Laura Clifton-Hadley

Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial

Summary Background Adverse effects on reproductive function are a key concern in young women treated with chemotherapy for advanced Hodgkins lymphoma. We aimed to identify risk factors for the extent of ovarian damage in women with Hodgkins lymphoma treated with different chemotherapy regimens to inform accurate advice on options for fertility preservation. Methods We recruited female participants from the randomised phase 3 RATHL trial, aged 18–45 years, based on availability of participants at recruiting sites in the UK. The RATHL trial key inclusion criteria were histologically confirmed classic Hodgkins lymphoma, stage IIB–IV or IIA with adverse features (bulky disease or more than two sites of involvement), no previous treatments, and a performance status of 0–3. As part of RATHL, participants were treated with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD followed by an interim PET-CT scan. Participants who had negative interim scans (PET score of 1 to 3 according to the Lugano classification) were randomly assigned (1:1) by use of minimisation, stratified by interim PET score and study centre, to continue ABVD or AVD for four more cycles. Participants with positive scans (PET score of 4 or 5) were escalated to treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP-14 or escalated BEACOPP) for four cycles. For the protocol-driven prospective cohort substudy, ovarian function was assessed before treatment, during chemotherapy, and then annually for 3 years by use of serum antimüllerian hormone and follicle-stimulating hormone measurements. The RATHL study is registered with ClinicalTrials.gov, number NCT00678327. Findings Between Dec 13, 2010, and Dec 19, 2012, 67 eligible participants were recruited for this prospective cohort study; 57 had received ABVD or AVD (ABVD-AVD group) and ten BEACOPP-14 or escalated BEACOPP (BEACOPP group). Follow-up was fixed at 3 years. Antimüllerian hormone concentrations decreased during both chemotherapy regimens. At 1 year after chemotherapy, antimüllerian hormone concentrations recovered to a median of 10·5 pmol/L (IQR 4·3–17·3) in the ABVD-AVD group, but little recovery was seen after BEACOPP (median 0·11 pmol/L [0·07–0·20]). Age also affected the extent of ovarian function recovery, with antimüllerian hormone recovery in participants aged 35 years or older in the ABVD-AVD group to 37% (SD 10) of their before treatment concentrations, compared with full recovery to 127% (SD 12) in those younger than 35 years (p<0·0001). Follicle-stimulating hormone recovery to less than 25 IU/L occurred for 95% of women younger than 35 years in the ABVD-AVD group by 2 years and was also dependent on age (hazard ratio 0·49, 95% CI 0·37–0·65; p<0·0001). Interpretation Reduced recovery of ovarian function observed in women older than 35 years treated with ABVD or AVD compared with younger women indicates that treatment could reduce their reproductive lifespan and supports discussion of fertility preservation before treatment. Women treated with BEACOPP should be informed of its potential high gonadotoxicity. These findings warrant further investigation in large, prospective studies with fertility and reproductive lifespan as outcomes. Funding Medical Research Foundation and Cancer Research UK.

Dose specification for hippocampal sparing whole brain radiotherapy (HS WBRT): considerations from the UK HIPPO trial QA programme

OBJECTIVE The HIPPO trial is a UK randomized Phase II trial of hippocampal sparing (HS) vs conventional whole-brain radiotherapy after surgical resection or radiosurgery in patients with favourable prognosis with 1-4 brain metastases. Each participating centre completed a planning benchmark case as part of the dedicated radiotherapy trials quality assurance programme (RTQA), promoting the safe and effective delivery of HS intensity-modulated radiotherapy (IMRT) in a multicentre trial setting. METHODS Submitted planning benchmark cases were reviewed using visualization for radiotherapy software (VODCA) evaluating plan quality and compliance in relation to the HIPPO radiotherapy planning and delivery guidelines. RESULTS Comparison of the planning benchmark data highlighted a plan specified using dose to medium as an outlier by comparison with those specified using dose to water. Further evaluation identified that the reported plan statistics for dose to medium were lower as a result of the dose calculated at regions of PTV inclusive of bony cranium being lower relative to brain. CONCLUSION Specification of dose to water or medium remains a source of potential ambiguity and it is essential that as part of a multicentre trial, consideration is given to reported differences, particularly in the presence of bone. Evaluation of planning benchmark data as part of an RTQA programme has highlighted an important feature of HS IMRT dosimetry dependent on dose being specified to water or medium, informing the development and undertaking of HS IMRT as part of the HIPPO trial. Advances in knowledge: The potential clinical impact of differences between dose to medium and dose to water are demonstrated for the first time, in the setting of HS whole-brain radiotherapy.

Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma

Background Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. Methods and Findings This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. Conclusions Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. Trial Registration ClinicalTrials.gov NCT01310855

LenD: a study to establish the safety and efficacy of lenalidomide and dexamethasone in patients with relapsed or refractory chronic lymphocytic leukemia

Satyen Harish Gohil, Nicola Maciocia, Pip Patrick, Thomas Roberts, Nicholas Counsell, Paul Smith, Laura Clifton-Hadley, Kate Cwynarski, Andrew Pettitt and Amit Chunilal Nathwani Department of Academic Haematology, University College London Cancer Institute, London, UK; Department of Haematology, University College London Hospital, University College Hospital, London, UK; CRUK & UCL Cancer Trials Centre, London, UK; North West Cancer Research Centre, University of Liverpool, Liverpool, UK; National Health Services Blood and Transplant, Watford, Hertfordshire, UK

Whole-body MRI for staging and interim response monitoring in paediatric and adolescent Hodgkin’s lymphoma: a comparison with multi-modality reference standard including 18 F-FDG-PET-CT

ObjectivesTo prospectively investigate concordance between whole-body MRI (WB-MRI) and a composite reference standard for initial staging and interim response evaluation in paediatric and adolescent Hodgkin’s lymphoma.MethodsFifty patients (32 male, age range 6–19 years) underwent WB-MRI and standard investigations, including 18F-FDG-PET-CT at diagnosis and following 2–3 chemotherapy cycles. Two radiologists in consensus interpreted WB-MRI using prespecified definitions of disease positivity. A third radiologist reviewed a subset of staging WB-MRIs (n = 38) separately to test for interobserver agreement. A multidisciplinary team derived a primary reference standard using all available imaging/clinical investigations. Subsequently, a second multidisciplinary panel rereviewed all imaging with long-term follow-up data to derive an enhanced reference standard. Interobserver agreement for WB-MRI reads was tested using kappa statistics. Concordance for correct classification of all disease sites, true positive rate (TPR), false positive rate (FPR) and kappa for staging/response agreement were calculated for WB-MRI.ResultsThere was discordance for full stage in 74% (95% CI 61.9–83.9%) and 44% (32.0–56.6%) of patients against the primary and enhanced reference standards, respectively. Against the enhanced reference standard, the WB-MRI TPR, FPR and kappa were 91%, 1% and 0.93 (0.90–0.96) for nodal disease and 79%, < 1% and 0.86 (0.77–0.95) for extra-nodal disease. WB-MRI response classification was correct in 25/38 evaluable patients (66%), underestimating response in 26% (kappa 0.30, 95% CI 0.04–0.57). There was a good agreement for nodal (kappa 0.78, 95% CI 0.73–0.84) and extra-nodal staging (kappa 0.60, 95% CI 0.41–0.78) between WB-MRI readsConclusionsWB-MRI has reasonable accuracy for nodal and extra-nodal staging but is discordant with standard imaging in a substantial minority of patients, and tends to underestimate disease response.Key Points• This prospective single-centre study showed discordance for full patient staging of 44% between WB-MRI and a multi-modality reference standard in paediatric and adolescent Hodgkin’s lymphoma.• WB-MRI underestimates interim disease response in paediatric and adolescent Hodgkin’s lymphoma.• WB-MRI shows promise in paediatric and adolescent Hodgkin’s lymphoma but currently cannot replace conventional staging pathways including18F-FDG-PET-CT.

High-dose chemotherapy and autologous stem cell transplantation in enteropathy-associated and other aggressive T-cell lymphomas: a UK NCRI/Cancer Research UK Phase II Study

In the original version of this article, the mention of ‘ifosfamide 1500 mg/m2 days 1–3’ should, in fact, read ‘ifosfamide 1500 mg/m2 bd days 1–3’. This has now been updated in the original version of the article.

