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Acute Leukemia with M3 Morphology Without Cytogenetic Abnormalities Related to Acute Promyelocytic Leukemia: Description of a Refractory Pediatric Case
Case Report Acute Leukemia with M3 Morphology Without Cytogenetic Abnormalities Related to Acute Promyelocytic Leukemia: Description of a Refractory Pediatric Case Morgani Rodrigues, José Mauro Kutner, Andreza Alice Feitosa Ribeiro, Luci Tabacow Hidal, Adalberto Stape, Nydia Bacal, Nelson Hamerschlak Abstract Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML). APL is characterized by specific genetic abnormality t(15;17), which results in fusion between the promyelocytic leukemia (PML) gene and the retinoic acid receptor-A (RARA). We describe the case of a 4-year-old boy who was admitted to hospital with severe infection of the oropharynx due to a peritonsillar abscess, along with hepatomegaly and splenomegaly. The initial laboratory tests showed a condition compatible with AML. The cytologic morphology, cytochemistry, and immunophenotyping were compatible with the AML M3 variant but with normal karyotype, fluorescence in situ hybridization and polymerase chain reaction (PCR) negative for t(15;17), and PCR negative for t(11;17). There was resistance to the initial chemotherapy, but the patient experienced an excellent result from nonrelative umbilical cord transplantation. The case represents an atypical situation of AML with promyelocytic characteristics and normal cytogenetics showing a poor prognosis that responded only to bone marrow transplantation. Clinical Leukemia, Vol. 3, No. 2, E27-E30, 2009; DOI: 10.3816/CLK.2009.n.012 Keywords: Cord blood stem cell transplantation, Myeloid leukemia, Neoplasm drug resistance, Promyelocytes, Retinoic acid receptors
Introduction Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML). APL is characterized by specific genetic abnormality t(15;17), which results in fusion between the promyelocytic leukemia (PML) gene and retinoic acid receptor-A (RARA). Variations in this chromosomal translocation (for example, t[11;17], t[5;17]) can be found in < 5% of cases of promyelocytic leukemia. In addition to its characteristic morphology, APL is associated with severe hemorrhagic syndrome.1 The incidence of APL accounts for approximately 10% of all acute leukemia cases, although there are reports of increased incidence of up to 25% in populations of Latin American origin. In pediatric populations, its incidence is between 4% and 11% of children with AML.2 Compared with adults, APL in children is more frequently associated with a high rate of hyperleukocytosis (> 10 × 109/L), together with the AML-M3 microgranular morphologic subtype.2,3 Because of the characteristic cytogenetic abnormality of AML-M3, it presents sensitivity to cell-differentiating retinoid agents, such as all-trans-retinoic acid (ATRA) and to new agents like arsenic trioxide (AS2O3).4-7 Therefore, it can evolve from a fatal disease to a potentially curable one.1 Programa de Hematologia e Oncologia, Instituto Israelita de Ensino e Pesquisa Albert Einstein, São Paulo (SP), Brazil Submitted: Jun 18, 2008; Revised: Oct 20, 2008; Accepted: Nov 11, 2008 Address for correspondence: Nelson Hamerschlak, MD, PhD, Programa de Hematologia e Oncologia, Instituto Israelita de Ensino e Pesquisa Albert Einstein, Ave Albert Einstein, 627/701, Piso Chinuch, São Paulo (SP), Brazil, CEP 05651-901 Fax: 55-11-3747-0302; e-mail: [email protected] This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA. Electronic forwarding or copying is a violation of US and international copyright laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
Clinical Leukemia • August 2009
E27
Refractory Atypical Acute Promyelocytic Leukemia in a Child
Figure 1
Morphologic Features Compatible With the Promyelocytic Variant of Acute Myeloid Leukemia in Blasts From Peripheral Blood and Bone Marrow
Hematoxylin and eosin stain. Magnification x 50 and x 100, respectively.
