Acquired aplastic anemia: Is bystander insult to autologous hematopoiesis driven by immune surveillance against malignant cells?

Abstract

We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations (GCPs). This patient experienced three recurrences over the ensuing one year of intermittent GCP treatments, with each recurrence occurring 7-8 wk from a GCP. After his third recurrence, he was prescribed successive treatment with rifampicin, berberine, and monthly administered GCP for 4 mo, and he developed an erythroid proliferative neoplasma and an overwhelming enteropathy, and eventually died of septic shock. Laboratory investigations had validated the resolution of myelosuppression and the appearance of malignant clonal hematopoiesis. From the treatment process and laboratory investigations, it is reasonably inferred that the engagement of gut inflammation is critically required in sustaining the overall pathophysiology of acquired aplastic anemia probably by creating a chronic inflammatory state. Incorporation of rifampicin, berberine, and monthly GCP into cyclosporine can enhance the immunosuppressive effect. In a subgroup of acquired aplastic anemia patients whose pathogenesis is associated with genotoxic exposure, the suppressed normal hematopoiesis may result from the bystander insult that is mediated by the soluble inflammatory cytokines generated in response to the immunogenic products of damaged hematopoietic cells in the context of chronic inflammatory state and may offer a protective antineoplastic mechanism against malignant proliferation.

Glucocorticoid and Antibiotic Treatment-induced Recapitulated Hematological Remissions in Acute Myeloid Leukemia: Implications for Ligand-dependent Growth and Survival Advantage

“…This ligand could be intestine-derived pathogen-associated molecular pattern, cytokine or colony stimulating factor produced in response to infectious offending [18][19][20][21][22]. After the second relapse, he demonstrated resistance to antibiotic and glucocorticoid treatment and died of septic shock probably due to the acquisition of a new pathogenic infection like our previously reported case [23] Taken together, the recapitulated antibiotic and glucocorticoid treatment-induced hematological remissions strongly indicated a ligand-dependent growth advantage in AML emergence. This phenomenon warrants further investigations and may be helpful in improving therapeutic outcome in a subgroup of AML.…”

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

“…Leukemic transformation in SAA patients can also occur after successful treatment of underlying infections and is frequently separated by a short duration of hematological remission. A rapid increase in leukemic blasts is the representative presentation of leukemic hematopoiesis ( 33 – 35 ). Moreover, patients with definitively diagnosed MNs can develop an aplastic crisis during infectious episodes.…”

“…The transformation between AHF and clinically overt MNs (MDS with excessive blasts or AML in which an increased percentage of myeloblasts is the most representative parameter in determining leukemic hematopoiesis) can reciprocally occur. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammatory conditions ( 33 – 36 ). Extramedullary infectious diseases have a conspicuous impact on phenotypic presentations.…”

“…During active inflammatory episodes, normal and leukemic hematopoieses are simultaneously suppressed with regression of leukemic blasts on cytological examination and Th1-predominant responses on immunological analysis. Aplastic cytopenia, the disappearance of leukemic blasts, Th1-predominant responses, and a small number of nucleated blood cells for identification of dysplasia result in cytological and immunological features that meet the criteria for the diagnosis of AA ( 33 – 36 ). Following successful control of the inflammatory episodes and a short duration of hematological remission, quickly expanded leukemic clones lead to the appearance of substantial leukemic blasts and symptomatic MNs ( 33 – 35 ).…”

“…Aplastic cytopenia, the disappearance of leukemic blasts, Th1-predominant responses, and a small number of nucleated blood cells for identification of dysplasia result in cytological and immunological features that meet the criteria for the diagnosis of AA ( 33 – 36 ). Following successful control of the inflammatory episodes and a short duration of hematological remission, quickly expanded leukemic clones lead to the appearance of substantial leukemic blasts and symptomatic MNs ( 33 – 35 ). Patients with clinically overt MNs can develop an aplastic crisis during active inflammatory episodes in which systemic inflammatory stress is dramatically aggravated ( 35 , 36 ).…”