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Objectives: The seroprevalence of antibodies against Cytomegalovirus (CMV) is an established poor prognostic factor for patients receiving an allogeneic stem cell transplantation. However, the impact of CMV serology on outcome after autologous stem cell transplantation remains unknown., Methods: Here, we analyzed the CMV immunoglobulin (Ig) serology of 446 newly-diagnosed multiple myeloma (MM) patients of the GMMG-MM5 phase III trial with a median follow-up of 58 months., Results: CMV IgG and IgM positivity was seen in 51% and 6% of the patients, respectively. In multivariate analysis CMV IgG and CMV IgM serology show an age-depending effect for PFS. We identified positive CMV IgG/positive CMV IgM serology as an age-depending beneficial factor on PFS., Discussion: Younger patients with a positive CMV IgG/positive CMV IgM serology experienced a favorable effect on PFS, whereas a positive CMV IgG/positive CMV IgM serology at older age has a disadvantageous effect on PFS.

In the setting of a first relapse of multiple myeloma (MM), a second autologous stem cell transplant (ASCT) following carfilzomib-lenalidomide-dexamethasone (KRd) is an option, although there is scarce data concerning this approach. We performed a retrospective study involving 22 EBMT-affiliated centers. Eligible MM patients had received a second-line treatment with KRd induction followed by a second ASCT between 2016 and 2018. Primary objective was to estimate progression-free survival (PFS) and overall survival (OS). Secondary objectives were to assess the response rate and identify significant variables affecting PFS and OS. Fifty-one patients were identified, with a median age of 62 years. Median PFS after ASCT was 29.5 months while 24- and 36-months OS rates were 92.1% and 84.5%, respectively. Variables affecting PFS were an interval over four years between transplants and the achievement of a very good partial response (VGPR) or better before the relapse ASCT. Our study suggests that a relapse treatment with ASCT after KRd induction is an effective strategy for patients with a lenalidomide-sensitive first relapse. Patients with at least four years of remission after a frontline ASCT and who achieved at least a VGPR after KRd induction appear to benefit the most from this approach., (© 2023. The Author(s).)

UNFOLDER (Unfavorable Young Low-Risk Densification of R-Chemo Regimens) is an international phase-3 trial in patients 18-60 years with aggressive B-cell lymphoma and intermediate prognosis defined by age-adjusted International Prognostic Index (aaIPI) of 0 and bulky disease (≥7.5 cm) or aaIPI of 1. In a 2 × 2 factorial design patients were randomized to 6× R-CHOP-14 or 6× R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso[lo]ne) and to consolidation radiotherapy to extralymphatic and bulky disease or observation. Response was assessed according to the standardized response criteria published in 1999, not including F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET). Primary endpoint was event-free survival (EFS). A total of 695 of 700 patients were eligible for the intention-to-treat analysis. Totally 467 patients qualified for radiotherapy of whom 305 patients were randomized to receive radiotherapy (R-CHOP-21: 155; R-CHOP-14: 150) and 162 to observation (R-CHOP-21: 81, R-CHOP-14: 81). Two hundred twenty-eight patients not qualifying for radiotherapy were randomized for R-CHOP-14 versus R-CHOP-21. After a median observation of 66 months 3-year EFS was superior in the radiotherapy-arm versus observation-arm (84% versus 68%; P = 0.0012), due to a lower rate of partial responses (PR) (2% versus 11%). PR often triggered additional treatment, mostly radiotherapy. No significant difference was observed in progression-free survival (PFS) (89% versus 81%; P = 0.22) and overall survival (OS) (93% versus 93%; P = 0.51). Comparing R-CHOP-14 and R-CHOP-21 EFS, PFS and OS were not different. Patients