De novo acute megakaryoblastic leukemia with p210 BCR/ABL and t(1;16) translocation but not t(9;22) Ph chromosome
© Min et al; licensee BioMed Central Ltd. 2011
Received: 27 August 2011
Accepted: 10 November 2011
Published: 10 November 2011
Acute megakaryoblastic leukemia (AMKL) is a type of acute myeloid leukemia (AML), in which majority of the blasts are megakaryoblastic. De novo AMKL in adulthood is rare, and carries very poor prognosis. We here report a 45-year-old woman with de novo AMKL with BCR/ABL rearrangement and der(16)t(1;16)(q21;q23) translocation but negative for t(9;22) Ph chromosome. Upon induction chemotherapy consisting of homoharringtonine, cytarabine and daunorubicin, the patient achieved partial hematological remission. The patient was then switched to imatinib plus one cycle of CAG regimen (low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor), and achieved complete remission (CR). The disease recurred after 40 days and the patient eventually died of infection. To the best of our knowledge, this is the first report of de novo AMKL with p210 BCR/ABL and der(16)t(1;16)(q21;q23) translocation but not t(9;22) Ph chromosome.
Acute megakaryoblastic leukemia (AMKL), also known as M7 under the French-American-British (FAB) classification, represents < 5% of acute myeloid leukemia (AML) [1–3]. In adults, AMKL constitutes only 0.5% - 1% of de novo AML cases . Ph chromosome is a rare cytogenetic abnormality (≈ 1%) in AML [5, 6]. The incidence of t(9;22) in AMKL varies considerably in the literature: from < 20% to > 60%, possibly due to inconsistency in the inclusion/exclusion of blastic phase of chronic myeloid leukemia (CML)[7–9].
The clinical course of the patient
Induction chemotherapy consisting of homoharringtonine, cytarabine and daunorubicin began.
Bone marrow smear showed 20.4% megakaryoblasts and 24.8% promegakaryocytes (chemotherapy failure);
Second induction chemotherapy.
Bone marrow smear showed 6% megakaryoblasts and 11% promegakaryocytes (partial remission);
Imatinib treatment started (600 mg/d) and CAG regimen
WBC: 3.5 × 109/L.
Imatinib reduced to 400 mg/d.
Imatinib discontinued (WBC: 0.9 × 109/L).
Imatinib restarted (200 mg/d);
WBC: 4.3 × 10 9 /L (d106)
Imatinib increased to 400 mg/d
d110: complete hematological remission
WBC:3.2 × 109/L (d110); 3.5 × 109/L (d120); 4.2 × 109/L (d130)
Imatinib discontinued (due to financial reasons)
A 45-year-old woman was hospitalized on May 16th, 2008 with two weeks of fatigue, dizziness and low fever. The body temperature was 37.9°C. On auscultation, a II/VI systolic murmur was noticed over the apical region. The liver was palpable at 2 cm below the ribcage. The spleen was palpable at 2 cm below the left costal margin. Abdominal ultrasound confirmed slight hepatosplenomegaly. The patient had no history of toxic substance exposure. Family history was non-remarkable.
On the basis of the above reported clinical and biological features, a diagnosis of de novo acute AMKL. The patient received induction had regimen consisting of: homoharringtonine (2 mg/m2/day on day 1 - 7), cytarabine (100 mg/m2/day on day 1 - 7) and daunorubicin (45 mg/m2/day on day 1 - 3). A bone marrow smear at one month later showed no improvement. A partial remission was achieved after the induction treatment was repeated. The patient then received imatinib (600 mg/d, p.o.) and one cycle of CAG regimen (cytarabine 30 mg/day for 14 days, aclarubicin 10 mg/day on days 1 - 8, and granulocyte colony-stimulating factor 300 μg/day on days 1 - 14). Imatinib was discontinued after 2 weeks due to severe bone marrow suppression. Plasma LDH and liver enzymes remained within the normal range during the treatment. A complete hematological response was achieved upon evaluation at 50 days after initiating imatinib treatment, and the patient was discharged. She was hospitalized for high fever and dyspnea after 40 days. Hemoglobin was 90 g/L. White blood cell count was 19 × 109/L, with 21% blast cells. Relapse was established with bone marrow smear. The patient was treated with cytarabine (2 g/m2/day on days 1 - 3) and daunorubicin (45 mg/m2/day on days 1 - 3), with no apparent improvement. She died of fungal infection after 27 days.
Although the first AMKL was described as early as 1931, reports have been sporadic because of both the rarity of the disease and the lack of well-established diagnostic criteria. In fact, precise diagnostic criteria were added to the French-American-British classification only in 1985 (FAB M7) . The bone marrow aspirate shows a leukemic cell infiltrate that comprises 30% or more of all cells. These cells are identified as being of megakaryocyte lineage by platelet peroxidase reaction on electron microscopy or by tests with monoclonal or polyclonal platelet-specific antibodies (CD41a, CD42 or CD61). Myelofibrosis or increased bone marrow reticulin are a prominent aspect in most AMKL patients. In some cases, megakaryoblastic crisis could be the first presentation of CML, and not distinguishable from de novo AMKL [12–16]. This case represents de novo AMKL in our opinion, because the patient had no basophilia and eosinophilia upon presentation, which are often seen in blast crisis of CML . Basophilia, a frequent feature of blast crisis, is uncommon in acute leukemias . Furthermore, our patient had only mild splenomegaly. Moderate or severe splenomegaly is common in blast crisis of CML [13, 16].
