A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.

Ibrutinib for mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase which acts by downstream inhibition of the B-cell receptor. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile in relapsed/refractory MCL. Although the majority of disease responses are partial, efficacy data are impressive with more than two-thirds of patients demonstrating a durable response. This article focuses on all aspects of ibrutinib in the context of MCL, including a summary of the basic pharmacology and pharmacokinetics; a review of the safety and efficacy data published to date and a discussion of the future implications in MCL.

Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences.

We present data from a phase II study investigating a novel treatment strategy for relapsed/refractory mantle cell lymphoma (MCL). Twenty-six patients received lenalidomide 25 mg/d (days 1-21 of a 28-d cycle) for up to 6 cycles followed by low-dose maintenance lenalidomide (15 mg) in responding patients. Eight patients achieved complete or partial response to give an overall response rate of 31% with median response duration of 22·2 months [95% confidence interval (CI) 0·0-53·6] and median progression-free survival (PFS) of 3·9 months (95% CI 0·0-11·1). An additional six patients (23%) achieved stable disease. Eleven patients received maintenance with median PFS of 14·6 months (95% CI 7·3-21·9). Correlative studies showed that peripheral T and Natural Killer (NK) cells increased in responding patients by 40-60% over the first 6 cycles with an initial dip in NK cells suggestive of tumour infiltration. Peripheral regulatory T cells were increased in MCL patients (P = 0·001) and expanded further following lenalidomide. Sequential plasma analysis showed increased IL12 p40 and IL7 alongside decreased MMP9, IL10, and adiponectin. Finally, a significant correlation (P = 0·02) between gender and response suggested that female MCL patients were more sensitive to lenalidomide than males. In summary, we confirm the activity, safety and immunomodulatory properties of lenalidomide in MCL and highlight its potential as a low-dose maintenance agent.

Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia.

PURPOSE: Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL. PATIENTS AND METHODS: Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20-150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day). RESULTS: Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study. CONCLUSIONS: Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).

On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors.

The PI3K inhibitor copanlisib has efficacy and manageable safety in patients with indolent lymphoma and solid tumors. Pharmacodynamic effects relative to copanlisib dose and plasma exposure were evaluated. Patients with lymphoma or solid tumors received copanlisib 0.4 or 0.8 mg/kg on days 1, 8, and 15 of a 28-day cycle. Primary variables were maximum changes in phosphorylated AKT (pAKT) levels in platelet-rich plasma (PRP) and plasma glucose. Other evaluations included PI3K signaling markers and T-lymphocytes in paired tumor biopsies, the relationship between estimated plasma exposure and pharmacodynamic markers, response, and safety. Sixty-three patients received copanlisib. PRP pAKT levels showed sustained reductions from baseline following copanlisib [median inhibition: 0.4 mg/kg, 73.8% (range -94.9 to 144.0); 0.8 mg/kg, 79.6% (range -96.0 to 408.0)]. Tumor pAKT was reduced versus baseline with copanlisib 0.8 mg/kg in paired biopsy samples (P < 0.05). Dose-related transient plasma glucose elevations were observed. Estimated copanlisib plasma exposure significantly correlated with changes in plasma pAKT and glucose metabolism markers. There were two complete responses and six partial responses; seven of eight responders received copanlisib 0.8 mg/kg. Adverse events (all grade) included hyperglycemia (52.4%), fatigue (46.0%), and hypertension (41.3%). Copanlisib demonstrated dose-dependent pharmacodynamic evidence of target engagement and PI3K pathway modulation/inhibition in tumor and immune cells. Results support the use of copanlisib 0.8 mg/kg (or flat-dose equivalent of 60 mg) in solid tumors and lymphoma, and provide a biomarker hypothesis for studies of copanlisib combined with immune checkpoint inhibitors (NCT03711058).

Superior quality and duration of responses among patients with mantle-cell lymphoma treated with fludarabine and cyclophosphamide with or without rituximab compared with prior responses to CHOP.

Sixteen patients with relapsed mantle-cell lymphoma (MCL) were treated with the combination of fludarabine and cyclophosphamide (FC) with or without rituximab. All patients had received prior CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) chemotherapy, with a response rate of 63.5% (25% complete response), and a median duration of response of 10 months (range 1-32 months). Subsequent treatment with FC +/- rituximab produced a response rate of 75% with a higher complete response rate (56% P = 0.07 vs. CHOP), and a median duration of response of 11 months (4-25+ months). This study demonstrates that FC is a highly active regimen in patients relapsing following CHOP chemotherapy.

A critical appraisal of ibrutinib in the treatment of mantle cell lymphoma and chronic lymphocytic leukemia.

