Search

Background: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). Methods: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18–60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1–3, 100 mg/m2 oral procarbazine on days 1–7, 40 mg/m2 oral prednisone on days 1–14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. Findings: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7–61·2), 5-year progression-free survival was 97·3% (95% CI 94·5–98·7) in the standard combined-modality treatment group and 95·1% (92·0–97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226–1·211]). The between-group difference was 2·2% (95% CI −0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. Interpretation: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. Funding: Deutsche Krebshilfe.

BACKGROUND: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. METHODS: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). FINDINGS: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. INTERPRETATION: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. FUNDING: Karyopharm Therapeutics Inc.

Background: Relapsed or refractory diffuse large B‑cell lymphoma (RR DLBCL) is an aggressive cancer with a median survival of less than 6 months. The SADAL trial aims to assess the response to the oral selective inhibitor of nuclear export (SINE) selinexor in patients with RR DLBCL who have no therapeutic options of demonstrated clinical benefit. Methods: SADAL was a multicenter, open-label Phase 2b study conducted at 59 sites globally. Patients 18 years with previously treated, pathologically confirmed de novo DLBCL, or DLBCL transformed from previously diagnosed indolent lymphoma, and having received at least two prior therapies were enrolled. Germinal center B-cell (GCB) or non-GCB tumor subtype and double/triple expressor status were determined by immunohistochemistry and double/triple hit status was determined by cytogenetic assays. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The primary outcome was overall response rate (ORR) by central radiologic review. A modified intent-to-treat population was used for all efficacy endpoints. Findings: 127 patients were enrolled from October 21, 2015 through November 2, 2019. The ORR was 28.3% (95% CI: 20.7%, 37.0%), including complete response in 15 (11.8%) and partial response in 21 (16.5%) patients. Median overall survival (OS) was 9.1 months (95% CI: 6.6, 15.1) with longer OS observed in responding patients. Responses were observed across different subgroups regardless of age, gender, prior therapy, DLBCL subtype, refractory status or prior ASCT therapy. Adverse events were generally reversible and managed with dose modifications and/or standard supportive care. Interpretation: In both GCB- and non-GCB DLBCL subtypes, single agent oral selinexor induced durable responses which were associated with longer survival. Selinexor may be a new oral, non-cytotoxic treatment option for patients with RR DLBCL after two lines of chemo-immunotherapy. Trial Registration: This trial is registered at ClinicalTrials.gov, NCT02227251. Funding Statement: This study (NCT02227251) was funded by Karyopharm Therapeutics Inc, Newton, Massachusetts, USA, which provided all study materials. Declaration of Interests: NK reports research support from Verastem, Gilead, Celgene, and Roche, as well as honoraria from Gilead, Janssen, and Karyopharm. FC reports personal fees from Takeda, Gilead, and Janssen, outside the submitted work. MC reports personal fees from Celgene, Gilead, Janssen, Karyopharm, Novartis, Roche, Sandoz, and Servier outside the submitted work. GF reports personal fees from Karyopharm and Roche, outside the submitted work. AG reports personal fees and honoraria from AstraZeneca, personal fees and board membership from Cota and Kite/Gilead, personal fees from Janssen, Celgene, Acerta, and research funding from Constellation, Bayer, CALBG, Genentech, Hoffman-La Roche, MD Anderson, Morphosys, Pharmacyclics, and the University of Nebraska, outside the submitted work. OC reports grants, personal fees, and non-financial support from Roche, personal fees and non-financial support from Takeda, BMS, Amgen, Janssen, Abbvie, grants and personal fees from Gilead, and personal fees from Merck, outside the submitted work. BH reports grants and personal fees from Karyopharm, outside the submitted work. UJ reports personal fees from Karyopharm, during the conduct of the study; grants and personal fees from AbbVie, Celgene, Gilead, Janssen, Novartis, Roche, Takeda, Amgen, Miltenyi, and BMS, outside the submitted work. JMS reports honoraria from Roche, Janssen, Gilead, Celgene, Novartis outside the submitted work. MS reports personal fees from Karyopharm during the conduct of the study, and personal fees from Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Genentech, and Seattle Genetics, outside the submitted work. TPV reports honoraria from WinMedica, Astellas, and Gilead, honoraria, advisory board membership and research support from Takeda, honoraria and advisory board membership from Roche, Bristol, Genesis, and Novartis, advisory board membership at Janssen, honoraria and research support from Merck and Amgen, and research support from Pfizer and Karyopharm. AJ reports personal fees from Karyopharm Therapeutics during the conduct of the study. YL reports personal fees from Karyopharm Therapeutics, outside the submitted work. HC, YL, XM, KC, DM, HW, JS, JRS, SS, and MK are employees of Karyopharm. AJ is a consultant for Karyopharm. MK and SS are stockholders of Karyopharm. SS holds patents (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents (PCT/US12/048319, 499/2012, PI20102724, and 2012000928) on hydrazide-containing nuclear transport modulators and uses. All other authors declare no competing interests. Ethics Approval Statement: The institutional review board or independent ethics committee at each study center approved the protocol, and the study was performed in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.