AMKL is associated with no specific cytogenetic abnormality, and the majority of cases present with a complex karyotype. In a recent study by Le Groupe Francais de Cytogenetique Hematologique (GFCH), complex karyotypes of unbalanced changes, such as -5/del5q or -7/del(7q), 3q21q26, dic(1;15)(p11;p11), inv(4)(p15q11), t(14;21)(q24;q22), der(7)t(7;17)(q11;q11) and t(6;13)(p22;q14), were common in adult de novo AMKL . In addition, the t(X;16) translocation has also been reported in 2 adult de novo AMKL cases . One translocation was 46,XY,t(16;21)(p11;q22), another was t(16;16)(p13;q22). The present case serves to identify a novel translocation der(16)t(1;16)(q21;q23), providing further insight into the heterogeneity of genomic rearrangement in this subset of AML.
Data concerning the incidence of the Ph chromosome or BCR/ABL rearrangement in de novo AMKL are scarce. The Ph chromosome is one of the most common chromosomal abnormalities associated with adult AMKL according the report of the GFCH . For example, Ph chromosome was found in four out of a total of 23 AMKL cases (17%) . In fact, only two cases were de novo AMKL (9%). In an early study of 14 AMKL patients with cytogenetic data, Ph chromosome was found in two cases of megakaryoblastic transformation of chronic myelogenous leukemia, but not in de novo AMKL . Ohyashiki et al. reported three cases with AMKL, but none had Ph chromosome .
Literature review of Ph chromosome or BCR/ABL rearrangement in de novo acute megakaryoblastic leukemia
BCR/ABL fusion transcripts
Balatzenko, et al
46,XX,t(9;22)(q34;q11)/(4n) 92,XXXX,t(9;22)x2 /(8n)184,XXXXXXXX,t(9;22)x4 
Dastugue, et al 
Dastugue, et al
Dastugue, et al 
Kaloutsi, et al
Corm, et al 
Ahmad, et al
To the best of our knowledge, this is the first report of de novo AMKL with rare variant of Philadelphia rearrangement and a novel translocation der(16)t(1;16)(q21;q23). Our case and the case reported by Kaloutsi et al.  suggested that the FISH should be considered for detection of variant Philadelphia rearrangement in de novo AMKL patients.
Written informed consent was obtained from the husband of the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
This work was supported in part by the Nature Science Foundation Committee (#30800402).
- Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C: Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the French-American-British Cooperative Group. Ann Intern Med. 1985, 103: 460-462.View ArticlePubMedGoogle Scholar
- San Miguel JF, Gonzalez M, Cañizo MC, Ojeda E, Orfao A, Caballero MD, Moro MJ, Fisac P, Lopez Borrasca A: Leukemias with megakaryoblastic involvement: clinical, hematologic, and immunologic characteristics. Blood. 1988, 72: 402-407.PubMedGoogle Scholar
- Tallman MS, Neuberg D, Bennett JM, Francois CJ, Paietta E, Wiernik PH, Dewald G, Cassileth PA, Oken MM, Rowe JM: Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience. Blood. 2000, 96: 2405-2411.PubMedGoogle Scholar
- Castoldi GL, Liso V, Fenu S, Vegna ML, Mandelli F: Reproducibility of the morphological diagnostic criteria for acute myeloid leukemia: the GIMEMA group experience. Ann Hematol. 1993, 66: 171-174. 10.1007/BF01703231.View ArticlePubMedGoogle Scholar
- Cuneo A, Ferrant A, Michaux JL, Demuynck H, Boogaerts M, Louwagie A, Doyen C, Stul M, Cassiman JJ, Dal Cin P, Castoldi G, Van den Berghe H: Philadelphia chromosome-positive acute myeloid leukemia: cytoimmunologic and cytogenetic features. Haematologica. 1996, 81: 423-427.PubMedGoogle Scholar
- Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB: Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther. 2000, 295: 139-145.PubMedGoogle Scholar
- Cuneo A, Mecucci C, Kerim S, Vandenberghe E, Dal Cin P, Van Orshoven A, Rodhain J, Bosly A, Michaux JL, Martiat P: Multipotent stem cell involvement in megakaryoblastic leukemia: cytologic and cytogenetic evidence in 15 patients. Blood. 1989, 74: 1781-1790.PubMedGoogle Scholar
