome so those protocols were excluded (CCG 102, CCG 241, CCG 251). AAML0431 ending in 2011 is the most recent completed study. Only protocols that included patients with Down syndrome were included in the query. This yielded 7 protocols. In these seven protocols, three had patients with Down syndrome who later developed ALL for a total of five patients (CCG 213, A2971 and AAML0431). The number of Down syndrome patients is included under the study number. The treatment protocol is briefly listed for each study.

Statistical considerations

The cumulative incidence of the development of ALL after treatment for AML was determined in patients with Down syndrome and patients without Down syndrome. This was defined as time from study entry to development of ALL where deaths were competing events. Patients without an event and without at least five years of follow up were otherwise censored at the date of last contact. Gray’s test was used to compare the cumulative incidence between groups of patients. The five year estimate was reported with 95% confidence interval (CI). Descriptive data including time to development of ALL, survival outcomes, leukemia blast phenotype and mutation status were reported for all cohorts.

Results

Case Presentation

MDACC patient is now a nine-year-old Hispanic female with Down syndrome diagnosed with acute megakaryocytic leukemia at the age of 17 months. She was treated in a manner similar to COG protocol AAML0431. Therapy was successfully completed. She remained in remission until just after her seventh birthday when a routine complete blood count demonstrated peripheral blasts. Laboratory results reported a white blood cell count of 26 500 with hemoglobin of 12 gm/dL and platelets of 21 000. A bone marrow specimen was obtained that showed B-cell acute lymphoblastic leukemia (See flow cytometry and karyotype results in table 1 case 6). She was treated per COG standard risk therapy for ALL and is currently in remission two years after diagnosis of ALL.

Table 1:

Patient clinical and cytogenetic characteristics at AML and ALL diagnosis

AML DS Study/Published case Age at AML DX (years) Sex TMD Cytogenetics (ISCN) at AML DX Age at ALL DX (years) Cytogenetics at ALL DX Outcome
Case 1 Tomizawa et al 2 F No 48xx der(3)t(1;3)(q25;q29)+11+21 8 47xxder(16)t(1;16)(q12;q12.1)+21 6 Y EFS after Allo BMT
Case 2 Tomizawa et al 2 M Yes 47xy inv(9) (p11q13)+21 [11/12] 47, idem, −7+mar[1/12] 7 47xyinv(9)(p11q13)t(11;14)(q23;q23)+21 11 y EFS
Case 3 Tomizawa et al 1 F Yes 47xx inv(9p+q-)12q-+21 15 47xxinv(9)(p11q13)+21 12 y EFS
Case 4 Tomizawa et al 1 F No 52xxd(q21;q2)+22 15 47xx+21 Death 2 mo after DX from fulminant hepatitis
Case 5 Hellebostad et al 3 F Yes 51 XX +8 +13 +14 +21c +21[13]/47 XX + 21c[2] 6 N/A Remission 2 y
Case 6 *MDACC* AAML0431 1 F No 48,XX,+8,+21c[12]; 48,XX,+8,del(12)(p12p13),+21c[2]; 50,XX,+X,+2,+8,+21c[1] and 47,XX,+21c[5] 7 48,XX,−13,del(14)(q22q31),+21,+21c,+mar[12]/47,XX,+21c[8] Remission 2 y
Case 7 AAML0431 2 F N/A 46,XX,add(7)(p15),der(14;21)(q10;q10)c,add(17)(p11.2),+21c,der(22)t(11;22)(q13;p10)[12]/46,XX,der(14;21)(q10;q10)c,+21c[8] 4.4 N/A 9.7 y OS
Case 8 AAML0431 1 F N/A 47,XX,+21c[20] 5.2 N/A 5.5 y OS
Case 9 A2971 - Arm A only (TMD) 0 M N/A Unknown 2 N/A 10.2 y OS
Case 10 A2971 - Arm A only (TMD) 0 M N/A Unknown 2.3 N/A 10 y OS
Case 11 CCG-213 2 M N/A +21 with other abnormalities (ISCN is unknown) 12.6 N/A 12.2 OS
Open in a new tab