Background: Efficacy of rituximab in Primary Central Nervous System Lymphoma (PCNSL) is unknown: low penetration of the large rituximab molecule through the blood brain barrier may limit its effect. We aimed to establish the value of rituximab in PCNSL. Methods: This international, multicentre, open-label, randomised phase III study was performed at 24 sites in The Netherlands, Australia and New Zealand. Non-immunocompromised patients aged 18-70 years with newly-diagnosed PCNSL were randomly assigned to 2 cycles of Methotrexate-BCNU-teniposide-prednisone (MBVP) chemotherapy with or without rituximab using an online randomisation tool employing minimisation by centre, age (60 vs 61 years) and PS group (0-1 vs. 2-3). Patients subsequently received high dose cytarabine and, in those ≤60 years, low-dose whole brain radiotherapy (WBRT). Primary endpoint was 1-year event free survival (EFS1y) adjusted for age and PS on analysis by intention to treat. Secondary endpoints were response rates, progression-free and overall survival. The trial was registered in The Netherlands National Trial Register, NTR 2427, and the Australian New Zealand Clinical Trials Registry, ACTRN12610000908033. It was closed on May 27, 2016, after achieving complete accrual; follow-up is on-going. Findings: between August 2010 and June 2016, 200 patients were enrolled; 55% were men; median age was 61 years (range 26-70). EFS1y was 49% without and 52% with rituximab; HR 1.00, 95% CI 0.70-1.43, p=0.99. CR/CRu rate was 66% for MBVP and 68% for R-MBVP. Overall response rate was 87% in both arms. An unplanned subgroup analysis suggested a potential benefit for rituximab in patients

BACKGROUND: The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy.METHODS: In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041.FINDINGS: Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy.INTERPRETATION: Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting.FUNDING: Deutsche Krebshilfe and the Swiss Federal Government.

BACKGROUND. Recent genome-wide association studies have identified at least 20 germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer incidence. Common genetic variation is likely also related to survival after colorectal cancer diagnosis; however, the genome-wide analysis approach has not been widely applied to the study of colorectal cancer survival. METHODS. Full genome scans, and imputation to HapMap, were conducted for 2,822 men and women with invasive colorectal cancer who were enrolled in one of six studies: the Health Professionals Follow-up Study (N=173), the Nurses' Health Study (N=298), the Physicians' Health Study (N=325), the Vitamins and Lifestyle Study (N=285), the Postmenopausal Hormones Study (N=280), and the Women's Health Initiative (N=1,461). We used Cox proportional hazards regression to assess SNPspecific associations with disease-specific survival and overall survival in models adjusted for age, sex, and principal components. SNPs were modeled additively to reflect associations per copy of the minor allele. Results were combined across studies via fixed-effects metaanalysis. To account for multiple-testing, a p-value threshold of p,1x10-8 was required for genome-wide significance. RESULTS. No common SNPs (i.e., minor allele frequency ≥5%) were significantly associated with survival outcomes, including previously identified colorectal cancer susceptibility SNPs. Two SNPs of low minor allele frequency were associated with disease-specific survival at a level exceeding or approaching genome-wide significance: the minor allele in one SNP near APC2, with a frequency of 1%, was associated with significantly poorer survival (p=1.2x10-9), and the minor allele in another SNP near PRIM2, present in 3% of cases, attained borderline significance in relation to poorer survival (p= 2.0x10-8). Two other SNPs, one near MAML2 and one near ZNF804B, exhibited adverse associations of borderline significance with both overall survival (p=8.4x10-7 and 6.7x107, respectively) and disease-specific survival (p=1.1x10-7 and 5.0x10-7); both of these SNPs also had low minor allele frequencies (1% and 2%, respectively). CONCLUSIONS. Common genetic variation, particularly with respect to polymorphisms present in ≥5% of the population, does not appear to be significantly associated with colorectal cancer survival. There is still, however, some indication that germline genetic variation is related to colorectal cancer survival outcomes. Our findings for SNPs with lowminor allele frequencies provide suggestive evidence of adverse survival outcomes in those with specific, less common polymorphisms. In light of the low frequency of the minor alleles in these SNPs, false-positive results are possible; thus, further follow-up is needed.