Combining brentuximab vedotin with dexamethasone, high-dose cytarabine and cisplatin as salvage treatment in relapsed or refractory Hodgkin lymphoma: the phase II HOVON/LLPC Transplant BRaVE study.

Achieving a metabolic complete response (mCR) before high-dose chemotherapy (HDC) and autologous peripheral blood stem-cell transplant (auto-PBSCT) predicts progression free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL). We added brentuximab vedotin (BV) to DHAP to improve the mCR rate. In a Phase I dose-escalation part in 12 patients, we showed that BV-DHAP is feasible. This Phase II study included 55 R/R cHL patients (23 primary refractory). Treatment consisted of three 21-day cycles of BV 1.8 mg/kg on day 1, and DHAP (dexamethasone 40mg days 1-4, cisplatin 100mg/m2; day 1 and cytarabine 2x2g/m2; day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central FDG-PET-CT review, 42 of 52 evaluable patients (81% [95% CI: 67-90]) achieved an mCR before HDC/auto-PBSCT, five had an mPR and five had progressive disease (three were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. The 2-year PFS was 74% [95% CI: 63-86], and the overall survival 95% [95% CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematological toxicity, fever, nephrotoxicity, ototoxicity (grade 1/2) and transiently elevated liver enzymes during BV-DHAP. Eighteen patients developed new onset peripheral neuropathy (maximum grade 1/2) and all recovered. In conclusion, BV-DHAP is a very effective salvage regimen in R/R cHL patients, but patients should be monitored closely for toxicity. ClinicalTrials.gov identifier: NCT02280993.

Prognostic relevance of CD163 and CD8 combined with EZH2 and gain of chromosome 18 in follicular lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium.

In follicular lymphoma, studies addressing the prognostic value of microenvironment-related immunohistochemical markers and tumor cell-related genetic markers have yielded conflicting results, precluding implementation in practice. Therefore, the Lunenburg Lymphoma Biomarker Consortium performed a validation study evaluating published markers. To maximize sensitivity, an end of spectrum design was applied for 122 uniformly immunochemotherapy-treated follicular lymphoma patients retrieved from international trials and registries. The criteria were: early failure, progression or lymphoma-related death <2 years versus long remission, response duration of >5 years. Immunohistochemical staining for T cells and macrophages was performed on tissue microarrays from initial biopsies and scored with a validated computer-assisted protocol. Shallow whole-genome and deep targeted sequencing was performed on the same samples. The 96/122 cases with complete molecular and immunohistochemical data were included in the analysis. EZH2 wild-type (P=0.006), gain of chromosome 18 (P=0.002), low percentages of CD8+ cells (P=0.011) and CD163+ areas (P=0.038) were associated with early failure. No significant differences in other markers were observed, thereby refuting previous claims of their prognostic significance. Using an optimized study design, this Lunenburg Lymphoma Biomarker Consortium study substantiates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of early failure to immunochemotherapy in follicular lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP [-like]), while refuting the prognostic impact of various other markers.

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). METHODS: In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. FINDINGS: Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. INTERPRETATION: Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. FUNDING: Genentech.

Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study.

New treatments are required for rituximab-refractory follicular lymphoma (FL). In the present study, patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 mAb; dose 1, 300 mg and doses 2-8, 500 or 1000 mg; N = 116). The median age of these patients was 61 years, 47% had high-risk Follicular Lymphoma International Prognostic Index scores, 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. The median progression-free survival was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation, and the median progression-free survival for these patients was 9.1 months. The most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions, none of which were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is therefore now being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. The present study was registered at www.clinicaltrials.gov as NCT00394836.

The reliability of immunohistochemical analysis of the tumor microenvironment in follicular lymphoma: a validation study from the Lunenburg Lymphoma Biomarker Consortium.

