PMC6900957_01
Clinical course of induction chemotherapy. On the horizontal axis, day 1 was set as the first day of induction chemotherapy. WBC, white blood cell; Neu, neutrophil; Hb, hemoglobin; Plt, platelet; Pro, promyelocyte; ATRA, all-trans retinoic acid; rTM, recombinant human thrombomodulin; mPSL, methylprednisolone; CZOP, cefozopran; RCC, red cell concentrate; PC, platelet concentrate; FFP, fresh frozen plasma.
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Induction chemotherapy was performed with oral all-trans retinoic acid (ATRA) at a dosage of 45 mg/m2 as a single agent, following the JALSG APL204 protocol (Figure 1).
Prolonged myelosuppression during three courses of consolidation chemotherapy. (a) First course; (b) second course; (c) third course. As the consolidation therapy progressed, myelosuppression prolonged. Back pain and coccygeal pain became milder during the later course of consolidation therapy. On horizontal axis, day 1 was set as the first day of each course of chemotherapy. WBC, white blood cell; Neu, neutrophil; Hb, hemoglobin; Plt, platelet; RCC, red cell concentrate; PC, platelet concentrate; FFP, fresh frozen plasma; Ara-C, cytarabine; MIT, mitoxantrone; DNR, daunorubicin; IDA, idarubicin; CZOP, cefozopran; ABK, arbekacin; DRPM, doripenem; CPFG, caspofungin; TMP/SMX, trimethoprim/sulfamethoxazole; IT, intrathecal injection.
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First consolidation chemotherapy involved cytarabine 200 mg/m2 for 5 days and mitoxantrone 7 mg/m2 for 3 days (Figure 2(a)). Second consolidation chemotherapy involved cytarabine 200 mg/m2 for 5 days with daunorubicin 50 mg/m2 for 3 days (Figure 2(b)). Third consolidation chemotherapy involved cytarabine 140 mg/m2 for 5 days with idarubicin 12 mg/m2 for 3 days (Figure 2(c)).
Phlegmonous gastritis. (a, b) Upper endoscopy. The gastric mucosa was reddish, and the folds were markedly thickened. (c) Abdominal CT. Fluid level was noted in the stomach. Arrow, thickened wall of the antrum and the pylorus with hypodense areas inside. Arrowheads, ascites.
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Upper endoscopy (Figures 3(a) and 3(b)) revealed dark-red bloody fluid in the stomach. Computed tomography (Figure 3(c)) revealed markedly thickened wall of the antrum and the pylorus with hypodense areas.
Serial bone marrow biopsies (hematoxylin-eosin (HE) and silver staining (Ag)). Only mild reticulin fibrosis was observed at the time of diagnosis. Fibrosis progressed as treatment progressed, and collagenous fibrosis was recognized. Magnification, 40x.
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To investigate the cause of progressive myelosuppression, bone marrow biopsy samples were re-evaluated retrospectively (Figure 4).
Histopathology of bone marrow biopsy at diagnosis. (a)-(b) Hematoxylin-Eosin stain showed that the bone trabecula border in contact with leukemic cells shows osteolysis-like appearance. (a) Magnification, 100x; (b) magnification, 400x; (c) parathyroid hormone-related protein stain. Positive cells were stained brown. Magnification, 100x.
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Intriguingly, at diagnosis, the bone trabecular border in contact with leukemic cells showed osteolysis-like appearance (Figures 5(a) and 5(b)). PTH-related protein (PTH-rP) and receptor activator of nuclear factor kappa-Beta ligand (RANKL), the molecules involved in bone remodeling, was performed. PTH-rP was positive in some of the leukemic cells (Figure 5(c)), while RANKL was negative (data not shown).
Multilayered osteoblasts in the bone marrow after induction chemotherapy. Osteoblasts multilayered along the trabecular bone. Magnification, 40x.
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In addition, immunostaining of osterix (Osx), an osteoblast-specific transcription factor, demonstrated multilayered osteoblasts along the trabecula in the bone marrow only after induction chemotherapy (Figure 6).