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Ibrutinib has transformed the management of chronic lymphocytic leukemia (CLL), though its use is limited by toxicity and resistance. In this study, we utilized an "add on" approach for patients who had been treated with ibrutinib in the front-line or relapsed/refractory settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment-free observation (TFO).Patients were eligible if they received ibrutinib in any line of therapy for at least 6 months and had detectable MRD (flow cytometry,1 cell in 10-4 cutoff for U-MRD). U2 was added to ibrutinib, and patients were monitored serially for MRD. Once U-MRD was achieved or a total of 24 cycles were administered, patients entered a period of TFO. The primary study objective was rate of U-MRD. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation.Twenty-eight patients were enrolled of whom 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7-67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol whereas 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, and increased ALT/AST 4%.This triplet approach utilizes the addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable in ongoing follow-up.

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7520 Background: Zilovertamab (Zilo) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and has demonstrated additive/synergistic activity with many anti-cancer agents, including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment-naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), multiple doses were examined. Zilo 600 mg IV starting q2wks x3 then q4wks + Ibr qD was selected as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Zilo+Ibr vs. Ibr alone). Results: As of 18Jan2022 data cutoff, 26 evaluable RR MCL pts, including pts who received prior Ibr (5) or auto-SCT (7), and 34 evaluable CLL pts (12 TN and 22 RR) were enrolled into Parts 1&2. In Part 3, 22 evaluable pts were randomized (2:1) to receive either Zilo+Ibr (15) or Ibr (7). Safety: Treatment-emergent adverse events (TEAEs) (≥30%, N = 84), regardless of relationship, included fatigue (41.7%), contusion (39.3%), and diarrhea (38.1%). Most common (≥5%) Grade ≥3 TEAEs included hypertension (10.7%), pneumonia (7.1%), atrial fibrillation, fatigue, and neutropenia (all 6.0%). Grade ≥3 neutrophil decrease observed in 9.4% or 17.6%, platelet decrease in 12.5% or 2.9%, or hemoglobin decrease in 9.4% or 0% of pts with MCL or CLL, respectively in Parts 1&2. Investigators scored TEAEs as due to Ibr in 78.1% or 85.3%, or to Zilo in 15.6% or 23.5% of pts with MCL or CLL, respectively. Efficacy (MCL): Objective response rate (ORR) was 80.8% (34.6% CR, 46.2% PR). ORR for pts with prior Ibr was 80% (2CR, 2PR) and median duration of response (mDOR) was 13.7 months (M) (95%CI: 11.93, NE). ORR was 100% in pts who had prior SCT+/- CAR-T (5CR, 2PR), and mDOR was 34.1 M (95% CI 13.84, NE). Overall median PFS (mPFS) was 35.9 M (95% CI: 17.3, NE) at median follow-up of 15.0 M. For MCL pts with TP 53 aberrancy (6), Ki67 > 30% (13), ≥ 3 prior lines of therapies (4), blastoid histology (3), bulky disease ≥5 cm (4), intermediate MIPIb (6), or high MIPIb (11), the mPFS (in M) was 17.3 (95% CI: 2.85, NE), Not Reached (NR) (95% CI: 2.85, NE), 35.9 (95% CI: 16.52, NE), NR (min 9.18, max 27.87), 26.6 (95% CI: 0.03, NE), 35.9 (min 8.30, max 35.9) or 16.5 (95% CI: 2.72, NE). Efficacy (CLL): In Parts 1&2 ORR was 91.2% (8.8% CR, 82.3% PR/PR-L), and 8.8% had stable disease (SD). At median follow-up of 31.4 M, mDOR was 33.5 M and mPFS was NR (95% CI: 36.3, NE); the mPFS (in M) for pts with 1, 2, or ≥ 3 prior therapies was NR (min 19.3, max 41.3), NR (min 31.3, max 36.8) or 36.3 (95% CI: 15.7, NE). At median follow-up of 21.1 M in Part 3, mPFS was NR for TN or RR in both Zilo+Ibr and Ibr arms. Conclusions: Zilo+Ibr is well-tolerated. Striking responses were observed in MCL pts, with mPFS of 35.9 M (95% CI: 17.3, NE) and CR of 34.6%, which compares favorably to mPFS of 12.8 M (95% CI 8.5, 16.6) and CR of 20% reported for single agent Ibr (Rule 2017). For CLL, ORR and PFS compare very favorably to Ibr monotherapy data (Byrd 2019). Clinical trial information: NCT03088878.

Introduction. The diagnosis of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin’s lymphoma (cHL), also referred to as grey zone lymphoma (GZL), is a challenging diagnosis. There are no standardized guidelines; however, evidence strongly suggests that DLBCL-based regimens are effective in the treatment of GZL. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate that has established efficacy in relapsed/refractory Hodgkin and some T-cell lymphomas. There is some evidence that BV has a positive response in non-Hodgkin lymphoma (NHL) with a wide range of CD30 expressions—including GZL. Case. We present a case of a patient initially diagnosed with cHL who underwent repeat biopsy which was revealed to be GZL. Based on PET scanning and immunohistochemical studies, she was classified as a stage IIIA CD20+/CD30+ GZL patient. Given her strong CD30 expression, she underwent 6 cycles of R-BV-CHP (rituximab, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone) chemotherapy and achieved complete response (CR) both clinically and radiographically. Discussion. Given the rarity of GZL, this case illustrates the immense challenges in making the diagnosis, discusses the current treatment options, and suggests that BV may be a viable therapeutic candidate in the treatment of GZL.

PURPOSE Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL. PATIENTS AND METHODS In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20–based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety. RESULTS The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients. CONCLUSION Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event–related discontinuations.