Acute megakaryoblastic leukemia
Acute megakaryoblastic leukemia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Synonyms and keywords: Leukemia, megakaryoblastic, acute; megakaryoblastic leukemia, acute; AMKL; leukemia, myeloid, acute, M7; megakaryocytic leukemia; megakaryocytic leukemia, acute; myeloid leukemia, acute, M7
Overview
Historical Perspective
Classification
Pathophysiology
- It is associated with GATA1, and risks are increased in individuals with Down syndrome.[1] However, not all cases are associated with Down syndrome,[2] and other genes can also be associated with AMKL.[3]
- According to the report of the French-American-British Cooperative Group, this category of AML (M7 subtype) is associated with 30% or more blasts in the bone marrow. Blasts are identified as being of megakaryocyte lineage by; expression of megakaryocyte specific antigens and platelet peroxidase reaction on electron microscopy.[4]
- Myelofibrosis is usually associated with AMKL; however, the exact underlying pathophysiology is controversial. The investigators did not find any direct correlation between acute myelofibrosis and the fibroblasts obtained from the bone marrow of patients with AMKL. Nevertheless, it was proposed that some humoral factors may play a key role in developing bone marrow fibrosis.[5]
- Transforming Growth Factor-β (TG-β) was identified to be the significant contributor in AMKL associated myelofibrosis in addition to some other unknown factors due to the strong stimulatory effects on collagen.[6]
Causes
Differentiating [disease name] from other Diseases
Distinguishing features from other subtypes of AML are following:
- Thrombocytopenia is more common and severe in AMKL compared with myelodysplastic syndrome (MDS). Blast cells in the bone marrow are <30% in MDS versus >30% in AMKL.[7]
- Presence of megakaryocytic specific antigens (CD41, CD61)[8] and markers (glycoprotein 1b) and platelets peroxidase activity. Karyotype analysis also helpful due to its complex and unusual karyotypic presentation (t(1;22)(p13;q13).[9][10]
Differential Diagnoses:[11]
Acute myeloid leukemia otherwise not specified as per WHO classification:
- Acute myeloid leukemia with minimal differentiation
- Acute myeloid leukemia without maturation
- Acute myeloid leukemia with maturation
- Acute myelomonocytic leukemia
- Acute monoblastic/monocytic leukemia
- Acute erythroid leukemia
- Pure erythroid leukemia
- Erythroleukemia, erythroid/myeloid
- Acute basophilic leukemia
- Acute panmyelosis with myelofibrosis (a.k.a acute myelofibrosis)
Epidemiology and Demographics
- AMKL is the most common subtype of AML reported in Down syndrome patients.[12] It is more common in children compared with adults. The prevalence in children and adults is ~15% and 0.6%, respectively.[13][14]
- Down syndrome patients carry a 200 fold increased risk of developing AMKL vs. non-Down syndrome patients.[15] Similarly, another review proposed a 500 fold increased risk.[16] It almost exclusively occurs in the first 3 years of life.[17][18]
- Transient leukemia (TL) occurs in approximately 10% of Down syndrome infants, which is also attributed to transient myeloproliferative disorder.[19][20] In most cases, TL spontaneously resolves; however, during the first four years of life, it progresses to acute megakaryoblastic leukemia in 13% to 33% of patients.[21]
Risk Factors
- Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
Natural History, Complications and Prognosis
Due to the rarity of this subtype of hematological malignancy, limited data is available on the natural course or prognosis.
- Clonal proliferation of early megakaryoblasts in the bone marrow results in acute megakaryoblastic leukemia (AMKL).[22] It has a bimodal onset of presentation—occurs both in the pediatric age group (<4 years) and adults.[23]
- In childhood, it is more prevalent in patients with Down syndrome. While it is rare in adults, approximately 0.6% (24/3603) reported in the GIMEMA trial.[14]
- Cases of AMKL secondary to chronic myelogenous leukemia and essential thrombocytosis have been reported in the medical literature.[24][25]
Complications
- Periorbital swelling
- Periosteal elevation
- Osteolytic lesions, especially in long bones, e.g., femur[26]
- Osteoporosis with pathologic fractures[27][28]
- Sweet syndrome (SS)[29]
- Leukemia cutis[30]
- Hypercalcemia[31]
Prognosis
Apart from AMKL in Down syndrome patients, the prognosis of AMKL is poor. The efficacy profile of AMKL in Down syndrome patients is favorable, but it comes with a lot of treatment-related toxicity.