randomized to radiotherapy had a superior EFS, largely due to a lower PR rate requiring less additional treatment (NCT00278408, EUDRACT 2005-005218-19)., Competing Interests: L. Thurner has received travel grants from Abbvie, Janssen and EUSA-Pharm, and has indicated consultancy for Takeda, Astra-Zeneca, Merck, EUSA-pharm. DK-M has received personal fees from Novartis, Astra-Zeneca, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, and nonfinancial support from Gilead Sciences, Janssen-Cilag, Takeda, Novartis. AV has received honoraria from Roche, Amgen, Kite, Gilead, Novartis, Bristol-Myers Squibb and has indicated a membership of the advisory board of Roche, Amgen, Kite, Gilead, Novartis, Bristol-Myers Squibb. UBK has received honoraria and advisory fees from Roche, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Gilead, Hexal, Pfizer, Astra- Zeneca, Pentixapharm, Amgen, Novartis, MSD and has received clinical study support for Celgene, Takeda, BMS, Roche, Astra-Zeneca, Novartis, MSD, Janssen-Cilag, Pfizer. MN has received travel grants from Roche, Celgene and MSD and personal fees from Roche, Celgene, MSD, Janssen, Amgen, Incyte and Abbvie. FG participates in advisory board of Roche, Boehringer Ingelheim, Abbvie, Merck, Takeda, MSD, Sanofi, Pfizer, Novartis, Amgen and Janssen. RT has received grants from Atara and Roche and travel support from Roche, Atara, Celgene, Janssen and Abbvie; he has indicated a membership of the advisory board of Atara and Abbvie and has indicated consultancy for s Atara. PdNB has indicated consultancy for Roche, Incyte and Novartis. FM has received travel grants from Roche, Takeda, Janssen and Gilead and has indicated consultancy and advisory role for Roche, Gilead, Janssen, MSD, Takeda and Novartis. SS has received grants from Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys and has indicated consultancy for for Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys; he has received drug/equipment supplied by entity from Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys. VP has received grants from Deutsche Krebshilfe (German Cancer Aid), Chugai, Abbvie, Amgen, Roche and Bristol Myers Squibb. GH has received grants from Roche and Bristol Myers Squibb and personal fees from Bristol Myers Squibb, Roche, Amgen, Spectrum and MSD. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Purpose: Evidence on the effect of self-protection via social distancing and wearing face-masks on infections during chemotherapy is currently not available. We asked if the occurrence of acute infections during chemotherapy for advanced-stage Hodgkin lymphoma (HL) decreased when COVID-19 protection measures were in effect., Methods: We analyzed the occurrence of infections during all documented eBEACOPP cycles starting between 01 March and 30 June of 2017 to 2020 in patients treated within the GHSG HD21 study in Germany and compared the infection rates and characteristics by logistic regression models and means of descriptive statistics., Results: We analyzed 911 cycles of 313 adult patients treated with 4 to 6 cycles of eBEACOPP. We found a significant decrease in the occurrence of infections during chemotherapy for HL during COVID-19 lockdown from 131 (19.6%) of 670 cycles in 2017-2019 to 30 (12.6%) of 239 cycles during COVID-19 lockdown [OR 0.574 (95% CI 0.354-0.930), P = 0.024]. The strongest effect was evident for unspecified infections with 39 cycles (5.8%) during 2017-2019 in comparison to 5 cycles (2.1%) during COVID-19 lockdown. 20 (24.1%) of 83 patients had an infection during the COVID-19 lockdown versus 99 (43.2%) of 229 patients in the years 2017-2019 (P = 0.0023)., Conclusion: The significant decrease of infections during chemotherapy for HL during COVID-19 lockdown reveals the protective measures' potential to shield patients from transmissible pathogens. We conclude that these measures could be recommended for HL patients at risk for infections during chemotherapy., (© 2022. The Author(s).)

