Christopher Pocock

Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia

BACKGROUND In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Brutons tyrosine kinase, in patients at risk for a poor outcome. METHODS In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points. RESULTS At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group. CONCLUSIONS Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).

Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles

BACKGROUND Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups. METHODS Patients (aged ≥18 years) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). R-CHOP-21 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1·4 mg/m(2) (maximum dose 2 mg), and rituximab 375 mg/m(2) on day 1, and oral prednisolone 40 mg/m(2) on days 1-5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 2 mg, rituximab 375 mg/m(2) on day 1, and oral prednisolone 100 mg on days 1-5, administered every 14 days for six cycles, followed by two further infusions of rituximab 375 mg/m(2) on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISRCTN 16017947. FINDINGS 1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35-57), 2-year OS was 82·7% (79·5-85·9) in the R-CHOP-14 group and 80·8% (77·5-84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70-1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8-79·1, and R-CHOP-21 74·8%, 71·0-78·4; 0·94, 0·76-1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups. INTERPRETATION R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study. FUNDING Chugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of Cancer Research.

Rituximab versus a watch-and-wait approach in patients with advanced- stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial

BACKGROUND Patients with advanced-stage, low-tumour-burden follicular lymphoma have conventionally undergone watchful waiting until disease progression. We assessed whether rituximab use could delay the need for chemotherapy or radiotherapy compared with watchful waiting and the effect of this strategy on quality of life (QoL). METHODS Asymptomatic patients (aged ≥18 years) with low-tumour-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned centrally (1:1:1), by the minimisation approach stratified by institution, grade, stage, and age, to watchful waiting, rituximab 375 mg/m(2) weekly for 4 weeks (rituximab induction), or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance rituximab). On Sept 30, 2007, recruitment into the rituximab induction group was closed and the study was amended to a two-arm study. The primary endpoints were time to start of new treatment and QoL at month 7 (ie, 6 months after completion of rituximab induction). All randomly assigned patients were included in the analysis of time to start of new treatment on an intention-to-treat basis. The main study is now completed and is in long-term follow-up. The study is registered with ClinicalTrials.gov, NCT00112931. FINDINGS Between Oct 15, 2004, and March 25, 2009, 379 patients from 118 centres in the UK, Australia, New Zealand, Turkey, and Poland were randomly assigned to watchful waiting or maintenance rituximab. 84 patients were recruited to the rituximab induction group before it was closed early. There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) of patients in the watchful waiting group not needing treatment at 3 years compared with 88% (83-92) in the maintenance rituximab group (hazard ratio [HR] 0·21, 95% CI 0·14-0·31; p<0·0001). 78% (95% CI 69-87) of patients in the rituximab induction group did not need treatment at 3 years, which was significantly more than in the watchful waiting group (HR 0·35, 95% CI 0·22-0·56; p<0·0001), but no different compared with the maintenance rituximab group (0·75, 0·41-1·34; p=0·33). Compared with the watchful waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (p=0·0004), and Illness Coping Style score (p=0·0012) between baseline and month 7. Patients in the rituximab induction group did not show improvements in their QoL compared with the watchful waiting group. There were 18 serious adverse events reported in the rituximab groups (four in the rituximab induction group and 14 in the maintenance rituximab group), 12 of which were grade 3 or 4 (five infections, three allergic reactions, and four cases of neutropenia), all of which fully resolved. INTERPRETATION Rituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma. FUNDING Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.

Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders.

The BCR–ABL‐negative chronic myeloproliferative disorders (CMPD) and myelodysplastic/myeloproliferative diseases (MDS/MPD) are a spectrum of related conditions for which the molecular pathogenesis is poorly understood. Translocations that disrupt and constitutively activate the platelet‐derived growth factor receptor β(PDGFRB) gene at chromosome band 5q33 have been described in some patients, the most common being the t(5;12)(q33;p13). An accurate molecular diagnosis of PDGFRB‐rearranged patients has become increasingly important since recent data have indicated that they respond very well to imatinib mesylate therapy. In this study, we have tested nine patients with a CMPD or MDS/MPD and a translocation involving 5q31–33 for disruption of PDGFRB by two‐colour fluorescence in situ hybridization (FISH) using differentially labelled, closely flanking probes. Normal control interphase cells gave a false positive rate of 3% (signals more than one signal width apart). Six patients showed a pattern of one fused signal (from the normal allele) and one pair of signals separated by more than one signal width in > 85% of interphase cells, indicating that PDGFRB was disrupted. These individuals had a t(1;5)(q21;q33), t(1;5)(q22;q31), t(1;3;5)(p36;p21;q33), t(2;12;5)(q37;q22;q33), t(3;5) (p21;q31) and t(5;14)(q33;q24) respectively. The remaining three patients with a t(1;5)(q21;q31), t(2;5)(p21;q33) and t(5;6)(q33;q24–25) showed a normal pattern of hybridization, with ≥ 97% interphase cells with two fusion signals. We conclude that two‐colour FISH is useful to determine the presence of a PDGFRB rearrangement, although, as we have shown previously, this technique may not detect subtle complex translocations at this locus. Our data indicate that several PDGFRB partner genes remain to be characterized.

