Advanced systemic mastocytosis (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms ...and organ damage (eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss). Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level.
We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator–related symptoms in patients with advSM.
In 116 patients with systemic mastocytosis (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study ClinicalTrials.gov identifier NCT00782067), QOL and symptom burden were assessed during treatment with midostaurin by using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale patient-reported questionnaires, respectively. MC mediator–related symptoms were evaluated by using a specific physician-reported questionnaire.
Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and Memorial Symptom Assessment Scale scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator–related symptoms.
QOL and MC mediator–related symptoms significantly improve with midostaurin treatment in patients with advSM (ClinicalTrials.gov identifier, NCT00782067).
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Idelalisib, a selective inhibitor of PI3Kδ, is approved for the treatment of patients with relapsed chronic lymphocytic leukaemia (CLL) in combination with rituximab. We aimed to assess the efficacy ...and safety of idelalisib in combination with a second-generation anti-CD20 antibody, ofatumumab, in a similar patient population.
In this global, open-label, randomised, controlled phase 3 trial, we enrolled patients with relapsed CLL progressing less than 24 months from last therapy. Patients refractory to ofatumumab were excluded. Patients were stratified by relapsed versus refractory disease, presence or absence of del(17p) or TP53 mutation, or both, and IGHV mutated versus unmutated. We randomised patients in a 2:1 ratio using a web-based interactive system that generated a unique treatment code, and assigned patients to receive either idelalisib plus ofatumumab (oral idelalisib 150 mg twice daily continuously plus ofatumumab 300 mg intravenously in week 1, then 1000 mg intravenously weekly for 7 weeks, and every 4 weeks for 16 weeks) or ofatumumab alone (ofatumumab dosing as per the combination group, except 2000 mg was substituted for the 1000 mg dose). An independent review committee assessed response, including progressive disease, based on imaging using modified International Workshop on Chronic Lymphocytic Leukaemia 2008 criteria. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. We did a primary analysis (data cutoff Jan 15, 2015) and an updated analysis (data cutoff Sept 1, 2015). This trial is registered with Clinicaltrials.gov, number NCT01659021.
Between Dec 17, 2012, and March 31, 2014, we enrolled 261 patients (median age 68 years IQR 61-74, median previous therapies three IQR 2-4). At the primary analysis, median progression-free survival was 16·3 months (95% CI 13·6-17·8) in the idelalisib plus ofatumumab group and 8·0 months (5·7-8·2) in the ofatumumab group (adjusted hazard ratio HR 0·27, 95% CI 0·19-0·39, p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib plus ofatumumab group were neutropenia (59 34% patients vs 14 16% in the ofatumumab group), diarrhoea (34 20% vs one 1%), and pneumonia (25 14% vs seven 8%). The most frequent grade 3 or worse adverse events in the ofatumumab group were neutropenia (14 16%), pneumonia (seven 8%), and thrombocytopenia (six 7% vs 19 11% in the idelalisib plus ofatumumab group). Serious infections were more common in the idelalisib plus ofatumumab group and included pneumonia (23 13% patients in the idelalisib plus ofatumumab group vs nine 10% in the ofatumumab group), sepsis (11 6% vs one 1%), and Pneumocystis jirovecii pneumonia (eight 5% vs one 1%). 22 treatment-related deaths occurred in the idelalisib plus ofatumumab group (the most common being sepsis, septic shock, viral sepsis, and pneumonia). Six treatment-related deaths occurred in the ofatumumab group (the most common being progressive multifocal leukoencephalopathy and pneumonia).
The idelalisib plus ofatumumab combination resulted in better progression-free survival compared with ofatumumab alone in patients with relapsed CLL, including in those with high-risk disease, and thus might represent a new treatment alternative for this patient population.
Gilead Sciences, Inc.
