Mary Gleeson

Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study

BACKGROUND The first-in-class small molecule inhibitor OTX015 (MK-8628) specifically binds to bromodomain motifs BRD2, BRD3, and BRD4 of bromodomain and extraterminal (BET) proteins, inhibiting them from binding to acetylated histones, which occurs preferentially at super-enhancer regions that control oncogene expression. OTX015 is active in haematological preclinical entities including leukaemia, lymphoma, and myeloma. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. We report the results from a cohort of patients with lymphoma or multiple myeloma (non-leukaemia cohort). METHODS In this dose-escalation, open-label, phase 1 study, we recruited patients from seven university hospital centres (in France [four], Switzerland [one], UK [one], and Italy [one]). Adult patients with non-leukaemia haematological malignancies who had disease progression on standard therapies were eligible to participate. Patients were treated with oral OTX015 once a day continuously over five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg), using a conventional 3 + 3 design, with allowance for evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity (DLT) in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582. FINDINGS Between Feb 4, 2013, and Sept 5, 2014, 45 patients (33 with lymphoma and 12 with myeloma), with a median age of 66 years (IQR 55-72) and a median of four lines of prior therapy (IQR 3-5), were enrolled and treated. No DLTs were observed in the doses up to and including 80 mg once a day (first three patients). We then explored a schedule of 40 mg twice a day (21 of 21 days). DLTs were reported in five of six patients receiving OTX015 at this dose and schedule (all five patients had grade 4 thrombocytopenia). We explored various schedules at 120 mg once a day but none was tolerable, with DLTs of thrombocytopenia, gastrointestinal events (diarrhoea, vomiting, dysgeusia, mucositis), fatigue, and hyponatraemia in 11 of 18 evaluable patients. At this point, the Safety Monitoring Committee decided to establish the feasibility of 80 mg once a day on a continuous basis, and four additional patients were enrolled at this dose. DLTs (grade 4 thrombocytopenia) was noted in two of the patients. In light of these DLTs and other toxicities noted at 120 mg, the dose of 80 mg once a day was selected, although on a schedule of 14 days on, 7 days off. Common toxic effects reported in the study were thrombocytopenia (43 [96%] patients), anaemia (41 [91%]), neutropenia (23 [51%]), diarrhoea (21 [47%]), fatigue (12 [27%]), and nausea (11 [24%]). Grade 3-4 adverse events were infrequent other than thrombocytopenia (26 [58%]). OTX015 plasma peak concentrations and areas under the concentration versus time curve increased proportionally with dose. Trough concentrations increased less than proportionally at lower doses, but reached or exceeded the in-vitro active range at 40 mg twice a day and 120 mg once a day. Three patients with diffuse large B-cell lymphoma achieved durable objective responses (two complete responses at 120 mg once a day, and one partial response at 80 mg once a day), and six additional patients (two with diffuse large B-cell lymphoma, four with indolent lymphomas) had evidence of clinical activity, albeit not meeting objective response criteria. INTERPRETATION The once-daily recommended dose for oral, single agent oral OTX015 in patients with lymphoma is 80 mg on a 14 days on, 7 days off schedule, for phase 2 studies. OTX015 is under evaluation in expansion cohorts using this intermittent administration (14 days every 3 weeks) to allow for recovery from toxic effects. FUNDING Oncoethix GmbH (a wholly owned subsidiary of Merck Sharp & Dohme Corp).

Rituximab, Gemcitabine, Cisplatin and Methylprednisolone (R-GEM-P) is an effective regimen in relapsed diffuse large B-cell lymphoma

Patients with relapsed diffuse large B‐cell lymphoma (DLBCL) have a poor prognosis. Gemcitabine, methylprednisolone, cisplatin +/− rituximab (GEM‐P+/−R) is a salvage regimen with limited overlap in toxicity with first‐line therapy and short duration of inpatient delivery.

CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial

Summary Background Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients. Methods We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I to stage IV disease (WHO performance status 0–3), previously untreated peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic γδ T-cell lymphoma. We randomly assigned patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2 mg] on day 1, and oral prednisolone 100 mg on days 1–5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine 1000 mg/m2 on days 1, 8, and 15, cisplatin 100 mg/m2 on day 15, and oral or intravenous methylprednisolone 1000 mg on days 1–5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20% superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and had an end-of-treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18). Findings Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and 44 to GEM-P. A planned unmasked review of efficacy data by the independent data monitoring committee in November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of 27·4 months (IQR 16·6–38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0·52, 95% CI 0·21–1·31; p=0·164). The most common adverse events of grade 3 or worse in both groups were neutropenia (17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P, and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both in the GEM-P group, from lung infections. Interpretation The number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma. Funding Bloodwise and the UK National Institute of Health Research.

Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial.

Abstract Background Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. Patients and methods The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I–IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. Results 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a ‘high-risk’ extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. Conclusion Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. ClinicalTrials.gov ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.

Outcomes for transformed follicular lymphoma in the rituximab era: the Royal Marsden experience 2003-2013

Abstract Survival for transformed follicular lymphoma (tFL) has improved in the rituximab era and the need for upfront stem cell transplantation (SCT) is unclear. We evaluated the outcomes for all patients treated with first-line chemotherapy for histologically-proven tFL at our institution from 2003–2013 (n = 87). The majority of patients (89.7%) did not receive a SCT as part of first-line management. With a median follow-up of 7.8 years the 5-year overall survival (OS) for all patients was 61.7%. Patients treated with R-CHOP without upfront SCT (n = 55/87) had a 5-year OS of 64.3%. In a Cox regression analysis of the entire cohort (n = 87) International Prognostic Index (IPI) risk group and presence of B symptoms at transformation were independently associated with OS in multivariate analysis (MVA). Our analysis confirms the improved survival of tFL in the rituximab era even in the absence of upfront SCT consolidation.

Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‐CHOP) in the management of primary mediastinal B‐cell lymphoma: a subgroup analysis of the UK NCRI R‐CHOP 14 versus 21 trial

We performed a subgroup analysis of the phase III UK National Cancer Research Institute R‐CHOP‐14 versus R‐CHOP‐21 (two‐ versus three‐weekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) trial to evaluate the outcomes for 50 patients with World Health Organization 2008 classified primary mediastinal B‐cell lymphoma identified from the trial database. At a median follow‐up of 7·2 years the 5‐year progression‐free survival and overall survival was 79·8% and 83·8%, respectively. An exploratory analysis raised the possibility of a better outcome in those who received R‐CHOP‐14 and time intensification may still, in the rituximab era, merit testing in a randomised trial in this subgroup of patients.

Caution in the Use of Immunohistochemistry for Determination of Cell of Origin in Diffuse Large B-Cell Lymphoma

TO THE EDITOR: The article by Nowakowski et al 1 reported the results from their phase II study, in which lenalidomide was administered in addition to standard first-line R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) to 64 patients with diffuse large B-cell lymphoma (DLBCL). In that study, the authors compared the study cohort to an historical control group of 87 patients who received R-CHOP alone. They concluded that the additionoflenalidomide25mg(administeredfromday1today10)to R-CHOP overcomes the inferior prognosis associated with non‐ germinal center B-cell or activated B-cell (ABC) types of DLBCL treated with R-CHOP alone. The rationale for selecting the ABC subtype of DLBCL (ABCDLBCL) as a targeted subgroup for treatment with lenalidomide is strong,becausethisagentisaknowninhibitorofthenuclearfactorB pathway that is constitutively activated in ABC-DLBCL 2,3 ; however, we would advise caution in the interpretation of the results of Nowakowski et al. First, an historical control group was used for the comparison. Second and more important, the Hans algorithm, an immunohistochemistry(IHC)method,wasusedtodeterminethecell

Outcomes following front-line chemotherapy in peripheral T-cell lymphoma: 10-year experience at The Royal Marsden and The Christie Hospital

Abstract We evaluated the outcomes for patients with peripheral T-cell lymphoma (PTCL) undergoing front-line chemotherapy at our institutions between 2002 and 2012. One hundred and fifty-six patients were eligible, comprising PTCL not otherwise specified (NOS) (n = 50, 32.0%), angioimmunoblastic T-cell lymphoma (AITL) (n = 44, 28.2%), anaplastic large-cell lymphoma (ALCL) ALK negative (n = 23, 14.7%), ALCL ALK positive (n = 16, 10.3%), and other (n = 23, 14.7%). Most patients received CHOP (66.0%) and 13.0% received an autologous hematopoietic progenitor cell transplant (HPCT). With a median follow-up of 63.4 months, 5-year overall survival (OS) and progression-free survival (PFS) was 38.8% and 19.8% respectively. Independent risk factors for inferior OS were age >60 years, International Prognostic Index (IPI) ≥ 2 and lack of complete response to induction. When responding patients were compared by receipt of an autologous HPCT versus not, HPCT was associated with improved PFS (p = .001) and OS (p = .046) and remained significant for PFS in multivariate analysis suggesting a possible therapeutic benefit.

