Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti-PD-1 Therapy.

Antibodies aimed at blocking the interaction between programmed cell death-1 (PD-1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodysplastic syndrome (MDS) in the blood following treatment with an anti-PD-1 agent. Myeloid blasts comprised <1% of peripheral blood mononuclear cells (PBMC) 1 month after the start of treatment. Six months after starting therapy, myeloid blasts comprised 5% of PBMCs, and a bone marrow biopsy confirmed refractory anemia with excess blasts-2 (RAEB-2). Longitudinal mass cytometry immunophenotyping comprehensively characterized blast phenotype evolution and revealed elevated PD-1 expression on the surface of nonblast myeloid cells. These findings highlight the clinical significance of cytomic monitoring, indicate that the myeloid compartment should be monitored during checkpoint inhibitor therapy, and emphasize the value of systems immunology in medicine. Cancer Immunol Res; 4(6); 474-80. ©2016 AACR.

[Case report: RAEB in a patient with rheumatoid arthritis treated with methotrexate and infliximab]. / Anemia refrattaria con eccesso di blasti (AREB) in paziente con artrite reumatoide in trattamento con methotrexate ed infliximab: descrizione di un caso clinico.

Anti TNF-alpha drugs seem to be the new frontier of Rheumatoid Arthritis (RA) therapy. The association infliximab methotrexate has been approved for the treatment of RA not responding to the classic therapy, but the short clinical experience in using antiTNF-alpha molecules brings to segnalation of new risks or adverse events. We describe a case of a patient, treated for many years with classic RA therapy, which developed a refractory anemia after treatment with association infliximab-methotrexate.

Alternating dose-dense chemotherapy in patients with high volume disseminated non-seminomatous germ cell tumours.

Only about half of patients with a poor-prognosis non-seminomatous germ-cell tumours can achieve a cure. The aim of this phase II study was to assess the efficacy and toxicity of a dose-dense alternating chemotherapy regimen in this subset of patients. High volume non-seminomatous germ-cell tumours was defined as follows: at least two sites of non pulmonary metastases, an extragonadal primary tumour, a serum human chorionic gonadotropin level higher than 10 000 mIU x ml(-1), or a alpha-foetoprotein level higher than 2000 mIU ml(-1). Patients who fulfilled these criteria were treated with the so-called BOP-CISCA-POMB-ACE regimen (bleomycin, vincristine, and cisplatin; cisplatin, cyclophosphamide, and doxorubicin; cisplatin, vincristine, methotrexate, and bleomycin; etoposide, dactinomycin, and cyclophosphamide) plus granulocyte colony-stimulating factor. A total of 58 patients were enrolled. Patients were retrospectively classified according to the International Germ-Cell Cancer Consensus Group classification; 38 patients (66%) had poor-prognosis disease and 19 patients (33%) had intermediate-prognosis. Patients received a median of 2.5 courses (range 0.25 to five courses) of the BOP-CISCA-POMB-ACE regimen. Forty-two patients (72.4%) had a complete response to therapy. With a median follow-up time of 31 months, the 3-year progression-free survival rate was 71% (95% confidence interval, 60 to 84%) and the 3-year overall survival rate was 73% (95% confidence interval: 62 to 86%). The 3-year PFS rates were 83% (95% confidence interval: 68 to 100%) in the intermediate-prognosis group and 65% (95% confidence interval: 51 to 82%) in the poor-prognosis group. Early side effects included mainly grade 4 haematologic toxicity (neutropaenia in 79% of patients, thrombocytopaenia in 69%, anaemia in 22%), grade 4 stomatitis (19%), and four early deaths (7% of patients), at least partially related to toxicity. The dose-dense BOP-CISCA-POMB-ACE regimen is highly active in patients with non-seminomatous germ-cell tumours classified as intermediate-prognosis or poor-prognosis according to the International Germ-Cell Cancer Consensus Group. Because outcomes with this regimen compare favourably with outcome after standard therapy, dose-dense chemotherapy should be further investigated in this subset of patients.

Therapy-related myelodysplastic syndrome (t-MDS) in a patient with anaplastic astrocytoma: successful treatment with allogeneic bone marrow transplant.

OBJECTIVE: and importance Therapy-related myelodysplastic syndrome (t-MDS) is a rare and typically fatal complication of therapy for cancer, including brain tumors. We report successful therapy of t-MDS that developed after treatment for an anaplastic astrocytoma. CLINICAL PRESENTATION: t-MDS developed four and one-half years after successful therapy (resection, radiation and chemotherapy) administered for a cerebral anaplastic astrocytoma in a 34-year-old patient. INTERVENTION: The patient was treated with allogeneic bone marrow transplant (BMT) for t-MDS. CONCLUSION: She is alive three years after BMT with no evidence of brain tumor and in complete remission from t-MDS. To our knowledge, this is the first report of allogeneic BMT administered for t-MDS in an adult brain tumor patient. Clinicians must be alert to the development of t-MDS following chemotherapy for brain tumors and initiate appropriate treatment promptly.

[Cervical tuberculous lymphadenopathy--a rare complication of myelodysplastic syndrome]. / Zervikale tuberkulöse Lymphadenopathie--Eine seltene Komplikation des Myelodysplastischen Syndroms.

Patients with myelodysplasia are susceptible to infections due to their compromised immunity. If presenting with a cervical lymphadenopathy patients must, in addition to other causes, be evaluated for tuberculosis, especially if they show a concurrent erythema nodosum.

