Therapy-Related Myelodysplasia and Acute Myeloid Leukemia

Bhatia, Smita

doi:10.1053/j.seminoncol.2013.09.013

Cited by 161 publications

(134 citation statements)

References 96 publications

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“…13 However, recent evidence from our studies and others has revealed that t-MN driver mutations preexist as CHIP before patients are exposed to chemotherapy/radiation therapy. [4][5][6] The current data provide additional evidence that t-MN-associated CNAs can also preexist as CHIP.…”

Section: Discussionmentioning

confidence: 72%

Copy number alterations detected as clonal hematopoiesis of indeterminate potential

Takahashi

Wang

Kantarjian³

et al. 2017

Blood Advances

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Key Points• CNAs can be detected as part of CHIP.Recent studies have revealed that clonal hematopoiesis of indeterminate potential (CHIP) is an important risk factor for therapy-related myeloid neoplasms (t-MNs). CHIP is currently defined as a clonal hematopoietic population carrying somatic point mutations in 1 of the leukemia-associated genes. Patients with t-MNs often present with chromosomal abnormalities in addition to somatic point mutations. It remains unclear whether chromosomal abnormalities can cooccur with point mutations as part of CHIP. Here we report that 3 of 14 patients with t-MNs had low amplitude but detectable chromosome arm-level copy number alterations (CNAs) in the peripheral blood samples that were taken at the time of their primary cancer diagnosis and before exposure to therapy. These CNAs were the same CNAs seen in t-MN bone marrow samples and affected the same allele, suggesting the same clonal origin. These data suggest that not only somatic point mutations but also chromosome armlevel CNAs are detectable as CHIP and preexist before patients' exposure to chemotherapy and/or radiation therapy. These data suggest that screening of both somatic point mutations and CNAs might allow more complete ascertainment of CHIP.

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Section: Discussionmentioning

confidence: 72%

Copy number alterations detected as clonal hematopoiesis of indeterminate potential

Takahashi

Wang

Kantarjian³

et al. 2017

Blood Advances

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“…6,7,[13][14][15][16] Here we present a retrospective long-term followup analysis of 79 unselected consecutive t-MDS/t-AML patients who underwent aHCT after predominantly RIC (73.4%) between 1995 and 2014. With a median follow-up of 7.5 years, this is one of the longest reported follow-up studies for this specific patient clientele, revealing a 10 year OS and DFS rate of 24% (13-36%) and 24% (14-36%), respectively, whereas the NRM rate was 32% (22-46%).…”

Section: Discussionmentioning

confidence: 99%

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation

Finke

Schmoor

Bertz

et al. 2016

Bone Marrow Transplant

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The outcome of patients with therapy-related myelodysplasia (t-MDS) or t-AML is very poor. The only curative treatment option implements allogeneic hematopoietic cell transplantation (aHCT); however, long-term follow-up data beyond 5 years are scarce. Here we report on a cohort of 79 consecutive patients with a median age of 58 years (range (r): 20-76) at transplantation and a median follow-up of 7.5 years (r: 0.07-19.0). Only 19 (24.1%) patients were in CR before aHCT. Non-relapse mortality and relapse rates were 23% (95% confidence interval, 15-35%) and 42% (32-55%) at 5 years, and 32% (22-46%) and 44% (34-57%) at 10 years, respectively. Disease-free survival (DFS) and overall survival (OS) rates were 35% (24-46%) and 38% (27-49%) at 5 years, and 24% (14-36%) and 24% (13-36%) at 10 years, respectively. Although cytogenetic aberrations were associated with shorter DFS and higher relapse risk, persistent disease at the time of transplantation, an unrelated donor and patient age were not associated with shorter OS. In conclusion, long-term survival beyond 10 years of t-MDS/t-AML patients after aHCT is possible, even for refractory patients. Therefore, early donor search and rapid transplantation are warranted, also to decrease the risk of disease-related deterioration of patients' performance status.Bone Marrow Transplantation (2016) 51, 771-777; doi:10.1038/bmt.2015.338; published online 11 January 2016 INTRODUCTION Cytotoxic agents, especially alkylating and topoisomerase II targeting drugs, as well as ionizing radiotherapy in the successful treatment of most cancer types and to some extent also in nonmalignant diseases, bear a significant long-term risk of developing therapy-related malignancies such as myelodysplasia (t-MDS) and t-AML. 1,2 Despite intensive efforts to reduce the risk of developing t-MDS/t-AML by using fewer cycles of dose-intense chemotherapy for a given primary disease and thus to decrease cumulative doses, this late occurring side effect remains a challenging clinical problem. 3 Treatment of t-MDS/t-AML, which often occurs with other comorbidities, is complex and the outcome of patients treated with low-or even high-dose chemotherapy alone remains poor. Beyond other factors, this is especially attributed to older age, therapy resistance and cytogenetic abnormalities including monosomies or complex karyotypes. 4,5 In recent years, it has become evident that the most successful curative treatment concept for t-MDS/t-AML patients resulting in substantial remission rates implements allogeneic hematopoietic cell transplantation (aHCT). Using a myeloablative conditioning regimen in 77% of patients in a cohort of 868 patients with a median age of 40 years, Litzow et al. 6 reported an overall survival (OS) rate of 22% (95% confidence interval (CI), 19-26%) after 5 years, although the non-relapse mortality (NRM) and relapse rate at that time were 48% (95% CI, 44-51%) and 31% (95% CI, 28-34%), respectively. In another study from the European Group for Blood and Marrow Transplantation, Kröger et al. 7...