Patient Characteristics of Reported Cases of ALL following AML in Down Syndrome Patients in the reported cases in the literature review and CCG/POG/COG query (*MDACC* represents our patient). The clinical details were reported for five patients in the literature review, four patients from the Japanese case series and one patient from Norway. In the COG/CCG/POG query five patients were discovered, two patients from the AAML0431 study, two from the A2971 and one from CCG-213. The age of presentation for AML ranged from one month to 32 months with a mean and median of 15 months. There were two females and three males. Cytogenetics for AML diagnosis are shown if available. There was no commonality detectable within cytogenetics. Age at ALL diagnosis ranged from two years to 12.6 years with a mean of 5.3 years and a median of 5.2 years. All but one patient were alive and well at last contact with a follow up of about 10 years on average.

Literature Review

When we reviewed the literature for cases of ALL following AML in patients with Down syndrome, eight cases were reported, published in three manuscripts [5–7]. A case report by Hellebostad et al from Norway and a case series of four patients by Tomizawa et al in Japan were published with detailed patient demographics and clinical findings (Table 1) [5 6]. A clinical trial from the Nordic Society of Paediatric Haematology and Oncology (NOPHO), Dutch Childhood Oncology Group (DCOG) and AML-BFM study group in 2006 focusing on reduced total dose of etoposide in their Down syndrome cohort by Uffman et al reported three cases of ALL 1.6–2.1 years following AML therapy, of which two patients died [7]. They did not publish clinical information for these three patients.

Within these three publications, the age range for diagnosis of AML was typical of AML presentation in the Down syndrome population. There was a female predominance in the published cases and presence of transient abnormal myelopoiesis preceding AML diagnosis was reported in half of the patients. GATA1 mutation information was largely unavailable but was present in the one patient tested in the Japanese cohort [6]. There were no common genetic alterations between any of the published cases other than Inv(9)(p11q13) in the Japan case series [6]. The range of patient ages at diagnosis was 6–15 years, presenting 1.6 – 14 years following AML diagnosis. Of the published cases there were three reported deaths, one in the Japanese cohort and two in the clinical trial from NOPHO/DCOG/AML-BFM. The other five surviving patients, including the MDACC patient remain in clinical remission 2–12 years after diagnosis of ALL.

COG Retrospective Review

A review of Children’s Oncology Group, Children’s Cancer Group, and Pediatric Oncology Group studies of AML was performed to assess associations between the presence of Down syndrome and treatment period with the development of ALL post AML therapy. In the COG/CCG/POG review seven protocols were queried. These studies included a total of 786 eligible patients with Down syndrome. Five patients with Down syndrome were discovered to have ALL following AML, two patients from the AAML0431 study, two from A2971 and one from CCG-213. The age of presentation of AML ranged from one month to 32 months with a mean and median of 15 months. There were two females and three males in this small cohort. Available cytogenetics for the AML diagnoses are shown in Table 1. There was no commonality detectable in regards to cytogenetics. GATA1 mutation status was only done for one patient and was positive. Age at ALL diagnosis ranged from 2–12.6 years with a mean of 5.3 years and a median of 5.2 years. All patients were alive and well at last contact with a follow up of approximately ten years on average. We found by five years, four AML survivors with Down syndrome had developed ALL. We calculated the cumulative incidence of developing ALL after AML to be 0.58% (95% CI: 0.20%−1.4%) at five years. The prevalence of de novo ALL in the Down syndrome population is 0.71% [8].

