CLINICAL
AND
LABORATORY OBSERVATIONS
Therapy-induced Secondary Acute Myeloid Leukemia With t(11;19)(q23;p13.1) in a Pediatric Patient With Relapsed Acute Promyelocytic Leukemia Daniel N. Dang, MD,* Heather D. Morris, DO,* James H. Feusner, MD,w Prasad Koduru, PhD,* Kathleen Wilson, MD,* Charles F. Timmons, MD, PhD,* MaryEllen Cavalier, MD,z and Hung S. Luu, PharmD, MD*
Summary: Acute myeloid leukemia is classified based upon recurrent cytogenetic abnormalities. The t(15;17)(q24.1;q21.1) abnormality is found in 5% to 8% of de novo acute myeloid leukemia and is diagnostic of acute promyelocytic leukemia (APL). The translocation results in fusion of the retinoic acid receptor-a (RARA) gene at 17q21.1 and the promyelocytic leukemia (PML) gene at 15q24.1. Standard APL therapy is a combination of alltrans retinoic acid and anthracycline-based chemotherapy. Anthracycline treatment is associated with secondary clonal chromosomal aberrations that can lead to therapy-related secondary myeloid neoplasms. We present a pediatric case of relapsed APL coexistent with treatment-associated secondary myeloid neoplasm with t(11;19)(q23;p13.1). Key Words: acute promyelocytic leukemia, cytogenetics, molecular genetics, therapy induced
(J Pediatr Hematol Oncol 2014;36:e546–e548)
A
cute promyelocytic leukemia (APL) is defined as an acute myeloid leukemia (AML) with t(15;17)(q24.1;q21.1) resulting in a population of aberrant promyelocytes.1 The translocation creates a PML-RARA fusion protein that joins the retinoic acid receptor-a (RARA) gene on chromosome 17q21.1 with the promyelocytic leukemia (PML) gene on 15q24.1. This hallmark translocation is found in over 97% of APL cases.2 PML-RARA acts in a dominant negative manner by preventing transcription of genes involved in myeloid differentiation. Earlier studies in the 1980s and 1990s demonstrated that retinoic acid (RA) and arsenic trioxide can overcome this block as evidenced by myeloid differentiation and clinical remission in a majority of patients.3 It has been postulated that both RA and arsenic induce PML-RARA instability leading to its degradation.2 The age-adjusted incidence of APL is 2.7 per 1,000,000 person years.4 In the United States, APL comprises only Received for publication November 13, 2013; accepted April 30, 2014. From the *Department of Pathology, Parkland Health and Hospital System, Children’s Medical Center; zDepartment of Pediatrics, Division of Hematology-Oncology, UT Southwestern Medical Center, Dallas, TX; and wDepartment of Pediatrics, Division of Hematology/Oncology, Children’s Hospital & Research Center Oakland, Oakland, CA. The authors declare no conflict of interest. Reprints: Hung S. Luu, PharmD, MD, Department of Pathology, Parkland Health and Hospital System, Children’s Medical Center, UT Southwestern Medical Center, 1935 Medical District Drive, Dallas, TX 75235 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
e546 | www.jpho-online.com
5% to 10% of AMLs found in pediatric populations.5 Despite its low incidence, the disease can have drastic consequences due to its ability to release cytoplasmic contents such as enzymes and granules that can cause coagulopathy, hemorrhage, and disseminated intravascular coagulation.2 Despite effective treatment, some patients have disease relapse. Furthermore, although rare in the literature, APL patients may have therapy-induced secondary cytogenetic abnormalities. We present a case of APL in a pediatric patient with therapy-induced secondary myeloid neoplasm with a t(11;19)(q23;p13.1).