Rituximab Plus Chlorambucil As First-Line Treatment for Chronic Lymphocytic Leukemia: Final Analysis of an Open-Label Phase II Study

PURPOSE Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL. PATIENTS AND METHODS Patients with first-line CLL were treated with rituximab (375 mg/m(2) on day 1, cycle one, and 500 mg/m(2) thereafter) plus chlorambucil (10 mg/m(2)/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety. RESULTS A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached. CONCLUSION These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments.

A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia.

Combination fludarabine (F), cyclophosphamide (C) and rituximab (R) is the standard front‐line therapy in chronic lymphocytic leukaemia (CLL), but appropriate treatment of relapsed/refractory CLL is less clear. Combined FC and mitoxantrone (M) has been reported to be effective in a single arm study, and rituximab when added to chemotherapy in CLL is synergistic. A randomized, two‐stage, Phase II trial of FCM and FCM‐R was conducted in relapsed CLL. The primary endpoint was response rate 2 months after therapy, assessed according to the 2008 International Workshop CLL criteria. In addition, minimal residual disease (MRD) in the marrow was studied 2 months after therapy, with MRD negativity defined as <0·01% CLL cells. Fifty‐two patients were entered, 26 in each arm. The overall response rates to FCM and FCM‐R were 58% and 65% respectively. Combined complete response (CR) and CR with incomplete marrow recovery [CR(i)] was 15% (95% confidence interval [CI]:4–35%) for FCM and 42% (95%CI:23–63%) for FCM‐R, with eight patients achieving MRD negativity (3 FCM; 5 FCM‐R). The toxicity of both regimens was acceptable. In conclusion, the addition of rituximab to FCM improves the response rates in relapsed CLL, resulting in more complete remissions and without additional safety concerns. Efficacy and safety should be fully tested in a randomized Phase III trial.

De Novo Treatment of Diffuse Large B-Cell Lymphoma With Rituximab, Cyclophosphamide, Vincristine, Gemcitabine, and Prednisolone in Patients With Cardiac Comorbidity: A United Kingdom National Cancer Research Institute Trial

PURPOSE The treatment of patients with diffuse large B-cell lymphoma (DLBCL) with cardiac comorbidity is problematic, because this group may not be able to receive anthracycline-containing chemoimmunotherapy. We designed a single-arm phase II multicenter trial of rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone (R-GCVP) in patients considered unfit for anthracycline-containing chemoimmunotherapy because of cardiac comorbidity. PATIENTS AND METHODS Sixty-one of 62 patients received R-GCVP, administered on day 1 with gemcitabine repeated on day 8 of a 21-day cycle. Median age was 76.5 years. All patients had advanced disease; 27 (43.5%) had left ventricular ejection fraction of ≤ 50%, and 35 (56.5%) had an ejection fraction of > 50% and comorbid cardiac risk factors such as ischemic heart disease, diabetes mellitus, or hypertension [Corrected]. Primary end point was overall response rate at the end of treatment. RESULTS Thirty-eight patients (61.3%; 95% CI, 49.2 to 73.4) achieved disease response (complete response [CR], n = 18; undocumented/unconfirmed CR, n = 6; partial response, n = 14). Two-year progression-free survival for all patients was 49.8% (95% CI, 37.3 to 62.3), and 2-year overall survival was 55.8% (95% CI, 43.3 to 68.4). Thirty-four patients experienced grade ≥ 3 hematologic toxicity. There were 15 cardiac events, of which seven were grade 1 to 2, five were grade 3 to 4, and three were fatal, reflecting the poor cardiac status of the study population. CONCLUSION Our phase II multicenter trial showed that the R-GCVP regimen is an active, reasonably well-tolerated treatment for patients with DLBCL for whom anthracycline-containing immunochemotherapy was considered unsuitable because of coexisting cardiac disease.