The cellular microenvironment in follicular lymphoma is of biological and clinical importance. Studies on the clinical significance of non-malignant cell populations have generated conflicting results, which may partly be influenced by poor reproducibility in immunohistochemical marker quantification. In this study, the reproducibility of manual scoring and automated microscopy based on a tissue microarray of 25 follicular lymphomas as compared to flow cytometry is evaluated. The agreement between manual scoring and flow cytometry was moderate for CD3, low for CD4, and moderate to high for CD8, with some laboratories scoring closer to the flow cytometry results. Agreement in manual quantification across the 7 laboratories was low to moderate for CD3, CD4, CD8 and FOXP3 frequencies, moderate for CD21, low for MIB1 and CD68, and high for CD10. Manual scoring of the architectural distribution resulted in moderate agreement for CD3, CD4 and CD8, and low agreement for FOXP3 and CD68. Comparing manual scoring to automated microscopy demonstrated that manual scoring increased the variability in the low and high frequency interval with some laboratories showing a better agreement with automated scores. Manual scoring reliably identified rare architectural patterns of T-cell infiltrates. Automated microscopy analyses for T-cell markers by two different instruments were highly reproducible and provided acceptable agreement with flow cytometry. These validation results provide explanations for the heterogeneous findings on the prognostic value of the microenvironment in follicular lymphoma. We recommend a more objective measurement, such as computer-assisted scoring, in future studies of the prognostic impact of microenvironment in follicular lymphoma patients.

Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium.

The Lunenburg Lymphoma Biomarker Consortium (LLBC) evaluated the prognostic value of IHC biomarkers in a large series of patients with diffuse large B-cell lymphoma (DLBCL). Clinical data and tumor samples were retrieved from 12 studies from Europe and North America, with patients treated before or after the rituximab era. Using tissue microarrays from 1514 patients, IHC for BCL2, BCL6, CD5, CD10, MUM1, Ki67, and HLA-DR was performed and scored according to previously validated protocols. Optimal cut points predicting overall survival of patients treated in the rituximab era could only be determined for CD5 (P = .003) and Ki67 (P = .02), whereas such cut points for BCL2, BCL6, HLA-DR, and MUM1 could only be defined in patients not receiving rituximab. A prognostic model for patients treated in the rituximab era identified 4 risk groups using BCL2, Ki67, and International Prognostic Index (IPI) with improved discrimination of low-risk patients. Newly recognized correlations between specific biomarkers and IPI highlight the importance of carefully controlling for clinical and biologic factors in prognostic models. These data demonstrate that the IPI remains the best available index in patients with DLBCL treated with rituximab and chemotherapy.

Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial.

BACKGROUND: Patients with follicular lymphoma can have long survival times, but disease progression typically occurs 3-5 years after initial treatment. We assessed the potential benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma receiving a rituximab plus chemotherapy regimen. METHODS: The randomised, open-label PRIMA study was undertaken in 223 centres in 25 countries. 1217 patients with previously untreated follicular lymphoma needing systemic therapy received one of three non-randomised immunochemotherapy induction regimens used in routine practice. 1019 patients achieving a complete or partial response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m(2) every 8 weeks) or observation. Treatment was assigned equally by centralised block randomisation, stratified by induction regimen, response, region, and centre. Neither the participants nor those giving the interventions, assessing outcomes, and analysing data were masked to group assignments. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00140582. FINDINGS: 505 patients were assigned to rituximab maintenance and 513 to observation (one patient died during randomisation). With a median follow-up of 36 months (IQR 30-42), PFS was 74·9% (95% CI 70·9-78·9) in the rituximab maintenance group (130 patients progressed) and 57·6% (53·2-62·0) in the observation group (218 progressed; hazard ratio [HR] 0·55, 95% CI 0·44-0·68, p<0·0001). 2 years after randomisation, 361 patients (71·5%) in the rituximab maintenance group were in complete or unconfirmed complete response versus 268 (52·2%) in the observation group (p=0·0001). Overall survival did not differ significantly between groups (HR 0·87, 95% CI 0·51-1·47). Grade 3 and 4 adverse events were recorded in 121 patients (24%) in the rituximab maintenance group and 84 (17%) in the observation group (risk ratio 1·46, 95% CI 1·14-1·87; p=0·0026). Infections (grades 2-4) were the most common adverse event, occurring in 197 (39%) and 123 (24%) patients, respectively (risk ratio 1·62, 95% CI 1·35-1·96; p<0·0001). INTERPRETATION: 2 years of rituximab maintenance therapy after immunochemotherapy as first-line treatment for follicular lymphoma significantly improves PFS. FUNDING: Groupe d'Etude des Lymphomes de l'Adulte (GELA) and F Hoffmann-La Roche.