CASE REPORT A 10-year-old boy initially presented with a one and a half week history of cyclical fevers and vomiting. He was subsequently found to be pancytopenic with a complete blood count showing a white blood count of 0.3 109/L; hemoglobin, 4.7 g/dL; and platelets, 10 109/L. The differential revealed 93% lymphocytes, 5% monocytes, and 2% neutrophils. A bone marrow biopsy demonstrated 31% atypical promyelocytes by manual differential. Flow cytometry of the bone marrow demonstrated a 61% population of large, immunophenotypically aberrant myeloid cells consistent with promyelocytes that were positive for CD117, CD33, CD13, CD64, and CD45 and variably to partially positive for CD4, CD38, and CD15 and negative for CD34, HLA-DR, Tdt, myeloperoxidase, and other lymphoid and myeloid markers. Conventional cytogenetic analysis showed an abnormal male karyotype with t(15;17)(q24.1;q21.1) and a t(2;9)(q35;q22) (Fig. 1A). Seventy-five percent of these cells showed, in addition, trisomy 8. Fluorescence in situ hybridization (FISH) studies of the bone marrow detected the PML-RARA rearrangement in 70% of 200 interphase nuclei (Fig. 1B). The patient was started on all-trans retinoic acid (ATRA) and idarubicin and achieved morphologic and cytogenetic remission by day 29. Chromosome analysis of a PHA-stimulated peripheral blood indicated that the t(2;9) is a constitutional abnormality. During maintenance chemotherapy consisting of ATRA, 6mercaptopurine, and oral methotrexate, he presented with bleeding approximately 19 months after initial diagnosis and was found to have relapsed disease. Flow cytometry analysis detected an expanded population of promyelocytes with immunophenotypic and light-scattered properties similar to prior analysis. Salvage chemotherapy consisting of ATRA and arsenic trioxide was initiated. Cytogenetic evaluation of the bone marrow aspirate identified the presence of 2 unrelated clones, one with a t(15;17) in 13 of 20 metaphases, and a second unrelated clone with a t(11;19)(q23;p13.1) in the remaining 7 metaphases (Fig. 1C). Both clones showed the constitutional t(2;9)(q35;q22). The clone with trisomy 8 and t(15;17) seen at diagnosis was no longer detected. FISH and polymerase chain reaction assay confirmed the coexistence of t(15;17) and t(11;19) abnormalities in this specimen. Follow-up bone marrow examination 35 days later demonstrated
J Pediatr Hematol Oncol
Volume 36, Number 8, November 2014
J Pediatr Hematol Oncol
Volume 36, Number 8, November 2014
Therapy-induced Secondary Acute Myeloid Leukemia
FIGURE 1. Cytogenetic and fluorescence in situ hybridization (FISH) findings at first recurrence. A, 46,XY,t(2;9)(q35;q21.2)c,t(15;17) (q24;q21.1). Conventional cytogenetics showed an abnormal clone containing t(15;17) (red arrows) in 13 of 20 examined cells. In addition, all cells contain a reciprocal (2;9) translocation (green arrows) shown to be constitutional. B, PML-RARA interphase FISH demonstrating the standard dual-fusion probe set pattern consistent with the presence of a (15;17) translocation in 180 of 200 examined cells. C, 46,XY,t(2;9)c,t(11;19)(q23;p13.1). A representative conventional cytogenetics study showing the patient’s (11;19) translocation (red arrows). Green arrows highlight the constitutional t(2;9). D, MLL break-apart FISH probe showing the MLL gene rearrangement evidenced by the separation of the red and green signals.
resolution of the t(11;19) clone but persistence of the t(15;17) clone (Table 1). Treatment was reinitiated with ATRA plus daunomycin, cytarabine, and etoposide. FISH evaluation of the bone marrow aspirate 43 days after the previous cytogenetic analysis demonstrated persistence of the t(15;17) clone as well as recurrence of t(11;19) clone by FISH (Table 1). Therapy was modified to ATRA, cytarabine, and mitoxantrone plus dexrazoxane. Follow-up marrow examination 48 days later demonstrated normal trilineage hematopoiesis and no evidence for hematolymphoid malignancy. FISH studies demonstrated resolution of the t(15;17) clone but
TABLE 1. Summary of the Patient’s Cytogenetic Analyses and Therapeutic Modifications
t(15;17) t(11;19) (q22;q12) (q23;q13.1)
Therapy Regimen
Diagnosis
+
Initiation: ATRA, idarubicin Maintenance: ATRA, methotrexate, 6mercaptopurine ATRA, arsenic trioxide ATRA, daunomycin, cytarabine, etoposide
Relapse 1-mo followup 3-mo followup 4-mo followup
+ +
+
+
+
ATRA, cytarabine, mitoxantrone, dexrazoxane
+
Hematopoietic stem cell transplantation
ATRA indicates all-trans retinoic acid.