THE ROLE OF 18F FDG-PET/CT IN PERIPHERAL T-CELL LYMPHOMA (PTCL): INITIAL RESULTS OF THE UK NCRI MULTICENTRE PHASE II RANDOMISED CHEMO-T TRIAL PET/CT SUBSTUDY

ent from score 2 (21/47, 45%; P = 0.023) and 4 (24/27, 89%; P = 0.030), we categorized patients into 3 groups: Deauville score 1– 2, 3, and 4–5. With a median follow‐up of 54.7 months (IQR, 30.2–84.5), 5‐year PFS rate was 35.7% (95% CI, 30.0–41.4), and OS rate was 47.1% (95% CI, 40.8–53.4). NCCN‐IPI risk and post‐treatment PET‐CT scan were independently associated with PFS in multivariate analysis (for LI NCCN‐IPI, hazard ratio [HR] 1.615, 95% CI 0.838–3.113; HI NCCN‐ IPI, HR 3.063, 95% CI 1.626–5.769; high NCCN‐IPI 4.475, 95% CI 2.231–8.977; P < 0.001: for post‐treatment Deauville score 3, HR 1.895, 95% CI 1.281–2.801; score 4–5, HR 6.916, 95% CI 4.948– 9.667; P < 0.001). We stratified patients into 5 groups based on risk of progression: low (low NCCN‐IPI and Deauville score 1–2), INT‐1 (low NCCN‐IPI and score 3, or LI NCCN‐IPI and score 1–2), INT‐2 (HI NCCN‐IPI and score 1–2), high (high NCCN‐IPI and score 1–2, or LI to high NCCN‐IPI and score 3), and very high (score 4–5). The risk model showed a strong association with PFS and OS (Figure 1). Conclusion: This study proposes a new risk stratification model incorporating baseline NCCN‐IPI in combination with post‐treatment Deauville score on PET‐CT scan in patients with newly diagnosed nodal PTCL.

DNMT3A-2 EXPRESSION LEVELS CHARACTERISE DIFFUSE LARGE B-CELL LYMPHOMA WITH DISTINCT METHYLATION PATTERNS AND OUTCOME

U133plus2.0 GEP: cases were defined as positive if >10% of the neoplastic cells nuclei were pETS1 positive. Results: pETS1 was detected in ABC, not in GCB cell lines (100% vs 0%, P < .05), but also in 2/3 Type 3 (67%). All the cell lines expressed ETS1 and its upstream activator ERK. The ABC marker IRF4 was expressed only in ABC (100%). p‐ERK was expressed in 6/8 ABC (75%), 2/3 Type 3 (67%), and 0/8 GCB (0%). pETS1 was present predominantly in the nucleus (5/5), while total ETS1 was in both cytoplasm and nucleus in 4/5, and only in the nucleus in 1/5.To evaluate the mechanisms sustaining pETS1, 2 ABC cell lines (U2932, TMD8) were treated with the PI3K‐delta inhibitor idelalisib (1μM), the BTK inhibitor ibrutinib (0.5μM), and the MEK inhibitor pimasertib (0.5μM) with or without anti‐IgM. BTK or MEK inhibition decreased pETS1 baseline levels but only MEK inhibition inhibited the IgM stimulation‐ induced pETS1 increase. PI3K‐delta inhibition only lead to a minimal reduction of baseline pETS1 levels. Similar changes were seen for pERK. To understand the clinical significance of our findings, we assessed pETS1 expression in 315 GEP‐classified, RCHOP‐treated DLBCL cases from The International DLBCL Rituximab‐CHOP Consortium Program Study. pETS1 was more frequent in ABC than in GCB: 79% (123/155) vs 57% (91/160) (P < .001). In GCB, pETS1 positivity was associated with inferior progression free survival (PFS) at univariate analysis (P 0.034). The prognostic impact was also maintained in a multivariate analysis including the IPI. No effect on the outcome was seen in ABC. The pETS1 positive GCB (n = 91) presented a statistically significant enrichment of gene expression signatures related to cell cycle (mitotic spindle, NES 1.8 FDR 0.003; E2F targets NES 1.7 FDR 0.003; MYC targets NES 1.5 FDR 0.04) when compared to pETS1 negative GCB (n = 69). Conclusions: pETS1 is associated with the ABC phenotype in cell lines and clinical specimens. pETS1 positive GCB are characterized by poor PFS and cell cycle‐related gene expression signatures. Pharmacological interventions worth of preclinical investigation for pETS1 DLBCL positive cases could comprise drugs targeting BTK, MEK, and cell cycle.