–Dyskeratosis Congenita (X-lioed mutations in the dyskerin or autosomal recessive forms with mutations in genes regulating telomere maintenance and RNA processing).

•Other rare inherited disorders with a propensity to develop AML include

–Congenital Amegakaryocytic Thrombocytopenia (defects in the CFFA2 gene and thrombopoletia receptor gene, c-mpl),

–autosomal dominant macrothrombocytopenia (Fechtner Syndrome, MYH9 gene), familial platelet disorder with propensity to myeloid matignancy (FPD/ AMI, germ line mutations in the RUNX1/CEPB-alpha gene).

•In addition,

–mutations in the neurofibromin gene, encoding a RAS inactivating GTPase, is responsible for Neurofibromatosis type 1 and an increased incidence of juvenile myelomenocytic leukemia (JMML) and AML.

–Mutations in the PTPN11 gene, which encodes a SHP-2 tyrosine phesphatase, leads to Noonan Syndrome and increased predisposition to JMML.

–Mutations in CBL, encoding an E3 ubiquitin ligase, have been reported to be associated with a dominant inheritance of a developmental disorder and predisposition to JMML.

–Patients with Lt-Fraumeni Syndrome and Bloom Syndrome, involved defects in p53 and the BLM helicase gene respectively, have also been reported to have a propensity to development leukemia, including AML.

•The increased incidence of AML in a twin or sibling of a patient with AML (or ALL) can vary from nearly 100% concordance in monozygotic or identical twins to approximately 20% in fraternal twins up until about 6 years of age, when the incidence decreases to that of the general population.

•Non-twin, fantilial cases of AML are rare and often associated with constitu- tional translocations, such as t(7;20 and t(3;6) or monosomy 7.

3.8Relapse of AML

The overall survival for patients with AML that has relapsed is poor except for those with initial favorable cytogenetics, such as t(8;21) and inv(16).

•Response to reinduction is less successful; resistance against drugs is high

•Continuous, long-term remission without transplantation, less than 20% (exception: after first remission of more than 1 year, 5-year survival rate is 30–40%, although cure without transplantation is essentially zero)

•Patients who have a relapse affecting the CNS frequently have a simultaneous systemic relapse

•Induction therapy with high-dose ARAC in combination with mitoxantrone, etoposide, fludarabine, or 2-chlorodeoxyadenosine or other agents are commonly used; patients with AML should ideally be treated on clinical trials

•Prognosis is unfavorable without stem cell transplantation (allogeneic, matched or partially matched), cord blood stem cell transplantation, haploidentical transplantation

•Infusion of donor lymphocytes for increase of GVL-effect may be considered after transplantation if relapse occurs

•In APL (M3) the rate of second remission is greater than 80% and overall cure rates with autologous transplantation (e.g., for patients who are MRD negative by sensitive molecular detection methods) or allogeneic HSCT is approximately 70%

3.9Detailed Reference

Arceci RJ, Meshinchi S, Rosenblat TL, Jurcic JG, Tallman HC Childhood Adolescent and Young Adult (CAYA) Acute Myeloid Leukemia. In: Saito MS, and Parkins SL eds. World Scientific Publishing Co. Inc: Hackensack, 2011, Submitted.