We investigated the prognostic impact of time-dependent serum free light chain ratio (FLCr) normalization in 590 patients with secretory multiple myeloma (MM) during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. Serum free light chains (sFLC) were assessed by the Freelite test at baseline, after induction, mobilization, autologous blood stem cell transplantation, consolidation and every three months during maintenance or follow up within two years after the start of maintenance. The proportion of patients with a normal or normalized FLCr increased from 3.6% at baseline to 23.2% after induction and 64.7% after consolidation. The achievement of FLCr normalization at any one time before the start of maintenance was associated with significantly prolonged progression-free survival (PFS) ( p < 0.01, hazard ratio (HR) = 0.61, 95% confidence interval (95% CI) = 0.47-0.79) and overall survival (OS) ( p = 0.02, HR = 0.67, 95% CI = 0.48-0.93) in multivariable time-dependent Cox regression analyses. Furthermore, reaching immune reconstitution, defined as the normalization of uninvolved immunoglobulins, before maintenance was associated with superior PFS ( p = 0.04, HR = 0.77, 95% CI = 0.60-0.99) and OS ( p = 0.01, HR = 0.59, 95% CI = 0.41-0.86). We conclude that FLCr normalization during therapy is an important favorable prognostic factor in MM. Therefore, we recommend serial measurements of sFLC during therapy until achieving FLCr normalization, even in patients with secretory MM., Competing Interests: E.-M.K.: travel, accommodations, expenses: AMGEN, BMS, Janssen. D.T.: no COI. H.J.S.: honoraria: Janssen Cilag, Takeda, Amgen, BMS/Celgene, Sanofi, Oncopeptides, Abbvie, GSK, Chugai, Pfizer; travel, accommodations, expenses: Janssen, Takeda, Amgen, BMS/Celgene, Sanofi, GSK. E.K.M.: honoraria: Janssen, Celgene, Takeda, GSK; consulting or advisory role: Janssen, Celgene, Takeda, GSK; research funding: Takeda, Celgene/BMS, GSK; travel, accommodations, expenses: Janssen, Takeda, Celgene/BMS, Onyx, Mundipharma, GSK. J.D.: consulting or advisory role: Celgene; speakers bureau: Celgene; travel, accommodations, expenses: Celgene. K.C.W.: honoraria: AMGEN, BMS, Celgene, Novartis, Janssen, Takeda; consulting or advisory role: AMGEN, BMS, Celgene, Juno, Janssen, Adaptive, Sanofi, Takeda; research funding: AMGEN, Celgene, Sanofi, Janssen. A.B.: no COI. U.B.: travel, accommodations, expenses: Sanofi. M.A.: no COI. B.B.: no COI. M.M.: honoraria: Janssen, BMS, Takeda, Celgene, Amgen; consulting or advisory role: Janssen, BMS, Takeda, Celgene, Amgen; research funding: BMS, Incyte; travel, accommodations, expenses: Janssen, BMS, Takeda, Amgen. H.-W.L.: no COI. D.H.: consulting or advisory role: I. Lamkap Bio AG, Discoveric AG; research funding: Celgene AG, Sanofi, Engmab AG; travel, accommodations, expenses: Celgene. A.S.: consulting or advisory role: I. Lamkap Bio AG, Discoveric AG; research funding: Celgene AG, Sanofi, Engmab AG. S.L.: no COI. A.J.: no COI. A.E.: consulting or advisory role: Amgen; travel, accommodations, expenses: Janssen, Amgen. S.F.: consulting or advisory role: Sanofi, BMS, Amgen. P.B.: consulting or advisory role: BMS, AMGEN, Roche, MSD; research funding: BMS; travel, accommodations, expenses: BMS. M.G.: no COI. H.B.: no COI. M.S.R.: honoraria: Celgene, BMS, Novartis, Janssen, Takeda; consulting or advisory role: Celgene, BMS, Novartis, Janssen, Takeda; research funding: Celgene, Novartis, AMGEN; travel, accommodations, expenses: Janssen, BMS, Takeda. I.W.B.: research funding: Celgene, BMS, Janssen. M.H.: honoraria: Novartis, Amgen, Roche, Takeda; consulting or advisory role: Celgene. C.S.: honoraria: BMS, Janssen, Celgene, Novartis, Amgen, Takeda; consulting or advisory role: BMS, Janssen, Celgene, Novartis, Amgen, Takeda; speakers bureau: Takeda; research funding: Takeda, Novartis; travel, accommodations, expenses: BMS, Janssen, Celgene, Novartis, Amgen, Takeda. H.G.: honoraria: Amgen, BMS, Celgene, Chugai, Janssen, Novartis, Takeda; consulting or advisory role: Amgen, BMS, Celgene, Chugai, Janssen, Novartis, Takeda; speakers bureau: Amgen, BMS, Celgene, Janssen, Novartis, Takeda; research funding: Amgen, BMS, Celgene, Chugai, Janssen, Novartis, Takeda; travel, accommodations, expenses: BMS, Celgene, Janssen, Novartis, Takeda. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

