Alkylating agents
Topoisomerase II inhibitors
Latency
3–8 years
2–3 years
Incidence
2–20 %
2–12 %
Myelodysplastic phase
Present
Absent
FAB type
M1, M2
M4, M5
Cytogenetics
5-, 7-, 5q-, 7q-
11q23 deletion and translocation
Pathogenesis
Tumor suppressor genes, RAS mutations
Translocations
a.
Alkylating agents
i.
Latency period of 3–8 years.
ii.
Commonly associated cytogenetic abnormalities include 5-, 7-, 5q-, and 7q-.
iii.
May present with myelodysplasia.
b.
Topoisomerase inhibitors
i.
Latency period of 2–3 years.
ii.
Commonly associated cytogenetic abnormalities include 11q23 deletion and translocation.
iii.
Does not typically present with myelodysplasia.
c.
Lenalidomide maintenance therapy post-autologous HSCT for myeloma
i.
Increasing utilization given studies which have shown a benefit in both progression-free and overall survival.
ii.
Randomized trials have shown an increased numerical incidence of secondary primary malignancies of 8 % in patients receiving lenalidomide maintenance compared to 3–4 % of those patients not receiving maintenance therapy . This observation was not statistically significant.
iii.
Cause is likely multifactorial.
iv.
Additional long-term follow-up will be required for confirmation of these findings.
v.
In a recently published trial of approximately 2500 multiple myeloma patients who received lenalidomide as primary therapy, the cumulative incidence of second malignancies at 5 years was 6.9 %, compared to 4.8 % in patients who did not receive lenalidomide.
3.8 % incidence of solid malignancy
3.1 % incidence of hematologic malignancy
Significantly increased risk of secondary hematologic malignancy in patients who received lenalidomide + melphalan compared with patients who received melphalan alone (HR 4.86)
3.
Chronic graft-versus-host disease (cGVHD) following allogeneic HSCT
a.
Genomic alterations have been identified, especially in the epithelium of the oral cavity.
b.
Frequency of these events exceeds the incidence of secondary malignancies suggesting additional factors play a role in the pathogenesis.
i.
Complex immune defect associated with cGVHD
4.
Oncogenic viruses including human papilloma virus (HPV) and Epstein Barr virus (EBV)
5.
Predisposition to carcinogenesis
a.
Age
b.
Gender
c.
Lifestyle choices
31.2 Incidence
1.
Reported cumulative incidence of secondary malignancies remains low
a.
Post-allogeneic HSCT
i.
1.2–1.6 % at 5 years
ii.
2.2–6.1 % at 10 years
iii.
3.8–14.9 % at 15 years
b.
Post-autologous HSCT for lymphoma
i.
2.54 % at 5 years
ii.
6.79 % at 10 years
iii.
9.14 % at 15 years
c.
Post-autologous HSCT for myeloma
i.
5.3 % at 5 years
ii.
11.2 % at 10 years
31.3 Onset
1.
Typically, there is a latency period of 3–5 years preceding the development of secondary malignancies following HSCT but cases occurring earlier have been reported.
31.4 Types of Secondary Malignancies
1.
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) following autologous HSCT
a.
Estimates of incidence of therapy-related MDS and AML (tMDS/AML) vary widely between 1 and 14 % at 3–15 years after autologous HSCT for lymphoma
i.
3.1 % at 5 years
ii.
4.5 % at 10 years
iii.
6.8 % at 15 years
b.
tMDS/AML is felt to be a consequence of the initial cytotoxic therapy for the primary malignancy rather than of the HSCT procedure and may represent a mutated stem cell pool that is transferred within the thawed cryopreserved product.
c.
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Risk factors
i.
Age
ii.
Extent of pre-HSCT therapy
iii.
Exposure to alkylating agents and TBI
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