r
2014 Lippincott Williams & Wilkins
persistence of the MLL gene rearrangement in 5 of 200 cells examined, consistent with minimal residual disease of the secondary AML (Fig. 1D). The patient underwent matched unrelated donor hematopoietic stem cell transplantation and has been disease free by morphology and cytogenetics for more than 1 year.
DISCUSSION Historically, APL therapy has included topoisomerase II inhibitors, for example, idarubicin, notwithstanding the serious complications that anthracyclines and topoisomerase II inhibitors pose: topoisomerase II inhibitors not only contribute to therapy-related mucositis and hematologic toxicity, but they also pose risk for the development of additional genetic abnormalities in the primary clone, as well as the development of secondary neoplasms. Such therapy-related myeloid neoplasms are associated with fusion gene translocations involving 11q23 and the MLL gene and are characterized by a short latency period.6 It is clear that AML is a genetically heterogeneous disorder both at diagnosis and relapse.7,8 Recent genome sequencing studies of AML have identified some mechanisms of both primary genetic aberration as well as those critical to clonal evolutions. Examination of bone marrow from healthy donors via whole exome sequencing demonstrates that random mutations are accumulated over time. Using whole exome sequencing and whole genome sequencing techniques, variant alleles can be captured as a genetic signature when a progenitor stem cell transforms to a leukemic myeloid blast. The ratio of the number of reads of the variant allele compared with total number of reads at www.jpho-online.com |
e547
Dang et al
a particular locus—the variant allele frequency (VAF)— permits identification of when a mutation was acquired. Heterozygous mutations have a VAF of approximately 50% indicating an earlier, and potentially primary, genetic event. By contrast, aberrations which have lower VAFs— owing to their being present in fewer cells—were acquired later in a subclone.9 The identification of variants using whole genome sequencing with subsequent quantification of VAFs by targeted sequencing has demonstrated 2 patterns of clonal evolution in relapsed AML patients: acquisition of additional aberrations in the primary clone and expansion of a clone genetically unrelated to the primary clone.9 The clonal evolution of the relapsed AML described in this case report is consistent with these very recently described molecular mechanisms of AML clonal evolution. Our patient’s diagnostic bone marrow showed both the primary clone with the t(15;17) and a second clone with a cytogenetic aberration (trisomy 8) in addition to the t(15;17). Over the course of this patient’s treatment, a third clone evolved that contained a t(11;19) and an MLL gene rearrangement and which was genetically unrelated to the primary clone. Although the MLL rearrangement-bearing clone was presumptively the result of previous treatment with topoisomerase II inhibitors, underlying molecular changes (bearing a different molecular profile from the primary clone) may have predisposed to the MLL aberration.10 Fortunately, therapy-induced genetic abnormalities are rare in APL. Lobe et al11 reported 0.97% or 6 of 677 patients who developed therapy-related myelodysplastic syndrome after treatment for APL. A retrospective study reported 12 of 123 patients with APL who developed a secondary clonal population with cytogenetic abnormalities.12 Burnett et al13 reported 9 of 285 patients who relapsed with AML without the PML-RARa transcript, consistent with secondary disease, after being treated with Medical Research Council chemotherapy plus ATRA (2 patients) or anthracycline plus ATRA (7 patients). Although novel treatment strategies aiming to eliminate or decrease the cumulative dose of anthracycline have been frustrated by the rarity of APL, several recent trials suggest that anthracycline-free treatment strategies