The growth capacity of hematopoietic progenitor cells in severe neutropenia induced by famotidine

Abstract

In four cases of severe neutropenia of unknown origin we found a strong inhibition of the growth of granulocyte-macrophage (GM) progenitor cells. The development of GM colonies in culture (GM-CFU-c) was more than 80% reduced in comparison to the control group. In particular, the interleukin 3-(IL-3) and granulocyte macrophage colony-stimulating factor-(GM-CSF) dependent growth was affected; a combination of growth factors (IL-3, GM-CSF, and G-CSF, the granulocyte colony-stimulating factor) resulted in a less reduced growth. The findings were primarily compatible with drug-induced bone marrow failure. Among the medications given to the patients, famotidine, an H2-receptor blocker, was discussed as an agent which possibly triggers off this process. After the withdrawal of famotidine, in three cases a continual increase of the growth of GM precursors was detected, reaching the normal level 7-17 days later. In one case, further investigations of the progenitor cells could not be carried out due to the death of the patient, but the rapid increase of neutrophils in the peripheral blood after withdrawal of famotidine pointed to the recovery of hematopoiesis. In vitro studies showed that famotidine, depending on the dose, inhibits the single growth factor-dependent colony growth (IL-3, GM-CSF, or G-CSF) of bone marrow progenitors from a concentration as low as 10 micrograms/ml. With the combination of all three growth factors only slight inhibitory effects were detectable (up to 150 micrograms/ml famotidine). These results indicate that famotidine, in common with other H2-receptor antagonists, can affect hematopoietic progenitor cells. However, the plasma concentration of famotidine normally used in ulcer therapy does not seem to influence the hematopoiesis. Apparently, the progenitor cells of only a few patients possess a higher sensitivity to the blockade of H2-receptors at this concentration of famotidine. This was demonstrated in one case (patient 3) 2 years after the patient had recovered from famotidine-induced neutropenia. The growth of peripheral myeloid, erythroid, and multilineage progenitor cells of this patient was remarkably reduced even at famotidine concentrations of 0.1-5.0 micron/ml whereas in the control group no inhibition was detected at these famotidine concentrations. Again, the IL-3-dependent colony formation was more affected than in the case of the combination of IL-3, GM-CSF, and G-CSF. After the removal of accessory cells the inhibitory effect of famotidine persisted, demonstrating that accessory cells do not play a major role in this process.

Intravenous immunoglobulin for pembrolizumab‐induced bullous pemphigoid‐like eruption: A case report

“…5 Furthermore, famotidine is known to induce neutropenia and even agranulocytosis. 6 In our case, the neutrophil count had gradually decreased even before the IVIG, and the agranulocytosis occurred 11 days after the IVIG cessation (Figure 1D). Additionally, restarting the pembrolizumab did not induce neutropenia.…”

Agranulocytosis Associated with Initiation of Famotidine Therapy

“…2 In some patients, this adverse effect may be due to an enhanced sensitivity to the blocking effect of the drug. In fact, in one case, 5 2 years after discontinuation of famotidine secondary to severe neutropenia, the growth of the pa-tient's peripheral myeloid, erythroid, and multilineage progenitor cells in vitro was remarkably reduced when famotidine was added at concentrations of 0.5-5.0 µg/mL. In a control group, no such inhibition was detected at these famotidine concentrations.…”

“…Liersch et al 5 investigated the mechanism of famotidine-induced neutropenia in 4 patients. The authors recorded a strong inhibition of the in vitro growth of granulocytemacrophage (GM) progenitor cells during treatment with famotidine in these patients.…”

Aplastic anemia associated with initiation of nizatidine therapy in a hemodialysis patient

“…In a previous study, the in vitro growth of granulocyte-macrophage progenitor cells was markedly inhibited in patients with neutropenia associated with H2-receptor antagonists. 8 This inhibition was reduced after withdrawal of H2-receptor antagonists. In addition, H2-receptor antagonists had an inhibitory effect on the growth and differentiation of normal bone marrow progenitor cells.…”