To determine cumulative incidence of ALL following AML in patients without Down syndrome, four additional COG phase three de novo AML trials were queried. We found six de novo AML patients who developed ALL from the four protocols AAML0531, AAML03P1, CCG 2961, and CCG 2891. Among these six patients, three survived with a median follow-up time of 6.1 years from development of ALL, and three died. Time of death occurred at 756, 866, and 988 days from development. The cumulative incidence of developing ALL after AML among patients from these four protocols (total=3,148) was 0.28% (95% CI: 0.11%−0.58%) at five years. A comparison of the cumulative incidence for the patients with Down syndrome versus patients without Down syndrome from the seven studies previously described yielded p=0.126 by Gray’s test.

To discover potential associations between the development of ALL after treatment for AML with specific anti-cancer agents received for treatment of AML in both patients with Down syndrome and without Down syndrome, we reviewed the chemotherapy regimens for the protocols queried (see summary in Figure 1). The majority of the patients with subsequent ALL were treated per protocols after 1995 with the exception being CCG-213. There was no apparent relationship between AML therapy received and the development of ALL, although power was limited.

The COG review indicates overall survival of ALL following AML is 50% in non-Down syndrome patients and 78.6% in Down syndrome patients (Table 2).

Table 2:

Survival of ALL following treatment for AML in Down Syndrom

Patient Cohort Survival
Down Syndrome COG 5/5 (100%)
Down Syndrome Lit review 5/8 (63%)
Our patient 1/1 (100%)
Down Syndrome Total 11/14 (79%)
Non-Down Syndrome Total 3/6 (50%)
Open in a new tab

Overall Survival in Published and Queried cases of ALL following AML in Down syndrome and non-Down syndrome Patients. In all the known patients with Down syndrome who have developed ALL following AML, there have been 3 deaths. The deaths were reported in the Japanese case series and the ML-DS 2006 trial. In the 6 non-Down syndrome patients discovered in the COG query there were 3 deaths.

Discussion

The presentation of the MD Anderson patient with Down syndrome who developed ALL after treatment for AML sparked an investigation that led to the assembly of a series of 14 patients with Down syndrome that developed ALL following otherwise successful treatment of AML. We also detected six additional patients without Down syndrome who also developed ALL following successful treatment of AML. Using the COG database this provides a five year cumulative incidence of 0.58% and 0.28% for patients with Down syndrome and non-Down patients, respectively (p=0.126). It is possible that some cases of ALL following AML could have developed that were not recorded in the COG database, however greater than 80% of patients have longer than five year follow up. Also intriguing is the outcome for the population with Down syndrome seems to be similar to patients with de novo ALL without the use of extraordinary therapy (only one patient that we know of had a bone marrow transplant, for example). The data set also stimulated us to consider two additional questions: 1) Is this a new disease and 2) is this phenomenon a secondary malignancy caused by the first cancer or its therapy versus a true second primary malignancy unrelated to the first neoplasm versus the manifestation of a mixed lineage leukemia that was not quite effectively treated initially.

The COG data base query demonstrated patients with Down syndrome and AML who developed ALL with seemingly increased frequency through the three decades spanning the query. This may be a reflection of the improved survival of Down syndrome patients with AML over this period of time; in order to be affected a second cancer the patient has to survive the first. On the other hand, it would be important to discover whether or not some aspect of the treatment for the initial cancer (AML) contributes to the seeming increase in frequency of the ALL.