Myelodysplastic syndrome following successful therapy of acute promyelocytic leukemia.

We describe a patient with acute promyelocytic leukemia (APL) who was successfully induced into remission with all-trans retinoic acid (ATRA) and idarubicin, but developed myelodysplastic syndrome (MDS) with monosomy 7 shortly after conclusion of maintenance therapy with idarubicin alternating with 6-mercaptopurine, vincristine, methotrexate and prednisone. Patients on combination regimens of ATRA or other retinoids and chemotherapy, which are being increasingly used in recent years, should be closely monitored for the development of potentially new complications including MDS.

Leukemogenic risk of hydroxyurea therapy in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.

In polycythemia vera (PV), treatment with chlorambucil and radioactive phosphorus (p32) increases the risk of leukemic transformation from 1% to 13-14%. This risk has been estimated to be 1-5.9% with hydroxyurea (HU) therapy. When compared with historical controls, the risk with use of HU does not appear to be statistically significant. The leukemogenic risk of HU therapy in essential thrombocytosis (ET) and in myelofibrosis with myeloid metaplasia (MMM) is unknown. HU remains the main myelotoxic agent in the treatment of PV, ET, and MMM. We studied 64 patients with these three disorders, seen at our institution during 1993-1995. The patients were studied for their clinical characteristics at diagnosis, therapies received, and development of myelodysplasia or acute leukemia (MDS/AL). Forty-two had PV, 15 ET, and 6 MMM, and 1 had an unclassified myeloproliferative disorder. Of the 42 patients with PV, 18 were treated with phlebotomy alone, 16 with HU alone, 2 with p32, 2 with multiple myelotoxic agents, and 2 with interferon-alpha (IFN-alpha). Two patients from the phlebotomy-treated group, one from the HU-treated group, and 1 from the multiple myelotoxic agent-treated group developed MDS/AL. In the larger group, 11 received no treatment or aspirin alone, 18 were treated with phlebotomy alone, 25 with HU, 5 with multiple myelotoxic agents, 2 with p32, 2 with IFN-alpha, and 1 with melphalan. Study of the entire group of 64 patients showed that only one additional patient (total of 5 out of 64) developed MDS/AL. This patient had been treated with HU alone. Statistical analysis did not show any association between clinical characteristics at diagnosis, or HU therapy, and development of MDS/AL (P=0.5). Thus, our data provide no evidence suggestive of increased risk of transformation to MDS/AL with HU therapy in PV, ET, and MMM. Larger, prospective studies are needed to study this issue further.

Idarubicin, high-dose cytarabine and etoposide for remission induction in therapy-related acute myeloid leukemia.

Five patients with therapy-related acute myeloid leukemia received combination induction chemotherapy with idarubicin, high-dose cytarabine, and etoposide. Complete remission was achieved in all patients with a single course of therapy. Treatment-related toxicity included nausea, vomiting, mucositis, diarrhea, and liver and kidney function abnormalities, and was low in all patients. There were no deaths during induction therapy. We conclude that this combination is well-tolerated in induction of remission in secondary acute myeloid leukemia, and warrants further assessment because of a very good complete remission rate.

Unbalanced 1;7 translocation in myelodysplastic syndrome following treatment of acute myeloblastic leukemia with an 8;21 translocation.

The chromosome der(1;7)(q10;p10) consists of the short arm of chromosome 7 and the long arm of chromosome 1, and is a common abnormality in treatment-related leukemia and myelodysplastic syndrome. Here we describe a 39-year-old Japanese man with acute myeloblastic leukemia (FAB-M2) exhibiting t(8;21)(q22;q22). He entered complete remission after induction therapy, and intensification therapy including alkylating agents was subsequently continued for 3 years. The patient then developed pancytopenia; bone marrow aspiration revealed myelodysplastic syndrome exhibiting the der (1;7) chromosome. To our knowledge, this is the first reported case of such an abnormality in myelodysplastic syndrome secondary to acute myeloblastic leukemia with the 8;21 translocation.

[Secondary myelodysplastic syndrome in a boy with non-Hodgkin's lymphoma]. / Sekundární myelodysplastický syndrom u chlapce s NH lymfomem.

The authors describe the case-history of a boy with secondary myelodysplastic syndrome (MDS) which developed into acute leukaemia. The latter was quite resistant to treatment. The disease was preceded by treatment of NH lymphoma with a high grade of malignity by radiotherapy and chemotherapy. The authors give the total doses of all cytostatics which were administered to the patient. One year prior to diagnosis of MDS cytogenetic examination of peripheral blood revealed a highly pathological karyotype, from the numerical and structural aspect. Among others monosomy of chromosome no. 5 was found which is typical for MDS and these changes indicate as a rule a poor prognosis and relatively early transformation to acute leukaemia.

Acute non-lymphocytic leukemia following FAM combination adjuvant chemotherapy for gastric and lung adenocarcinoma.

We report 2 cases of acute non-lymphocytic leukemia with distinct clinical and karyotypic features shared by therapy-related acute non-lymphocytic leukemia occurring after adjuvant chemotherapy including 5-fluorouracil, doxorubicin and mitomycin C. Our observation suggests a causal relationship between exposure to mitomycin C and the occurrence of acute non-lymphocytic leukemia.