Therapy Related Myeloid Neoplasms

Definition

• Myeloid neoplasms arising as complications of chemotherapy or radiation therapy

Diagnostic Criteria

• Myeloid neoplasms arising as complications of therapy should be classified separately due to their generally poor prognosis
• Category includes development of:
• Therapy related acute myeloid leukemia (tAML)
• Therapy related myelodysplastic syndromes (tMDS)
• Therapy related myelodysplastic/myeloproliferative neoplasms (tMDS/MPN)
• Transformation of myeloproliferative neoplasms is excluded
• Morphologic features are those of the corresponding non-treatment related disorders
• See specific diseases for criteria (Classification/Lists)
• Morphologic subclassification, including blast percentage, not as prognostically important as in de novo myeloid neoplasms
• Most develop 1-10 years post therapy (see Clinical)
  • Associated with treatment of a variety of prior disorders
• Cytogenetics highly prognostic – (see Supplemental Studies)
  • By contrast, the WHO categories for de novo myeloid neoplasms do not identify significantly better prognosis subgroups
• Special differential diagnostic considerations:
  • De novo myeloid neoplasia
  • Transient mild dyspoiesis in the setting of ongoing or recent chemotherapy
  • For both, correlate with cytogenetic studies (see Supplemental Studies) and clinical course

Dita Gratzinger MD PhD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting: 12/17/11

Supplemental Studies

• Cytogenetics is highly prognostic
  • Poor prognosis: del/loss chromosome 5 or 7, complex karyotype, 11q23 abnormality
• Prognosis may be better, though likely still worse than de novo:
• Acute myeloid leukemia with t(15;17)(q22;q12)
• Acute myeloid leukemia with inv or t(16)(p13.1q22)
• Caution: isolated del(20q) is uncommon in this setting, and  if seen in the absence of convincing dysplasia or increased blasts, may not indicate a therapy-related myeloid neoplasm (Sun 2011).

Clinical

• Most commonly associated with alkylating agents, topoisomerase II inhibotors and ionizing radiation
  • May also occur with antimetabolites, antitubulin agents, radioiodine
• Associated with treatment of a variety of prior disorders
• Most are neoplasms, hematologic and non-hematologic
• May also be seen with treatment of non-neoplastic disorders
• May also be seen following chemotherapy with autologous hematopoietic stem cell transplant
• Two main presentation groups that may overlap
• Many patients have received multiple chemotherapeutic agents and are thus difficult to assign to the following groups
• About 70% of cases develop 5-10 years post therapy
• Associated with alkylating agents and/or ionizing radiation
• Most develop tMDS and bone marrow failure
• Fewer develop tMDS/MPN or tAML
• Primarily associated with unbalanced chromosomal abnormalities
• About 20-30% of cases develop 1-5 years post therapy
• Associated with topoisomerase II inhibitors
• Most present with tAML without an MDS phase
• Most associated with balanced chromosomal translocations
• Overall poor prognosis, median survival < 1 year

Classification / Lists

WHO 2008 Classification of Myeloid Neoplasms

Myeloproliferative Neoplasms (MPN)

• Chronic myeloid leukemia, BCR-ABL1 pos
• Chronic neutrophilic leukemia
• Chronic eosinophilic leukemia NOS
  • (see also Idiopathic hypereosinophilic syndrome)
• Polycythemia vera
• Essential thrombocythemia
• Primary myelofibrosis
• Mastocytosis
• Myeloproliferative neoplasm unclassifiable

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

• Chronic myelomonocytic leukemia (CMML)
• Atypical chronic myeloid leukemia, BCR-ABL1 negative
• Juvenile myelomonocytic leukemia
• Myelodysplastic / myeloproliferative neoplasm, unclassifiable
• Refractory anemia with ring sideroblasts associated with marked thrombocytosis
• Myelodysplastic / myeloproliferative neoplasm with isolated isochromosome 17q

Myelodysplastic Syndromes (MDS)

• Refractory cytopenia with unilineage dysplasia (RCUD)
  • Refractory anemia
  • Refractory neutropenia
  • Refractory thrombocytopenia
• Refractory cytopenia with multilineage dysplasia (RCMD)
• Refractory anemia with ring sideroblasts (RARS)
• Refractory anemia with excess blasts (RAEB)
• MDS associated with isolated del(5q)
• Childhood myelodysplastic syndrome
  • Refractory cytopenia of childhood
• MDS unclassifiable
• Additional features that may be superimposed on above classification:
  • MDS with fibrosis
  • MDS, hypocellular

Therapy Related Myeloid Neoplasms

Bibliography

• Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2008
• Carney DA et al, Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy. Leukemia aop, (2010) Dec;24(12):2056-62.
• Schroeder T et al, Therapy-related myeloid neoplasms following treatmentwith radioiodine. Haematologica. 2011 Oct 11. [Epub ahead of print]
• Leone G, Fianchi L, Voso MT Therapy-related myeloid neoplasms. Curr Opin Oncol. 2011 Nov;23(6):672-80.
• Kayser S, Döhner K, Krauter J, et al. The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood 2011; 117:2137–2145.
• Sun J et al, Chromosome 20q deletion: a recurrent cytogenetic abnormality in patients with chronic myelogenous leukemia in remission. Am J Clin Pathol. 2011 Mar;135(3):391-7.
• Lin RJ et al, Therapy-Related Myeloid Neoplasms (t-MN) in 71 Patients Following Radiation Therapy (RT) Only, ASH Annual Meeting Abstracts 2011 118:3522
• Singh ZN et al, Therapy-related myelodysplastic syndrome: morphologic subclassification may not be clinically relevant. Am J Clin Pathol. 2007 Feb;127(2):197-205