Klyukhin, Vladislav Valeryevich

Klyukhin V.V., Kalinina I.I., Salimova T.Y., Osipova I.V., Shapiro V.Y., Sharapova G.R., Maschan A.A.

Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignant neoplasms, the substrate of which is the clonal proliferation of myelopoiesis progenitor cells. The key AML features are uncontrolled proliferation and arrest of cell differentiation, which leads to specific damage of various organs and systems; in the absence of specific therapy, death occurs quite quickly.Spontaneous AML remission is considered a rare phenomenon. In 1878, the first mention of AML clinical manifestations regression after acute infectious disease was made, but the remission was short and a relapse soon occurred.The article presents a literature review and 3 clinical cases, systematizing information on known cases of spontaneous AML remission in children. Attention is focused on various mechanisms that may contribute to spontaneous AML remission in children. These may be either immune-mediated reactions to leukemic cells or the influence of infectious agents, which in some cases activate antitumor immunity. In some cases, a direct correlation is observed between the presence of infectious processes and a decrease of tumor cells number, which emphasizes the importance of further studying the molecular mechanisms of interaction between immune and tumor cells.There is no evidence of a correlation between age and spontaneous remission. Spontaneous remission, although rare, may be a significant factor to consider when planning a treatment strategy.Further clinical studies are needed to better understand the spontaneous remission mechanisms in childhood AML. This may lead to improved treatment results and increased chances of a favorable outcome for patients.

Imataki O., Ishida T., Kida J., Uemura M., Fujita H., Kadowaki N.

Abstract Background Acute myeloid leukemia (AML) is a progressive hematological malignancy that can be fatal when left untreated. However, spontaneous remission is rarely observed in the presence of infectious diseases. Case presentation We treated an 80-year-old woman with AML who spontaneously underwent remission after infections. Spontaneous remission was observed after each of three independent clinical infections caused by different pathogens—nontuberculous Mycobacterium infection, pulmonary aspergillosis, and Escherichia coli bacteremia. All infections were treated promptly with antimicrobials. Mycobacterium avium infection was treated with azithromycin, rifampin, and ethambutol. Pulmonary aspergillosis was treated with itraconazole followed by voriconazole. E. coli infection was treated with meropenem. During each infectious episode, leukemic cells disappeared from the patient’s peripheral blood and pancytopenia improved without routine blood transfusion. These clinical effects lasted for several months. The patient has survived for > 2 years beyond the median survival time of end-stage AML. Thus, this case represents an immunological antileukemic effect of systemic infections. Conclusions We have discussed a common mechanism of spontaneous remission of AML without chemotherapy, clinically exhibited by infection immunology. We believe that infections exert a limited immunological effect against AML, which may prolong survival among elderly individuals with AML.

Bradley T., Zuquello R.A., Aguirre L.E., Mackrides N., Chapman J., Cimmino L., Thomassen A., Watts J.

Acute myeloid leukemia (AML) is defined by the presence of ≥ 20% myeloblasts in the blood or bone marrow. Spontaneous remission (SR) of AML is a rare event, with few cases described in the literature. SR is generally associated with recovery from an infectious or immunologic process, and more recently possibly with clonal hematopoiesis. We review the literature and assess the trends associated with SR, and report a new case of a 58-year-old man with a morphologic diagnosis of AML associated with a severe gastrointestinal (GI) tract infection. The patient had an NF1 variant that was previously unreported in AML as the only clonal abnormality. After treatment of the infection, the increased blast population subsided with no leukemia-directed therapy, and the patient has remained in a continuous, spontaneous complete remission for > 2 years.

Helbig D., Quesada A.E., Xiao W., Roshal M., Tallman M.S., Knorr D.A.

Khalife-Hachem S., Pegliasco J., Saada V., Hernandez E., Camara-Clayette V., Cotteret S., Benabdelali R., de Botton S., Marzac C., Micol J.

Hoshino T., Taki T., Takada S., Hatsumi N., Sakura T.

The translocation t(8;16)(p11;p13), which results in fusion of the MOZ/MYST3/KAT6A gene (8p11) and CBP/CREBBP gene (16p13), is characterized by unique morphologic and clinical findings in acute mye...

Vachhani P., Mendler J.H., Evans A., Deeb G., Starostik P., Wallace P.K., Wang E.S.

Spontaneous remission (SR) of acute myeloid leukemia (AML) is a very rare phenomenon. AML characterized byFLT3internal tandem duplication (FLT3ITD) is typically associated with an aggressive clinical course with rapid progression, relapse, and short overall survival in the absence of transplantation. We report here the first case of SR ofFLT3ITD mutant AML in the literature. Our patient was an elderly woman with relapsedNPM1andFLT3ITD mutant AML whose disease underwent SR for a brief duration without precipitating cause. We review the potential immune mechanisms underlying SR in AML and discuss the implications for novel immunotherapeutic approaches forFLT3mutant AML.

Camus V., Etancelin P., Jardin F., Lenain P., Contentin N., Daliphard S., Buchonnet G., Lemasle E., Lanic H., Leprêtre S., Penther D., Dubois S., Tilly H., Bastard C., Stamatoullas A.

Patients with NPM1-mutated AML M5 who develop spontaneous remission (SR) after antibiotic therapy at diagnosis seem to form a favorable prognosis and chemo sensitive subtype. We report three cases of AML M5 patients with the same genotype that experienced transient SR and are now leukemia free after standard treatment.