Therapy related leukemia is a well-documented phenomenon observed since 1970 with the most common malignancy being AML at an incidence of 2–10% [9]. There is strong data indicating ionizing radiation, alkylating agents and topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines) increases the probability of secondary AML [10–12]. Therapy related ALL, although much less common, has been reported as 5–10% of all secondary acute leukemias [10 11]. In adults, secondary ALL has been reported with common cytogenetic abnormalities including t(4;11)(q21;q23) and hypodiploidy with loss of chromosomes 5, 7, 17 and KMT2A rearrangement [6 10–13]. Anderson et al published a report of secondary ALL that included six pediatric cases age two years to thirteen years with various primary cancer diagnoses including non-Hodgkin lymphoma, osteosarcoma, neuroblastoma, and hepatocellular carcinoma. In this report secondary ALL developed, on average, two years after original cancer diagnosis and all patients had an MLL mutation or chromosome 11 and 23 rearrangements [13]. One of the Japanese cases showed a KMT2A rearrangement in the ALL cytogenetics, a common cytogenetic abnormality found in epipodophyllotoxin-induced leukemia [6]. However, there were no common cytogenetic markers in any of the other ALL diagnoses as have been described in therapy related leukemias. Data is limited as the patients from the COG query were not enrolled on study with their second leukemia diagnosis. Furthermore, the prognosis of patients with secondary ALL is typically poor, likely attributable to the associated high-risk cytogenetic abnormalities that these cases harbor. The patients in this report in general have few or none of the biological characteristics of secondary malignancies induced by prior cancers or cancer therapies and their clinical outcome is much better. Also, notably, while Down syndrome patients are more likely to experience therapy related late effects, they are less likely to experience secondary malignancies [14]. These points argue against these cases being yet another complication or late effect of cancer therapy.

Mixed Lineage leukemia expresses surface antigens of multiple hematogenic lines [15–21]. A study by Mirro et al immunophenotyping pediatric ALL patient samples found up to 20% of ALL blast samples expressed myeloid associated cell markers [17]. While less than five percent of cases of acute leukemia are truly bi-phenotypic according to the EGIL classification, mixed lineage markers are relatively common and could represent a blast arising from a pluripotenet stem cell with the capability to mutate and transform to a leukemia of a different lineage [16–18 20–23]. For the eleven patients in the COG/CCG/POG query the phenotypic diagnosis confidently ruled out biphenotypic acute leukemia, and likely mixed lineage leukemia. The phenotypic descriptions provided by the published cases also do not describe a mixed lineage leukemia. There does not seem to be any common cytogenetic factors linking the subsequent ALL to the initial diagnosis of AML in the case studies published, other than Inv(9)(p11q13) in the Japan case series, which is a common cytogenetic variant found in 1–1.6% of healthy people, and was still present after remission of ALL in the published case [6]. Additionally, the Norway case study showed a GATA1 mutation at diagnosis of AML but not at diagnosis of ALL, suggesting different leukemogenic mutations from separate clones [5]. The information provided in the prior reports, and current case series, suggest that this is not a mixed lineage or biphenotypic leukemia recurrence.

In this ALL following AML cohort the occurrence of two separate malignancies is the most likely development. In the Down syndrome population there is evidence suggesting the hematologic abnormalities from trisomy 21 could potentiate multiple hematologic malignancies [24]. Research has identified multiple genes on chromosome 21 that are associated with hematologic malignancies and suggests the trisomy 21 mutation alters hematopoiesis throughout life, with varying affects at varying stages of development [24]. The risk of ALL in children with Down syndrome with previous AML was not significantly different than the risk of de novo ALL in the Down syndrome population, however, it is possible there are unreported cases or reported cases were indexed in such a way that the literature review did not pick it up. The age range of diagnosis and survival were also similar to the typical features of de novo ALL in patients with Down syndrome. This phenomenon of two primary leukemias occurring in a predisposed patient population is further supported by publications from Roy et al, Kusters et al and Roberts et al who propose megakaryocyte-erythroid expansion during the proliferative period prior to diagnosis of AML might compromise the development of B-lymphoid cell lines, causing the increased susceptibility to B-ALL in the future [24–26].

The lower incidence of secondary ALL in non-Down syndrome patients compared to patients with Down syndrome mimics the de novo occurrence of ALL in these populations [1]. Though, this does not explain the occurrence of two hematologic malignancies in the non-down syndrome patients. It is possible there are unreported predispositions in these patients causing them to be at increased risk. The normal karyotype suggests these do not represent therapy related ALL, but also do not elude to any genetic predisposition to hematopoietic malfunction.

