Successful treatment of a patient with Klinefelter's syndrome complicated by mediastinal germ cell tumor and AML(M7)

Hiramatsu, Hidefumi; Morishima, Tatsuya; Nakanishi, H; Mizushima, Yutaka; Miyazaki, Makito; Matsubara, Hiroshi; Kobayashi, Masashi; Nakahata, Tatsutoshi; Adachi, Souichi

doi:10.1038/sj.bmt.1705991

Cited by 26 publications

(14 citation statements)

References 10 publications

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“…The prognosis for these patients is extremely poor, with a median overall survival of only ∼5 mo ( Hartmann et al 2000 ). Allogeneic stem cell transplant represents the only curative approach for patients, but few patients are able to move forward to transplantation ( Hiramatsu et al 2008 ).…”

Section: Discussionmentioning

confidence: 99%

A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia

Riedell

Miller

et al. 2016

Cold Spring Harb Mol Case Stud

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We report the findings from a patient who presented with a concurrent mediastinal germ cell tumor (GCT) and acute myeloid leukemia (AML). Bone marrow pathology was consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7), and biopsy of an anterior mediastinal mass was consistent with a nonseminomatous GCT. Prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous GCTs, and it was recently suggested that a common founding clone initiated both cancers. We performed enhanced exome sequencing on the GCT and the AML M7 from our patient to define the clonal relationship between the two cancers. We found that both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). The mutations in PTEN and TP53 were present at ∼100% variant allele frequency (VAF) in both tumors. In addition, we detected and validated five other shared somatic mutations. The copy-number analysis of the AML exome data revealed an amplification of Chromosome 12p. We also identified a heterozygous germline variant in FANCA (S858R), which is known to be associated with Fanconi anemia but is of uncertain significance here. In summary, our data not only support a common founding clone for these cancers but also suggest that a specific set of distinct genomic alterations (in PTEN and TP53) underlies the rare association between GCT and AML. This association is likely linked to the treatment resistance and extremely poor outcome of these patients. We cannot resolve the clonal evolution of these tumors given limitations of our data.

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Section: Discussionmentioning

confidence: 99%

A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia

Riedell

Miller

et al. 2016

Cold Spring Harb Mol Case Stud

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“…The prognosis for GCT with a concurrent hematologic malignancy is poor, as the disease is usually refractory to conventional chemotherapy and patients are unable to attain a clinical remission [ 9 ]. For those that do attain a remission, relapse without consolidative allogeneic stem cell transplant is inevitable, and successful outcomes are limited to two cases in which patients underwent allogeneic hematopoietic stem cell transplant early in the first complete remission [ 1 , 10 ]. Given these dismal outcomes, novel therapeutic approaches are needed.…”

Section: Introductionmentioning

confidence: 99%

Functional and genetic screening of acute myeloid leukemia associated with mediastinal germ cell tumor identifies MEK inhibitor as an active clinical agent

et al. 2016

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BackgroundHematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management.Case PresentationHerein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient’s leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient’s blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time.ConclusionsThis case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0258-1) contains supplementary material, which is available to authorized users.

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“…Successful allogeneic stem cell transplant for MNSGCT-associated acute megakaryoblastic leukemia and myelodysplastic syndrome, respectively, has been reported. 12 , 13 Therefore, we hypothesized that incorporating alemtuzumab in reduced intensity stem cell transplantation might be effective through the direct attack on MH/HS cells, and enhancing the indirect graft-versus-MH/HS immunity.…”

Section: Discussionmentioning

confidence: 99%

Mediastinal Germ Cell Tumor-associated Histiocytic Proliferations Treated With Thalidomide Plus Chemotherapy Followed by Alemtuzumab-containing Reduced Intensity Allogeneic Peripheral Blood Stem Cell Transplantation

et al. 2016

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Mediastinal nonseminomatous germ cell tumor (MNSGCT)-associated histiocytic proliferations are rare and rapidly fatal disorders. Standard treatment modalities have yet to be established.We report a case of MNSGCT-associated hemophagocytic syndrome that evolved into malignant histiocytosis/disseminated histiocytic sarcoma (MH/HS), which was initially treated with intravenous immunoglobulin, corticosteroids, and cyclosporine. Then, thalidomide plus cyclophosphamide, adriamycin, oncovin, prednisolone chemotherapy followed by alemtuzumab-containing reduced-intensity allogeneic peripheral blood stem cell transplantation (PBSCT) was used as salvage therapy.The severe constitutional symptoms and pancytopenia resolved shortly after thalidomide with cyclophosphamide, adriamycin, oncovin, prednisolone. After PBSCT, the patient developed steroid-dependent skin graft-versus-host disease, but maintained a functional life for 1.5 years. Rapid resolution of chronic graft-versus-host disease preceded the fulminant recurrence of hemophagocytic syndrome and MH/HS.Thalidomide plus chemotherapy followed by alemtuzumab-containing reduced intensity allogeneic PBSCT is effective in allaying MNSGCT-associated histiocytic disorders, but does not prevent eventual relapse. However, further posttransplant immune modulation should be developed to completely eradicate the residual MH/HS cells.

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Successful treatment of a patient with Klinefelter's syndrome complicated by mediastinal germ cell tumor and AML(M7)

Cited by 26 publications

References 10 publications

A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia

A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia

Functional and genetic screening of acute myeloid leukemia associated with mediastinal germ cell tumor identifies MEK inhibitor as an active clinical agent

Mediastinal Germ Cell Tumor-associated Histiocytic Proliferations Treated With Thalidomide Plus Chemotherapy Followed by Alemtuzumab-containing Reduced Intensity Allogeneic Peripheral Blood Stem Cell Transplantation

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