This phase II, single-arm, multicenter study examined the efficacy and safety of coltuximab ravtansine (an anti-CD19 antibody drug conjugate) in 61 patients with histologically documented (
or ...transformed) relapsed or refractory diffuse large B-cell lymphoma who had previously received rituximab-containing immuno-chemotherapy. Patients had received a median of 2.0 (range 0-9) prior treatment regimens for diffuse large B-cell lymphoma and almost half (45.9%) had bulky disease (≥1 lesion >5 cm) at trial entry. Patients received coltuximab ravtansine (55 mg/m
) in 4 weekly and 4 biweekly administrations until disease progression or unacceptable toxicity. Forty-one patients were eligible for inclusion in the per protocol population. Overall response rate (International Working Group criteria) in the per protocol population, the primary end point, was 18/41 43.9%; 90% confidence interval (CI:) 30.6-57.9%. Median duration of response, progression-free survival, and overall survival (all treated patients) were 4.7 (range 0.0-8.8) months, 4.4 (90%CI: 3.02-5.78) months, and 9.2 (90%CI: 6.57-12.09) months, respectively. Common non-hematologic adverse events included asthenia/fatigue (30%), nausea (23%), and diarrhea (20%). Grade 3-4 adverse events were reported in 23 patients (38%), the most frequent being hepatotoxicity (3%) and abdominal pain (3%). Eye disorders occurred in 15 patients (25%); all were grade 1-2 and none required a dose modification. Coltuximab ravtansine monotherapy was well tolerated and resulted in moderate clinical responses in pre-treated patients with relapsed/refractory diffuse large B-cell lymphoma. (Registered at:
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Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia ...(CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses.
treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-κB gene transcription.
, ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib.
This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation.
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The Bruton tyrosine kinase (BTK) inhibitor ibrutinib improves patient outcomes in chronic lymphocytic leukemia (CLL); however, some patients experience adverse events (AEs) leading to ...discontinuation. Acalabrutinib is a potent, covalent BTK inhibitor with greater selectivity than ibrutinib. We evaluated the safety and efficacy of 100 mg of acalabrutinib twice daily or 200 mg once daily in patients with CLL who discontinued ibrutinib because of intolerance as determined by the investigators. Among 33 treated patients (61% men; median age, 64 years; range, 50-82 years), median duration of prior ibrutinib treatment was 11.6 months (range, 1-62 months); median time from ibrutinib discontinuation to acalabrutinib start was 47 days (range, 3-331 days). After a median of 19.0 months (range, 0.2-30.6 months), 23 patients remained on acalabrutinib; 10 had discontinued (progressive disease, n = 4; AEs, n = 3). No acalabrutinib dose reductions occurred. During acalabrutinib treatment, the most frequent AEs included diarrhea (58%), headache (39%), and cough (33%). Grade 3/4 AEs occurred in 58%, most commonly neutropenia (12%) and thrombocytopenia (9%). Of 61 ibrutinib-related AEs associated with intolerance, 72% did not recur and 13% recurred at a lower grade with acalabrutinib. Overall response rate was 76%, including 1 complete and 19 partial responses and 5 partial responses with lymphocytosis. Among 25 responders, median duration of response was not reached. Median progression-free survival (PFS) was not reached; 1-year PFS was 83.4% (95% confidence interval, 64.5%-92.7%). Acalabrutinib was well tolerated with a high response rate in patients who were previously intolerant to ibrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02029443.
•Acalabrutinib had good tolerability in patients with relapsed or refractory CLL who were intolerant to ibrutinib.•Acalabrutinib demonstrated a high response rate (81%) in patients with relapsed or refractory CLL who were intolerant to ibrutinib.
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Thiotepa/carmustine (TT-BCNU) is a commonly used autologous transplant (ASCT) conditioning regimen for primary DLBCL of the CNS (PCNSL). The total thiotepa dose varies among TT-BCNU recipients, with ...some centers administering a total dose of 20 mg/kg, while others using 10 mg/kg. We retrospectively assessed the impact of thiotepa dose intensity on ASCT outcomes in 218 adult PCNSL patients who underwent a first ASCT with TT-BCNU conditioning and received either a total thiotepa dose of 10 mg/kg (TT-10 group; N = 90), or 20 mg/kg (TT-20 group; N = 128). The median follow-up of survivors was 22 months. The cumulative incidence of 1-year non-relapse mortality (NRM) for TT-10 and TT-20 cohorts were 6% (95%CI = 2-12%) vs. 4% (95%CI = 1-8%), respectively (p = 0.66). The 3-year cumulative incidence of relapse (15% vs. 13%; p = 0.67), progression-free survival (PFS) (71% vs. 80%; p = 0.25) and overall survival (OS) (79% vs. 83%; p = 0.56) were similar in the TT-10 and TT-20 groups, respectively. On multivariate analysis compared to TT-10, the TT-20 cohort was not associated with significantly different risk of NRM (Hazard ration HR = 0.77; p = 0.64), relapse/progression (HR = 0.87; p = 0.74), PFS (HR = 0.80; p = 0.48) or OS (HR = 1.10; p = 0.80). In conclusion thiotepa dose-intensity in TT-BCNU conditioning does not impact ASCT outcomes of PCNSL patients.
Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. ...Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.
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