Outcomes of older patients with follicular lymphoma using individual data from 5922 patients in 18 randomized controlled trials.

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin <12 g/dL, ECOG PS ≥2, and elevated ß2-microglobulin. Median follow-up was 5.6 years. Patients >70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.

In-depth cell-free DNA sequencing reveals genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive residual disease detection.

BACKGROUND: Individualization of treatment in Hodgkin's lymphoma is necessary to improve cure rates and reduce treatment side effects. Currently, it is hindered by a lack of genomic characterization and sensitive molecular response assessment. Sequencing of cell-free DNA is a powerful strategy to understand the cancer genome and can be used for extremely sensitive disease monitoring. In Hodgkin's lymphoma, a high proportion of cell-free DNA is tumor-derived, whereas traditional tumor biopsies only contain a little tumor-derived DNA. METHODS: We comprehensively genotype and assess minimal residual disease in 121 patients with baseline plasma as well as 77 follow-up samples from a subset of patients with our targeted cell-free DNA sequencing platform. FINDINGS: We present an integrated landscape of mutations and copy number variations in Hodgkin's lymphoma. In addition, we perform a deep analysis of mutational processes driving Hodgkin's lymphoma, investigate the clonal structure of Hodgkin's lymphoma, and link several genotypes to Hodgkin's lymphoma phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cell-free DNA sequencing, as early as a week after treatment initiation, predicts treatment response and progression-free survival, allowing highly improved treatment guidance and relapse prediction. CONCLUSIONS: Our targeted cell-free DNA sequencing platform reveals the genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive detection of minimal residual disease. FUNDING: Mildred Scheel School of Oncology Aachen-Bonn-Cologne-Düsseldorf MD Research Stipend, Next Generation Sequencing Competence Network grant 423957469, Deutsche Krebshilfe grant 70112502, Deutsche Forschungsgemeinschaft (DFG) grant EN 179/13-1, the HL MRD consortium, and the Frau-Weiskam und Christel Ruranski-Stiftung.

Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease.

BACKGROUND: Treatment of early-stage Hodgkin's disease is usually tailored in line with prognostic factors that allow for reductions in the amount of chemotherapy and extent of radiotherapy required for a possible cure. METHODS: From 1993 to 1999, we identified 1538 patients (age, 15 to 70 years) who had untreated stage I or II supradiaphragmatic Hodgkin's disease with favorable prognostic features (the H8-F trial) or unfavorable features (the H8-U trial). In the H8-F trial, we compared three cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) combined with doxorubicin, bleomycin, and vinblastine (ABV) plus involved-field radiotherapy with subtotal nodal radiotherapy alone (reference group). In the H8-U trial, we compared three regimens: six cycles of MOPP-ABV plus involved-field radiotherapy (reference group), four cycles of MOPP-ABV plus involved-field radiotherapy, and four cycles of MOPP-ABV plus subtotal nodal radiotherapy. RESULTS: The median follow-up was 92 months. In the H8-F trial, the estimated 5-year event-free survival rate was significantly higher after three cycles of MOPP-ABV plus involved-field radiotherapy than after subtotal nodal radiotherapy alone (98% vs. 74%, P<0.001). The 10-year overall survival estimates were 97% and 92%, respectively (P=0.001). In the H8-U trial, the estimated 5-year event-free survival rates were similar in the three treatment groups: 84% after six cycles of MOPP-ABV plus involved-field radiotherapy, 88% after four cycles of MOPP-ABV plus involved-field radiotherapy, and 87% after four cycles of MOPP-ABV plus subtotal nodal radiotherapy. The 10-year overall survival estimates were 88%, 85%, and 84%, respectively. CONCLUSIONS: Chemotherapy plus involved-field radiotherapy should be the standard treatment for Hodgkin's disease with favorable prognostic features. In patients with unfavorable features, four courses of chemotherapy plus involved-field radiotherapy should be the standard treatment. (ClinicalTrials.gov number, NCT00379041 [ClinicalTrials.gov].).