- According to the Children’s Oncology Group (COG) AML0431 trial results, the 5-year event-free survival and overall survival rates were 90% and 93% in 204 eligible Down syndrome with AMKL patients.[32]
- Similarly, the reported 3-year overall survival rate was 100% among 3 AMKL with Down syndrome patients while (47±12%) in non-Down syndrome patients.[33]
- The 5-year overall survival rate in AMKL was 10.6% versus 17.5% in non-M7 Acute myeloid leukemia subtypes.[34] Currently, chemotherapy and allogenic bone marrow transplant (Allo-BMT) are main therapy. Treatment-related toxicity is a big challenge. To address this issue, elaborated large future clinical studies are required.
Diagnosis
Diagnostic Criteria
History and Symptoms
- Acute megakaryoblastic leukemia (AMKL) has a wide array of presentations. The onset is either acute or insidious. The degree of pancytopenia varies among patients.[35] Other features include fever, irritability, headache, fatigue, bone pain,[36] hepatosplenomegaly (HSM), and lymphadenopathy,[37][26] pallor, generalized pain, temporal swelling, bruising, and difficulty walking.[38]
- Greater than 50% of leukemia patients demonstrate skeletal features and are mostly related to the AMKL subtype.[39]
Physical Examination
Down syndrome features are present in patients with Down syndrome associated AMKL.
Laboratory Findings
The diagnosis of AMKL (M7) is based on the following:
- Bone marrow biopsy demonstrating 30% or more leukemic cells of megakaryocytic lineage
- Conducting tests that detect platelet-specific antibodies which could be monoclonal or polyclonal.
- Bone marrow biopsy is recommended in patients who developed myelofibrosis. Visualization of blasts and mature megakaryocytes on biopsy sections is diagnostic.
Electrocardiogram
There are no ECG findings associated with
X-ray
Echocardiography or Ultrasound
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
- In adults, the features include
- Pancytopenia with low blast counts in the blood
- Myelofibrosis
- An absence of lymphadenopathy and hepatosplenomegaly
- Poor response to chemotherapy,and short clinical course.
- In children, the same clinical presentation but with variable course especially in very young children; both leukocytosis and organomegaly may be present in children with M7. Complete remission and long term survival are more common in children than adults.
- The morphology of cells was observed by means of Bone marrow smear
- The immunophenotype was detected by flow cytometry and immunohistochemistry assay.[41]
- In blood and bone marrow smears megakaryoblasts are usually medium sized to large cells with a high nuclear- cytoplasmic ratio. Nuclear chromatin is dense and homogeneous. There is scanty, variable basophilic cytoplasm which may be vacuolated. An irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present. The megakaryoblasts lack myeloperoxidase activity and stain negatively with Sudan black B (SBB).
- They are alpha naphthyl butyrate esterase negative and manifest variable alpha naphthyl acetate esterase activity usually in scattered clumps or granules in the cytoplasm. PAS staining also varies from negative to focal or granular positivity, to strongly positive staining.
- A marrow aspirate is difficult to obtain in many cases because of variable degree of myelofibrosis.
- More precise identification by immunophenotyping or with electron microscopy (EM). Immunophenotyping using MoAb to megakaryocyte restricted antigen (CD41 and CD61) may be diagnostic.[42]
Karyotype analysis:
- It is essential owing to the fact that AMKL has complex karyotype with peculiar presentation (t(1;22)(p13;q13).[9][10]
Radiographic features:
- Using Chest X-ray (CXR), skeletal survey, CT scan, and bone scan are:
- Osteolytic lesions in the ribs, diffuse metaphysical lucency, periostitis with periosteal reaction, and pathologic fractures involving long bones, such as femoral bones, and increase uptake in the involved bones.[26]
Treatment
Medical Therapy
- According to the AML-BFM (Berlin–Frankfurt–Münster) 98 and AML-BFM ((Berlin–Frankfurt–Münster) 93 clinical studies, intensive AML targeted chemotherapy in Down syndrome-associated AMKL results in high event-free survival rates versus non-Down syndrome patients. However, they are also prone to develop treatment-related toxicity at standard doses due to chemo sensitivity.[43]
The treatment is divided into induction therapy and consolidation therapy.