incorporating ATO and ATRA are equivalent to anthracycline-containing regimens with regard to both event-free and overall survival rates in patients with low-risk or intermediate-risk APL.14 Lo-Coco et al15 conducted a phase 3 multicenter, noninferiority trial comparing ATRA plus chemotherapy (ATRA-idarubicin induction followed by 3 cycles of consolidation with ATRA plus chemotherapy and maintenance with low-dose chemotherapy plus ATRA) with ATRA plus ATO in 156 adult patients with low-risk or intermediate-risk (white blood count r10 109/L) APL. Median follow-up was 34.4 months. All 77 patients in the ATRA-ATO group achieved complete remission, versus 75 of 79 randomized to the ATRA-chemotherapy group. Two-year event-free survival rates were 97% in the ATRA-ATO group and 86% in the ATRA-chemotherapy group (P < 0.001 for noninferiority and P = 0.02 for superiority of ATRA-ATO). The ATRA-ATO regimen presented less hematologic toxicity, although it posed greater hepatotoxicity. A phase II trial investigating ATRA, ATO plus gemtuzumab ozogamicin is underway for children aged 10 years and older. We present a highly pertinent case report concerning a 10-year-old patient with the rare finding of therapy-induced secondary AML with t(11;19) that developed concurrently
e548 | www.jpho-online.com
J Pediatr Hematol Oncol
Volume 36, Number 8, November 2014
with APL relapse. This case illustrates the importance of further defining the role of anthracyclines, in particular topoisomerase II inhibitors, in the treatment of APL; indeed, the development of current and future studies exploring the prospect of omitting or minimizing anthracycline exposure without sacrificing historic event-free and overall survival rates have already been spurred by recent therapeutic trials incorporating ATRA plus ATO as firstline therapy for low-risk and intermediate-risk disease. Furthermore, this case underscores the importance of cytogenetic/molecular screening for secondary cytogenetic aberrations and the tailoring of chemotherapy regimens based upon cytogenetic findings. Finally, this case highlights the urgent need for obtaining a greater understanding of the clonal evolution of AML, a topic that is becoming less elusive due to recent advances in genomic sequencing. ACKNOWLEDGMENT The authors thank Brian Levenson, Franklin Fuda, Victor M. Aquino, Carlos A. Tirado, and Kirthi Kumar who contributed to the care of the patient and the manuscript. REFERENCES 1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours and Haematopoietic and Lymphoid Tissues. Lyon: IARC; 2008:110–123. 2. Le Bras M, Lallemand-Breitenbach V. Acute promyelocytic leukemia, arsenic, and PML bodies. J Cell Biol. 2012;198:11–21. 3. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111:2505–2515. 4. Dores GM, Devesa SS, Curtis RE, et al. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood. 2012;119:34–43. 5. Ravindranath Y, Yeager AM, Chang MN, et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med. 1996;334:1428–1434. 6. Estey E, Do¨hner H. Acute myeloid leukaemia. Lancet. 2006; 368:1894–1907. 7. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–1089. 8. Patel C, Stenke L, Varma S, et al. Multidrug resistance in relapsed acute myeloid leukemia: evidence of biological heterogeneity. Cancer. 2013;119:3076–3083. 9. White BS, DiPersio JF. Genomic tools in acute myeloid leukemia: From the bench to the bedside. Cancer. 2014;120:1134–1144. 10. Diamond HR, Ornellas MH, Orfao A, et al. Acute myeloid leukemia of donor origin after allogeneic stem cell transplantation from a sibling who harbors germline XPD and XRCC3 homozygous polymorphisms. J Hematol Oncol. 2011;4:39–47. 11. Lobe I, Rigal-Huguet F, Vekhoff A, et al. Myelodysplastic syndrome after acute promyelocytic leukemia: the European APL group experience. Leukemia. 2003;17:1600–1604. 12. Batzios C, Hayes LA, He SZ, et al. Secondary clonal cytogenetic abnormalities following successful treatment of acute promyelocytic leukemia. AM J Hematol. 2009;84:715–719. 13. Burnett AK, Hills RK, Grimwade D, et al. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013;27:843–851. 14. Breccia M, Cicconi L, Lo-Coco F. ATRA + ATO: has a new standard of care been established in low-risk acute promyelocytic leukaemia? Curr Opin Hematol. 2014;21:95–101. 15. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–121. r