Outcomes overall were very good for the Down syndrome population but not for the non-Down syndrome cohorts. The overall survival of ALL following AML in patients with Down syndrome of 78.6% is slightly better than the previously published event free survival of 56% in de novo ALL from 1983–1995 [27]. Although with a very small sample size it is difficult to deduce if the survival is significantly different. There is also, of note, limited follow up information from the literature review case reports for ALL in the Down syndrome population to verify long term survival. Still, the prognosis reassures clinicians they can treat per risk stratification as if this were a de novo ALL. This is particularly significant when considering dose limitations, particularly of anthracyclines, given the prior AML treatment. The poorer survival in non-Down syndrome ALL following AML patients may be limited by sample size.

In summary, we have identified fourteen patients with Down syndrome and six patients without Down syndrome who developed ALL following successful treatment for AML and provided clinical information about their presentation and course. The cumulative incidence of this event at five years is 0.58% in Down syndrome and 0.28% in non-Down syndrome survivors of AML. The clinical outcome of these patients was 79% and 50% overall survival respectively. Review of the available clinical data suggests that this phenomenon probably represents a second primary malignancy rather than a treatment related malignancy or recurrence of a single mixed lineage leukemia. This deserves more investigation in both the Down syndrome and non-Down syndrome populations. The overall prognosis is promising for patients with Down syndrome, but the mechanisms of ALL following AML needs to be further clarified. A population at risk for multiple hematologic malignancies warrants identification of causal factors, heritable and non-heritable. The purpose of this article is to report the incidence and known clinical characteristics of this rare occurrence to assist clinicians and researchers appropriately diagnose, treat, and monitor patients.

Abbreviations

ALL

Acute Lymphoblastic Leukemia

AML

Acute Myeloid Leukemia

COG

Children’s Oncology Group

CCG

Children’s Cancer Group

POG

Pediatric Oncology Group

DCOG

Dutch Childhood Oncology Group

NOPHO

Nordic Society of Paediatric Haematology and Oncology

Footnotes

The Authors have no conflicts of interest to disclose.

