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In the Literature

TOP - November 2016, Vol 9, No 4 - In the Literature
In This Article



Inotuzumab Ozogamicin Shows Benefit in Acute Lymphoblastic Leukemia

Many patients with B-cell acute lymphoblastic leukemia (ALL) who achieve complete remission will have disease relapse. Because of the poor prognosis for adults with relapsed ALL, investigators assessed the efficacy and safety of using the investigative single-agent inotuzumab ozogamicin compared with standard intensive chemotherapy in patients with relapsed or refractory B-cell ALL. Inotuzumab ozogamicin is an anti-CD22 antibody conjugated to the cytotoxic antibiotic calicheamicin (Kantarjian HM, et al. N Engl J Med. 2016;375:740-753).

This open-label, 2-group, phase 3 clinical trial randomized 326 adults with relapsed or refractory ALL to receive inotuzumab ozogamicin or standard intensive therapy in a 1:1 ratio. Inotuzumab ozogamicin was administered intravenously at a starting dose of 1.8 mg/m2 per cycle, with 0.8 mg on day 1 of each cycle, and 0.5 mg on days 8 and 15; cycle 1 lasted 21 days, and the following cycles lasted for 28 days, with treatment continued for ≤6 cycles. Among the patients who achieved complete remission with or without incomplete hematologic recovery, the dose administered on day 1 of each cycle was reduced to 0.5 mg. Standard chemotherapy consisted of the investigator’s choice of fludarabine, cytarabine, and granulocyte colony-stimulating factor therapy for up to four 28-day cycles; cytarabine plus mitoxantrone for up to four 15- to 20-day cycles; or high-dose cytarabine for up to one 12-dose cycle. The primary end points were complete remission, including complete remission with incomplete hematologic recovery, and overall survival (OS).

Treatment with inotuzumab ozogamicin was associated with a significantly higher rate of complete remission (80.7%) compared with standard chemotherapy (29.4%). Median duration of remission was 4.6 months in the inotuzumab ozogamicin group and 3.1 months in the standard chemotherapy group. In addition, median progression-free survival was 5 months in patients receiving inotuzumab ozogamicin versus 1.8 months in those getting standard therapy; similarly, median OS was longer in the inotuzumab ozogamicin group than in the standard therapy group (7.7 months vs 6.7 months, respectively).

The safety profile of inotuzumab ozogamicin was consistent with previously reported data. The most common grade ≥3 nonhematologic adverse events were liver-related. Rates of veno-occlusive liver disease of any grade were 11% with inotuzumab ozogamicin versus 1% with standard chemotherapy.

These results show that inotuzumab ozogamicin increases the rate of complete remission and improves OS for patients with relapsed or refractory ALL. Furthermore, more patients receiving inotuzumab ozogamicin had results below the threshold for minimal residual disease.

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Adding Daratumumab to Combination Therapy Improves Progression-Free Survival in Patients with Multiple Myeloma

Early-phase studies of daratumumab (Darzalex) in combination with proteasome inhibitors and immunomodulatory drugs showed high response rates, and the combination was well-tolerated in patients with multiple myeloma. In a recent study, researchers reported results from a prespecified interim analysis that compared the addition of daratumumab to the combination of bortezomib (Velcade) plus dexamethasone versus bortezomib and dexamethasone combination in patients with relapsed and/or refractory multiple myeloma (Palumbo A, et al. N Engl J Med. 2016;375:754-766).

This multicenter, open-label, active-controlled, phase 3 trial randomized 498 patients with relapsed and/or refractory multiple myeloma with ≥1 previous lines of therapy, at least a partial response to ≥1 of their previous therapies, and documented progressive disease. Patients were randomized to receive ≤8 cycles of bortezomib plus dexamethasone with or without daratumu­mab. Patients randomized to bortezomib plus dexamethasone were given 1.3 mg/m2 of bortezomib subcutaneously, and 20 mg of oral dexamethasone; patients who received daratumumab were administered daratumumab 16 mg/kg intravenously once weekly during cycles 1 to 3, once every 3 weeks during cycles 4 to 8, and then once every 4 weeks until the patient withdrew consent, experienced disease progression, or had unacceptable toxic effects. The primary end point was progression-free survival (PFS). Secondary end points were time to disease progression, overall response rate, proportion of patients who achieved very good partial response or better, duration of response, time to response, and overall survival.

The daratumumab group exhibited significantly longer PFS than the control group at 12 months (60.7% vs 26.9%, respectively), which translated to a 61.4% lower risk for disease progression in patients receiving daratumumab compared with those who did not. The median PFS was not reached in the daratumumab cohort after a median follow-up of 7.4 months and was 7.2 months in the control group. The rate of overall response was higher in patients who received daratumumab compared with those who did not (82.9% vs 63.2%, respectively). In addition, the number of patients achieving a complete response or better and a very good partial response or better was significantly in the daratumumab group compared with the control group (19.2% and 59.2% vs 9.0% and 29.1%, respectively).

The daratumumab group had higher rates of grade 3 or 4 adverse events, particularly thrombocytopenia, neutropenia, and lymphopenia. Infusion-related reactions occurred in 45.3% of patients in the daratumumab group, most of which (98.2%) occurred during the first infusion.

“Overall these findings are consistent with observations from phase 1 and phase 1/2 trials that showed an additive benefit of daratumumab in combination with proteasome inhibitors or immunomodulatory drugs (pomalidomide or lenalidomide) and dexamethasone and highlight the advantages of combination therapy,” concluded the researchers.

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Last modified: January 9, 2017