Kirit M. Ardeshna

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.

Central nervous system chemoprophylaxis in non-Hodgkin lymphoma: current practice in the UK

Central nervous system (CNS) involvement in non‐Hodgkin lymphoma (NHL) is a well‐recognised complication. There is no consensus regarding indications for prophylaxis or a standard CNS chemoprophylaxis regimen. Current UK practice was evaluated using a questionnaire. A total of 223 questionnaires were sent to clinicians who administered chemotherapy to patients with NHL; 158 (71%) evaluable questionnaires were returned. The overwhelming majority of respondents used prophylaxis in all cases of lymphoblastic lymphoma (97%) and Burkitt lymphoma (96%). Ninety‐six per cent of respondents required risk factors to be present before prophylaxis was initiated in cases of diffuse large B‐cell lymphoma. The commonest risk factor was site of involvement (paranasal sinus 88%, testicular 85%, orbital cavity 78%, bone marrow 65% and bone 28%). Other risk factors included stage IV, high International Prognostic Index score, >1 extranodal site and raised lactate dehydrogenase levels (34%, 21%, 16% and 10%). A total of 82% did not give prophylaxis in follicular lymphoma and 90% used intrathecal chemotherapy as their preferred method of prophylaxis. The most popular regimen was 12·5 mg methotrexate with each cycle of chemotherapy for six courses. Thirty‐nine per cent used systemic chemotherapy for CNS prophylaxis either alone (4%) or as an adjunct to intrathecal prophylaxis (35%). These variations in the indications and methods of prophylaxis indicate that this subject deserves further review.

Conventional second-line salvage chemotherapy regimens are not warranted in patients with malignant lymphomas who have progressive disease after first-line salvage therapy regimens

This study aimed to determine the outcome of patients with relapsed or refractory lymphoma who have an inadequate response to first‐line salvage therapy (1°ST) and who subsequently receive a second‐line salvage regimen (2°ST) with the intention of ultimately proceeding to high‐dose therapy. The outcome of 57 patients [Hodgkins Lymphoma 17, histologically‐aggressive non‐Hodgkins Lymphoma (NHL) 26, histologically‐indolent NHL 14] who received more than one modality of conventional‐dose salvage therapy was analysed. Sixteen patients had a partial response (PR) to 1°ST, but subsequently received 2°ST because the PR was judged to be inadequate (iPR) because of persisting disease bulk or marrow infiltration. Of these 16 patients, 10 (63%) continued to respond to 2°ST. Of the 15 patients who had stable disease following 1°ST, 5 (33%) responded to 2°ST. Only one of the 24 (4%) with progressive disease (PD) following 1°ST, responded to 2°ST. 25 of the 57 patients ultimately underwent stem cell transplantation. The 2‐year progression‐free survival (PFS) and the 3‐year overall survival (OS) for all patients was 24% and 31%, respectively. Long‐term survival was highly dependent on response to 1°ST (P = 0·0001); in patients with PD following 1°ST, the PFS and OS at 3 years was only 4%. This analysis indicates that patients with malignant lymphomas, who have PD on 1°ST, are not rescued by subsequent salvage regimens. They should either be treated palliatively or novel approaches should be explored.

Monocyte-derived dendritic cells do not proliferate and are not susceptible to retroviral transduction

Dendritic cells may be generated ex vivo from CD34+ progenitor cells or peripheral blood mononuclear cells. Initial reports suggested that monocyte‐derived dendritic cells (MoDCs) arise from a proliferating precursor and several groups subsequently reported successful retroviral transduction of these cells, again implying that cell division occurs. As this is of importance in the development of immunotherapy protocols, we investigated whether monocytes proliferate as they differentiate into MoDCs and also their susceptibility to retroviral transduction. During MoDC differentiation, there was a 51 ± 12% reduction in cell number, 98% of cells were in G0/G1, no DNA synthesis was detectable and the cell cycle regulatory proteins pRb and p130 were in the hypophosphorylated forms observed in non‐cycling cells. As expected from these results, MoDCs were refractory to transduction with a GALV1 pseudotyped Moloney murine leukaemia virus (MoMLV)‐based retroviral vector. In contrast, generation of DCs from purified CD34 progenitors was accompanied by rapid entry into the cell cycle and a 41.1‐fold cell expansion at the end of 14 d culture.

