A phase 1/2 trial of ublituximab,a novel anti‐CD20 monoclonal antibody,in patients with B‐cell non‐Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab

This phase 1/2 study evaluated the safety, pharmacokinetic behavior and anti‐tumour activity of ublituximab, a unique type I, chimeric, glycoengineered anti‐CD 20 monoclonal antibody, in rituximab‐relapsed or ‐refractory patients with B‐cell non‐Hodgkin lymphoma (B‐NHL ) or chronic lymphocytic leukaemia (CLL ). Induction therapy (doses of 450–1200 mg) consisted of 4 weekly infusions in cycle 1 for NHL and 3 weekly infusions in cycles 1 and 2 for CLL . Patients received ublituximab maintenance monthly during cycles 3–5, then once every 3 months for up to 2 years. Enrolled patients with B‐NHL (n  = 27) and CLL (n  = 8) had a median of 3 prior therapies. No dose‐limiting toxicities or unexpected adverse events (AE s) occurred. The most common AE s were infusion‐related reactions (40%; grade 3/4, 0%); fatigue (37%; grade 3/4, 3%); pyrexia (29%; grade 3/4, 0%); and diarrhoea (26%; grade 3/4, 0%). Common haematological AE s were neutropenia (14%; grade 3/4, 14%) and anaemia (11%; grade 3/4, 6%). The overall response rate for evaluable patients (n  = 31) was 45% (13% complete responses, 32% partial responses). Median duration of response and progression‐free survival were 9·2 months and 7·7 months, respectively. Ublituximab was well‐tolerated and efficacious in a heterogeneous and highly rituximab‐pre‐treated patient population.     

A phase I/II trial of bortezomib combined concurrently with gemcitabine for relapsed or refractory DLBCL and peripheral T‐cell lymphomas

There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) and peripheral T‐cell lymphoma (PTCL). We conducted a phase I/II trial with bortezomib (dose‐escalated to 1·6 mg/m²) given concurrently with gemcitabine (800 mg/m²) days 1 + 8 q21 d. Of 32 patients, 16 each had relapsed/refractory PTCL and DLBCL. Median prior therapies were 3 and 35% had failed transplant. Among the first 18 patients, 67% experienced grade 3/4 neutropenia and/or grade 3/4 thrombocytopenia resulting in repeated treatment delays (relative dose intensity: 46%). Thus, the study was amended to give bortezomib and gemcitabine days 1 + 15 q28 d, which resulted in markedly improved tolerability. Among all patients, the overall response rate (ORR) was 24% with 19% complete remission (CR; intent‐to‐treat (ITT) ORR 16%, CR 13%), which met criteria for futility. The ORR for DLBCL was 10% (CR 10%) vs. 36% for PTCL (CR 27%). Among 6 PTCL patients treated on the modified schedule, ORR by ITT was 50% (CR 30%). Altogether, concurrent bortezomib/gemcitabine given days 1 + 8 q21 d was not tolerable, while modification to a bi‐monthly schedule allowed consistent treatment delivery. Whereas efficacy of this combination was low in heavily pre‐treated DLBCL, there was a signal of activity in relapsed/refractory PTCL utilizing the modified schedule.     

Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory,indolent non‐Hodgkin lymphoma

This phase II study evaluated the safety and efficacy of lenalidomide in combination with rituximab in patients with relapsed/refractory, indolent non‐Hodgkin lymphoma (NHL). Patients were treated with daily lenalidomide in 28‐d cycles and weekly rituximab for 4 weeks. Lenalidomide was continued until progression or unacceptable toxicity. Twenty‐two patients were assessed for FCGR3A polymorphisms. Thirty patients were enrolled; 27 were evaluable for response. The overall response rate (ORR) was 74% including 44% complete responses (CR); median progression‐free survival (PFS) was 12·4 months. The 13 rituximab refractory patients had an ORR of 61·5% (four CR/unconfirmed CR). The ORR was 77% in the 22 follicular lymphoma patients (nine CR/unconfirmed CR). At a median follow‐up time of 43 months, the median duration of response and time to next therapy were 15·4 and 37·4 months, respectively. Most common grade 3/4 adverse events were lymphopenia (45%), neutropenia (55%), fatigue (23%) and hyponatraemia (9%). The ORR and PFS in patients with low‐affinity FCGR3A polymorphisms (F/F and F/V) suggest that lenalidomide may improve the activity of rituximab in these patients. These data suggest that combining lenalidomide with rituximab can produce durable responses with acceptable toxicity in patients with indolent NHL.     