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“…1,2 The etiology of therapy-related myeloid neoplasms is thought to be related to the mutagenic effect of cytotoxic therapy, including alkylating agents, ionizing radiation therapy, and topoisomerase inhibitors. 1 Typically, therapy-related myeloid neoplasms carry complex and usually unbalanced karyotypic abnormalities, particularly loss of material on the long arm of chromosomes 5 and 7 and rearrangements of the 11q23 region involving the MLL gene. 3 The prognosis of therapy-related myeloid neoplasms is poor, likely due at least in part to the high proportion of cases with adverse karyotype.…”

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confidence: 99%

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

Cleven

Nardi

et al. 2015

Modern Pathology

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Identification of p53-positive cells by immunohistochemistry in bone marrow from primary myelodysplastic syndrome patients correlates with the presence of TP53 mutations and poor prognosis. Mutations in the tumor suppressor gene TP53 are more frequent in therapy-related acute myeloid leukemia and myelodysplastic syndrome than in de novo disease, but the role of p53 immunohistochemistry in the therapy-related setting has not been specifically investigated. We studied p53 protein immunoreactivity in bone marrow biopsies of therapy-related myeloid neoplasms and correlated protein expression with TP53 mutation status, clinicopathologic features and outcome. We first studied 32 patients with therapy-related acute myeloid leukemia and 63 patients with therapy-related myelodysplastic syndrome/chronic myelomonocytic leukemia from one institution and then validated our results in a separate group of 32 patients with therapy-related acute myeloid leukemia and 56 patients with therapy-related myelodysplastic syndrome from a different institution. Strong p53 immunostaining in Z1% of bone marrow cells was highly predictive of a TP53 gene mutation (Po0.0001) and was strongly associated with a high-risk karyotype (Po0.0001). The presence of Z1% p53 strongly positive cells was associated with poorer overall and disease-specific survival, particularly in the subset of patients treated with stem-cell transplantation. In a multivariable Cox regression model, the presence of Z1% p53 strongly expressing cells was an independent prognostic marker for overall survival in both cohorts, with hazard ratios of 3.434 (CI: 1.751-6.735, Po0.0001) and 3.156 (CI: 1.502-6.628, P ¼ 0.002). Our data indicate that p53 protein expression, evaluated in bone marrow biopsies by a widely available immunohistochemical method, prognostically stratifies patients with therapy-related myeloid neoplasms independent of other risk factors. p53 immunostaining thus represents an easily applicable method to assess risk in therapy-related acute myeloid leukemia/myelodysplastic syndrome patients. Therapy-related myeloid neoplasms include acute myeloid leukemia, myelodysplastic syndrome, and less commonly myelodysplastic/myeloproliferative neoplasms such as chronic myelomonocytic leukemia. Therapy-related myeloid neoplasms occur as late complications of cytotoxic chemotherapy and/or radiotherapy given to treat malignancies or non-malignant conditions. 1,2 The etiology of therapy-related myeloid neoplasms is thought to be related to the mutagenic effect of cytotoxic therapy, including alkylating agents, ionizing radiation therapy, and topoisomerase inhibitors. 1 Typically, therapy-related myeloid neoplasms carry complex and usually unbalanced karyotypic abnormalities, particularly loss of material on the long arm of chromosomes 5 and 7 and rearrangements of the 11q23 region involving the MLL gene. 3 The prognosis of therapy-related myeloid neoplasms is poor, likely due at least in part to the high

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Therapy-Related Myelodysplasia and Acute Myeloid Leukemia

Cited by 161 publications

References 96 publications

Copy number alterations detected as clonal hematopoiesis of indeterminate potential

Copy number alterations detected as clonal hematopoiesis of indeterminate potential

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

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