First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial.

Ofatumumab is a unique monoclonal antibody that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic leukemia cells with low CD20-antigen density and high expression of complement inhibitory molecules. In a phase 1/2 trial evaluating safety and efficacy of ofatumumab in relapsed or refractory follicular non-Hodgkin lymphoma (FL) grade 1 or 2, 4 dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg. Patients had a median of 2 prior FL therapies and 13% had elevated lactate dehydrogenase. No safety concerns or maximum tolerated dose was identified. A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median time to progression for all patients/responders was 8.8/32.6 months, and median duration of response was 29.9 months at a median/maximum follow-up of 9.2/38.6 months. Ofatumumab is currently being evaluated in patients with rituximab-refractory FL. This trial was registered at www.clinicaltrials.gov as #NCT00092274.

HuMab-7D8, a monoclonal antibody directed against the membrane-proximal small loop epitope of CD20 can effectively eliminate CD20 low expressing tumor cells that resist rituximab-mediated lysis.

BACKGROUND: Incorporation of the chimeric CD20 monoclonal antibody rituximab in the treatment schedule of patients with non-Hodgkin's lymphoma has significantly improved outcome. Despite this success, about half of the patients do not respond to treatment or suffer from a relapse and additional therapy is required. A low CD20-expression level may in part be responsible for resistance against rituximab. We therefore investigated whether the CD20-expression level related resistance to rituximab could be overcome by a new group of CD20 mAbs (HuMab-7D8 and ofatumumab) targeting a unique membrane-proximal epitope on the CD20 molecule. DESIGN AND METHODS: By retroviral transduction of the CD20 gene into CD20-negative cells and clonal selection of transduced cells a system was developed in which the CD20-expression level is the only variable. These CD20 transduced cells were used to study the impact of rituximab and HuMab-7D8 mediated complement-dependent cytotoxicity. To study the in vivo efficacy of these mAbs an in vivo imaging system was generated by retroviral expression of the luciferase gene in the CD20-positive cells. RESULTS: We show that HuMab-7D8 efficiently killed CD20(low) cells that are not susceptible to rituximab-induced killing in vitro. In a mouse xenograft model, we observed a comparable increase in survival time between HuMab-7D8 and rituximab-treated mice. Most significantly, however, HuMab-7D8 eradicated all CD20-expressing cells both in the periphery as well as in the bone marrow whereas after rituximab treatment CD20(low) cells survived. CONCLUSIONS: Cells that are insensitive to in vitro and in vivo killing by rituximab as the result of their low CD20-expression profile may be efficiently killed by an antibody against the membrane-proximal epitope on CD20. Such antibodies should, therefore, be explored to overcome rituximab resistance in the clinic.

Quality of life after successful treatment of early-stage Hodgkin's lymphoma: 10-year follow-up of the EORTC-GELA H8 randomised controlled trial.

BACKGROUND: Little is known about the longitudinal course of health-related quality of life (HRQoL) in patients with Hodgkin's lymphoma during their post-treatment follow-up and re-adaptation to normal life. We report on the HRQoL of patients treated in the randomised H8 trial of the European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group and the Groupe d'Etudes des Lymphomes de l'Adulte (GELA). We aimed to assess HRQoL and fatigue following treatment, to analyse relations with treatment, and to identify factors that predict persistent fatigue. METHODS: Patients received HRQoL questionnaires at the end of primary therapy and during follow-up. The EORTC QLQ-C30 was used to assess HRQoL, and the Multidimensional Fatigue Inventory (MFI-20) was used to assess fatigue. Changes of mean HRQoL scores over time were analysed with mixed models. Multiple polytomic nominal logistic regression was done to identify independent baseline predictors of fatigue within MFI-20 dimensions. Analyses were done on an intention-to-treat basis. This study is registered with www.ClinicalTrials.gov, number NCT00379041. FINDINGS: 2666 assessments from 935 patients were analysed. Mean follow-up was 90 months (range 52-118). Age affected all functioning and symptom scores except emotional functioning, with younger age associated with higher functioning and lower severity of symptoms; improvement with time showed similar patterns between age groups. Women reported lower HRQoL and higher symptom scores than did men. Overall, 3.2% (14/439 for role functioning) to 9.7% (43/442 for social functioning) and 5.8% (29/498 for reduced motivation) to 9.9% (49/498 for general fatigue) of patients reported impairments of 10 points or more (on a 0-100 scale) in QLQ-C30 and MFI-20 scores, respectively, independent of age and sex. Emotional domains were more affected than physical ones. There was no relation between HRQoL outcome and type of treatment. Fatigue (MFI-20 scores) at the end of treatment was the only predictive variable for persistent fatigue, with odds ratios varying from 2.58 (95% CI 1.00-6.67) to 41.51 (12.02-143.33; p