- Induction therapy — involves two cycles (four weeks apart ) of Ara-Cytarabine (Ara-C) at 100 mg/m2 /day continuous infusion for 7 days, vincristine at 0.7 mg/m2 on day 7, and pirarubicin at 25 mg/m2 by 60 min infusion on days 2, and 4 (AVC1).[44]
- Consolidation therapy — follows once complete remission is achieved with the following regimen; etoposide & high-dose Ara-C (EC), mitoxantrone and continuous-dose Ara-C (MC), and pirarubicin, vincristine, and continuous-dose Ara-C (AVC2).[45]
The doses are given below:[46]
MC regimen:
- Ara-C at 100 mg/m2 /day continuous infusion for 5 days and
- Mitoxantrone at 3.5 mg/m2 by 60 min infusion on days 2–4
EC regimen
- High-dose Ara-C 1 g/m2 every 12 hrs on days 1–5,
- Etoposide 66 mg/m2 by 2 h infusion on days 2–4), and
AVC2 regimen
- Ara-C at 100 mg/m2 /day on days 1–5,
- Pirarubicin 35 mg/m2 by 60 min infusion on day 2, and
- Vincristine at 0.7 mg/m2 on day 5
In relapsed state, re-induction with fludarabine and Ara-C combination or same AVC regimen can be utilized. Allogenic bone marrow transplant (Allo-BMT) from a suitable donor is justified if the patients achieved second complete remission. Currently, there is no recommended definitive therapy for non-Down syndrome with AMKL cohort. Novel therapeutic interventions are undertaken.[47]
- Some study groups proposed that non-Down syndrome with AMKL is a high-risk condition; therefore, allogeneic hematopoietic stem cell transplantation (Allo-HSCT) during first complete remission is recommended to benefit the patients. In contrast, no benefit of Allo-HSCT is evident over chemotherapy without remission.[16]
- In AML-BFM 04 trial, patients were randomized to receive induction therapy with either (Ara-C), liposomal daunorubicin, and etoposide (ADxE) or Ara-C, idarubicin, and etoposide (AIE) regimen. Consolidation therapy with 2-chloro-2-deoxyadenosine (2-CDA) and Ara-C and idarubicin was preceded by second induction therapy with HAM (high-dose Ara-C, mitoxantrone, cytarabine i.th). However, no significant results were obtained regarding event-free survival (EFS) and overall survival (OS).[48]
Surgery
Prevention
References
- ↑ Hitzler JK, Cheung J, Li Y, Scherer SW, Zipursky A (2003). "GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome". Blood. 101 (11): 4301–4. doi:10.1182/blood-2003-01-0013. PMID 12586620.
- ↑ Hama A, Yagasaki H, Takahashi Y; et al. (2008). "Acute megakaryoblastic leukaemia (AMKL) in children: a comparison of AMKL with and without Down syndrome". Br. J. Haematol. 140 (5): 552–61. doi:10.1111/j.1365-2141.2007.06971.x. PMID 18275433.
- ↑ Gu TL, Mercher T, Tyner JW; et al. (2007). "A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia". Blood. 110 (1): 323–33. doi:10.1182/blood-2006-10-052282. PMID 17360941.
- ↑ Bennett, John M. (1985). "Criteria for the Diagnosis of Acute Leukemia of Megakaryocyte Lineage (M7)". Annals of Internal Medicine. 103 (3): 460. doi:10.7326/0003-4819-103-3-460. ISSN 0003-4819.
- ↑ Clare, Nanette; Elson, David; Manhoff, Louis (1982). "Cytogenetic Studies of Peripheral Myeloblasts and Bone Marrow Fibroblasts in Acute Myelofibrosis". American Journal of Clinical Pathology. 77 (6): 762–766. doi:10.1093/ajcp/77.6.762. ISSN 0002-9173.
- ↑ Terui, T; Niitsu, Y; Mahara, K; Fujisaki, Y; Urushizaki, Y; Mogi, Y; Kohgo, Y; Watanabe, N; Ogura, M; Saito, H (1990). "The production of transforming growth factor-beta in acute megakaryoblastic leukemia and its possible implications in myelofibrosis". Blood. 75 (7): 1540–1548. doi:10.1182/blood.V75.7.1540.1540. ISSN 0006-4971.
