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Late Effects

Second Malignant Neoplasm

 

Leukemia as a Second Malignancy

 

Types of secondary leukemia:

1. Acute myeloid leukemia:

  • Commonest
  • Hematopoietic colony-stimulating factors in the setting of intensive chemotherapy may further increase the risk of secondary AML

2. Acute lymphoblastic leukemia:

  • Reported after therapy with topoisomerase II inhibitors
  • Frequently shows t(4;11)(q21;q23) chromosomal translocation

3. Chronic myelogenous leukemia is associated with prior chemotherapy (rare)

 

AML:

Both chemotherapy and RT can induce AML5 (risk after chemo is significantly higher)

Two syndromes of chemotherapy-related AML have been described.  These are related to:

  • Alkylating agents
  • Topoisomerase II inhibitors

Alkylating agents that can induce human leukemia include:

  • Busulfan
  • Carmustine
  • Chlorambucil
  • Cyclophosphamide
  • Dihydroxybusulfan
  • Lomustine
  • Mechlorethamine
  • Melphalan
  • Prednimustine
  • Semustine

Procarbazine has an underlying mechanism of action similar to alkylating agents, but there is no clear link with secondary leukemia

After treatment with alkylating agents:

  • Leukemia risk begins to increase at 1 to 2 years, peaks at 5 to 10 years, and then decreases
  • Usually there is a preceding myelodysplastic syndrome
  • Typical chromosomal abnormalities frequently include unbalanced translocations or deletions involving portions of chromosome 5 and/or 7 consisting of loss of all or part of the long arm of the chromosome.
  • Risk of alkylating agent-related AML increases with increasing cumulative dose or duration of therapy
  • Leukemias secondary to alkylating agents are generally refractory to treatment and associated with poor survival
  • In one series the median survival after the development of acute leukemia among Hodgkin lymphoma (HL) patients was only 0.4 year, with a 5-year relative survival rate of 5% or so

 

Platinum compounds

  • Previously not considered human leukemogens despite their formation of intrastrand and interstrand DNA cross-links similar to bifunctional alkylating agents
  • Recent studies of patients treated with platinum-based regimens for ovarian cancer or testis cancer showed that cumulative dose of cisplatin was associated with significantly increased risk of leukemia (multivariable analyses taking into account other treatment factors)
  • Study of secondary leukemia among ovarian cancer patients6:
    • Overall risk of leukemia following platinum-based chemotherapy was 4.0.
    • Relative risks for cumulative platinum doses of <500, 500 to 749, 750 to 999, and 1,000 mg were 1.9, 2.1, 4.1, and 7.6, respectively (P trend < 0.001)
    • Risk also increased with duration of platinum-based chemotherapy, with a relative risk of 7.0 among women who were treated for >12 months
    • Women who received RT and platinum-based chemotherapy had a significantly higher risk of leukemia than those who received platinum alone

 

Topoisomerase II inhibitor-related AML

Drugs that target DNA topoisomerase II include7:

  • Epipodophyllotoxins
  • Etoposide and teniposide.

Anthracyclines doxorubicin and epidoxorubicin may be rarely associated with this type of leukemia

These leukemias tend to have a shorter induction period, with a median latency of only 2 to 3 years

Risk related to intensity of the dosing schedule

Morphology is usually monoblastic or myelomonocytic, and balanced chromosomal translocations occur8, frequently involving 11q23 (the MLL gene), typically t(9;11), t(11;19), and t(6;11) or 21q22.

See 11q23 rearrangements in therapy related leukaemias

Patients who develop topoisomerase II inhibitor-related AML usually respond to therapy comparably with patients who develop de novo leukemia of the same subtype

 

Hodgkin lymphoma (HL) and secondary leukemia:

HL is associated with a significantly increased risk of secondary leukemia9

Combination chemotherapy including mechlorethamine and procarbazine, frequently given with vincristine and prednisone in the MOPP regimen is associated with the highest risks of leukemia

Overall relative risk estimates range from 3.5 to 24

The relative risk of leukemia increases both with increasing cumulative dose and with increasing number of cycles of MOPP

The cumulative risk of leukemia at 15 years:

  • After treatment with MOPP ranges from 3.4% to 9.5%
  • After treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is much smaller, ranging from 0.7% to 1.3%
  • The risk of leukemia following MOPP/ABVD combination regimens is intermediate, with a 10-year cumulative risk of 2.1%

 

Radiation therapy (RT) associated leukemia:

Risk is considerably smaller than after chemotherapy (about 2-fold)

Leukemia risk is usually greatest about 5 to 9 years after RT and then slowly declines

RT related leukemia risk is a function of10:

  • Dose to the active bone marrow
  • Dose rate
  • Percentage of exposed marrow

The excess risk of leukemia per unit of radiation dose is larger at low doses than at high doses due to cell killing at higher doses. Many studies show that high RT doses to limited fields are associated with little or no increased risk of leukemia

Low-dose TBI (total body irradiation) is associated with high risks of leukemia

RT is associated with increased risks of AML, chronic myelogenous leukemia, and acute lymphoblastic leukemia. Only chronic lymphocytic leukemia has not been linked with either prior RT or chemotherapy

 

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