2014 Lippincott Williams & Wilkins
AND
LABORATORY OBSERVATIONS
Therapy-induced Secondary Acute Myeloid Leukemia With t(11;19)(q23;p13.1) in a Pediatric Patient With Relapsed Acute Promyelocytic Leukemia Daniel N. Dang, MD,* Heather D. Morris, DO,* James H. Feusner, MD,w Prasad Koduru, PhD,* Kathleen Wilson, MD,* Charles F. Timmons, MD, PhD,* MaryEllen Cavalier, MD,z and Hung S. Luu, PharmD, MD*
Summary: Acute myeloid leukemia is classified based upon recurrent cytogenetic abnormalities. The t(15;17)(q24.1;q21.1) abnormality is found in 5% to 8% of de novo acute myeloid leukemia and is diagnostic of acute promyelocytic leukemia (APL). The translocation results in fusion of the retinoic acid receptor-a (RARA) gene at 17q21.1 and the promyelocytic leukemia (PML) gene at 15q24.1. Standard APL therapy is a combination of alltrans retinoic acid and anthracycline-based chemotherapy. Anthracycline treatment is associated with secondary clonal chromosomal aberrations that can lead to therapy-related secondary myeloid neoplasms. We present a pediatric case of relapsed APL coexistent with treatment-associated secondary myeloid neoplasm with t(11;19)(q23;p13.1). Key Words: acute promyelocytic leukemia, cytogenetics, molecular genetics, therapy induced
(J Pediatr Hematol Oncol 2014;36:e546–e548)
A
cute promyelocytic leukemia (APL) is defined as an acute myeloid leukemia (AML) with t(15;17)(q24.1;q21.1) resulting in a population of aberrant promyelocytes.1 The translocation creates a PML-RARA fusion protein that joins the retinoic acid receptor-a (RARA) gene on chromosome 17q21.1 with the promyelocytic leukemia (PML) gene on 15q24.1. This hallmark translocation is found in over 97% of APL cases.2 PML-RARA acts in a dominant negative manner by preventing transcription of genes involved in myeloid differentiation. Earlier studies in the 1980s and 1990s demonstrated that retinoic acid (RA) and arsenic trioxide can overcome this block as evidenced by myeloid differentiation and clinical remission in a majority of patients.3 It has been postulated that both RA and arsenic induce PML-RARA instability leading to its degradation.2 The age-adjusted incidence of APL is 2.7 per 1,000,000 person years.4 In the United States, APL comprises only Received for publication November 13, 2013; accepted April 30, 2014. From the *Department of Pathology, Parkland Health and Hospital System, Children’s Medical Center; zDepartment of Pediatrics, Division of Hematology-Oncology, UT Southwestern Medical Center, Dallas, TX; and wDepartment of Pediatrics, Division of Hematology/Oncology, Children’s Hospital & Research Center Oakland, Oakland, CA. The authors declare no conflict of interest. Reprints: Hung S. Luu, PharmD, MD, Department of Pathology, Parkland Health and Hospital System, Children’s Medical Center, UT Southwestern Medical Center, 1935 Medical District Drive, Dallas, TX 75235 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
e546 | www.jpho-online.com
5% to 10% of AMLs found in pediatric populations.5 Despite its low incidence, the disease can have drastic consequences due to its ability to release cytoplasmic contents such as enzymes and granules that can cause coagulopathy, hemorrhage, and disseminated intravascular coagulation.2 Despite effective treatment, some patients have disease relapse. Furthermore, although rare in the literature, APL patients may have therapy-induced secondary cytogenetic abnormalities. We present a case of APL in a pediatric patient with therapy-induced secondary myeloid neoplasm with a t(11;19)(q23;p13.1).