- ↑ Zipursky, A.; Thorner, P.; De Harven, E.; Christensen, H.; Doyle, J. (1994). "Myelodysplasia and acute megakaryoblastic leukemia in down's syndrome". Leukemia Research. 18 (3): 163–171. doi:10.1016/0145-2126(94)90111-2. ISSN 0145-2126.
- ↑ O Olatunji, Philip (2018). "A case of acute megakaryoblastic leukaemia (FAB M7), a rare type of acute myeloid leukemia (AML), in a teenager". Malawi Medical Journal. 30 (4): 298. doi:10.4314/mmj.v30i4.15. ISSN 1995-7262.
- ↑ 9.0 9.1 Döhner, Hartmut; Estey, Elihu H.; Amadori, Sergio; Appelbaum, Frederick R.; Büchner, Thomas; Burnett, Alan K.; Dombret, Hervé; Fenaux, Pierre; Grimwade, David; Larson, Richard A.; Lo-Coco, Francesco; Naoe, Tomoki; Niederwieser, Dietger; Ossenkoppele, Gert J.; Sanz, Miguel A.; Sierra, Jorge; Tallman, Martin S.; Löwenberg, Bob; Bloomfield, Clara D. (2010). "Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet". Blood. 115 (3): 453–474. doi:10.1182/blood-2009-07-235358. ISSN 0006-4971.
- ↑ 10.0 10.1 De Marchi, Federico; Araki, Marito; Komatsu, Norio (2019). "Molecular features, prognosis, and novel treatment options for pediatric acute megakaryoblastic leukemia". Expert Review of Hematology. 12 (5): 285–293. doi:10.1080/17474086.2019.1609351. ISSN 1747-4086.
- ↑ Döhner, Hartmut; Estey, Elihu H.; Amadori, Sergio; Appelbaum, Frederick R.; Büchner, Thomas; Burnett, Alan K.; Dombret, Hervé; Fenaux, Pierre; Grimwade, David; Larson, Richard A.; Lo-Coco, Francesco; Naoe, Tomoki; Niederwieser, Dietger; Ossenkoppele, Gert J.; Sanz, Miguel A.; Sierra, Jorge; Tallman, Martin S.; Löwenberg, Bob; Bloomfield, Clara D. (2010). "Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet". Blood. 115 (3): 453–474. doi:10.1182/blood-2009-07-235358. ISSN 0006-4971.
- ↑ Xavier, Ana C.; Ge, Yubin; Taub, Jeffrey W. (2009). "Down Syndrome and Malignancies: A Unique Clinical Relationship". The Journal of Molecular Diagnostics. 11 (5): 371–380. doi:10.2353/jmoldx.2009.080132. ISSN 1525-1578.
- ↑ Xavier, Ana C.; Ge, Yubin; Taub, Jeffrey W. (2009). "Down Syndrome and Malignancies: A Unique Clinical Relationship". The Journal of Molecular Diagnostics. 11 (5): 371–380. doi:10.2353/jmoldx.2009.080132. ISSN 1525-1578.
- ↑ 14.0 14.1 Pagano, L; Pulsoni, A; Vignetti, M; Mele, L; Fianchi, L; Petti, MC; Mirto, S; Falcucci, P; Fazi, P; Broccia, G; Specchia, G; Di Raimondo, F; Pacilli, L; Leoni, P; Ladogana, S; Gallo, E; Venditti, A; Avanzi, G; Camera, A; Liso, V; Leone, G; Mandelli, F (2002). "Acute megakaryoblastic leukemia: experience of GIMEMA trials". Leukemia. 16 (9): 1622–1626. doi:10.1038/sj.leu.2402618. ISSN 0887-6924.
- ↑ Zipursky, Alvin; Peeters, Marie; Poon, Annette (2009). "Megakaryoblastic Leukemia and Down's Syndrome: A Review". Pediatric Hematology and Oncology. 4 (3): 211–230. doi:10.3109/08880018709141272. ISSN 0888-0018.