Use of Zidovudine and Interferon Alfa With Chemotherapy Improves Survival in Both Acute and Lymphoma Subtypes of Adult T-Cell Leukemia/Lymphoma

PURPOSE Adult T-cell leukemia/lymphoma (ATLL) is a mature (post-thymic) T-cell lymphoma associated with human T-lymphotropic virus type 1 infection. Survival in aggressive subtypes remains poor, and treatment resistance is frequent. Use of zidovudine (ZDV) and interferon alfa (IFN-α) has been associated with improved response rates in small studies and prolonged overall survival in leukemic ATLL subtypes in a recent meta-analysis. PATIENTS AND METHODS We report the clinicopathologic characteristics, treatment, and outcome of 73 patients with aggressive ATLL (acute ATLL, 29; lymphoma ATLL, 44) diagnosed and treated in England between 1999 and 2009. The impact of ZDV/IFN-α on treatment response and survival was assessed. RESULTS The overall response rate ranged from 49% with chemotherapy alone to 81% with combined first-line therapy (chemotherapy with concurrent/sequential ZDV/IFN-α). Median overall survival (OS) was 9 months: 7.5 months for acute ATLL and 10 months for lymphoma ATLL. Use of ZDV/IFN-α at any time prolonged survival in acute (P < .001) and lymphoma ATLL (P < .001) and was the sole factor associated with reduction in risk of death in aggressive ATLL (hazard ratio, 0.23; 95% CI, 0.09 to 0.60; P = .002). Combined first-line therapy prolonged median OS in acute (P = .0081) and lymphoma ATLL (P = .001) compared with chemotherapy alone. CONCLUSION These data support the use of low-dose ZDV/IFN-α with chemotherapy in first-line treatment of acute and lymphoma ATLL.

Rituximab in combination with CODOX-M/IVAC: a retrospective analysis of 23 cases of non-HIV related B-cell non-Hodgkin lymphoma with proliferation index >95%

The safety and efficacy of rituximab with CODOX‐M/IVAC (cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine) was retrospectively analysed in 23 patients with non‐human immunodeficiency virus‐related B‐cell non‐Hodgkin lymphoma with proliferation index >95% [14 with classical Burkitt lymphoma (BL), five with B‐cell lymphoma unclassifiable, with features intermediate between diffuse large B cell lymphoma (DLBCL) and BL, and four with DLBCL]. Six (26%) low‐risk (LR) patients received three cycles of CODOX‐M and 17 (74%) high‐risk (HR) cases were assigned to four cycles of alternating CODOX‐M/IVAC. Rituximab 375 mg/m2 was infused on days 1 and 10 of each cycle. Toxicity was comparable to that reported with CODOX‐M/IVAC, with no treatment‐related death. Two patients developed grade 3 rituximab‐induced delayed neutropenia, with no adverse outcome. After completing treatment, 83% LR patients and 71% HR patients achieved CR by positron emission tomography–computerized tomography (PET–CT). Three (13%) patients received salvage treatment. At a median follow‐up of 34 months (range = 18–75), 19 (83%) patients (100% LR and 74% HR) were alive, including one case undergoing salvage for late relapse. Four HR patients (17%) had died, three from primary progressive disease and one from treatment‐refractory relapse 2 months after achieving CR. These results with R‐CODOX‐M/R‐IVAC compare favourably with existing data using CODOX‐M/IVAC and warrant further prospective studies. The potential pitfalls of PET–CT to assess response are highlighted.

Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The ORCHARRD Study

Purpose We compared the efficacy of ofatumumab (O) versus rituximab (R) in combination with cisplatin, cytarabine, and dexamethasone (DHAP) salvage treatment, followed by autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients with CD20+ DLBCL age ≥ 18 years who had experienced their first relapse or who were refractory to first-line R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like treatment were randomly assigned between three cycles of R-DHAP or O-DHAP. Either O 1,000 mg or R 375 mg/m2 was administered for a total of four infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 and 3 of DHAP). Patients who experienced a response after two cycles of treatment received the third cycle, followed by high-dose therapy and ASCT. Primary end point was progression-free survival (PFS), with failure to achieve a response after cycle 2 included as an event. Results Between March 2010 and December 2013, 447 patients were randomly assigned. Median age was 57 years (range, 18 to 83 years); 17% were age ≥ 65 years; 63% had stage III and IV disease; 71% did not achieve complete response (CR) or experience response for < 1 year on first-line R-CHOP. Response rate for O-DHAP was 38% (CR, 15%) versus 42% (CR, 22%) for R-DHAP. ASCT on protocol was completed by 74 patients (33%) in the O arm and 83 patients (37%) in the R arm. PFS, event-free survival, and overall survival were not significantly different between O-DHAP versus R-DHAP: PFS at 2 years was 24% versus 26% (hazard ratio [HR], 1.12; 95% CI, 0.89 to 1.42; P = .33); event-free survival at 2 years was 16% versus 18% (HR, 1.10; P = .35); and overall survival at 2 years was 41% versus 38% (HR, 0.90; P = .38). Positron emission tomography negativity before ASCT was highly predictive for superior outcome. Conclusion No difference in efficacy was found between O-DHAP and R-DHAP as salvage treatment of relapsed or refractory DLBCL.

The upregulation of CC chemokine receptor 7 and the increased migration of maturing dendritic cells to macrophage inflammatory protein 3β and secondary lymphoid chemokine is mediated by the p38 stress‐activated protein kinase pathway

Summary. Using the p38 stress‐activated protein kinase (p38SAPK) inhibitor, SB203580, increased responsiveness of monocyte‐derived dendritic cells (MoDCs) to secondary lymphoid chemokine (SLC) and macrophage inflammatory protein 3β (MIP3β), following lipopolysaccharide‐induced MoDC maturation, was shown to be mediated by the p38SAPK pathway. This was due to the complete abrogation of upregulation of CC chemokine receptor 7, the receptor for MIP3β/SLC. Once mature, MoDCs utilized both the p38SAPK and phosphoinositide‐3 kinase pathways to migrate in response to SLC or MIP3β. These findings have implications for the mechanism of action of p38SAPK inhibitors, currently in use in clinical trials for patients with autoimmune diseases.

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

Elevated lactate dehydrogenase levels detected during routine follow-up do not predict relapse in patients with diffuse large B-cell lymphoma who achieve complete remission after primary treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone-like immunochemotherapy.

Abstract A significant minority of patients with diffuse large B-cell lymphoma (DLBCL) who enter a complete remission following standard first-line immunochemotherapy will relapse. A primary aim of follow-up is to detect early relapse, with the hope of improving outcome following salvage chemotherapy. It is often routine to measure lactate dehydrogenase (LDH) as part of follow-up; however, the evidence for the utility of LDH as a predictor for relapse is scant. A retrospective analysis of the LDH results recorded during the follow-up of 102 patients with DLBCL who achieved a CR following treatment was undertaken in order to determine the utility of LDH as a predictor for relapse (median follow-up 24 months). Despite the fact that the sensitivity of LDH was 69% (95% confidence interval [CI] 39–91), the positive predictive value (PPV) of a raised LDH was only 9/63, 14% (95% CI 6.7–25). Furthermore, in eight of the nine patients who had a raised LDH prior to relapse, symptoms suggestive of relapse were documented simultaneously. As the PPV of a raised LDH is so low and because a raised LDH may cause unnecessary worry, leading to unnecessary radiological investigations, routine evaluation of LDH in patients with DLBCL who achieve CR and who are asymptomatic is not recommended.