A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Although initial rituximab‐containing chemotherapies achieve high response rates, indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B‐NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21‐d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression‐free survival (PFS). Fifty‐six eligible patients were enrolled; 50 patients (39 with FL, seven with other B‐NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab‐containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.     

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open‐label studies

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B‐cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression‐free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non‐blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0–1, non‐bulky disease and non‐blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease.     

Phase Ib trial of the PI3K/mTOR inhibitor voxtalisib (SAR245409) in combination with chemoimmunotherapy in patients with relapsed or refractory B‐cell malignancies

This phase Ib, dose‐escalation study investigated the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and preliminary efficacy of the pan‐class I phosphoinositide 3‐kinase (PI3K) and mechanistic target of rapamycin (mTOR) inhibitor voxtalisib [30 or 50 mg twice daily (BID)], in combination with rituximab (voxtalisib+rituximab) or rituximab plus bendamustine (voxtalisib+rituximab+bendamustine), in relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma (NHL), mantle cell lymphoma and chronic lymphocytic leukaemia (CLL). MTD and RP2D of voxtalisib were determined using a 3 + 3 dose‐escalation design. Adverse events (AEs), plasma PK and disease response were recorded. Thirty‐seven patients were enrolled. The RP2D of voxtalisib in combination with rituximab or rituximab+bendamustine was 50 mg BID. Four patients experienced a total of five dose‐limiting toxicities. The most frequent AEs were nausea (45·9%), fatigue (37·8%) headache (32·4%) and pyrexia (32·4%). The most frequent grade ≥3 AEs were neutropenia (27·0%), thrombocytopenia (24·3%), anaemia (16·2%) and febrile neutropenia (10·8%). Voxtalisib PK parameters were not affected by co‐administration with rituximab or rituximab+bendamustine. Of 35 efficacy‐evaluable patients, four (11·4%) achieved complete response and 13 (37·1%) achieved partial response. Voxtalisib, in combination with rituximab or rituximab+bendamustine, demonstrated an acceptable safety profile and encouraging anti‐tumour activity in relapsed or refractory B‐cell malignancies.     

Bendamustine,lenalidomide and dexamethasone (BRd) has high activity as 2nd‐line therapy for relapsed and refractory multiple myeloma – a phase II trial

The combination of lenalidomide (Revlimid^®, R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM ). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR )]. The combination of bendamustine (B), lenalidomide and dexamethasone (BR d) has shown high efficacy in patients with advanced rrMM . However, dose‐limiting haematotoxicity restricted its use in extensively pre‐treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BR d in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46–83]) and were treated with B 75 mg/m² days 1, 2; R 25 mg days 1–21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28‐day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol‐defined criteria. The study aimed to demonstrate a complete response (CR )/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR /VGPR . Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BR d is a safe and efficacious regimen as a second line treatment for rrMM , leading to high quality responses in a considerable proportion of patients.     

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

Patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) with deletion 17p [del(17p)] have poor outcomes with chemoimmunotherapy. Ibrutinib is indicated for the treatment of CLL/SLL, including del(17p) CLL/SLL, and allows for treatment without chemotherapy. This integrated analysis was performed to evaluate outcomes in 230 patients with relapsed/refractory del(17p) CLL/SLL from three ibrutinib studies. With a median of 2 prior therapies (range, 1–12), 18% and 79% of evaluable patients had del(11q) or unmutated IGHV, respectively. With a median follow‐up of 28 months, overall response rate was 85% and estimated 30‐month progression‐free and overall survival rates were 57% [95% confidence interval (CI) 50–64] and 69% (95% CI 61–75), respectively. Patients with normal lactate dehydrogenase or no bulky disease had the most favourable survival outcomes. Sustained haematological improvements in haemoglobin, platelet count and absolute neutrophil count occurred in 61%, 67% and 70% of patients with baseline cytopenias, respectively. New onset severe cytopenias and infections decreased in frequency over time. Progression‐free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL. These results provide further evidence of the robust clinical activity of ibrutinib in difficult‐to‐treat CLL/SLL populations.     