- ↑ 16.0 16.1 Athale, Uma H.; Razzouk, Bassem I.; Raimondi, Susana C.; Tong, Xin; Behm, Frederick G.; Head, David R.; Srivastava, Deo K.; Rubnitz, Jeffrey E.; Bowman, Laura; Pui, Ching-Hon; Ribeiro, Raul C. (2001). "Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience". Blood. 97 (12): 3727–3732. doi:10.1182/blood.V97.12.3727. ISSN 1528-0020.
- ↑ Xavier, Ana C.; Ge, Yubin; Taub, Jeffrey W. (2009). "Down Syndrome and Malignancies: A Unique Clinical Relationship". The Journal of Molecular Diagnostics. 11 (5): 371–380. doi:10.2353/jmoldx.2009.080132. ISSN 1525-1578.
- ↑ Zipursky, Alvin; Peeters, Marie; Poon, Annette (2009). "Megakaryoblastic Leukemia and Down's Syndrome: A Review". Pediatric Hematology and Oncology. 4 (3): 211–230. doi:10.3109/08880018709141272. ISSN 0888-0018.
- ↑ Zipursky, Alvin (2003). "Transient leukaemia - a benign form of leukaemia in newborn infants with trisomy 21". British Journal of Haematology. 120 (6): 930–938. doi:10.1046/j.1365-2141.2003.04229.x. ISSN 0007-1048.
- ↑ Pine, Sharon R.; Guo, Qianxu; Yin, Changhong; Jayabose, Somasundaram; Druschel, Charlotte M.; Sandoval, Claudio (2007). "Incidence and clinical implications of GATA1 mutations in newborns with Down syndrome". Blood. 110 (6): 2128–2131. doi:10.1182/blood-2007-01-069542. ISSN 0006-4971.
- ↑ Klusmann, Jan-Henning; Creutzig, Ursula; Zimmermann, Martin; Dworzak, Michael; Jorch, Norbert; Langebrake, Claudia; Pekrun, Arnulf; Macakova-Reinhardt, Katarina; Reinhardt, Dirk (2008). "Treatment and prognostic impact of transient leukemia in neonates with Down syndrome". Blood. 111 (6): 2991–2998. doi:10.1182/blood-2007-10-118810. ISSN 0006-4971.
- ↑ Tallman MS, Neuberg D, Bennett JM, Francois CJ, Paietta E, Wiernik PH; et al. (2000). "Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience". Blood. 96 (7): 2405–11. PMID 11001891.
- ↑ Gassmann, Winfried; Löffler, Helmut (2009). "Acute Megakaryoblastic Leukemia". Leukemia & Lymphoma. 18 (sup1): 69–73. doi:10.3109/10428199509075307. ISSN 1042-8194.
- ↑ ecancermedicalscience. doi:10.3332/ecancer.2013.375. ISSN 1754-6605. Missing or empty
|title=(help) - ↑ Radaelli, Franca; Mazza, Rita; Curioni, Elisabetta; Ciani, Alberto; Pomati, Mauro; Maiolo, Anna-Teresa (2002). "Acute megakaryocytic leukemia in essential thrombocythemia: an unusual evolution?". European Journal of Haematology. 69 (2): 108–111. doi:10.1034/j.1600-0609.2002.02734.x. ISSN 0902-4441.
- ↑ 26.0 26.1 26.2 26.3 Athale, Uma H.; Kaste, Sue C.; Razzouk, Bassem I.; Rubnitz, Jeffrey E.; Ribeiro, Raul C. (2002). "Skeletal Manifestations of Pediatric Acute Megakaryoblastic Leukemia". Journal of Pediatric Hematology/Oncology. 24 (7): 561–565. doi:10.1097/00043426-200210000-00014. ISSN 1077-4114.
- ↑ Athale, Uma H.; Kaste, Sue C.; Razzouk, Bassem I.; Rubnitz, Jeffrey E.; Ribeiro, Raul C. (2002). "Skeletal Manifestations of Pediatric Acute Megakaryoblastic Leukemia". Journal of Pediatric Hematology/Oncology. 24 (7): 561–565. doi:10.1097/00043426-200210000-00014. ISSN 1077-4114.
