Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%-15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.

Accumulating evidence demonstrates that autoimmune hematopoietic failure and myeloid neoplasms have an intrinsic relationship with regard to clonal hematopoiesis and disease evolution. In approximately 10%-15% of patients with severe aplastic anemia (SAA), the disease phenotype is transformed into myeloid neoplasms following antithymocyte globulin plus cyclosporine-based immunosuppressive therapy. In some of these patients, myeloid neoplasms appear during or shortly after immunosuppressive therapy. Leukemic transformation in SAA patients during anti-tuberculosis treatment has not been reported.

A middle-aged Chinese female had a 6-year history of non-SAA and a 2-year history of paroxysmal nocturnal hemoglobinuria (PNH). With aggravation of systemic inflammatory symptoms, severe pancytopenia developed, and her hemoglobinuria disappeared. Laboratory findings in cytological, immunological and cytogenetic analyses of bone marrow samples met the diagnostic criteria for "SAA." Definitive diagnosis of disseminated tuberculosis was made in the search for infectious niches. Remarkable improvement in hematological parameters was achieved within 1 mo of anti-tuberculosis treatment, and complete hematological remission was achieved within 4 mo of treatment. Frustratingly, the hematological response lasted for only 3 mo, and pancytopenia reemerged. At this time, cytological findings (increased bone marrow cellularity and an increased percentage of myeloblasts that accounted for 16.0% of all nucleated hematopoietic cells), immunological findings (increased percentage of cluster of differentiation 34+ cells that accounted for 12.28% of all nucleated hematopoietic cells) and molecular biological findings (identification of somatic mutations in nucleophosmin-1 and casitas B-lineage lymphoma genes) revealed that "SAA" had transformed into acute myeloid leukemia with mutated nucleophosmin-1. The transformation process suggested that the leukemic clones were preexistent but were suppressed in the PNH and SAA stages, as development of symptomatic myeloid neoplasm through acquisition and accumulation of novel oncogenic mutations is unlikely in an interval of only 7 mo. Aggravation of inflammatory stressors due to disseminated tuberculosis likely contributed to the repression of normal and leukemic hematopoiesis, and the relief of inflammatory stressors due to anti-tuberculosis treatment contributed to penetration of neoplastic hematopoiesis. The concealed leukemic clones in the SAA and PNH stages raise the possibility of an inflammatory stress-fueled antileukemic mechanism.

Aggravated inflammatory stressors can repress normal and leukemic hematopoiesis, and relieved inflammatory stressors can facilitate penetration of neoplastic hematopoiesis.

It has been reported that prolonged neutropenia during post-remission chemotherapy is associated with a reduced risk of disease relapse in pediatric acute myeloid leukemia (AML) patients.

We retrospectively reviewed the charts of adult AML patients in first complete remission (CR1) who underwent consolidation chemotherapy with high-dose cytarabine. Those receiving allogeneic hematopoietic cell transplantation in CR1 were excluded. We calculated the D-index, which is an area-based neutropenia index. The patients were divided into 2 groups using the median value of the D-index during the first cycle of consolidation chemotherapy (C#1).

Fifty-six patients were included. The 2-year cumulative incidence of relapse was 54.8% (95% confidence interval (CI): 37.5-73.8) in patients with a D-index < 5,118 and 62.0% (95%CI: 42.7-81.4) in those with a D-index ≥ 5,118 (P = 0.56). In a multivariate analysis, intermediate / adverse cytogenetic risk (HR 2.76), performance status ≥ 2 (HR 5.55) and 2 cycles of induction chemotherapy required to achieve CR1 (HR 4.29) were identified as significant factors associated with relapse. The D-index at C#1 did not have a significant impact.

In contrast to pediatric patients, the severity of neutropenia is not associated with a risk of disease relapse in adult AML patients.

The variability in myelosuppression after chemotherapy for acute myeloid leukaemia (AML) can affect its prognosis; however, the underlying mechanism remains controversial. In the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study, we showed that prolonged neutropenia was associated with high overall survival (P = 0·011) and low frequency of relapse (P = 0·042) in patients without granulocyte-colony stimulating factor (G-CSF) who completed the indicated treatment protocol. Our data indicate that predisposition to prolonged neutropenia after chemotherapy is correlated with a better outcome of AML treatment. Our results promote the usage of individualised drug dosing strategies to improve the therapeutic outcome in AML patients.

Children with acute myeloid leukemia (AML) treated similarly show different toxicity and leukemic responses. We investigated associations between neutrophil recovery time after the first induction course, infection and relapse in children treated according to NOPHO-AML 2004 and DB AML-01.

Newly diagnosed patients with AML with bone marrow blast <5% between day 15 after the start of the treatment and the start of second induction course, and in complete remission after the second induction course were included (n = 279). Neutrophil recovery time was defined as the time from the start of the course to the last day with absolute neutrophil count <0.5 × 10⁹ /l. Linear and Cox regressions were used to investigate associations.

Neutrophil recovery time after the first induction course was positively associated with neutrophil recovery time after the remaining courses, and longer neutrophil recovery time (≥25 days) was associated with increased risk of grade 3-4 infections (hazard ratio 1.4, 95% confidence interval [CI], 1.1-1.8). Longer neutrophil recovery time after the first induction (>30 days) was associated with the increased risk of relapse (5-year cumulative incidence: 48% vs. 42%, hazard ratio 1.7, 95% CI, 1.1-2.6) for cases not treated with hematopoietic stem cell transplantation in first complete remission.

Longer neutrophil recovery time after the first induction course was associated with grade 3-4 infections and relapse. If confirmed, this knowledge could be incorporated into risk stratification strategies in pediatric AML.