Abstracts
PO2
Concurrent Bone Marrow Necrosis and Differentiation Syndrome During Ivosidenib Therapy in Acute Myeloid Leukemia
Introduction/Background/Significance:
Materials and Methods/Case Presentation/Objective: A 74-year-old woman presented with pancytopenia and disseminated intravascular coagulation (DIC). Marrow showed 86.8% blasts with NPM1 and IDH1 R132C mutations; no FLT3 mutation was detected, and the karyotype was normal. Ivosidenib plus azacitidine was initiated, resulting in disappearance of circulating blasts and rapid improvement of DIC.
Results/Description/Main Outcome Measure(s): On day 11, she abruptly developed fever, severe low-back pain, hypoxemia, weight gain, edema, acute kidney injury, and recurrent DIC. Lactate dehydrogenase (LDH) rose to 16,896 U/L and creatinine to 2.4 mg/dL. Blast-like immature cells transiently accounted for 15% of peripheral leukocytes but were morphologically indeterminate. Marrow aspiration yielded dark-red fluid with abundant necrotic cells; biopsy showed diffuse necrosis of hematopoietic tissue and fat with no identifiable viable blasts. No infectious focus was identified on CT, and blood cultures were negative; pulmonary infiltrates were absent. Ivosidenib was withheld, and dexamethasone 20 mg/day was started and tapered through day 61. Organ dysfunction improved, followed by sequential emergence of myelocytes and mature neutrophils. Prolonged pancytopenia required transfusions, but serial marrow examinations showed no relapse, and peripheral-blood WT1 mRNA levels decreased by more than 3 logs despite treatment interruption, from 150,000 copies/μg RNA at baseline to 8,900, 830, and 110 copies/μg RNA on days 13, 29, and 51, respectively. Blood counts and normal hematopoiesis recovered approximately 2 months later. Ivosidenib plus azacitidine was restarted on day 63, and three additional cycles were administered without recurrent BMN or evidence of relapse.
Conclusion(s).: The timing of onset, systemic features compatible with differentiation syndrome (DS), subsequent myeloid maturation, and improvement after corticosteroid treatment suggested that DS may have contributed to the clinical deterioration.[4] The absence of viable blast expansion on serial marrow examinations and the continued decline in peripheral-blood WT1 transcripts despite treatment interruption made early leukemia progression less likely. Previous reports of BMN during ATRA- or ATRA/ATO-based therapy for acute promyelocytic leukemia suggest that BMN can occur in the setting of pharmacologically induced myeloid differentiation, although the underlying mechanism remains uncertain.[2,3] In the present case, differentiation-associated inflammatory or endothelial changes may have impaired the marrow microcirculation, while recurrent DIC may have further aggravated microvascular obstruction and ischemia. However, a direct causal relationship between ivosidenib-associated DS and BMN cannot be established, and contributions from the underlying leukemia and DIC cannot be excluded. BMN should be considered when acute bone pain, marked LDH elevation, and worsening coagulopathy occur during IDH-inhibitor therapy.
Trademarked Items:
References: 1. Janssens A, et al. Cancer. 2000;88:1769-1780.
2. Hazenberg CLE, et al. Ann Hematol. 2022;101:1133-1134.
3. Cull GM, et al. Hematol Oncol. 1997;15:13-17.
4. Norsworthy KJ, et al. Clin Cancer Res. 2020;26:4280-4288.
Bone marrow necrosis (BMN) is rare and is attributed to marrow microcirculatory failure, usually associated with malignancy. BMN has been reported during all-trans retinoic acid (ATRA)/arsenic trioxide (ATO)-based differentiation therapy for acute promyelocytic leukemia (APL), but, to our knowledge, not with ivosidenib.[1-3]
Materials and Methods/Case Presentation/Objective: A 74-year-old woman presented with pancytopenia and disseminated intravascular coagulation (DIC). Marrow showed 86.8% blasts with NPM1 and IDH1 R132C mutations; no FLT3 mutation was detected, and the karyotype was normal. Ivosidenib plus azacitidine was initiated, resulting in disappearance of circulating blasts and rapid improvement of DIC.
Results/Description/Main Outcome Measure(s): On day 11, she abruptly developed fever, severe low-back pain, hypoxemia, weight gain, edema, acute kidney injury, and recurrent DIC. Lactate dehydrogenase (LDH) rose to 16,896 U/L and creatinine to 2.4 mg/dL. Blast-like immature cells transiently accounted for 15% of peripheral leukocytes but were morphologically indeterminate. Marrow aspiration yielded dark-red fluid with abundant necrotic cells; biopsy showed diffuse necrosis of hematopoietic tissue and fat with no identifiable viable blasts. No infectious focus was identified on CT, and blood cultures were negative; pulmonary infiltrates were absent. Ivosidenib was withheld, and dexamethasone 20 mg/day was started and tapered through day 61. Organ dysfunction improved, followed by sequential emergence of myelocytes and mature neutrophils. Prolonged pancytopenia required transfusions, but serial marrow examinations showed no relapse, and peripheral-blood WT1 mRNA levels decreased by more than 3 logs despite treatment interruption, from 150,000 copies/μg RNA at baseline to 8,900, 830, and 110 copies/μg RNA on days 13, 29, and 51, respectively. Blood counts and normal hematopoiesis recovered approximately 2 months later. Ivosidenib plus azacitidine was restarted on day 63, and three additional cycles were administered without recurrent BMN or evidence of relapse.
Conclusion(s).: The timing of onset, systemic features compatible with differentiation syndrome (DS), subsequent myeloid maturation, and improvement after corticosteroid treatment suggested that DS may have contributed to the clinical deterioration.[4] The absence of viable blast expansion on serial marrow examinations and the continued decline in peripheral-blood WT1 transcripts despite treatment interruption made early leukemia progression less likely. Previous reports of BMN during ATRA- or ATRA/ATO-based therapy for acute promyelocytic leukemia suggest that BMN can occur in the setting of pharmacologically induced myeloid differentiation, although the underlying mechanism remains uncertain.[2,3] In the present case, differentiation-associated inflammatory or endothelial changes may have impaired the marrow microcirculation, while recurrent DIC may have further aggravated microvascular obstruction and ischemia. However, a direct causal relationship between ivosidenib-associated DS and BMN cannot be established, and contributions from the underlying leukemia and DIC cannot be excluded. BMN should be considered when acute bone pain, marked LDH elevation, and worsening coagulopathy occur during IDH-inhibitor therapy.
Trademarked Items:
References: 1. Janssens A, et al. Cancer. 2000;88:1769-1780.
2. Hazenberg CLE, et al. Ann Hematol. 2022;101:1133-1134.
3. Cull GM, et al. Hematol Oncol. 1997;15:13-17.
4. Norsworthy KJ, et al. Clin Cancer Res. 2020;26:4280-4288.
