Malignant Tumors Occurring after Treatment of Aplastic Anemia

Socié, Gèrard; Henry-Amar, Michel; Bacigalupo, Andrea; Hows, Jill; Thewis, André; Ljungman, Per; McCann,; Frickhofen, Norbert; E, Van't Veer-Korthof; Gluckman, Éliane

doi:10.1056/nejm199310143291603

Cited by 420 publications

(171 citation statements)

References 31 publications

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“…Cumulative incidence of LM was 0.8% at 10 years and 2.5% at 20 years, respectively, which was much lower than those in previous reports. [3][4][5][6] As for conditioning regimen for SAA in patients with LM, four received radiation-containing regimen and one non-irradiation regimen. Comparisons of cumulative incidence of LM between radiation and non-radiation regimen did not reach statistical significance (2.5 vs 3.1% at 20 years, P ¼ 0.718).…”

Section: Resultsmentioning

confidence: 99%

“…As for conditioning regimen, radiation-containing regimen was not significantly associated with LM after HSCT in our series, although radiation was reported to be associated with LM after HSCT. [3][4][5] This is probably because of absolute low patient number who developed LM. Recently, Flu-based preconditioning regimen is widely used in HSCT for SAA from MSD or alternative donors.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 In SAA, LM are also reported in the patients with HSCT and its occurrence is related to radiation-containing conditioning regimen and GVHD grade in adults, 5,6 however, the incidence and prognostic factors of LM in children with SAA who undergo HSCT are totally unknown.…”

Section: Introductionmentioning

confidence: 99%

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Long-term outcome of childhood aplastic anemia patients who underwent allogeneic hematopoietic SCT from an HLA-matched sibling donor in Japan

Kikuchi

Yabe

Katô³

et al. 2012

Bone Marrow Transplant

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We report long-term outcomes of 329 childhood severe aplastic anemia (SAA) patients who underwent hematopoietic SCT (HSCT) from an HLA-matched sibling donor in the Japanese Hematopoietic Cell Transplantation Registry. OS and EFS at 10 years were as high as 89.7 þ / À 1.7% and 85.5 þ / À 2.0%, respectively. Five cases of late malignancies (LM) were identified (malignant peripheral nerve sheath tumor, thyroid carcinoma, colon carcinoma, MDS and hepatoblastoma). Cumulative incidence of LM was 0.8% at 10 years and 2.5% at 20 years, respectively, which was lower than that in previous reports. This low incidence is in keeping with the low occurrence of skin cancer in Japanese population and of acute GVHD in our study group. Radiation-containing conditioning was not significantly associated with the incidence of LM after HSCT probably because of absolute low patient number who developed LM in our series. In terms of LM development after HSCT, low-dose TBI in HSCT for SAA to avoid graft rejection, which is commonly used in Japan, might be tolerable in the Japanese population because of its low incidence. Keywords: aplastic anemia; childhood; hematopoietic SCT; long-term outcome; late malignancies INTRODUCTION Aplastic anemia is a hematopoietic disorder characterized by pancytopenia and BM hypoplasia. Therapeutic options for severe aplastic anemia (SAA) are immunosuppressive therapy and hematopoietic SCT (HSCT). In children, if an HLA-matched sibling donor (MSD) is available, HSCT is the first line of therapy for SAA. HSCT from MSD is an established standard therapy for SAA in children and high survival rates have already been reported. However, little is known about long-term outcomes of these children.Late malignancies (LM) are serious complications for patients who undergo HSCT. 3,4 In SAA, LM are also reported in the patients with HSCT and its occurrence is related to radiation-containing conditioning regimen and GVHD grade in adults, 5,6 however, the incidence and prognostic factors of LM in children with SAA who undergo HSCT are totally unknown.In this article, we report long-term outcomes of childhood SAA patients who underwent HSCT from MSD in the centers of the Japanese Hematopoietic Cell Transplantation Registry and describe the occurrence of LM.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Long-term outcome of childhood aplastic anemia patients who underwent allogeneic hematopoietic SCT from an HLA-matched sibling donor in Japan

Kikuchi

Yabe

Katô³

et al. 2012

Bone Marrow Transplant

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“…The cumulative incidence of MDS/AML increases after IST, ranging from 5% to 15% within the observation period of 5 to 11.3 years. 35,[38][39][40] Because the development of MDS/AML consistently conveys a dismal prognosis in AA patients, it is of particular importance Immune-mediated mechanism of AA and clonal evolution. (A) AA is thought to be initiated by recognition and destruction of HSCs by CTLs, which recognize some unknown antigen present on HSCs via their HLA class I molecule.…”

Section: Late Clonal Diseases In Aamentioning

confidence: 99%

Clonal hematopoiesis in acquired aplastic anemia

Ogawa

2016

Blood

158

130

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Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1. Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA.

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“…[9][10][11] Because G-CSF can stimulate the growth of leukemic clones, combined use of G-CSF with IST may facilitate the progression of AA to MDS/AML. 12,13 To elucidate whether the addition of G-CSF to IST increases the response rate, prevents infections during the treatment, improves the survival or relapse rate, and increases the risk for MDS/AML, we have started the prospective randomized controlled study comparing ATG and CyA therapy with or without G-CSF in adult patients with AA.…”

Section: Introductionmentioning

confidence: 99%

Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan

Teramura

Kimura

Iwase

et al. 2007

Blood

105

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We report the results of a randomized study to elucidate whether addition of granulocyte colony-stimulating factor (G-CSF) to immunosuppressive therapy is valuable for the treatment of severe aplastic anemia (SAA) in adults. A total of 101 previously untreated patients (median age, 54 years; range, 19 to 75 years) were randomized to receive antithymocyte globulin (ATG) and cyclosporin A (CyA) (G-CSF؊ group) or ATG, CyA, and G-CSF (G-CSF؉ group). In the G-CSF؉ group, the hematologic response rate at 6 months was higher (77% vs 57%; P ‫؍‬ .03) than in the G-CSF؊ group. No differences were observed between the groups in terms of the incidence of infections and febrile episodes. There were no differences between the G-CSF؊ group and the G-CSF؉ group in terms of survival (88% vs 94% at 4 years), and the development of myelodysplastic syndrome (MDS)/acute leukemia (AL) (1 patient vs 2 patients). However, the relapse rate was lower in the G-CSF؉ group compared with the G-CSF؊ group (42% vs 15% at 4 years; P ‫؍‬ .01). Further follow-up is required to elucidate the role of G-CSF in immunosuppressive therapy for adult SAA. (Blood.

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Malignant Tumors Occurring after Treatment of Aplastic Anemia

Abstract: Survivors of aplastic anemia are at high risk for subsequent malignant conditions. Myelodysplastic syndrome and acute leukemia tend to follow immunosuppressive therapy, whereas the incidence of solid tumors is similar after immunosuppression and after bone marrow transplantation.

Cited by 420 publications

References 31 publications

Long-term outcome of childhood aplastic anemia patients who underwent allogeneic hematopoietic SCT from an HLA-matched sibling donor in Japan

Long-term outcome of childhood aplastic anemia patients who underwent allogeneic hematopoietic SCT from an HLA-matched sibling donor in Japan

Clonal hematopoiesis in acquired aplastic anemia

Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan

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