Martelli M.P., Gionfriddo I., Mezzasoma F., Milano F., Pierangeli S., Mulas F., Pacini R., Tabarrini A., Pettirossi V., Rossi R., Vetro C., Brunetti L., Sportoletti P., Tiacci E., Di Raimondo F., et. al.

Key Points ATRA and ATO affect NPM1 protein levels in AML cells and induce cell growth inhibition and apoptosis. AML cells with mutated NPM1 respond to ATRA/ATO, and this might be exploited therapeutically.

Rashidi A., Fisher S.I.

Huang M., Thomas D., Li M.X., Feng W., Chan S.M., Majeti R., Mitchell B.S.

Mutations in exon 12 of the nucleophosmin (NPM1) gene (NPMc+ (NPM1 COOH terminal mutations)) define a distinct subset of acute myelogenous leukemias (AMLs), in which the NPMc+ protein localizes aberrantly to the leukemic cell cytoplasm. We have found that introduction of the most common NPMc+ variant into K562 and 32D cells sensitizes these cells to apoptosis induced by drugs such as bortezomib and arsenic trioxide (ATO) that induce reactive oxygen species (ROS) formation, and that cytotoxicity is prevented in the presence of N-acetyl-L-cysteine (NAC), an ROS scavenger. The substitution of tryptophan 288 (W288) by cysteine occurs in the great majority of NPM1c+ mutations. Mutagenesis of cysteine 288 to alanine re-localizes NPMc+ from the cytoplasm to the nucleolus and attenuates the sensitivity of cells expressing this mutation to bortezomib and ATO. Primary AML cells expressing NPMc+ are also significantly more sensitive than other AML cells to apoptosis induced by both drugs at pharmacologically achievable doses. We conclude that the presence of a cysteine moiety at position 288 results in the cytoplasmic localization of NPM1c+ and the increased sensitivity to bortezomib and ATO. These data suggest that bortezomib and ATO may have increased therapeutic efficacy in NPM1c+ leukemias.

Federici L., Falini B.

Nucleophosmin (NPM1) is an abundant, ubiquitously expressed protein mainly localized at nucleoli but continuously shuttling between nucleus and cytoplasm. NPM1 plays a role in several cellular functions, including ribosome biogenesis and export, centrosome duplication, chromatin remodeling, DNA repair, and response to stress stimuli. Much of the interest in this protein arises from its relevance in human malignancies. NPM1 is frequently overexpressed in solid tumors and is the target of several chromosomal translocations in hematologic neoplasms. Notably, NPM1 has been characterized as the most frequently mutated gene in acute myeloid leukemia (AML). Mutations alter the C-terminal DNA-binding domain of the protein and result in its aberrant nuclear export and stable cytosolic localization. In this review, we focus on the leukemia-associated NPM1 C-terminal domain and describe its structure, function, and the effect exerted by leukemic mutations. Finally, we discuss the possibility to target NPM1 for the treatment of cancer and, in particular, of AML patients with mutated NPM1 gene.

Müller-Schmah C., Solari L., Weis R., Pfeifer D., Scheibenbogen C., Trepel M., May A.M., Engelhardt R., Lübbert M.

Spontaneous complete remission (CR) is a rare, poorly understood phenomenon in acute myeloid leukemia (AML). We describe the 10-year follow-up of a patient with MLL-AF9-positive AML (Müller et al. Eur J Haematol 73:62–66, 2004), including ex vivo antileukemic immune responses which may contribute to the long-lasting spontaneous CR (tantamount to cure). We could demonstrate strong in vitro cytotoxic activity mediated by the patient’s serum (cryopreserved at diagnosis 2001) against myeloid cell lines. We also addressed cellular cytotoxic activity against myeloid leukemia cells. When the patient’s natural killer (NK) cells (obtained in 2007) were tested against the K562 cell line, upregulation of CD107 occurred, implying that long-term CR in this patient could be due to NK cell-mediated disease control.

Jain N., Hubbard J., Vega F., Vidal G., Garcia-Manero G., Borthakur G.

Spontaneous remission of acute myeloid leukemia (AML) is very rare, with < 100 reported cases in adults. We describe herein 3 patients with AML and 1 with high-risk myelodysplastic syndrome at our institution who had spontaneous remission. Spontaneous remissions are generally of short duration and therefore require close follow-up to detect relapses.

Beinart G., Jones D., Abruzzo L.V., Ravandi F.

We report a novel case of spontaneous hematologic and cytogenetic remission in a patient with acute myelogenous leukemia with inv(16)(p13q22) after a systemic infection as well as transfusion of blood. Although spontaneous complete remission is a rare occurrence, we present a review of the current literature, emphasizing a diagnostic approach and associated factors.

Estey E., Döhner H.

Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haemopoietic progenitor cells and the most common malignant myeloid disorder in adults. The median age at presentation for patients with AML is 70 years. In the past few years, research in molecular biology has been instrumental in deciphering the pathogenesis of the disease. Genetic defects are thought to be the most important factors in determining the response to chemotherapy and outcome. Whereas significant progress has been made in the treatment of younger adults, the prospects for elderly patients have remained dismal, with median survival times of only a few months. This difference is related to comorbidities associated with ageing and to disease biology. Current efforts in clinical research focus on the assessment of targeted therapies. Such new approaches will probably lead to an increase in the cure rate.