Immune haemolytic anaemia following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukaemia : association with leukaemic relapse and treatment with donor lymphocyte infusions

Immune haemolytic anaemia (IHA) is a recognised complication after allogeneic stem cell transplantation (SCT) and occurs more frequently if marrow cells have been subjected to T cell depletion (TCD). Among 58 consecutive patients who underwent TCD-allogeneic SCT from volunteer unrelated donors for the treatment of CML at the Hammersmith Hospital during a 3-year period (1 March 1996 to 28 February 1999) we identified nine cases of IHA. All patients had a strongly positive direct and indirect antiglobulin test and in eight patients the serological findings were typical of warm-type haemolysis often with antibody specificities within the Rh system. All nine cases had clinically significant haemolysis and were treated initially with prednisolone and immunoglobulin. The onset of IHA coincided with the occurrence of leukaemic relapse in six cases, and the presence of host haemopoiesis confirmed by lineage-specific chimerism in all four cases studied. Five patients received donor lymphocyte infusions (DLI); in three molecular remission and the restoration of full donor chimerism coincided with resolution of haemolysis. We conclude that in the context of leukaemic relapse, DLI is an effective therapy for IHA following allografts involving TCD. Bone Marrow Transplantation (2001) 28, 581–586.

Guideline on the management of primary resistant and relapsed classical Hodgkin lymphoma

Summary of key recommendations ● Repeat biopsy is generally recommended in Hodgkinlymphoma (HL) patients thought to have relapsed, andshould be considered in those who have residual fluoro-deoxyglucose (FDG)-avid lesions post-therapy (1C).● Positron-emission tomography/computerized tomogra-phy (PET-CT) is the preferred restaging modality aftersalvage therapy (1B).● The aim of salvage treatment should be to achieve anFDG-PET-negative remission (1B).● The choice of a first-line salvage regimen in patients eli-gible for autologous stem cell transplantation (ASCT)should be based on patient factors and familiarity ofthe treatment centre with the regimen (2C).● Regimens containing stem cell toxic agents (such as car-mustine and melphalan) should be avoided if possibleuntil stem cells have been successfully collected andcryopreserved if ASCT is planned (1B).● There is currently no evidence to support intensivesequential induction/consolidation strategies prior toASCT (1B).● Consider switching to an alternative non-cross-resistantsalvage regimen if there are residual FDG-avid lesionsafter first line salvage treatment and the intent is toproceed to ASCT (2B).● In patients not eligible for ASCT, combined modalitytherapy should be considered especially in early stagerelapse and in patients who have not received priorradiotherapy or who have relapsed outside of the initialradiotherapy field (2B).● In patients unlikely to tolerate the toxicities associatedwith more intensive regimens, palliation with either a sin-gle agent or with a multi-agent oral regimen with or with-out intravenous vinblastine should be considered (2C).● Early consideration of involvement of palliative care ser-vices is recommended, particularly in those not eligiblefor high dose therapy (1C).● ASCT is the standard treatment for patients withrelapsed disease who achieve an adequate response tosalvage therapy (1A).● ASCT is also the standard treatment for patients withprimary resistant disease who achieve an adequateresponse to salvage therapy (1B).● ASCT is not recommended in those failing to achievean adequate response (1B).Guideline

The addition of Rituximab to Fludarabine and Cyclophosphamide chemotherapy results in a significant improvement in overall survival in patients with newly diagnosed mantle cell lymphoma: results of a randomized UK National Cancer Research Institute trial

Mantle cell lymphoma is an incurable and generally aggressive lymphoma that is more common in elderly patients. Whilst a number of different chemotherapeutic regimens are active in this disease, there is no established gold standard therapy. Rituximab has been used widely to good effect in B-cell malignancies but there is no evidence that it improves outcomes when added to chemotherapy in this disease. We performed a randomized, open-label, multicenter study looking at the addition of rituximab to the standard chemotherapy regimen of fludarabine and cyclophosphamide in patients with newly diagnosed mantle cell lymphoma. A total of 370 patients were randomized. With a median follow up of six years, rituximab improved the median progression-free survival from 14.9 to 29.8 months (P<0.001) and overall survival from 37.0 to 44.5 months (P=0.005). This equates to absolute differences of 9.0% and 22.1% for overall and progression-free survival, respectively, at two years. Overall response rates were similar, but complete response rates were significantly higher in the rituximab arm: 52.7% vs. 39.9% (P=0.014). There was no clinically significant additional toxicity observed with the addition of rituximab. Overall, approximately 18% of patients died of non-lymphomatous causes, most commonly infections. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy significantly improves outcomes in patients with mantle cell lymphoma. However, these regimens have significant late toxicity and should be used with caution. This trial has been registered (ISRCTN81133184 and clinicaltrials.gov:00641095) and is supported by the UK National Cancer Research Network.