ANTI-CD20/CD3 ANTIBODY SHOWS ACTIVITY IN NON-HODGKIN LYMPHOMA
Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines
Patients with relapsed/refractory Non-Hodgkin lymphoma were treated with an anti-CD3/anti-CD20 bispecific antibody, mosunetuzumab, in the GO29781 study, presented by Stephen J. Schuster, MD (University of Pennsylvania, Philadelphia PA). Mosunetuzumab was administered using a step-up dosing schedule initially, followed by fixed dosing in this study population. Goals for this investigation included defining the maximum tolerated dose of mosunetuzumab and elucidating the objective response rate.
Across all dose levels, 270 patients have been treated and dose escalation is still ongoing. Thus far, a positive exposure-response relationship has been observed in both indolent (iNHL, n=85 with 67 eligible for evaluation at data cutoff) and aggressive (aNHL, n=180 with 124 eligible for evaluation at data cutoff) non-Hodgkin lymphoma, with ORR rates of 62.7% and 37.1% in iNHL and aNHL, respectively. For those patients who experienced a CR (43.4% of iNHL and 19.4% of aNHL), the responses appeared durable: 82.8% of iNHL and 70.8% of aNHL patients remained in remission at data cutoff. Given the broad therapeutic window that can be achieved with the step-up dosing approach, a maximum tolerated dose had not been defined. Cytokine release syndrome occurred in 28.9% of patients (n=78 of 270 safety evaluable patients), and was mainly grade 1 or 2 by Lee criteria (Lee, et al Blood 2014), occurring most commonly during the first therapy cycle (median onset at day 4, range 1-43 with a median duration of 2 days, range 1-59). Neurologic adverse events (CTCAE v4.0) also occurred in 43.7% of safety evaluable patients (n=118 of 270), and none of the side effects appeared to correlate with drug exposure. Notably, 94.4% of the safety evaluable patients (n=255 of 270) experienced an adverse event (AE), with the most common grade 3-4 AEs being neutropenia at 21.8%, hypophosphatemia at 13.3%, and anemia at 8.9%. There was one grade 5 event secondary to non-neutropenic pneumonia. In a subpopulation of patients (n=18) who were R/R to previous CAR-T therapy, ORR and CR rates of 38.9% and 22.2% were observed, with similar incidences of CRS and neurologic events as the entire population. Taken together, mosunetuzumab therapy has therefore shown promise in these difficult-to-manage patient populations.
MUTATIONS MAPPED THROUGHOUT AML PROGRESSION
Mapping the Evolution of the Mutational Landscape of Acute Myeloid Leukemia from Diagnosis to Post-Transplantation Relapse and Its Interplay with Immune Evasion Mechanisms
Elisa Sala, MD (IRCCS San Raffaele Scientific Institute, Milano, Italy) discussed an in-depth study of the mutational landscape of acute myeloid leukemia across the entire disease course. Samples were sequenced from patients at diagnosis, relapse after chemotherapy, and/or relapse after allogeneic hematopoietic stem cell transplantation to map the mutational profiles and elucidate mechanisms of immune evasion.
A total of 200 samples were analyzed, divided by stage in the disease course. At diagnosis, patient samples displayed an average of three mutations (range 0-8), with a total of 253 oncogenic mutations across the 84 samples in this group, which was in agreement with previous studies at this disease stage. Patients who relapsed following chemotherapy or transplant did not display a different overall burden of oncogenic mutations; rather, only two significant differences were noted, which included more frequent mutations in FLT3-ITD and WT1 at relapse. Many patients who experience relapse after stem cell transplantation present with a genomic loss of HLA. In these patients, no differences (relative to HLA-positive relapse) in mutational burden nor frequency of known driver mutations were noted; however, mutations of unknown oncogenic potential were found more frequently in these samples. Potential routes of clonal evolution were also tracked through this study, with such analyses indicating that certain genetic mutations may change their relative importance to leukemic survival throughout the disease and treatment course. These results and continued similar studies may provide additional therapeutic interventions for myeloid malignancies. pro
PEG-IFN PLUS NILOTINIB MAY DEEPEN RESPONSES IN CML
Nilotinib Vs Nilotinib Plus Pegylated Interferon α (Peg-IFN) Induction and Nilotinib or Peg-IFN Maintenance Therapy for Newly Diagnosed BCR-ABL1 Positive Chronic Myeloid Leukemia Patients in Chronic Phase (TIGER Study): The Addition of Peg-IFN Is Associated with Higher Rates of Deep Molecular Response
An interim analysis of a phase III trial comparing nilotinib monotherapy to nilotinib + pegylated interferon alpha (Peg-IFN) in patients with chronic myeloid leukemia was presented by Andreas Hochhaus, MD (Universitätsklinikum Jena, Jena, Germany). Patients were randomized 1:1 between the two treatment arms and, if they achieved a MMR (defined as BCR-ABL1 transcript levels <=0.1% international scale [IS]), then proceeded to the maintenance phase of either nilotinib monotherapy or Peg-IFN monotherapy. Patients could discontinue all therapy if they achieved a sustained MR4 for at least a year in the maintenance phase.
A total of 692 patients have been treated on this protocol with a median observation time since recruitment of 44.6 months. Of these, 504 patients have proceeded to the maintenance phase after achieving a MR, and 218 then discontinued all therapy. Across the two treatment arms, the rates of MMR at 12 and 18 months were similar; however, responses were deepened in the combination group, as significantly higher rates of both MR4 and MR4.5 were observed. The time to MMR or more deep responses was also shortened with the combination treatment. In competing risk analysis, median time to MMR was 5.7 vs 5.4 mo, to MR4 20.9 vs 12.5 mo, and to MR4.5 33.8 vs 23.2 mo for NIL vs NIL/Peg-IFN, respectively. For those patients who discontinued nilotinib but continued with maintenance Peg-IFN, the probability of relapse at 12 months was 12%. Any-grade adverse events occurred in at least 90% of both the nilotinib and combination arms, with grade 3-5 events in approximately 40%. As deeper responses could be achieved with the combination of nilotinib and Peg-IFN, this treatment option may provide longer treatment-free intervals for leukemia patients.