Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors

Abstract

We analyzed data on 612 patients who had undergone high-dose chemoradiotherapy (HDT) with autologous stem cell rescue for Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) at the City of Hope National Medical Center, to evaluate the incidence of therapy-related myelodysplasia (t-MDS) or therapy-related acute myeloid leukemia (t-AML) and associated risk factors. A retrospective cohort and a nested case-control study design were used to evaluate the role of pretransplant therapeutic exposures and transplant conditioning regimens. Twenty-two patients developed morphologic evidence of t-MDS/t-AML. The estimated cumulative probability of developing morphologic t-MDS/t-AML was 8.6% ± 2.1% at 6 years. Multivariate analysis of the entire cohort revealed stem cell priming with VP-16 (RR = 7.7, P = 0.002) to be independently associated with an increased risk of t-MDS/t-AML. The influence of pretransplant therapy on subsequent t-MDS/t-AML risk was determined by a case-control study. Multivariate analysis revealed an association between pretransplant radiation and the risk of t-MDS/t-AML, but failed to reveal any association with pretransplant chemotherapy or conditioning regimens. However, patients who had been primed with VP-16 for stem cell mobilization were at a 12.3-fold increased risk of developing t-AML with 11q23/21q22 abnormalities (P = 0.006). Patients undergoing HDT with stem cell rescue are at an increased risk of t-MDS/t-AML, especially those receiving priming with VP-16 for peripheral stem cell collection.

Myeloablative doses of yttrium‐90‐ibritumomab tiuxetan and the risk of secondary myelodysplasia/acute myelogenous leukemia

“…14 Secondary myelodysplastic syndrome (sMDS) and acute leukemia (sMDS/AML) are the predominant types of secondary malignancies observed after HDS-CT and ASCT, and the estimated 5-year cumulative probability of sMDS/AML ranges from 1% to 24% in different series. [15][16][17][18][19][20] The risk of sMDS/AML includes age and exposure to alkylating agents and likely is caused by prolonged or repetitive exposure to cytotoxic drugs as well as the relatively long natural history of underlying disease. 21,22 Whether bone marrow (BM) exposure to high radiation doses because of radiolabeled antibodies may further increase hematopoietic damage, thereby increasing the risk of sMDS/ AML, remains a matter of concern.…”

Therapy‐related chronic myelogenous leukaemia following autologous stem cell transplantation for Ewing's sarcoma

“…tr-MDS and tr-AML are the most common secondary malignancies after high-dose chemotherapy with autologous stem cell transplantation, and their epidemiological, clinical and pathogenic characteristics have been described (Krishan et al, 2000;Micallef et al, 2000;Park et al, 2000). The estimated incidences of tr-MDS/AML at 3-5 years after high-dose chemotherapy with autologous stem cell transplantation have ranged from 4% to 18% (Darrington et al, 1994;Miller et al, 1994;Krishan et al, 2000). On the other hand, only three cases (excluding our case) of CML after high-dose chemotherapy with autologous stem cell transplantation have been reported and its characteristics are not well established (Jackson et al, 1994;Waller et al, 1999a;Hsiao et al, 2000).…”

“…The survey (Krishan et al, 2000;Micallef et al, 2000;Park et al, 2000) of tr-MDS and tr-AML after high-dose chemotherapy and autologous stem cell transplantation has demonstrated that the actual risk of tr-MDS or tr-AML after high-dose chemotherapy with subsequent autologous stem cell transplantation is higher than that after conventional therapy (Krishan et al, 2000). Risk factors (Darrington et al, 1994;Park et al, 2000) for tr-MDS or tr-AML have been shown to be older age at transplantation, radiation therapy, a low platelet count at transplantation and a total dose of alkylating agents administered before transplantation.…”

Genetic variation as a modifier of association between therapeutic exposure and subsequent malignant neoplasms in cancer survivors

“…There have been reports of t-MDS/AML after conventional treatment for Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); acute lymphoblastic leukemia (ALL); sarcomas; and breast, ovarian, and testicular cancers [61][62][63][64][65][66][67] and after autologous hematopoietic cell transplantation (aHCT) for HL or NHL, in which it is the major cause of nonrelapse mortality. [68][69][70][71][72][73] The cumulative incidence of t-MDS/AML ranges from 2% at 15 years after conventional therapy 62 to 8.6% at 6 years after aHCT. 68 Two types are recognized by the World Health Organization classification: the alkylating agent-related type and the topo II inhibitor-related type.…”

“…[68][69][70][71][72][73] The cumulative incidence of t-MDS/AML ranges from 2% at 15 years after conventional therapy 62 to 8.6% at 6 years after aHCT. 68 Two types are recognized by the World Health Organization classification: the alkylating agent-related type and the topo II inhibitor-related type. 74 Alkylating agents associated with t-MDS/AML include cyclophosphamide, ifosfamide, mechlorethamine, melphalan, busulfan, nitrosureas, chlorambucil, dacarbazine, and platinum compounds.…”