CASE REPORT A 10-year-old boy initially presented with a one and a half week history of cyclical fevers and vomiting. He was subsequently found to be pancytopenic with a complete blood count showing a white blood count of 0.3 109/L; hemoglobin, 4.7 g/dL; and platelets, 10 109/L. The differential revealed 93% lymphocytes, 5% monocytes, and 2% neutrophils. A bone marrow biopsy demonstrated 31% atypical promyelocytes by manual differential. Flow cytometry of the bone marrow demonstrated a 61% population of large, immunophenotypically aberrant myeloid cells consistent with promyelocytes that were positive for CD117, CD33, CD13, CD64, and CD45 and variably to partially positive for CD4, CD38, and CD15 and negative for CD34, HLA-DR, Tdt, myeloperoxidase, and other lymphoid and myeloid markers. Conventional cytogenetic analysis showed an abnormal male karyotype with t(15;17)(q24.1;q21.1) and a t(2;9)(q35;q22) (Fig. 1A). Seventy-five percent of these cells showed, in addition, trisomy 8. Fluorescence in situ hybridization (FISH) studies of the bone marrow detected the PML-RARA rearrangement in 70% of 200 interphase nuclei (Fig. 1B). The patient was started on all-trans retinoic acid (ATRA) and idarubicin and achieved morphologic and cytogenetic remission by day 29. Chromosome analysis of a PHA-stimulated peripheral blood indicated that the t(2;9) is a constitutional abnormality. During maintenance chemotherapy consisting of ATRA, 6mercaptopurine, and oral methotrexate, he presented with bleeding approximately 19 months after initial diagnosis and was found to have relapsed disease. Flow cytometry analysis detected an expanded population of promyelocytes with immunophenotypic and light-scattered properties similar to prior analysis. Salvage chemotherapy consisting of ATRA and arsenic trioxide was initiated. Cytogenetic evaluation of the bone marrow aspirate identified the presence of 2 unrelated clones, one with a t(15;17) in 13 of 20 metaphases, and a second unrelated clone with a t(11;19)(q23;p13.1) in the remaining 7 metaphases (Fig. 1C). Both clones showed the constitutional t(2;9)(q35;q22). The clone with trisomy 8 and t(15;17) seen at diagnosis was no longer detected. FISH and polymerase chain reaction assay confirmed the coexistence of t(15;17) and t(11;19) abnormalities in this specimen. Follow-up bone marrow examination 35 days later demonstrated
J Pediatr Hematol Oncol
Volume 36, Number 8, November 2014
J Pediatr Hematol Oncol
Volume 36, Number 8, November 2014
Therapy-induced Secondary Acute Myeloid Leukemia
FIGURE 1. Cytogenetic and fluorescence in situ hybridization (FISH) findings at first recurrence. A, 46,XY,t(2;9)(q35;q21.2)c,t(15;17) (q24;q21.1). Conventional cytogenetics showed an abnormal clone containing t(15;17) (red arrows) in 13 of 20 examined cells. In addition, all cells contain a reciprocal (2;9) translocation (green arrows) shown to be constitutional. B, PML-RARA interphase FISH demonstrating the standard dual-fusion probe set pattern consistent with the presence of a (15;17) translocation in 180 of 200 examined cells. C, 46,XY,t(2;9)c,t(11;19)(q23;p13.1). A representative conventional cytogenetics study showing the patient’s (11;19) translocation (red arrows). Green arrows highlight the constitutional t(2;9). D, MLL break-apart FISH probe showing the MLL gene rearrangement evidenced by the separation of the red and green signals.
resolution of the t(11;19) clone but persistence of the t(15;17) clone (Table 1). Treatment was reinitiated with ATRA plus daunomycin, cytarabine, and etoposide. FISH evaluation of the bone marrow aspirate 43 days after the previous cytogenetic analysis demonstrated persistence of the t(15;17) clone as well as recurrence of t(11;19) clone by FISH (Table 1). Therapy was modified to ATRA, cytarabine, and mitoxantrone plus dexrazoxane. Follow-up marrow examination 48 days later demonstrated normal trilineage hematopoiesis and no evidence for hematolymphoid malignancy. FISH studies demonstrated resolution of the t(15;17) clone but
TABLE 1. Summary of the Patient’s Cytogenetic Analyses and Therapeutic Modifications
t(15;17) t(11;19) (q22;q12) (q23;q13.1)
Therapy Regimen
Diagnosis
+
Initiation: ATRA, idarubicin Maintenance: ATRA, methotrexate, 6mercaptopurine ATRA, arsenic trioxide ATRA, daunomycin, cytarabine, etoposide
Relapse 1-mo followup 3-mo followup 4-mo followup
+ +
+
+
+
ATRA, cytarabine, mitoxantrone, dexrazoxane
+
Hematopoietic stem cell transplantation
ATRA indicates all-trans retinoic acid.