- ↑ Kushner, David C.; Weinstein, Howard J.; Kirkpatrick, John A. (1980). "The radiologic diagnosis of leukemia and lymphoma in children". Seminars in Roentgenology. 15 (4): 316–334. doi:10.1016/0037-198X(80)90027-9. ISSN 0037-198X.
- ↑ Yokoyama K, Kojima M, Komatsumoto S, Nara M, Ohyashiki K, Ikeda Y; et al. (1993). "[Acute megakaryoblastic leukemia associated with Sweet's syndrome, including review of the literature]". Rinsho Ketsueki. 34 (3): 341–7. PMID 8479086.
- ↑ Tsurumi H, Takahashi T, Koshino Y, Oyama M, Matsutomo K, Yasuda M; et al. (1991). "[Acute megakaryoblastic leukemia with leukemia cutis, meningeal leukemia, and myelofibrosis]". Rinsho Ketsueki. 32 (11): 1475–80. PMID 1758056.
- ↑ Qayed M, Ahmed I, Valentini RP, Cushing B, Rajpurkar M (2009). "Hypercalcemia in pediatric acute megakaryocytic leukemia: case report and review of the literature". J Pediatr Hematol Oncol. 31 (5): 373–6. doi:10.1097/MPH.0b013e31819a5d29. PMID 19415024.
- ↑ Taub, Jeffrey W.; Berman, Jason N.; Hitzler, Johann K.; Sorrell, April D.; Lacayo, Norman J.; Mast, Kelley; Head, David; Raimondi, Susana; Hirsch, Betsy; Ge, Yubin; Gerbing, Robert B.; Wang, Yi-Cheng; Alonzo, Todd A.; Campana, Dario; Coustan-Smith, Elaine; Mathew, Prasad; Gamis, Alan S. (2017). "Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial". Blood. 129 (25): 3304–3313. doi:10.1182/blood-2017-01-764324. ISSN 0006-4971.
- ↑ Qi, Haixiao; Mao, Yan; Cao, Qian; Sun, Xingzhen; Kuai, Wenxia; Song, Junhong; Ma, Li; Hong, Ze; Hu, Jian; Zhou, Guoping (2020). "Clinical Characteristics and Prognosis of 27 Patients with Childhood Acute Megakaryoblastic Leukemia". Medical Science Monitor. 26. doi:10.12659/MSM.922662. ISSN 1643-3750.
- ↑ Giri, Smith; Pathak, Ranjan; Prouet, Philippe; Li, Bojia; Martin, Mike G. (2014). "Acute megakaryocytic leukemia is associated with worse outcomes than other types of acute myeloid leukemia". Blood. 124 (25): 3833–3834. doi:10.1182/blood-2014-09-603415. ISSN 0006-4971.
- ↑ Zipursky A, Peeters M, Poon A (1987). "Megakaryoblastic leukemia and Down's syndrome: a review". Pediatr Hematol Oncol. 4 (3): 211–30. doi:10.3109/08880018709141272. PMID 2978961.
- ↑ Paredes-Aguilera R, Romero-Guzman L, Lopez-Santiago N, Trejo RA (2003). "Biology, clinical, and hematologic features of acute megakaryoblastic leukemia in children". Am J Hematol. 73 (2): 71–80. doi:10.1002/ajh.10320. PMID 12749007.
- ↑ Jayasudha, A. V.; Nair, Rekha A.; Jacob, Priya Mary; Renu, S.; Anila, K. R.; Sindhu Nair, P.; Priya Kumari, T.; Kusuma Kumary, P. (2014). "Clinical and Hematological Profile of Acute Megakaryoblastic Leukemia: A 2 Year Study". Indian Journal of Hematology and Blood Transfusion. 31 (2): 169–173. doi:10.1007/s12288-014-0413-1. ISSN 0971-4502.
- ↑ Athale, Uma H.; Kaste, Sue C.; Razzouk, Bassem I.; Rubnitz, Jeffrey E.; Ribeiro, Raul C. (2002). "Skeletal Manifestations of Pediatric Acute Megakaryoblastic Leukemia". Journal of Pediatric Hematology/Oncology. 24 (7): 561–565. doi:10.1097/00043426-200210000-00014. ISSN 1077-4114.