RNA-Seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

CAN BASELINE PET-CT FEATURES PREDICT OUTCOMES IN ADVANCED HODGKIN LYMPHOMA? A PROSPECTIVE EVALUATION OF UK PATIENTS IN THE RATHL TRIAL (CRUK/07/033)

therapy were eligible. Pts received 2 (cohort 1) or 3 (cohort 2) cycles of weekly BV (1.2 mg/kg days 1, 8, 15 of 28 day cycles); PET‐negative pts proceeded directly to autologous stem cell transplant (ASCT) while PET‐positive pts received augICE before ASCT. Serum cytokines and chemokines (TARC, IL‐6, IL‐10, TNF‐α, IFN‐γ) were measured at baseline and after BV. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured at baseline, after BV and after augICE. Results: 65 pts enrolled (45 cohort 1, 20 cohort 2), including 34 (52%) females, 29 (45%) with advanced stage disease, 34 (52%) with refractory disease (lack of CR after front‐line therapy), 10 (15%) with B symptoms, 24 (37%) with extranodal disease, and 16 (25%) with bulk (any mass > 5 cm). Overall, 18 of 65 (28%) pts achieved complete response (defined as Deauville ≤2) following BV. 19 pts (18 with Deauville 2 response and 1 with Deauville 3 response after BV) proceeded directly to ASCT. Among the other 46 pts, 1 was lost to follow‐up; 45 received augICE chemotherapy of which 31 (69%) achieved CR. Overall, 49 (75%) of 65 pts achieved complete response and 64 pts proceeded to ASCT. 3‐year overall survival and EFS were 95% and 82%. Factors predictive for EFS by univariate analysis included age over 45 years (p = 0.016), refractory disease (p = 0.033), B‐symptoms (p = 0.032), advanced stage at relapse (p = 0.011), as well as baseline MTV, TARC, and TLG (all p < 0.001). Factors that remained prognostic by multivariate analysis were MTV (p < 0.001, HR 54, 95% CI 9‐319) and refractory disease (p = 0.001, HR 82, 95% CI 6.1‐1107). The optimal cut‐off for baseline MTV, determined by a grid search of log‐rank test p values, was 109.5 cm. Using this cutoff, the 3‐year EFS for pts with low (n = 48) and high (n = 12) MTV was 92% and 27% respectively (p < 0.001) (Figure). Conclusion: In this phase II study of PET‐adapted ST with BV and augICE for rel/ref HL, baseline MTV and refractory disease were independent prognostic factors for EFS. Additional studies are needed to confirm the prognostic significance and optimal cutoff for MTV in rel/ref disease. Future studies should optimize efficacy and tolerability of ST by stratifying pts according to risk factors such as baseline MTV.

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

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

OUTCOMES OF TREATMENT FOR OBESE PATIENTS WITH ADVANCED HODGKIN LYMPHOMA IN THE RATHL TRIAL (CRUK/07/033)

HL, and the other had residual FDG‐uptake in a location not amenable to biopsy. Both patients received ISRT. The 25 patients who completed combined modality therapy (CMT) have achieved CRs. To date, the duration of remission ranges from 2 to 13 months, and no relapses have occurred. The efficacy is similar across cohorts 1 and 2 with interim PET negative rates of ≥90%, and all patients who completed CMT have achieved a CR (Figure 1). In cohort 1, 2 patients had biopsy‐proven primary refractory HL after 4 cycles of chemotherapy, and in cohort 2, there have been no treatment failures. Conclusion: BV + AVD x 4 cycles followed by 20 Gy ISRT has promising preliminary efficacy for the treatment of early stage, unfavorable risk HL, including a high proportion of patients with bulky disease. As with 4 cycles of escalated BEACOPP tested in the GHSG HD11 clinical trial, 20 Gy ISRT may be adequate consolidation after BV + AVD x 4 cycles. We recommend that BV + AVD x 4 + 20 Gy ISRT is studied in a larger, randomized prospective study for early stage, bulky HL. Updated response data for all patients will be presented at the meeting.