First-line therapy for younger patients with peripheral T-cell non-Hodgkin lymphoma (T-NHL) consists of 6 courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without etoposide (CHOEP), consolidated by high-dose therapy and autologous stem cell transplantation (auto-SCT). We hypothesized that allogeneic stem cell transplantation (allo-SCT) could improve outcomes. 104 patients with peripheral T-cell non-Hodgkin lymphoma, except ALK+ anaplastic large cell lymphoma, 18 to 60 years, all stages, and all age adjusted International Prognostic Index scores, except 0 and stage I, were randomized to 4 cycles of CHOEP and 1 cycle of dexamethasone, cytosine-arabinoside, and platinum (DHAP) followed by high-dose therapy and auto-SCT or myeloablative conditioning and allo-SCT. The primary end point was event-free survival (EFS) at 3 years. After a median follow-up of 42 months, the 3-year EFS after allo-SCT was 43%, as compared with 38% after auto-SCT. Overall survival at 3 years was 57% vs 70% after allo- or auto-SCT, without significant differences between treatment arms. None of the 21 responding patients proceeding to allo-SCT relapsed, as opposed to 13 of 36 patients (36%) proceeding to auto-SCT. Eight of 26 patients (31%) and none of 41 patients died of transplant-related toxicity after allo- and auto-SCT, respectively. The strong graft-versus-lymphoma effect after allo-SCT was counterbalanced by transplant-related mortality. This trial is registered at www.clinicaltrials.gov as #NCT00984412., (© 2021 by The American Society of Hematology.)

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st-3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m 2 ), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65-1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52-1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.

Background: R-MegaCHOEP was the first phase 3 study comparing high-dose chemotherapy plus rituximab followed by autologous haematopoietic stem-cell transplantation (HSCT) with conventional chemotherapy plus rituximab in first-line therapy for patients aged 60 years or younger with high-risk aggressive B-cell lymphoma. Little is known about the long-term outcomes of these patients. We aimed to evaluate the long-term efficacy and safety of conventional chemotherapy versus high-dose chemotherapy after 10 years of follow-up in the R-MegaCHOEP trial., Methods: In this open-label, randomised, phase 3 trial done across 61 centres in Germany, patients aged 18-60 years with newly diagnosed, high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) aggressive B-cell lymphoma were randomly assigned (1:1, using Pocock minimisation) to eight cycles of conventional chemotherapy (cyclosphosphamide, doxorubicin, vincristine, etoposide, and prednisolone) plus rituximab (R-CHOEP-14) or four cycles of high-dose chemotherapy plus rituximab followed by autologous HSCT (R-MegaCHOEP). The trial was unmasked. Patients were stratified by age-adjusted IPI factors, presence of bulky disease (tumour mass ≥7·5 cm diameter), and treatment centre. The primary endpoint was event-free survival, analysed here 10 years after randomisation. 10-year overall survival, progression-free survival, conditional survival, relapse patterns, secondary malignancies, and molecular characteristics were also analysed. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00129090., Findings: Between March 3, 2003, and April 7, 2009, 275 patients were randomly assigned to R-CHOEP-14 (n=136) or R-MegaCHOEP (n=139). 130 patients in the R-CHOEP-14 group and 132 patients in the R-MegaCHOEP group were included in the intention-to-treat population. After a median follow-up of 9·3 years (IQR 5·1-11·1), 10-year event-free survival was 51% (95% CI 42-61) in the R-MegaCHOEP group and 57% (47-67) in the R-CHOEP-14 group (adjusted hazard ratio [HR] 1·3 [95% CI 0·9-1·8], p=0·23). 10-year progression-free survival was 59% (50-68) in the R-MegaCHOEP group and 60% (51-70) in the R-CHOEP-14 group (adjusted HR 1·1 [0·7-1·7], p=0·64). 10-year overall survival was 66% (57-76) in the R-MegaCHOEP group and 72% (63-81) in the R-CHOEP-14 group (adjusted HR 1·3 [0·8-2·1], p=0·26). Relapse occurred in 30 (16% [95% CI 11-22]) of 190 patients who had complete remission or unconfirmed complete remission; 17 (17%) of 100 patients in the R-CHOEP-14 group and 13 (14%) of 90 patients in the R-MegaCHOEP group. Seven (23%) of 30 patients had low-grade histology at relapse and had better outcomes compared with patients who relapsed with aggressive histologies. Lymphoma affected the CNS in 18 (28%) of 64 patients with treatment failure. 