Figure 2 A
Immunophenotyping Histograms: Bone Marrow With Blasts Compatible With the Classical Promyelocytic Variant of Acute Leukemia B
103
C
103
103
102
102
102
101
101
101
100
100
100
100
101
102
103
Blasts With Expression of CD33 (+) and CD15 (–)
D
100
102
0
103
1023
Blasts Without Expression of CD34 or HLA-DR
E
103
102
101
101
100
100
101
102
103
Blasts Without Expression of CD117 or CD41
Case Report We describe the case of a 4-year-old boy of Asian origin, previously healthy, who was admitted to hospital in March 2004 with a condition of severe infection of the oropharynx as a result of a
CD45 x SSC
103
102
100
E28
101
100
101
102
103
Blasts With Expression of CD13 and Without Expression of CD7
peritonsillar abscess. He also presented with hepatomegaly and splenomegaly. In the initial assessment, his laboratory tests showed a condition compatible with AML: hemoglobin of 7.7 g/dL, leukocytes of 22,100/μL, with 72% of blast cells, platelets of 82,000/μL,
Clinical Leukemia • August 2009
Morgani Rodrigues et al lactate dehydrogenase of 1677 U/L, and prothrombin time with 45% International Normalized Ratio of 1.67, with no other coagulation abnormalities, as shown in Table 1. The cytologic morphology, cytochemistry, and immunophenotyping were compatible with the classic M3 myeloid variant according to the French-AmericanBritish classification (Figures 1 and 2). The patient was started on chemotherapy to treat the leukemia, using a regimen of idarubicin 12 mg/m2 for 3 days, cytosine (ara-C) 100 mg/m2 continuously for 7 days, and ATRA for 15 days. After this regimen, cytogenetic tests, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR) were negative for t(15;17). Unfortunately, we did not have the opportunity to study NPM (nucleophosmin), NuMA (nuclear matrix associated gene), and STAT5. The karyotype was diploid (46,XY). The t(11;17) was also ruled out by PCR. ATRA was withdrawn because the presence of t(15;17) was not confirmed. At this point, the patient still presented a hemogram with persistence of promyelocytes and bone marrow infiltrated by leukemic cells. A new chemotherapy regimen was then instituted, consisting of ara-C 100 mg/m2 on days 1-7, etoposide 100 mg/m2 on days 1-5, and mitoxantrone 10 mg/m2 on days 1 and 2. This regimen did not produce any response either. Subsequently, a regimen of cladribine 9 mg/m2 on days 2-6 and ara-C 500 mg/m2 continuously on days 1-5 was used, without response and with signs of disease progression. In view of the refractory nature of the disease, nonrelative umbilical cord transplantation was performed (6/6 match), as no members of the patient’s family were HLA compatible. The transplantation was performed on May 21, 2004. The conditioning was performed using a traditional regimen of busulfan and cyclophosphamide.8 Prophylaxis for graft-versus-host disease (GVHD) was administered, consisting of prednisone 2 mg/kg of body weight from day 0 to day 17 and 1 mg/kg day 18 and cyclosporin in accordance with a protocol.9 Following the transplantation and for about 6 months after, the patient presented several serious complications, particularly bacterial infections, fungal infections (Candida spp.), reactivation of cytomegalovirus, pneumonia caused by Pneumocystis jiroveci, acute GVHD, and veno-occlusive liver disease. Despite his delicate clinical condition, the patient presented good evolution and overcame all the complications. He has now survived for 4 years without evidence of disease and presents excellent performance status.
Discussion Acute promyelocytic leukemia is characterized by a reciprocal translocation, t(15;17)(q22;q21), which deregulates the PML and RARA genes located on chromosomes 15q and 17q, respectively. t(15;17) results in fusion between 2 genes, the “retinoic acid receptor-alpha” (RARA) and the promyelocytic leukemia (PML) gene.10 It is now known that in around 2% of the cases, the RAR gene is fused with genes other than PML: t(11;17)(q23;q21), t(5;17)(q35;q21), and t(11;17)(q13;q21) and der(17). In these translocations, the RAR gene is fused with PLZF (promyelocytic leukemia zinc finger), NPM, and NuMA, respectively.11 The STAT5B gene, which is located at 17q21, was recently identified as a new partner for RAR in a case of APL with der(17).
