STEM CELL TRANSPLANTATIONFOR LEUKEMIAS FOLLOWING MYELODYSPLASTIC SYNDROMESOR SECONDARYTO CYTOTOXIC THERAPY

Abstract

Two main forms of therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) have been recognized. The most frequent type, occurring after treatment with alkylating agents, is characterized by abnormalities of chromosomes 5 and/or 7 and t-MDS/AML following treatment with topoisomerase II inhibitors and is associated with molecular aberrations of MLL (11q23) and AML-1 (21q22). Individuals with certain polymorphisms associated with impaired detoxification of cytotoxic agents have an increased risk of developing MDS or AML after treatment of unrelated cancers. Multidrug chemotherapy is less effective for patients with MDS, or AML following MDS, or t-MDS/AML when compared with primary AML, and results in lower complete remission (CR) rates and lower long-term survival. Patients with good risk cytogenetic features, such as t(15; 17), t(8; 21) and inversion 16 are an exception as their treatment outcome is comparable with primary AML patients. Patients who attain a polyclonal and/or a cytogenetic CR may be candidates for autologous stem cell transplantation. For the remaining patients, the only curative option is allogeneic stem cell transplantation with stem cells from a histocompatible sibling or an alternative donor. Reduced intensity conditioning regimens may be considered for patients older than 50 years or patients with comorbidities. The advice is to treat patients early after diagnosis and preferably before progression as these patients have the highest chance of a favorable outcome.

Etoposide‐initiated MLL rearrangements detected at high frequency in human primitive hematopoietic stem cells with in vitro and in vivo long‐term repopulating potential

“…This suggests a distinct set of repair mechanisms is used by early pluripotent cells capable of long-term proliferation and differentiation. Inversions of MLL are rarely associated with t-AML with only a single case reported in the literature (49). In this case the long latency (6 yr persistence of a clone with inv 11 in the bone marrow before development of t-AML) suggests a benign character of this genetic lesion and requirement of other collaborating mutations (49).…”

Hematologic aspects of myeloablative therapy and bone marrow transplantation

“…Although present data suggests that the initial response rates of most cases of this type of therapy-related leukemia to intensive initial chemotherapy is comparable to those of primary acute leukemia of the corresponding type, the long-term follow-up data to predict the ultimate survival in these patients is insufficient (184,206,208). de Witte et al (211) suggested that patients who attain a polyclonal and/or a cytogenetic complete remission may be candidates for autologous stem cell transplantation, but for the remaining patients allogeneic stem cell transplantation from a histocompatible sibling or an alternative donor is the best curative option at present (211,212).…”

“…In the uncommon cases where ALL is observed, the most frequent cytogenetic abnormality is t(4;11)(q21;q23) (204). The following are regarded as good risk cytogenetic features: t(15;17); t(18;21) and inv (16) (211). Although present data suggests that the initial response rates of most cases of this type of therapy-related leukemia to intensive initial chemotherapy is comparable to those of primary acute leukemia of the corresponding type, the long-term follow-up data to predict the ultimate survival in these patients is insufficient (184,206,208).…”

Leucemias agudas y síndromes mielodisplásicos secundarios al tratamiento oncológico

“…Múltiples estudios han demostrado que el principal factor pronóstico para conseguir la curación de la enfermedad es la ausencia de alteraciones citogenéticas desfavorables (5,81); en efecto, la RC a la quimioterapia sólo se da en el 13% de los pacientes con anormalidades del cromosoma 5 (del.5 o 5q-), independientemente de la presencia de anomalías en el cromosoma 7, en contraste con la respuesta en los pacientes con monosomía del cromosoma 7 o deleción del brazo largo (32%), con cromosomas extranumerarios (43%), o un cariotipo con otras anormalidades estructurales (65%). La presencia de las alteraciones citogenéticas favorables descritas en la LAM primaria, como t (15,17), t(8,21) e inv(16) es rara en las leucemias secundarias (5). En general, la mayor parte de estudios ha demostrado una tasa escasa de respuestas en los pacientes con alteraciones de los cromosomas 5 y 7, y tasas mayores en aquellos que presentan otras anormalidades cromosómicas.…”

“…Esta menor supervivencia parece deberse a un aumento de la mortalidad por el mayor número de recaídas y la mayor toxicidad del trasplante; son factores de peor pronóstico en estos pacientes la edad avanzada, el porcentaje de alteraciones citogenéticas, el número de blastos en médula ósea y la fibrosis de la médula, con la consiguiente menor reserva que favorece las muertes por toxicidad (4). A pesar de esos pobres resultados, el trasplante alogénico continúa siendo el tratamiento de elección (4)(5)(81)(82)(83). El uso de quimioterapia de inducción previo al trasplante no está claramente establecido: las tasas de RC son escasas (especialmente si hay alteraciones citogenéticas desfavorables), el riesgo de muerte durante la quimioterapia varía desde el 15 al 64% (4,81) (obviando a un porcentaje de pacientes del beneficio del trasplante) y no se ha podido demostrar que la realización del trasplante en RC mejore el pronóstico a largo plazo (4).…”