Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (337 page)

   Acute promyelocytic leukemia (APL) with t(15;17)(q24;q21), with the PML–RARA retinoic acid receptor-α translocation. Five percent to 8% of acute leukemias. Use of FISH analysis for
rapid diagnosis
may be useful for early initiation of ATRA therapy together with an anthracycline.

There are two varieties of APL: the majority (considered typical APL) have hypergranular promyelocytes, many containing large Auer rods and high incidence of acute DIC; the microgranular (variant) PML, presents with bilobed nuclei and very high WBC. APL provided the first paradigm of molecularly targeted therapy, ATRA. Variant RARA translocations can be detected by classical cytogenetics and by FISH and are important to distinguish, as not all variants respond to ATRA. Prognosis is most favorable among all AML subtypes when treated promptly with ATRA and an anthracycline.

   AML with t(9;11)(p22;q23); the MLL gene on chromosome 11q23 is involved in numerous translocations with different partner genes, most commonly in association with MLLT3 at 9p22. Most frequently, the morphology is monocytic or myelomonocytic. Detected in 9–12% of pediatric and 2% of adult AML. Intermediate prognosis; other MLL rearrangements tend to have poorer prognosis.

   AML with t(6;9)(p23;q34) fuses DEK on chromosome 6, with NUP214 (CAN) on chromosome 9. May have monocytic, basophilic, and multilineage dysplastic features. Incidence: 0.7–1.8% of AML. Presents with lower WBC than other AML and pancytopenia. Poor prognosis.

   AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) with rearrangement of EVII, and RPN1 genes may present de novo or evolve from MDS with normal or increased platelet counts and atypical megakaryocytes in the bone marrow. Comprises 1–2% of all AML. Trilineage dysplastic morphology is common; aggressive disease with short survival.

   AML (megakaryoblastic) with t(1;22)(p13;q13). Fusion of RBM15-MKL1 genes. Very rare leukemia that occurs in infants and young children. Marked hepatosplenomegaly.

   AML with MDS-related changes may have complex karyotypes, unbalanced abnormalities, such as −7/7q− or −5/5q−, or balanced abnormalities.

   Therapy-related myeloid neoplasms have abnormal karyotypes in >90% of cases. Approximately 70% of patients have unbalanced chromosomal aberrations, mainly whole or partial loss of chromosomes 5 and/or 7, frequently associated with other chromosomal abnormalities.

   
Molecular genetics
: In addition to the genetic mutations with cytogenetic abnormalities described above, specific gene mutations are also common and may be present in cases with or without detectable cytogenetic abnormalities. Mutations in FLT3 (fms-related tyrosine kinase 3) and NPM1 (nucleophosmin) are of particular prognostic import. In normal karyotype cases, FLT3-ITD (internal tandem duplication) carries an unfavorable prognosis, whereas NPM1 mutation is considered favorable. Similarly, CEBPA (CCAAT/ enhancer-binding protein α) mutation in a normal karyotype background is considered favorable.

   Monitoring of minimal residual disease (MRD) remains an active field of investigation. MRD is defined as any measurable disease or leukemic cells detectable above a certain threshold level. Finding of MRD after intensive therapy affects survival negatively. As of now, half of AML patients lack a molecular target suitable for MRD monitoring. For those patients with a suitable target, multiparameter flow cytometry can be applied to peripheral blood investigations. Protocols are in place for pediatric AML, but not for adults with the disease.

Suggested Readings

Arber DA, Brunning RD, LeBeau MM, et al. Acute myeloid leukaemia with recurrent genetic abnormalities. In:
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues
, 4th ed. Lyon, France: International Agency for Research on Cancer; 2008:110–123. (See also pp. 124–144.)

Grossmann V, Schnittger S, Kohlmann A, et al. A novel hierarchical prognostic model of AML solely based on molecular mutations.
Blood.
2012;120:2963–2972.

Paietta E. Minimal residual disease in acute myeloid leukemia: coming of age.
Hematology Am Soc Hematol Educ Program.
2012;2012:35–42.

Walter RB, Othus M, Burnett AK, et al. Significance of FAB subclassification of “acute myeloid leukemia, NOS” in the 2008 WHO classification: analysis of 5848 newly diagnosed patients.
Blood.
2013;121:2424–2431.

T LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (T-ALL)