Table 1
Initial Laboratory Findings Compatible With Acute Myeloid Leukemia in a Pediatric Patient Blood Test Variables
Hemoglobin
Results 7.7 g/dL
Hematocrit
22.5%
Leukocytes
22.100 μL
Metamyelocyte
3%
Segmented Cells
5%
Lymphocytes
9%
Monocytes
2%
Blasts Platelets Prothrombin Time Activated Partial Prothrombin Time
72% 85,000 μL 45% INR: 1.67 25.3/31 sec
Thrombin Time
14.1 sec
Blood Sedimentation Rate
64 mm
C-Reactive Protein
223 mg/dL
Fibrinogen
351 mg/dL
Bilirubins
0.3 mg/dL
Uric Acid
6.8 mg/dL
Lactate Dehydrogenase
1677 U/L
Alkaline Phosphatase
157 U/L
Aspartate Aminotransferase
142 U/L
Alanine Aminotransferase
22 U/L
Creatinine
0.4 mg/dL
Abbreviation: International Normalized Ratio
In common with APL associated with PLM-RAR, patients with fusion involving NPM and NuMA seem to be sensitive to ATRA. In contrast, patients with PLZF-RAR do not present a differentiation response to retinoids and if treated with ATRA, they present a poor prognosis. This demonstrates the importance of achieving the correct diagnosis of AML-M3. Despite the characteristic morphology, cytochemistry, and immunophenotyping, the patient in the current study did not present any of the atypical APL abnormalities. APL in children is related to the microgranular variant and a high leukocyte count, together with frequent expression of CD13, CD33, and CD9 and rare expression of HLA-DR, CD10, CD7, and CD11b.2,3,12 However, there may be other coexpressions, as observed by Guglielmi et al12 in a study evaluating 63 children with a confirmed diagnosis of APL, in which CD2 and CD34 coexpression was related, in these patients, to the microgranular variant and PML BCR3 breakage. CD19 expression was directly related to high leukocyte counts, and CD2 coexpression was positively related to a complete remission rate and survival free from the event. The patient described in the present case presented high leukocyte count, morphologic diagnosis of APL, and immunophenotyping with expression of CD33+ heterogeneous, CD2–, CD15–, HLA-DR–, CD34–, CD117–, CD13+, and CD7–, and CD11b–,
Clinical Leukemia • August 2009
E29
Refractory Atypical Acute Promyelocytic Leukemia in a Child compatible with classic APL.13,14 This patient also presented a high leukocyte count on diagnosis. In another study by a European group reviewing 60 cases of APL that did not present the classic t(15;17), Grimwade et al11 observed 5 cases (0.8%) of patients with morphologic evidence of APL without identifying rearrangement of RARA. The mean age of those patients was 58 years (range, 56-60 years). This older age was also observed in another case report,15 on a 50-year-old patient who presented morphology and immunophenotyping characteristic of APL but who was cytogenetically normal. However, FISH analysis showed ins(17;15)(q21;q22), and the patient responded to the use of ATRA. The identification of these cases suggests an alternative route that could mediate the blocking of maturation that characterizes APL as well as the formation of aberrant retinoid receptors, despite the additional possibility that RARA might be involved in mutation or an epigenetic mechanism.11 The present case showed a positive outcome from AML in a child, with the characteristics of APL but without the characteristic cytogenetic abnormalities. The possibilities of other variants were ruled out. The case was refractory to the initial chemotherapy but presented an excellent result for nonrelative umbilical cord transplantation.
Disclosures The authors have no relevant financial relationships to disclose.
References 1. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008; 111:2505-15. 2. Ortega JJ, Madero L, Martín G, et al. Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. J Clin Oncol 2005; 23:7632-40.
E30
3. Rovelli A, Biondi A, Cantù Rajnoldi A, et al. Microgranular variant of acute promyelocytic leukemia in children. J Clin Oncol 1992; 10:1413-8. 4. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100:4298-302. 5. Sanz MA, Martín G, Gonzáles M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004; 103:1237-43. 6. Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapse acute promyelocytic leukemia patients. Blood 1999; 94:3315-24. 7. Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated promyelocytic leukemia. Blood 2006; 107:3469-73. 8. Nevill TJ, Barnett MJ, Klingemann HG, et al. Regimen-related toxicity of a busulfan-cyclophosphamide conditioning regimen in 70 patients undergoing allogeneic bone marrow transplantation. J Clin Oncol 1991; 9:1224-32. 9. Gluckman E, Rocha V, Boyer-Chammard A, et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 1997; 337:373-81. 10. Melnick A, Lincht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93:3167-215. 11. Grimwade D, Biondi A, Mozziconacci MJ, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action “Molecular Cytogenetic Diagnosis in Haematological Malignancies.” Blood 2000; 96:1297-308. 12. Guglielmi C, Martelli MP, Diverio D, et al. Immunophenotype of adult and childhood acute promyelocytic leukaemia: correlation with morphology, type of PML gene breakpoint and clinical outcome. A cooperative Italian study on 196 cases. Br J Haematol 1998; 102:1035-41. 13. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasm. Blood 2008; 111:3941-67. 14. Orfao A, Chillón MC, Bortoluci AM, et al. The flow cytometric pattern of CD34, CD15 and CD13 expression in acute myeloblastic leukemia is highly characteristic of the presence of PML-RARalpha gene rearrangements. Haematologica 1999; 84:405-12. 15. Fujita K, Oba R, Harada H, et al. Cytogenetics, FISH and RT-PCR analysis of acute promyelocytic leukemia: structure of the fusion poit in a case lacking classic t(15;17) translocation. Leuk Lymphoma 2003; 44:111-5.