Clinical activity of everolimus in relapsed/refractory marginal zone B‐cell lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group

The International Extranodal Lymphoma Study Group coordinated a phase II trial to evaluate the activity and safety of everolimus in marginal zone lymphomas (MZLs). Thirty patients with relapsed/refractory MZLs received everolimus for six cycles or until dose‐limiting toxicity or progression. Median age was 71 years (range, 51–88 years). Twenty patients had extranodal, six splenic, four nodal MZL. Twenty‐four patients had stage III–IV. Median number of prior therapies was two (range 1–5). Seventeen patients had early treatment discontinuation, in most cases due to toxicity. Median number of cycles was 4·5 (range, 1–16). Among the 24 assessable patients, the overall response rate (ORR) was 25% (95% confidence interval: 10–47). Grade 3–4 adverse events were neutropenia and thrombocytopenia (17% of patients, each), infections (17%), mucositis and odontogenic infections (13%) and lung toxicity (3%). The median response duration was 6·8 months (range, 1·4–11·1+). After a median follow‐up of 14·5 months, five deaths were reported: four deaths were due to lymphoma, one was due to toxicity. In an intent‐to‐treat analysis, the projected median progression‐free survival was 14 months. The moderate antitumour activity of everolimus in relapsed/refractory MZLs and the observed toxicity limit its therapeutical applicability in these indolent entities. Lower doses of the drug and, perhaps, different strategies including combination with additional agents need to be explored.     

A phase II,single‐arm,multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B‐cell lymphoma

In this phase II, multicentre, single‐arm study, 52 patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) received the anti‐CD19 antibody–drug conjugate coltuximab ravtansine (55 mg/m²) and rituximab (375 mg/m²) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0–41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2–78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0–72·1%]) or first‐line therapy (15·4% [80% CI: 6·9–28·4%]). Median progression‐free survival, overall survival and duration of response were 3·9 [80% CI: 3·22–3·98], 9·0 [80% CI: 6·47–13·67] and 8·6 (range: 0–18) months, respectively. The pharmacokinetics of both drugs were unaffected by co‐administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBCL.     

Platinum and high‐dose cytarabine‐based regimens are efficient in ultra high/high‐risk chronic lymphocytic leukemia and Richter's syndrome: results of a French retrospective multicenter study

Ultra high‐risk chronic lymphocytic leukemia (CLL) and Richter's syndrome (RS) usually display a poor prognosis. Platinum and cytarabine‐based regimens have not been evaluated in large cohorts of patients with CLL or RS. This retrospective study was aimed to assess the efficacy of these regimens in 75 patients with relapsed/refractory (R/R) CLL or RS. Forty‐seven patients had R/R CLL (including 36 ultra high‐risk CLL) and 28 had RS. Median age was 62 years (range, 18–79 years). Median number of previous therapies was 3 (range, 1–7), including fludarabine‐based regimens (75%) and alemtuzumab (32%), and 61% of patients were refractory to their last treatment. Deletions of chromosomes 17p and 11q were found in 40% and 39% of cases, respectively. The overall response rates were 60% with 24% complete response (CR) in CLL, and 43% with 25% CR in RS. The median progression‐free survival and overall survival were 11 and 14.6 months, respectively. Fludarabine refractoriness and 17p deletion were not associated with a poorer outcome. The only factors predicting shorter survival were performance status ≥2 (P = 0.04) and albumin level <3.5 g/dL (P = 0.0004). Toxicities were mainly myelosuppression and infectious complications. Platinum and high‐dose cytarabine‐based regimens provide high response rates in high‐risk CLL and in RS. However, these results will be challenged by the new arriving agents at least in non‐transformed CLL.     

Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28‐d cycles of 85 mg/m² pixantrone dimaleate (equivalent to 50 mg/m² in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2–6) with pixantrone and 3 (2–6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression‐free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26–1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B‐cell NHL in the 3rd or 4th line setting, independently of previous rituximab.     

Advances in first‐line treatment of chronic lymphocytic leukemia: current recommendations on management and first‐line treatment by the German CLL Study Group (GCLLSG)

The management of patients with CLL is undergoing significant changes; during the last decade, the outcome of first‐line therapies has been markedly improved with the addition of anti‐CD20 antibodies to chemotherapy. Today, chemoimmunotherapy for physically fit patients ≤65 years should consist of fludarabine, cyclophosphamide, and rituximab (FCR). The combination of bendamustine and rituximab (BR) should be considered in physically fit patients >65 years and in patients with a higher risk of infections. Patients with reduced fitness and/or relevant comorbidity should receive chlorambucil with a CD20 antibody, preferably obinutuzumab. Regardless of their fitness, patients with CLL carrying genetic aberrations such as del(17p) and/or TP53 mutation poorly respond to chemoimmunotherapy and therefore require different therapeutic approaches. An increasing understanding of the disease biology has led to the development of targeted drugs for the treatment of CLL, such as the BTK inhibitor ibrutinib and PI3K inhibitor idelalisib. These agents have shown efficacy in high‐risk and relapsed/refractory patients and are currently being evaluated in clinical trials for first‐line therapy. It is anticipated that these compounds and further other novel agents will profoundly change the therapy of CLL.     