- Dastugue N, Lafage-Pochitaloff M, Pagès MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Léonard C, Bilhou-Nabéra C, Cabrol C, Capodano AM, Cornillet-Lefebvre P, Lessard M, Mugneret F, Pérot C, Taviaux S, Fenneteaux O, Duchayne E, Berger R, Groupe Français d'Hematologie Cellulaire: Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Français de Cytogénétique Hématologique (GFCH). Blood. 2002, 100: 618-626. 10.1182/blood-2001-12-0241.View ArticlePubMedGoogle Scholar
- Ohyashiki K, Ohyashiki JH, Hojo H, Ohtaka M, Toyama K, Sugita K, Nakazawa S, Sugiura K, Nakazawa K, Nagasawa T, Enomoto Y, Watanabe Y: Cytogenetic findings in adult acute leukemia and myeloproliferative disorders with an involvement of megakaryocyte lineage. Cancer. 1990, 65: 940-948. 10.1002/1097-0142(19900215)65:4<940::AID-CNCR2820650420>3.0.CO;2-W.View ArticlePubMedGoogle Scholar
- Saito K, Nakamura Y, Aoyagi M, Waga K, Yamamoto K, Aoyagi A, Inoue F, Nakamura Y, Arai Y, Tadokoro J, Handa T, Tsurumi S, Arai H, Kawagoe Y, Gunnji H, Kitsukawa Y, Takahashi W, Furusawa S: Low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (CAG regimen) for previously treated patients with relapsed or primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation. Int J Hematol. 2000, 71: 238-244.PubMedGoogle Scholar
- Pallisgaard N, Hokland P, Riishøj DC, Pedersen B, Jørgensen P: Multiplex reverse transcription-polymerase chain reaction for simultaneous screening of 29 translocations and chromosomal aberrations in acute leukemia. Blood. 1998, 92: 574-588.PubMedGoogle Scholar
- Campiotti L, Grandi AM, Biotti MG, Ultori C, Solbiati F, Codari R, Venco A: Megakaryocytic blast crisis as first presentation of chronic myeloid leukemia. Am J Hematol. 2007, 82: 231-233. 10.1002/ajh.20797.View ArticlePubMedGoogle Scholar
- Pelloso LA, Baiocchi OC, Chauffaille ML, Yamamoto M, Hungria VT, Bordin JO: Megakaryocytic blast crisis as a first presentation of chronic myeloid leukemia. Eur J Haematol. 2002, 69: 58-61. 10.1034/j.1600-0609.2002.01638.x.View ArticlePubMedGoogle Scholar
- Al-Shehri A, Al-Seraihy A, Owaidah TM, Belgaumi AF: Megakaryocytic blast crisis at presentation in a pediatric patient with chronic myeloid leukemia. Hematol Oncol Stem Cell Ther. 2010, 3: 42-46.View ArticlePubMedGoogle Scholar
- Pullarkat ST, Vardiman JW, Slovak ML, Rao DS, Rao NP, Bedell V, Said JW: Megakaryocytic blast crisis as a presenting manifestation of chronic myeloid leukemia. Leuk Res. 2008, 32: 1770-1775. 10.1016/j.leukres.2008.02.025.View ArticlePubMedGoogle Scholar
- Bryant BJ, Alperin JB, Elghetany MT: Paraplegia as the presenting manifestation of extramedullary megakaryoblastic transformation of previously undiagnosed chronic myelogenous leukemia. Am J Hematol. 2007, 82: 150-154. 10.1002/ajh.20777.View ArticlePubMedGoogle Scholar
- Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002, 100: 2292-2302. 10.1182/blood-2002-04-1199.View ArticlePubMedGoogle Scholar
- Peterson LC, Bloomfield CD, Brunning RD: Blast crisis as an initial or terminal manifestation of chronic myeloid leukemia. A study of 28 patients. Am J Med. 1976, 60: 209-220. 10.1016/0002-9343(76)90430-7.View ArticlePubMedGoogle Scholar
- Balatzenko G, Guenova M, Zechev J, Toshkov S: Acute megakaryoblastic leukaemia with extreme thrombocytosis and p190 (bcr/abl) rearrangement. Ann Hematol. 2004, 83: 381-385. 10.1007/s00277-003-0783-1.View ArticlePubMedGoogle Scholar
- Kaloutsi V, Hadjileontis C, Tsatalas C, Sambani C, Kostopoulos I, Papadimitriou C: Occurrence of a variant Philadelphia translocation, t(10;22), in de novo acute megakaryoblastic leukemia. Cancer Genet Cytogenet. 2004, 152: 52-55. 10.1016/j.cancergencyto.2003.08.022.View ArticlePubMedGoogle Scholar
- Corm S, Renneville A, Rad-Quesnel E, Grardel N, Preudhomme C, Quesnel B: Successful treatment of imatinib-resistant acute megakaryoblastic leukemia with e6a2 BCR/ABL: use of dasatinib and reduced-conditioning stem-cell transplantation. Leukemia. 2007, 21: 2376-2377. 10.1038/sj.leu.2404792.View ArticlePubMedGoogle Scholar
- Ahmad F, Dalvi R, Das BR, Mandava S: Novel t(8;17)(q23;q24.2) and t(9;22)(p24.1;q12.2) in acute megakaryoblastic leukemia AML-M7 subtype in an adult patient. Cancer Genet Cytogenet. 2009, 193: 112-115. 10.1016/j.cancergencyto.2009.04.018.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.