Kanako Mochizuki

Origin and fate of blood cells deficient in glycosylphosphatidylinositol‐anchored protein among patients with bone marrow failure

Peripheral blood from 489 recently diagnosed patients with aplastic anaemia (AA) and 316 with refractory anaemia (RA) of myelodysplastic syndrome was evaluated to characterize CD55−CD59− [paroxysmal nocturnal haemoglobinuria (PNH)]‐type blood cells associated with bone marrow (BM) failure. PNH‐type cells were detected in 57% and 20% of patients with AA and RA, respectively. The percentages of PNH‐type granulocytes ranged from 0·003% to 94·2% and the distribution was log‐normal with a median of 0·178%. Serial analyses of 75 patients with PNH‐type cells over 5 years revealed that the percentage of PNH‐type cells constantly increased in 13 (17%), persisted in 44 (59%), disappeared in the remaining 18 (24%) although even in the ‘Disappearance’ group, PNH‐type granulocytes persisted for at least 6 months. A scattergram profile of PNH‐type cells unique to each patient persisted regardless of the response to immunosuppressive therapy and only single PIGA mutations were detected in PNH‐type granulocytes sorted from four patients. These findings suggest that the PNH‐type cells in patients with BM failure are derived from single PIGA mutant haematopoietic stem cells even when their percentages are <1% and their fate depends on the proliferation and self‐maintenance properties of the individual PIGA mutants.

Mycophenolate Mofetil Is Effective and Well Tolerated in the Treatment of Refractory Acute and Chronic Graft-versus-Host Disease

We enrolled 11 patients with refractory graft-versus-host disease (GVHD) in a prospective trial evaluating the efficacy of mycophenolate mofetil (MMF). Four (67%) of the 6 patients with acute GVHD and all 5 patients with chronic GVHD responded to MMF. Ten (91%) of the 11 patients were able to decrease steroid use (median decrease, 86%; range, 25%-100%). After a median follow-up of 18 months (range, 1-65 months), 7 patients (64%) remained alive. The adverse events were infectious complications (36%), diarrhea (27%), and neutropenia (18%); the only patient discontinuing MMF did so because of grade 4 neutropenia. This preliminary study suggests that MMF is a well-tolerated agent and has a beneficial effect in the treatment of refractory acute and chronic GVHD.

Successful treatment of Trichosporon fungemia in a patient with refractory acute myeloid leukemia using voriconazole combined with liposomal amphotericin B

Trichosporon fungemia is a rare and fatal fungal infection that occurs in patients with prolonged neutropenia associated with hematologic malignancies. A 21‐year‐old male developed Trichosporon fungemia during remission induction therapy for acute myeloid leukemia (AML). Although two courses of induction therapy failed to induce a remission of AML, combination therapy with voriconazole and liposomal amphotericin B (L‐AmB) followed by monocyte colony‐stimulating factor ameliorated the Trichosporon fungemia and enabled the patient to receive reduced‐intensity bone marrow transplantation (BMT) from his human leukocyte antigen‐A one‐locus mismatched mother. The patient achieved a durable remission after BMT without exacerbation of Trichosporon fungemia. The combination therapy with voriconazole and L‐AmB may therefore be useful in controlling Trichosporon fungemia associated with prolonged neutropenia after remission induction therapy for AML.

Expansion of donor-derived hematopoietic stem cells with PIGA mutation associated with late graft failure after allogeneic stem cell transplantation

A small population of CD55(-)CD59(-) blood cells was detected in a patient who developed donor-type late graft failure after allogeneic stem cell transplantation (SCT) for treatment of aplastic anemia (AA). Chimerism and PIGA gene analyses showed the paroxysmal nocturnal hemoglobinuria (PNH)-type granulocytes to be of a donor-derived stem cell with a thymine insertion in PIGA exon 2. A sensitive mutation-specific polymerase chain reaction (PCR)-based analysis detected the mutation exclusively in DNA derived from the donor bone marrow (BM) cells. The patient responded to immunosuppressive therapy and achieved transfusion independence. The small population of PNH-type cells was undetectable in any of the 50 SCT recipients showing stable engraftment. The de novo development of donor cell-derived AA with a small population of PNH-type cells in this patient supports the concept that glycosyl phosphatidylinositol-anchored protein-deficient stem cells have a survival advantage in the setting of immune-mediated BM injury.

Increased glycosylphosphatidylinositol‐anchored protein‐deficient granulocytes define a benign subset of bone marrow failures in patients with trisomy 8

Trisomy 8 (+8), one of the most common chromosomal abnormalities found in patients with myelodysplastic syndromes (MDS), is occasionally seen in patients with otherwise typical aplastic anemia (AA). Although some studies have indicated that the presence of +8 is associated with the immune pathophysiology of bone marrow (BM) failure, its pathophysiology may be heterogeneous. We studied 53 patients (22 with AA and 31 with low‐risk MDS) with +8 for the presence of increased glycosylphosphatidylinositol‐anchored protein‐deficient (GPI‐AP−) cells, their response to immunosuppressive therapy (IST), and their prognosis. A significant increase in the percentage of GPI‐AP− cells was found in 14 (26%) of the 53 patients. Of the 26 patients who received IST, including nine with increased GPI‐AP− cells and 17 without increased GPI‐AP− cells, 14 (88% with increased GPI‐AP− cells and 41% without increased GPI‐AP− cells) improved. The overall and event‐free survival rates of the +8 patients with and without increased GPI‐AP− cells at 5 yr were 100% and 100% and 59% and 57%, respectively. Examining the peripheral blood for the presence of increased GPI‐AP− cells may thus be helpful for choosing the optimal treatment for +8 patients with AA or low‐risk MDS.