- ↑ Athale, Uma H.; Kaste, Sue C.; Razzouk, Bassem I.; Rubnitz, Jeffrey E.; Ribeiro, Raul C. (2002). "Skeletal Manifestations of Pediatric Acute Megakaryoblastic Leukemia". Journal of Pediatric Hematology/Oncology. 24 (7): 561–565. doi:10.1097/00043426-200210000-00014. ISSN 1077-4114.
- ↑ Paredes-Aguilera, Rogelio; Romero-Guzman, Lina; Lopez-Santiago, Norma; Trejo, Rosa Arana (2003). "Biology, clinical, and hematologic features of acute megakaryoblastic leukemia in children". American Journal of Hematology. 73 (2): 71–80. doi:10.1002/ajh.10320. ISSN 0361-8609.
- ↑ Lei Q, Liu Y, Tang SQ (2007). "[Childhood acute megakaryoblastic leukemia]". Zhongguo Shi Yan Xue Ye Xue Za Zhi (in Chinese). 15 (3): 528–32. PMID 17605859.
- ↑ Vardiman JW, Harris NL, Brunning RD (2002). "The World Health Organization (WHO) classification of the myeloid neoplasms". Blood. 100 (7): 2292–302. doi:10.1182/blood-2002-04-1199. PMID 12239137.
- ↑ Creutzig, U; Reinhardt, D; Diekamp, S; Dworzak, M; Stary, J; Zimmermann, M (2005). "AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity". Leukemia. 19 (8): 1355–1360. doi:10.1038/sj.leu.2403814. ISSN 0887-6924.
- ↑ Taga, Takashi; Shimomura, Yasuto; Horikoshi, Yasuo; Ogawa, Atsushi; Itoh, Masaki; Okada, Masahiko; Ueyama, Junichi; Higa, Takeshi; Watanabe, Arata; Kanegane, Hirokazu; Iwai, Asayuki; Saiwakawa, Yutaka; Kogawa, Kazuhiro; Yamanaka, Junko; Tsurusawa, Masahito (2011). "Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: Report from the Japanese children's cancer and leukemia study group (JCCLSG) AML 9805 down study". Pediatric Blood & Cancer. 57 (1): 36–40. doi:10.1002/pbc.22943. ISSN 1545-5009.
- ↑ Taga, Takashi; Shimomura, Yasuto; Horikoshi, Yasuo; Ogawa, Atsushi; Itoh, Masaki; Okada, Masahiko; Ueyama, Junichi; Higa, Takeshi; Watanabe, Arata; Kanegane, Hirokazu; Iwai, Asayuki; Saiwakawa, Yutaka; Kogawa, Kazuhiro; Yamanaka, Junko; Tsurusawa, Masahito (2011). "Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: Report from the Japanese children's cancer and leukemia study group (JCCLSG) AML 9805 down study". Pediatric Blood & Cancer. 57 (1): 36–40. doi:10.1002/pbc.22943. ISSN 1545-5009.
- ↑ Taga, Takashi; Shimomura, Yasuto; Horikoshi, Yasuo; Ogawa, Atsushi; Itoh, Masaki; Okada, Masahiko; Ueyama, Junichi; Higa, Takeshi; Watanabe, Arata; Kanegane, Hirokazu; Iwai, Asayuki; Saiwakawa, Yutaka; Kogawa, Kazuhiro; Yamanaka, Junko; Tsurusawa, Masahito (2011). "Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: Report from the Japanese children's cancer and leukemia study group (JCCLSG) AML 9805 down study". Pediatric Blood & Cancer. 57 (1): 36–40. doi:10.1002/pbc.22943. ISSN 1545-5009.
- ↑ De Marchi, Federico; Araki, Marito; Komatsu, Norio (2019). "Molecular features, prognosis, and novel treatment options for pediatric acute megakaryoblastic leukemia". Expert Review of Hematology. 12 (5): 285–293. doi:10.1080/17474086.2019.1609351. ISSN 1747-4086.
- ↑ Schweitzer, Jana; Zimmermann, Martin; Rasche, Mareike; von Neuhoff, Christine; Creutzig, Ursula; Dworzak, Michael; Reinhardt, Dirk; Klusmann, Jan-Henning (2015). "Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial". Annals of Hematology. 94 (8): 1327–1336. doi:10.1007/s00277-015-2383-2. ISSN 0939-5555.