Clinical Leukemia • August 2009
Introduction Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML). APL is characterized by specific genetic abnormality t(15;17), which results in fusion between the promyelocytic leukemia (PML) gene and retinoic acid receptor-A (RARA). Variations in this chromosomal translocation (for example, t[11;17], t[5;17]) can be found in < 5% of cases of promyelocytic leukemia. In addition to its characteristic morphology, APL is associated with severe hemorrhagic syndrome.1 The incidence of APL accounts for approximately 10% of all acute leukemia cases, although there are reports of increased incidence of up to 25% in populations of Latin American origin. In pediatric populations, its incidence is between 4% and 11% of children with AML.2 Compared with adults, APL in children is more frequently associated with a high rate of hyperleukocytosis (> 10 × 109/L), together with the AML-M3 microgranular morphologic subtype.2,3 Because of the characteristic cytogenetic abnormality of AML-M3, it presents sensitivity to cell-differentiating retinoid agents, such as all-trans-retinoic acid (ATRA) and to new agents like arsenic trioxide (AS2O3).4-7 Therefore, it can evolve from a fatal disease to a potentially curable one.1 Programa de Hematologia e Oncologia, Instituto Israelita de Ensino e Pesquisa Albert Einstein, São Paulo (SP), Brazil Submitted: Jun 18, 2008; Revised: Oct 20, 2008; Accepted: Nov 11, 2008 Address for correspondence: Nelson Hamerschlak, MD, PhD, Programa de Hematologia e Oncologia, Instituto Israelita de Ensino e Pesquisa Albert Einstein, Ave Albert Einstein, 627/701, Piso Chinuch, São Paulo (SP), Brazil, CEP 05651-901 Fax: 55-11-3747-0302; e-mail: [email protected] This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA. Electronic forwarding or copying is a violation of US and international copyright laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
Clinical Leukemia • August 2009
E27
Refractory Atypical Acute Promyelocytic Leukemia in a Child
Figure 1
Morphologic Features Compatible With the Promyelocytic Variant of Acute Myeloid Leukemia in Blasts From Peripheral Blood and Bone Marrow
Hematoxylin and eosin stain. Magnification x 50 and x 100, respectively.
Figure 2 A
Immunophenotyping Histograms: Bone Marrow With Blasts Compatible With the Classical Promyelocytic Variant of Acute Leukemia B
103
C
103
103
102
102
102
101
101
101
100
100
100
100
101
102
103
Blasts With Expression of CD33 (+) and CD15 (–)
D
100
102
0
103
1023
Blasts Without Expression of CD34 or HLA-DR
E
103
102
101
101
100
100
101
102
103
Blasts Without Expression of CD117 or CD41
Case Report We describe the case of a 4-year-old boy of Asian origin, previously healthy, who was admitted to hospital in March 2004 with a condition of severe infection of the oropharynx as a result of a
CD45 x SSC
103
102
100
E28
101
100
101
102
103
Blasts With Expression of CD13 and Without Expression of CD7
peritonsillar abscess. He also presented with hepatomegaly and splenomegaly. In the initial assessment, his laboratory tests showed a condition compatible with AML: hemoglobin of 7.7 g/dL, leukocytes of 22,100/μL, with 72% of blast cells, platelets of 82,000/μL,
Clinical Leukemia • August 2009
Morgani Rodrigues et al lactate dehydrogenase of 1677 U/L, and prothrombin time with 45% International Normalized Ratio of 1.67, with no other coagulation abnormalities, as shown in Table 1. The cytologic morphology, cytochemistry, and immunophenotyping were compatible with the classic M3 myeloid variant according to the French-AmericanBritish classification (Figures 1 and 2). The patient was started on chemotherapy to treat the leukemia, using a regimen of idarubicin 12 mg/m2 for 3 days, cytosine (ara-C) 100 mg/m2 continuously for 7 days, and ATRA for 15 days. After this regimen, cytogenetic tests, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR) were negative for t(15;17). Unfortunately, we did not have the opportunity to study NPM (nucleophosmin), NuMA (nuclear matrix associated gene), and STAT5. The karyotype was diploid (46,XY). The