r
2014 Lippincott Williams & Wilkins
persistence of the MLL gene rearrangement in 5 of 200 cells examined, consistent with minimal residual disease of the secondary AML (Fig. 1D). The patient underwent matched unrelated donor hematopoietic stem cell transplantation and has been disease free by morphology and cytogenetics for more than 1 year.
DISCUSSION Historically, APL therapy has included topoisomerase II inhibitors, for example, idarubicin, notwithstanding the serious complications that anthracyclines and topoisomerase II inhibitors pose: topoisomerase II inhibitors not only contribute to therapy-related mucositis and hematologic toxicity, but they also pose risk for the development of additional genetic abnormalities in the primary clone, as well as the development of secondary neoplasms. Such therapy-related myeloid neoplasms are associated with fusion gene translocations involving 11q23 and the MLL gene and are characterized by a short latency period.6 It is clear that AML is a genetically heterogeneous disorder both at diagnosis and relapse.7,8 Recent genome sequencing studies of AML have identified some mechanisms of both primary genetic aberration as well as those critical to clonal evolutions. Examination of bone marrow from healthy donors via whole exome sequencing demonstrates that random mutations are accumulated over time. Using whole exome sequencing and whole genome sequencing techniques, variant alleles can be captured as a genetic signature when a progenitor stem cell transforms to a leukemic myeloid blast. The ratio of the number of reads of the variant allele compared with total number of reads at www.jpho-online.com |
e547
Dang et al
a particular locus—the variant allele frequency (VAF)— permits identification of when a mutation was acquired. Heterozygous mutations have a VAF of approximately 50% indicating an earlier, and potentially primary, genetic event. By contrast, aberrations which have lower VAFs— owing to their being present in fewer cells—were acquired later in a subclone.9 The identification of variants using whole genome sequencing with subsequent quantification of VAFs by targeted sequencing has demonstrated 2 patterns of clonal evolution in relapsed AML patients: acquisition of additional aberrations in the primary clone and expansion of a clone genetically unrelated to the primary clone.9 The clonal evolution of the relapsed AML described in this case report is consistent with these very recently described molecular mechanisms of AML clonal evolution. Our patient’s diagnostic bone marrow showed both the primary clone with the t(15;17) and a second clone with a cytogenetic aberration (trisomy 8) in addition to the t(15;17). Over the course of this patient’s treatment, a third clone evolved that contained a t(11;19) and an MLL gene rearrangement and which was genetically unrelated to the primary clone. Although the MLL rearrangement-bearing clone was presumptively the result of previous treatment with topoisomerase II inhibitors, underlying molecular changes (bearing a different molecular profile from the primary clone) may have predisposed to the MLL aberration.10 Fortunately, therapy-induced genetic abnormalities are rare in APL. Lobe et al11 reported 0.97% or 6 of 677 patients who developed therapy-related myelodysplastic syndrome after treatment for APL. A retrospective study reported 12 of 123 patients with APL who developed a secondary clonal population with cytogenetic abnormalities.12 Burnett et al13 reported 9 of 285 patients who relapsed with AML without the PML-RARa transcript, consistent with secondary disease, after being treated with Medical Research Council chemotherapy plus ATRA (2 patients) or anthracycline plus ATRA (7 patients). Although novel treatment strategies aiming to eliminate or decrease the cumulative dose of anthracycline have been frustrated by the rarity of APL, several recent trials suggest that anthracycline-free treatment strategies incorporating ATO and ATRA are equivalent to anthracycline-containing regimens with regard to both event-free and overall survival rates in patients with low-risk or intermediate-risk APL.14 Lo-Coco et al15 conducted a phase 3 