High response rate and acceptable toxicity of a combination of rituximab,vinorelbine, ifosfamide,mitoxantrone and prednisone for the treatment of diffuse large B‐cell lymphoma in first relapse: results of the R‐NIMP GOELAMS study

The optimal management of relapsed diffuse large B‐cell lymphoma (DLBCL) is not standardized. The Groupe Ouest Est des Leucémies et aAutres Maladies du Sang developed a combination of vinorelbine, ifosfamide, mitoxantrone and prednisone (NIMP) for the treatment of relapsed DLBCL, and assessed its efficacy and safety in association with rituximab (R). This multicentric phase II study included 50 patients with DLBCL in first relapse, aged 18–75 years. Patients received rituximab 375 mg/m² day 1, ifosfamide 1000 mg/m² days 1–5, vinorelbine 25 mg/m² days 1 and 15, mitoxantrone 10 mg/m² day 1, and prednisone 1 mg/kg days 1–5, every 28 days for three cycles. Responding patients underwent autologous transplantation or received three additional R‐NIMP cycles. All patients were evaluable for toxicity and 49 for response. Centralized pathology review confirmed DLBCL in all cases. Toxicities were mainly haematological with infectious events needing hospitalization in nine cases. Two toxic deaths were observed. After three cycles, 22 patients (44%) achieved complete response/unconfirmed complete response, 11 achieved partial response (24%), 2 had stable disease and 13 progressed. The non‐germinal centre B immunophenotype was associated with shorter progression‐free survival. in conclusion, the R‐NIMP regimen displayed significant activity in relapsed DLBCL, with acceptable toxicity and should be considered a candidate for combination with new agents.     

A randomized,open‐label,multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine,cyclophosphamide and rituximab versus fludarabine,cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia

Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B‐cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open‐label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty‐seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression‐free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.     

Lenalidomide in combination with R‐ESHAP in patients with relapsed or refractory diffuse large B‐cell lymphoma: a phase 1b study from GELTAMO group

Diffuse large B‐cell lymphoma (DLBCL) patients failing rituximab‐containing therapy have a poor outcome with the current salvage regimens. We conducted a phase 1b trial to determine the maximum tolerated dose (MTD) of lenalidomide in combination with R‐ESHAP (rituximab, etoposide, cisplatin, cytarabine, methylprednisolone) (LR‐ESHAP) in patients with relapsed or refractory DLBCL. Efficacy data were collected as a secondary objective. Subjects received 3 cycles of lenalidomide at escalating doses (5, 10 or 15 mg) given on days 1–14 of every 21‐day cycle, in combination with R‐ESHAP. Responding patients received BEAM (carmustine, etoposide, cytarabine, melphalan) followed by autologous stem‐cell transplantation. Lenalidomide 10 mg/d was identified as the MTD because, in the 15 mg cohort, one patient experienced dose‐limiting toxicity (grade 3 angioedema) and two patients had mobilization failure. A total of 19 patients (3, 12 and 4 in the 5, 10 and 15 mg cohorts, respectively) were evaluable. All toxicities occurring during LR‐ESHAP cycles resolved appropriately and no grade 4–5 non‐haematological toxicities were observed. The complete remission and overall response rates were 47·4% and 78·9%, respectively. With a median follow‐up of 24·6 (17·4–38·2) months, the 2‐year progression‐free survival and overall survival were 44% and 63%, respectively. In conclusion, the LR‐ESHAP regimen is feasible and yields encouraging outcomes.     

Outcomes with ibrutinib by line of therapy and post-ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis

The efficacy of ibrutinib has been demonstrated in patients with chronic lymphocytic leukemia (CLL), including as first-line therapy. However, outcomes after ibrutinib discontinuation have previously been limited to higher-risk populations with relapsed/refractory (R/R) disease. The objective of this study was to evaluate outcomes of ibrutinib-treated patients based on prior lines of therapy, including after ibrutinib discontinuation. Data were analyzed from two multicenter phase 3 studies of single-agent ibrutinib: RESONATE (PCYC-1112) in patients with R/R CLL and RESONATE-2 (PCYC-1115) in patients with treatment-naive (TN) CLL without del(17p). This integrated analysis included 271 ibrutinib-treated non-del(17p) patients with CLL (136 TN and 135 R/R). Median progression-free survival (PFS) was not reached for subgroups with 0 and 1/2 prior therapies but was 40.6 months for patients with ≥3 therapies (median follow-up: TN, 36 months; R/R, 44 months). Median overall survival (OS) was not reached in any subgroup. Overall response rate (ORR) was 92% in TN and 92% in R/R, with depth of response increasing over time. Adverse events (AEs) and ibrutinib discontinuation due to AEs were similar between patient groups. Most patients (64%) remain on treatment. OS following discontinuation was 9.3 months in R/R patients (median follow-up 18 months, n = 51) and was not reached in TN patients (median follow-up 10 months, n = 30). In this integrated analysis, ibrutinib was associated with favorable PFS and OS, and high ORR regardless of prior therapies in patients with CLL. The best outcomes following ibrutinib discontinuation were for patients receiving ibrutinib in earlier lines of therapy.     