High-dose Ara-C and beam with autograft rescue in R-CHOP responsive mantle cell lymphoma patients.

Mantle cell lymphoma (MCL) has a dismal outcome when treated with conventional chemotherapy. This single arm phase 2 study evaluated intensive consolidation treatment of patients with newly diagnosed MCL up to the age of 65 years, responsive to R-CHOP (rituximab, cyclophosphamide, oncovin, adriamycin, prednisolone). Endpoints for evaluation were toxicity, failure-free survival (FFS) and overall survival (OS). Eighty-seven patients were treated with three cycles of R-CHOP. Sixty-six patients responded to R-CHOP with at least a partial response, 62 continued protocol treatment with high-dose cytarabine (Ara-C; 2000 mg/m(2), bid. over 4 d) and 61 patients received rituximab and stem cell harvest, followed by BEAM (carmustine, etoposide, Ara-C, melphalan) and autologous stem cell rescue. Non-haematological toxicity, grades III and IV, was seen in 8% of the patients after R-CHOP, in 22% after high-dose Ara-C and in 55% after BEAM. The overall response rate was 70% (complete response rate 64%, partial response rate 6%), FFS and OS at 4 years were 36 +/- 7% and 66 +/- 6%, respectively. The FFS and OS at 4 years from the evaluation after BEAM in the 61 R-CHOP responsive patients was 46 +/- 9% and 79 +/- 7%, respectively. In conclusion, high-dose Ara-C and BEAM with stem cell rescue in newly diagnosed MCL patients responsive to R-CHOP is a manageable treatment with respect to toxicity. This regimen leads to long-term, but probably not durable, remissions.

Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols.

BACKGROUND: The clinical behavior of follicular lymphoma is largely determined by properties of the non-malignant tumor microenvironment. The precise nature of the cell populations is still unclear and published data on their prognostic significance are highly conflicting. This may be partly due to heterogeneous composition and treatments. DESIGN AND METHODS: Pre-treatment biopsy samples of patients with follicular lymphoma treated in an EORTC/BNLI trial comparing fludarabine to cyclophosphamide, vincristine and prednisone (CVP) chemotherapy could be retrieved for 61 patients in five European countries. Immunohistochemical investigations were performed evaluate tumor cell characteristics, T-cell subsets, follicular dendritic cells and macrophages and associations with clinical outcome were studied. RESULTS: Some markers showed a homogeneous prognostic impact, while others had a different nd sometimes opposite effect in the treatment arms. CD69 expression on tumor cells was a poor prognostic sign and an interfollicular infiltrate of FoxP3-positive T cells was a good prognostic sign irrespective of the treatment arm. It is suggestive that a dense infiltrate of FoxP3-positive T cells, dense and interfollicular infiltrate of CD68-positive macrophages and complete follicular dendritic meshworks were associated with a favorable time to progression in CVP-treated patients, while being poor prognostic sign in fludarabine-treated patients. CONCLUSIONS: Our results suggest that characteristic properties of the microenvironment in follicular lymphoma determines the responses to essentially different chemotherapeutic approaches. These data may provide an explanation for the highly conflicting results on immunohistochemical markers and the prognostic role of the microenvironment in follicular lymphoma reported thus far and lay the basis for the development of predictive assays to tailor treatment in patients with follicular lymphoma.

Biomarkers and prognosis in malignant lymphomas.

