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Let’s turn now to a patient case. A 68‑year‑old man with a WBC count of 45,000 cells/mm3, a hemoglobin concentration of 7.8 g/dL, and a platelet count of 45,000 cells/mm3 presents to the hospital. The differential shows a large proportion of large immature‑appearing cells, consistent with leukemic blasts. A bone marrow biopsy is performed that reveals marrow involvement with 60% B‑cell lymphoid blasts; therefore, a diagnosis of B‑cell ALL is made. Karyotypic analysis is normal and there is no BCR‑ABL fusion detected. Lymphoid blasts are found to express both CD19 and CD22, but not CD20. The patient does not have a suitable donor for alloSCT.
The patient receives 1 cycle of induction chemotherapy per the CALGB 8811 protocol, which incorporates daunorubicin, vincristine, prednisone, asparaginase, and cyclophosphamide. He accomplishes count recovery after his course of induction, and bone marrow biopsy establishes a morphologic remission. Flow cytometry of the marrow aspirate reveals a 0.2% residual population of lymphoid blasts. The patient receives 2 additional cycles of chemotherapy, which he tolerates well, but a repeat marrow biopsy at that time reveals an increase to 6% lymphoid leukemic blasts. He then receives blinatumomab for 2 cycles but fails to respond, with continued progression of leukemia as assessed by marrow biopsy.
For this patient with relapsed/refractory B-cell ALL, I would recommend initiating treatment with InO, which is approved by the FDA for the treatment of adults with relapsed/refractory B‑cell ALL. This patient’s lymphoid blasts express CD22, the molecular target of InO. He has already progressed beyond upfront conventional chemotherapy and has failed to respond to blinatumomab. In addition, no BCR-ABL fusion is detected and the patient has no suitable donor for alloSCT. Therefore, InO appears to be the most promising therapeutic option for this patient. [Note: In the new Interactive Decision Support Tool for B-cell ALL, 3 of 5 experts also recommended InO with the other 2 recommending InO plus mini-hyper-CVD. To view this tool, please visit https://www.clinicaloptions.com/oncology/tools or download the CCO Decision Support App.]
CD22 expression is seen in > 90% of B‑cell ALL. In a phase I study in relapsed/refractory lymphomas, InO produced a high ORR of 68% in 22 people with follicular lymphoma and a lower ORR of 15% in 26 patients with diffuse large B-cell lymphoma. This study established a phase II dose of 1.8 mg/m2 every 3‑4 weeks with the dose‑limiting toxicity being thrombocytopenia.
InO was subsequently studied in patients with relapsed/refractory ALL. Initially, the drug was given on a monthly schedule at a dose of 1.8 mg/m2 on Day 1 of a 28‑day cycle to 49 patients, but was later changed to a weekly schedule at a dose of 0.8 mg/m2 on Day 1, and 0.5 mg/m2 on Day 8 and Day 15, again given in 28‑day cycles to 41 patients.
Overall, 19% achieved a CR, 30% achieved a CR with incomplete platelet recovery, and 9% achieved a complete bone marrow response with incomplete recovery (CRi). Response rates were similar regardless of monthly or weekly schedule for InO administration. The median OS in this small study was 5.0 months with the monthly schedule, and 7.3 months with the weekly schedule.
The incidence of bilirubin elevation, liver enzymes elevation, fever, and hypotension were higher in patients who received the monthly schedule of InO as opposed to the weekly schedule. Overall, 6 of 36 patients developed VOD after SCT, and this again seemed to be more pronounced in those on the monthly schedule.
The INO‑VATE ALL trial was a randomized, phase III study that compared InO vs conventional chemotherapy in 326 patients with relapsed/refractory CD22-positive ALL. InO was given on a weekly schedule, 0.8 mg/m2 on Day 1, and 0.5 mg/m2 on Days 8 and 15 of a 21-day to 28-day cycle (for up to 6 cycles). The conventional chemotherapy options included fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or cytarabine‑based regimens for up to 4 cycles. The primary endpoints were CR and OS.
INO-VATE ALL demonstrated significantly higher rates of CR/CRi (81% vs 29%; P < .001) and MRD negativity in CR/CRi patients (78% vs 28%; P < .001), as well as prolonged median OS (7.7 vs 6.2 months; P = .0105) in patients who received InO compared with those receiving traditional salvage chemotherapy.
In addition to improved median OS, the 2-year OS rate with InO was > 2-fold higher vs standard chemotherapy (23% vs 10%).
However, the rate of VOD (or SOS) was markedly higher in patients receiving InO vs conventional regimens (11% vs 1%). Over 20% of patients receiving InO who had an SCT developed VOD post-SCT. A multivariate analysis found that the incidence of VOD following SCT was significantly higher in those who had received dual alkylator conditioning vs single alkylator conditioning for their SCT.
VOD or SOS is a potentially fatal AE associated with InO. It may occur in patients receiving InO following SCT and, less frequently, with InO in the absence of SCT. Of note, VOD risk is the greatest in patients who receive more alkylator conditioning therapy or who are older.
The pathophysiology of VOD related to InO is still under investigation, although various theories have been proposed. Certain therapies can damage sinusoidal endothelial cells, leading to progressive narrowing of the sinusoidal vs lumen and obstruction of venous outflow, potentially contributing to postsinusoidal portal hypertension.
It is important to be aware of the clinical presentation of VOD, which classically includes hyperbilirubinemia, weight gain, ascites, and, if it progresses, ultimately multiorgan failure and frequently death.
The monitoring strategy for VOD includes the prophylactic use of ursodiol, daily monitoring of weight, monitoring of liver function tests before and after InO dosing, and monitoring of blood counts.[30-32]
VOD/SOS related to InO can occur within 21 days from SCT, although late onset may also occur. The criteria for early diagnosis include elevation in bilirubin plus 2 of the following: weight gain > 5%, painful hepatomegaly, or ascites.[33,34]
Prevention strategies include avoidance of double alkylator conditioning regimens, limiting cycles of InO before SCT to 2, avoiding concomitant hepatotoxic medication, and prophylactic use of ursodiol. Treatment of VOD/SOS related to InO includes permanent discontinuation of InO, supportive therapy including fluids and pain control, paracentesis for ascites, and the use of defibrotide in severe cases. Defibrotide is approved by the FDA for treating VOD/SOS with renal or pulmonary dysfunction following SCT. It has demonstrated significant reduction in VOD/SOS-related mortality and resolved VOD/SOS-related symptoms, with a manageable safety profile.
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