Ofatumumab retreatment and maintenance in fludarabine‐refractory chronic lymphocytic leukaemia patients

There are limited data on retreatment with monoclonal antibodies (mAb) in patients with chronic lymphocytic leukaemia (CLL). In a pivotal study, ofatumumab (human anti‐CD20 mAb) monotherapy demonstrated a 47% objective response rate (ORR) in fludarabine refractory CLL patients. From this study, a subset of 29 patients who had at least stable disease and then progressed were retreated with eight weekly ofatumumab infusions (induction treatment period), followed by monthly infusions for up to 2 years (maintenance treatment period). The ORR after 8 weeks of induction retreatment was 45% and 24% had continued disease control after maintenance at 52 weeks. Efficacy and safety of the retreated patients were compared with their initial results in the pivotal study. Response duration was 24·1 months vs. 6·8 months; time to next therapy was 14·8 months vs. 12·3 months; and progression‐free survival was 7·4 months vs. 7·9 months (medians). Upon retreatment, 72% had infusion reactions, mostly Grade 1–2. Three patients had fatal infections. In summary, ofatumumab retreatment and maintenance therapy was feasible in patients with heavily pretreated CLL and appeared to result in more durable disease control than initial ofatumumab treatment in this subset of patients who may have a more favourable disease profile.     

Phase II clinical trial for the evaluation of bortezomib within the reduced intensity conditioning regimen (RIC) and post‐allogeneic transplantation for high‐risk myeloma patients

The current study was designed to assess the safety and efficacy of bortezomib in combination with fludarabine and melphalan as reduced intensity conditioning before allogeneic stem cell transplantation in patients with high risk multiple myeloma. Sixteen patients were evaluable. The median number of previous line of treatment was 3; all patients had relapsed following a prior autograft and 13 had previously received bortezomib. Fifteen of them either remained stable or improved disease status at day +100 post‐transplant, including 11 patients with active disease. More specifically, nine patients (56%) and five patients (31%) reached complete remission and partial response, respectively. 25% developed grade III acute graft‐versus‐host disease. The cumulative incidence of non‐relapse mortality, relapse and overall survival were 25%, 54% and 41%, respectively, at 3 years. Regarding the non‐haematological toxicity (grade>2), two patients developed peripheral neuropathy, two patients liver toxicity and 1 pulmonary toxicity early post‐transplant. The haematological toxicity was only observed during the first three cycles mostly related to low haemoglobin and platelet levels. The current trial is the first one evaluating the safety and efficacy of bortezomib as part of a reduced intensity conditioning regimen among patients with high risk multiple myeloma.     

A phase IIb trial of vorinostat in combination with lenalidomide and dexamethasone in patients with multiple myeloma refractory to previous lenalidomide‐containing regimens

Clinical trials of vorinostat, a Class I/II histone deacetylase inhibitor, in combination with proteasome inhibitors and immunomodulatory agents have shown activity in relapsed/refractory multiple myeloma. This phase IIb, open‐label, single‐institution study evaluated the efficacy of vorinostat in combination with lenalidomide and dexamethasone in lenalidomide‐refractory patients. Patients were considered lenalidomide‐refractory if they had no clinical response (<minimal response) on a previous lenalidomide‐containing regimen (lenalidomide non‐responsive) or if they had progressive disease on or within 60 days of discontinuing a previous lenalidomide‐containing regimen (lenalidomide relapsed/refractory). Patients received oral vorinostat 400 mg days 1–7 and 15–21, lenalidomide 25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15 and 22 in 28‐day cycles. Twenty‐five patients were enrolled, median age was 65 years and patients had received a median of 5 prior regimens. The overall response rate was 24% (6 partial responses) and clinical benefit rate (≥stable disease) was 80%. Median time to a partial response was 1·9 months and median duration of response was 3·3 months. Median progression‐free survival was 5·3 months. Most common grade 3/4 adverse events were neutropenia (48%), thrombocytopenia (32%), anaemia (20%) and gastrointestinal toxicities (16%). In this heavily pre‐treated population, vorinostat in combination with lenalidomide and dexamethasone was active in lenalidomide‐refractory patients.