Approximately 100 hematologists and pathologists from Europe, the United States, and Canada participated in the workshop Biomarkers and Prognosis in Malignant Lymphomas, held in Mandelieu, France, April 11-13, 2008, under the leadership of Anton Hagenbeek, Randy Gascoyne, and Gilles Salles. International experts in the field (discussed herein) shared their experiences in exploring the role of a variety of biologic markers related to different types of non-Hodgkin lymphomas (follicular, diffuse large B-cell, mantle cell, and Burkitt lymphomas) as well as Hodgkin lymphoma. The final goal of this clinical research is to develop new biologic prognostic indices for these major subtypes of lymphoma. In recent years, various prognostic indices, mainly based on clinical characteristics of the patient at diagnosis, have served to determine the prognostic profile and to develop prognostic factor-based treatment strategies. However, it is now time to reconsider this based on the wealth of new biologic information directly related to lymphoma cells and the surrounding cells. In this workshop, organized by the European School of Hematology and the European Hematology Association, the latest developments on molecular pathogenesis, new biomarkers, and their relation to prognosis were extensively discussed. Herein, the major conclusions presented in the different sessions are summarized.

Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS).

BACKGROUND: Antibody-drug conjugates (ADCs) polatuzumab vedotin (pola) and pinatuzumab vedotin (pina) showed clinical activity and tolerability in phase 1 trials. The aim of this multicentre, open-label, phase 2 study was to compare rituximab plus pola (R-pola) or pina (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. METHODS: In this phase 2 randomised study at 39 investigational sites in six countries, patients were randomly assigned (1:1), by use of a dynamic hierarchical randomisation scheme, to receive R-pola or R-pina (375 mg/m2 rituximab plus 2·4 mg/kg ADCs) every 21 days until disease progression or unacceptable toxicity up to 1 year. Treatment allocations were not masked to the investigator, patients or sponsor after the patients were enrolled and randomly assigned. The primary objectives were safety and tolerability, and antitumour response. The study is registered with ClinicalTrials.gov, number NCT01691898, and is closed to accrual. FINDINGS: 81 patients with diffuse large B-cell lymphoma and 42 with follicular lymphoma were recruited between Sept 27, 2012, and Oct 10, 2013, and were assigned to treatment. 81 patients with diffuse large B-cell lymphoma and 41 patients with follicular lymphoma were eligible for analysis. Of the 42 patients with diffuse large B-cell lymphoma who received R-pina, 25 (60%, 95% CI 43-74) achieved an objective response and 11 (26%, 95% CI 14-42) achieved a complete response. Of the 39 patients in this cohort who received R-pola, 21 (54%, 95% CI 37-70) achieved an objective response, and eight (21%, 95% CI 9-36) achieved a complete response. Of the 21 patients in the follicular lymphoma cohort who received R-pina, 13 (62%, 95% CI 38-82) achieved an objective response, and one (5%, 95% CI 0·1-24) achieved a complete response. Of the 20 patients in this cohort who received R-pola, 14 (70%, 95% CI 46-88) achieved an objective response, and nine (45%, 95% CI 23-68) achieved a complete response. In the diffuse large B-cell lymphoma cohort, grade 3-5 adverse events occurred in 33 (79%) of 42 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [10%]; nine [21%] grade 5 adverse events, five of which were infection-related), and in 30 (77%) of 39 patients receiving R-pola (most common were neutropenia [23%], anaemia [8%] and diarrhoea [8%]; no grade 5 adverse events). In the follicular lymphoma cohort, grade 3-5 adverse events occurred in 13 (62%) of 21 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [14%]; no grade 5 adverse events) and in ten (50%) of 20 patients receiving R-pola (most common were neutropenia [15%] and diarrhoea [10%]; one grade 5 adverse event). INTERPRETATION: R-pina and R-pola are potential treatment options in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. Pola was selected by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response than pina, and an overall benefit-risk favouring R-pola. FUNDING: F Hoffmann-La Roche.

Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium.

PURPOSE: MYC rearrangement (MYC-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC-R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene. METHODS: The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC, BCL2, BCL6, and IG heavy and light chain loci was used, and results were correlated with clinical outcomes. RESULTS: A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC-R. MYC-R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC-R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001). CONCLUSION: The negative prognostic impact of MYC-R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.