Although chemo-immunotherapy remains at the forefront of first-line treatment for mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), small molecules, such as ibrutinib, are beginning to play a significant role, particularly in patients with multiply relapsed or chemotherapy-refractory disease and where toxicity is an overriding concern. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase, which functions by irreversible inhibition of the downstream signaling pathway of the B-cell receptor, which normally promotes cell survival and proliferation. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile even in elderly and multiply pretreated patient cohorts. Although the majority of disease responses tend to be partial, efficacy data have also been encouraging with more than two-thirds of patients with CLL and MCL demonstrating a durable response, even in the high-risk disease setting. Resistance mechanisms are only partially understood and appear to be multifactorial, including the binding site mutation C481S, and escape through other common cell-signaling pathways. This article appraises the currently available data on safety and efficacy from clinical trials of ibrutinib in the management of MCL and CLL, both as a single agent and in combination with other therapies, and considers how this drug is likely to be used in future clinical practice.

Does transcutaneous electrical nerve stimulation (TENS) alleviate the pain experienced during bone marrow sampling in addition to standard techniques? A randomised, double-blinded, controlled trial.

AIMS: Bone marrow aspiration and trephine (BMAT) biopsies remain important tests in haematology. However, the procedures can be moderately to severely painful despite standard methods of pain relief. To test the efficacy of transcutaneous electrical nerve stimulation (TENS) in alleviating the pain from BMAT in addition to standard analgesia using a numerical pain rating scale (NRS). METHODS: 70 patients requiring BMAT were randomised (1:1) in a double-blind, placebo-controlled trial. -35 patients received TENS impulses at a strong but comfortable amplitude (intervention group) and 35 patients received TENS impulses just above the sensory threshold (control group) (median pulse amplitude 20 and 7 mA, respectively). Patients and operators were blinded to group allocation. Pain assessments were made using a numerical pain scale completed after the procedure. RESULTS: No significant difference in NRS pain recalled after the procedure was detected (median pain score 5.7 (95% CI 4.8 to 6.6) in control vs 5.6 (95% CI 4.8 to 6.4) in the intervention group). However, 100% of patients who had previous experience of BMAT and >94% of participants overall felt they benefited from using TENS and would recommend it to others for this procedure. There were no side effects from the TENS device, and it was well tolerated. CONCLUSIONS: TENS is a safe, non-invasive adjunct to analgesia for reducing pain during bone marrow biopsy and provides a subjective benefit to most users; however, no objective difference in pain scores was detected when using TENS in this randomised controlled study. CLINICAL REGISTRATION NUMBER: NCT02005354.

Autoimmune haemolytic anaemia associated with mantle cell lymphoma.

Autoimmune haemolytic anaemia (AIHA) is a well-recognised complication of lymphoproliferative disorders, and has been reported in association with all B and T cell non-Hodgkin lymphoma subtypes with the exception of mantle cell lymphoma (MCL). We describe herein a case of MCL diagnosed in an initially asymptomatic 66-year-old woman who developed transfusion-dependent AIHA 6 months later coincident with lymphoma progression. The AIHA failed to respond satisfactorily to conventional treatment (high-dose oral prednisolone) but rapidly resolved following commencement of non-rituximab-containing combination chemotherapy in parallel with complete remission of the lymphoma. This is the first of such cases to be described in the literature and confirms that the immune environment of MCL can predispose to AIHA in the same way as in other lymphoma subtypes. Despite this being an infrequent occurrence, clinicians should be aware that AIHA is a potential complication of MCL and may be more successfully controlled by treating the underlying lymphoma rather than relying on conventional anti-haemolytic strategies such as steroids.

Toxicity of fludarabine and cyclophosphamide with or without rituximab as initial therapy for patients with previously untreated mantle cell lymphoma: results of a randomised phase II study.

The National Cancer Research Network (NCRN) is currently coordinating a Phase III randomised study (LY05) comparing fludarabine and cyclophosphamide (FC) with or without rituximab (R) for previously untreated mantle cell lymphoma (MCL). The combination of FC is well-recognised as significantly immunosuppressive and there are concerns that adding rituximab may increase infection risk further. The impact of rituximab on other markers of toxicity is also unclear. We analysed the toxicity data on 139 patients treated within the NCRN LY05 trial. Non-hematological toxicity was similar between the two treatment arms. The only difference in hematological toxicity was a higher rate of lymphocytopenia with fludarabine cyclophosphamide and rituximab (FCR), which did not translate into increased febrile episodes or infections. In conclusion, the addition of rituximab to FC for previously untreated MCL has no significant impact on toxicity.