multicenter, noninferiority trial comparing ATRA plus chemotherapy (ATRA-idarubicin induction followed by 3 cycles of consolidation with ATRA plus chemotherapy and maintenance with low-dose chemotherapy plus ATRA) with ATRA plus ATO in 156 adult patients with low-risk or intermediate-risk (white blood count r10 109/L) APL. Median follow-up was 34.4 months. All 77 patients in the ATRA-ATO group achieved complete remission, versus 75 of 79 randomized to the ATRA-chemotherapy group. Two-year event-free survival rates were 97% in the ATRA-ATO group and 86% in the ATRA-chemotherapy group (P < 0.001 for noninferiority and P = 0.02 for superiority of ATRA-ATO). The ATRA-ATO regimen presented less hematologic toxicity, although it posed greater hepatotoxicity. A phase II trial investigating ATRA, ATO plus gemtuzumab ozogamicin is underway for children aged 10 years and older. We present a highly pertinent case report concerning a 10-year-old patient with the rare finding of therapy-induced secondary AML with t(11;19) that developed concurrently
e548 | www.jpho-online.com
J Pediatr Hematol Oncol
Volume 36, Number 8, November 2014
with APL relapse. This case illustrates the importance of further defining the role of anthracyclines, in particular topoisomerase II inhibitors, in the treatment of APL; indeed, the development of current and future studies exploring the prospect of omitting or minimizing anthracycline exposure without sacrificing historic event-free and overall survival rates have already been spurred by recent therapeutic trials incorporating ATRA plus ATO as firstline therapy for low-risk and intermediate-risk disease. Furthermore, this case underscores the importance of cytogenetic/molecular screening for secondary cytogenetic aberrations and the tailoring of chemotherapy regimens based upon cytogenetic findings. Finally, this case highlights the urgent need for obtaining a greater understanding of the clonal evolution of AML, a topic that is becoming less elusive due to recent advances in genomic sequencing. ACKNOWLEDGMENT The authors thank Brian Levenson, Franklin Fuda, Victor M. Aquino, Carlos A. Tirado, and Kirthi Kumar who contributed to the care of the patient and the manuscript. REFERENCES 1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours and Haematopoietic and Lymphoid Tissues. Lyon: IARC; 2008:110–123. 2. Le Bras M, Lallemand-Breitenbach V. Acute promyelocytic leukemia, arsenic, and PML bodies. J Cell Biol. 2012;198:11–21. 3. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111:2505–2515. 4. Dores GM, Devesa SS, Curtis RE, et al. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood. 2012;119:34–43. 5. Ravindranath Y, Yeager AM, Chang MN, et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med. 1996;334:1428–1434. 6. Estey E, Do¨hner H. Acute myeloid leukaemia. Lancet. 2006; 368:1894–1907. 7. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–1089. 8. Patel C, Stenke L, Varma S, et al. Multidrug resistance in relapsed acute myeloid leukemia: evidence of biological heterogeneity. Cancer. 2013;119:3076–3083. 9. White BS, DiPersio JF. Genomic tools in acute myeloid leukemia: From the bench to the bedside. Cancer. 2014;120:1134–1144. 10. Diamond HR, Ornellas MH, Orfao A, et al. Acute myeloid leukemia of donor origin after allogeneic stem cell transplantation from a sibling who harbors germline XPD and XRCC3 homozygous polymorphisms. J Hematol Oncol. 2011;4:39–47. 11. Lobe I, Rigal-Huguet F, Vekhoff A, et al. Myelodysplastic syndrome after acute promyelocytic leukemia: the European APL group experience. Leukemia. 2003;17:1600–1604. 12. Batzios C, Hayes LA, He SZ, et al. Secondary clonal cytogenetic abnormalities following successful treatment of acute promyelocytic leukemia. AM J Hematol. 2009;84:715–719. 13. Burnett AK, Hills RK, Grimwade D, et al. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013;27:843–851. 14. Breccia M, Cicconi L, Lo-Coco F. ATRA + ATO: has a new standard of care been established in low-risk acute promyelocytic leukaemia? Curr Opin Hematol. 2014;21:95–101. 15. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–121. r
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