t(11;17) was also ruled out by PCR. ATRA was withdrawn because the presence of t(15;17) was not confirmed. At this point, the patient still presented a hemogram with persistence of promyelocytes and bone marrow infiltrated by leukemic cells. A new chemotherapy regimen was then instituted, consisting of ara-C 100 mg/m2 on days 1-7, etoposide 100 mg/m2 on days 1-5, and mitoxantrone 10 mg/m2 on days 1 and 2. This regimen did not produce any response either. Subsequently, a regimen of cladribine 9 mg/m2 on days 2-6 and ara-C 500 mg/m2 continuously on days 1-5 was used, without response and with signs of disease progression. In view of the refractory nature of the disease, nonrelative umbilical cord transplantation was performed (6/6 match), as no members of the patient’s family were HLA compatible. The transplantation was performed on May 21, 2004. The conditioning was performed using a traditional regimen of busulfan and cyclophosphamide.8 Prophylaxis for graft-versus-host disease (GVHD) was administered, consisting of prednisone 2 mg/kg of body weight from day 0 to day 17 and 1 mg/kg day 18 and cyclosporin in accordance with a protocol.9 Following the transplantation and for about 6 months after, the patient presented several serious complications, particularly bacterial infections, fungal infections (Candida spp.), reactivation of cytomegalovirus, pneumonia caused by Pneumocystis jiroveci, acute GVHD, and veno-occlusive liver disease. Despite his delicate clinical condition, the patient presented good evolution and overcame all the complications. He has now survived for 4 years without evidence of disease and presents excellent performance status.
Discussion Acute promyelocytic leukemia is characterized by a reciprocal translocation, t(15;17)(q22;q21), which deregulates the PML and RARA genes located on chromosomes 15q and 17q, respectively. t(15;17) results in fusion between 2 genes, the “retinoic acid receptor-alpha” (RARA) and the promyelocytic leukemia (PML) gene.10 It is now known that in around 2% of the cases, the RAR gene is fused with genes other than PML: t(11;17)(q23;q21), t(5;17)(q35;q21), and t(11;17)(q13;q21) and der(17). In these translocations, the RAR gene is fused with PLZF (promyelocytic leukemia zinc finger), NPM, and NuMA, respectively.11 The STAT5B gene, which is located at 17q21, was recently identified as a new partner for RAR in a case of APL with der(17).
Table 1
Initial Laboratory Findings Compatible With Acute Myeloid Leukemia in a Pediatric Patient Blood Test Variables
Hemoglobin
Results 7.7 g/dL
Hematocrit
22.5%
Leukocytes
22.100 μL
Metamyelocyte
3%
Segmented Cells
5%
Lymphocytes
9%
Monocytes
2%
Blasts Platelets Prothrombin Time Activated Partial Prothrombin Time
72% 85,000 μL 45% INR: 1.67 25.3/31 sec
Thrombin Time
14.1 sec
Blood Sedimentation Rate
64 mm
C-Reactive Protein
223 mg/dL
Fibrinogen
351 mg/dL
Bilirubins
0.3 mg/dL
Uric Acid
6.8 mg/dL
Lactate Dehydrogenase
1677 U/L
Alkaline Phosphatase
157 U/L
Aspartate Aminotransferase
142 U/L
Alanine Aminotransferase
22 U/L
Creatinine
0.4 mg/dL
Abbreviation: International Normalized Ratio
In common with APL associated with PLM-RAR, patients with fusion involving NPM and NuMA seem to be sensitive to ATRA. In contrast, patients with PLZF-RAR do not present a differentiation response to retinoids and if treated with ATRA, they present a poor prognosis. This demonstrates the importance of achieving the correct diagnosis of AML-M3. Despite the characteristic morphology, cytochemistry, and immunophenotyping, the patient in the current study did not present any of the atypical APL abnormalities. APL in children is related to the microgranular variant and a high leukocyte count, together with frequent expression of CD13, CD33, and CD9 and rare expression of HLA-DR, CD10, CD7, and CD11b.2,3,12 However, there may be other coexpressions, as observed by Guglielmi et al12 in a study evaluating 63 children with a confirmed diagnosis of APL, in which CD2 and CD34 coexpression was related, in these patients, to the microgranular variant and PML BCR3 breakage. CD19 expression was directly related to high leukocyte counts, and CD2 coexpression was positively related to a complete remission rate and survival free from the event. The patient described in the present case presented high leukocyte count, morphologic diagnosis of APL, and immunophenotyping with expression of CD33+ heterogeneous, CD2–, CD15–, HLA-DR–, CD34–, CD117–, CD13+, and CD7–, and CD11b–,