References

  • 1.Lange BJ, Kobrinsky N, Barnard DR, et al. Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children’s Cancer Group Studies 2861 and 2891. Blood 1998;91(2):608–15 [PubMed] [Google Scholar]
  • 2.Izraeli S, Vora A, Zwaan CM, Whitlock J. How I treat ALL in Down’s syndrome: pathobiology and management. Blood 2014;123(1):35–40 doi: 10.1182/blood-2013-07-453480[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 3.Bassal M, La MK, Whitlock JA, et al. Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer 2005;44(1):21–8 doi: 10.1002/pbc.20193[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 4.Athale UH, Puligandla M, Stevenson KE, et al. Outcome of children and adolescents with Down syndrome treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocols 00–001 and 05–001. Pediatr Blood Cancer 2018:e27256 doi: 10.1002/pbc.27256[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 5.Hellebostad M, Carpenter E, Hasle H, Mitchell C, Vyas P. GATA1 mutation analysis demonstrates two distinct primary leukemias in a child with down syndrome; implications for leukemogenesis. J Pediatr Hematol Oncol 2005;27(7):408–9 [DOI] [PubMed] [Google Scholar]
  • 6.Tomizawa D, Endo A, Kajiwara M, et al. Acute lymphoblastic leukemia in patients with Down syndrome with a previous history of acute myeloid leukemia. Pediatr Blood Cancer 2017;64(8) doi: 10.1002/pbc.26411[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 7.Uffmann M, Rasche M, Zimmermann M, et al. Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial. Blood 2017;129(25):3314–21 doi: 10.1182/blood-2017-01-765057[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 8.Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and solid tumours in individuals with Down’s syndrome. Lancet 2000;355(9199):165–9 doi: 10.1016/S0140-6736(99)05264-2[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 9.Michels SD, McKenna RW, Arthur DC, Brunning RD. Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases. Blood 1985;65(6):1364–72 [PubMed] [Google Scholar]
  • 10.Hijiya N, Hudson MM, Lensing S, et al. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 2007;297(11):1207–15 doi: 10.1001/jama.297.11.1207[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 11.Hijiya N, Ness KK, Ribeiro RC, Hudson MM. Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. Cancer 2009;115(1):23–35 doi: 10.1002/cncr.23988[published Online First: Epub Date]|. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Tang G, Zuo Z, Thomas DA, et al. Precursor B-acute lymphoblastic leukemia occurring in patients with a history of prior malignancies: is it therapy-related? Haematologica 2012;97(6):919–25 doi: 10.3324/haematol.2011.057752[published Online First: Epub Date]|. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Andersen MK, Christiansen DH, Jensen BA, Ernst P, Hauge G, Pedersen-Bjergaard J. Therapy-related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: report on two new cases and review of the literature since 1992. Br J Haematol 2001;114(3):539–43 [DOI] [PubMed] [Google Scholar]
  • 14.Goldsby RE, Stratton KL, Raber S, et al. Long-term sequelae in survivors of childhood leukemia with Down syndrome: A childhood cancer survivor study report. Cancer 2018;124(3):617–25 doi: 10.1002/cncr.31065[published Online First: Epub Date]|. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Hayashi Y, Pui CH, Behm FG, et al. 14q32 translocations are associated with mixed-lineage expression in childhood acute leukemia. Blood 1990;76(1):150–6 [PubMed] [Google Scholar]
  • 16.Mirro J, Kitchingman GR, Williams DL, Murphy SB, Zipf TF, Stass SA. Mixed lineage leukemia: the implications for hematopoietic differentiation. Blood 1986;68(2):597–9 [PubMed] [Google Scholar]
  • 17.Mirro J, Zipf TF, Pui CH, et al. Acute mixed lineage leukemia: clinicopathologic correlations and prognostic significance. Blood 1985;66(5):1115–23 [PubMed] [Google Scholar]
  • 18.Stass SA, Mirro J Jr. Lineage heterogeneity in acute leukaemia: acute mixed-lineage leukaemia and lineage switch. Clin Haematol 1986;15(3):811–27 [PubMed] [Google Scholar]
  • 19.Wolach O, Stone RM. How I treat mixed-phenotype acute leukemia. Blood 2015;125(16):2477–85 doi: 10.1182/blood-2014-10-551465[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 20.Wolach O, Stone RM. Mixed-phenotype acute leukemia: current challenges in diagnosis and therapy. Curr Opin Hematol 2017;24(2):139–45 doi: 10.1097/MOH.0000000000000322[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 21.Weinberg OK, Arber DA. Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia 2010;24(11):1844–51 doi: 10.1038/leu.2010.202[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 22.Al-Seraihy AS, Owaidah TM, Ayas M, et al. Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica 2009;94(12):1682–90 doi: 10.3324/haematol.2009.009282[published Online First: Epub Date]|. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Shi R, Munker R. Survival of patients with mixed phenotype acute leukemias: A large population-based study. Leuk Res 2015;39(6):606–16 doi: 10.1016/j.leukres.2015.03.012[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 24.Roberts I, Izraeli S. Haematopoietic development and leukaemia in Down syndrome. Br J Haematol 2014;167(5):587–99 doi: 10.1111/bjh.13096[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 25.Kusters MA, Verstegen RH, Gemen EF, de Vries E. Intrinsic defect of the immune system in children with Down syndrome: a review. Clin Exp Immunol 2009;156(2):189–93 doi: 10.1111/j.1365-2249.2009.03890.x[published Online First: Epub Date]|. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Roy A, Roberts I, Vyas P. Biology and management of transient abnormal myelopoiesis (TAM) in children with Down syndrome. Semin Fetal Neonatal Med 2012;17(4):196–201 doi: 10.1016/j.siny.2012.02.010[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]
  • 27.Whitlock JA, Sather HN, Gaynon P, et al. Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood 2005;106(13):4043–9 doi: 10.1182/blood-2003-10-3446[published Online First: Epub Date]|. [DOI] [PubMed] [Google Scholar]

RESOURCES