Clinical Leukemia • August 2009
E29
Refractory Atypical Acute Promyelocytic Leukemia in a Child compatible with classic APL.13,14 This patient also presented a high leukocyte count on diagnosis. In another study by a European group reviewing 60 cases of APL that did not present the classic t(15;17), Grimwade et al11 observed 5 cases (0.8%) of patients with morphologic evidence of APL without identifying rearrangement of RARA. The mean age of those patients was 58 years (range, 56-60 years). This older age was also observed in another case report,15 on a 50-year-old patient who presented morphology and immunophenotyping characteristic of APL but who was cytogenetically normal. However, FISH analysis showed ins(17;15)(q21;q22), and the patient responded to the use of ATRA. The identification of these cases suggests an alternative route that could mediate the blocking of maturation that characterizes APL as well as the formation of aberrant retinoid receptors, despite the additional possibility that RARA might be involved in mutation or an epigenetic mechanism.11 The present case showed a positive outcome from AML in a child, with the characteristics of APL but without the characteristic cytogenetic abnormalities. The possibilities of other variants were ruled out. The case was refractory to the initial chemotherapy but presented an excellent result for nonrelative umbilical cord transplantation.
Disclosures The authors have no relevant financial relationships to disclose.
References 1. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008; 111:2505-15. 2. Ortega JJ, Madero L, Martín G, et al. Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. J Clin Oncol 2005; 23:7632-40.
E30
3. Rovelli A, Biondi A, Cantù Rajnoldi A, et al. Microgranular variant of acute promyelocytic leukemia in children. J Clin Oncol 1992; 10:1413-8. 4. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100:4298-302. 5. Sanz MA, Martín G, Gonzáles M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004; 103:1237-43. 6. Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapse acute promyelocytic leukemia patients. Blood 1999; 94:3315-24. 7. Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated promyelocytic leukemia. Blood 2006; 107:3469-73. 8. Nevill TJ, Barnett MJ, Klingemann HG, et al. Regimen-related toxicity of a busulfan-cyclophosphamide conditioning regimen in 70 patients undergoing allogeneic bone marrow transplantation. J Clin Oncol 1991; 9:1224-32. 9. Gluckman E, Rocha V, Boyer-Chammard A, et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 1997; 337:373-81. 10. Melnick A, Lincht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93:3167-215. 11. Grimwade D, Biondi A, Mozziconacci MJ, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action “Molecular Cytogenetic Diagnosis in Haematological Malignancies.” Blood 2000; 96:1297-308. 12. Guglielmi C, Martelli MP, Diverio D, et al. Immunophenotype of adult and childhood acute promyelocytic leukaemia: correlation with morphology, type of PML gene breakpoint and clinical outcome. A cooperative Italian study on 196 cases. Br J Haematol 1998; 102:1035-41. 13. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasm. Blood 2008; 111:3941-67. 14. Orfao A, Chillón MC, Bortoluci AM, et al. The flow cytometric pattern of CD34, CD15 and CD13 expression in acute myeloblastic leukemia is highly characteristic of the presence of PML-RARalpha gene rearrangements. Haematologica 1999; 84:405-12. 15. Fujita K, Oba R, Harada H, et al. Cytogenetics, FISH and RT-PCR analysis of acute promyelocytic leukemia: structure of the fusion poit in a case lacking classic t(15;17) translocation. Leuk Lymphoma 2003; 44:111-5.
Clinical Leukemia • August 2009