22 secondary malignancies were reported in the intention-to-treat population; in 12 (9%) of 127 patients in the R-CHOEP-14 group and ten (8%) of 126 patients in the R-MegaCHOEP group., Interpretation: Event-free survival and overall survival were similar between groups after 10 years of follow-up; outcomes were not improved in the R-MegaCHOEP group by high-dose chemotherapy and autologous HSCT. Patients who relapsed with aggressive histology showed a high incidence of CNS involvement and poor prognosis. For these patients, novel therapies are greatly warranted., Funding: Deutsche Krebshilfe (German Cancer Aid)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis., Methods: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m 2 ), doxorubicin (50 mg/m 2 ), and vincristine (1·4 mg/m 2 , with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m 2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421., Findings: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy., Interpretation: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population., Funding: Deutsche Krebshilfe., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m 2 ), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept., Methods: GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life., Results: Since this is the publication of a study protocol of an ongoing study, no results can be presented., Discussion: This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab., Trial Registration: NCT02495922 on June 24th, 2015.

To further improve outcome in young high-risk patients with diffuse large B-cell lymphoma (DLBCL) the number of rituximab (R) infusions was doubled in combination with standard CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone) chemotherapy. Seventy-seven patients (aged 18-60 years) with an age-adjusted International Prognostic Index of 2-3 received 12 × R (375 mg/m 2 ) on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 99 together with eight cycles of CHOEP-14. Results were retrospectively compared to those of patients receiving 6 × R and 8 × CHOEP-14 in the standard arm of the randomized R-MegaCHOEP trial. Two-year overall survival (OS) was 82% [95% confidence interval (CI) 73%-92%]; 2-year event-free (EFS) and progression-free survival (PFS) was 69% (95% CI 59-80%) and 76% (95% CI 66%--6%), respectively. Comparing 12 to six doses of R revealed no differences (univariate/multivariate) in EFS (at 2 years: 69% vs. 71%), PFS (76% vs. 75%) and OS (82% vs. 85%), with P = 0·766, P = 0·871 and P = 0·843, respectively. Doubling the number of R infusions concomitant to CHOEP did not improve treatment outcomes. Nonetheless, OS and PFS of young high-risk patients who received only six infusions of R combined with CHOEP remain excellent and were confirmed in an independent cohort of patients., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

We investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON)-65/German-Speaking MM Group (GMMG)-HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation. Subclones were defined either by presence of different copy numbers of the same chromosome loci and/or CA present in at least 30% less and maximally 2/3 of cells compared with the main clone CA. Patients with subclones harbored more frequently high risk (31.0%) or hyperdiploid main clone aberrations (24.8%) than patients with t(11;14) in the main clone (10.1%). Gains and deletions of c-MYC were the only CA that occurred more frequently as subclone (8.1%/20.5%) than main clone (6.2%/3.9%, respectively). Treatment with bortezomib completely overcame the negative prognosis of high-risk CA in patients without subclones, but not in patients with additional subclonal CA. High-risk patients treated without bortezomib showed dismal outcome whether subclones were present or not. Cytogenetic heterogeneity defined by subclonal CA is of major prognostic significance in newly diagnosed MM patients treated with bortezomib within the HOVON-65/GMMG-HD4 trial., Competing Interests: Conflict-of-interest disclosure: M.M. received travel grants from Celgene, Abbvie, Amgen, and Janssen and acts on advisory boards for Amgen. D.H. received research funding from Sanofi and EngMab, as well as personal fees outside this work from Celgene. H.S. received speakers honoraria and travel grants from Celgene, Amgen, and Sanofi. I.G.H.S.-W. received research funding from Janssen and Novartis. C.S. received funding outside this work from Novartis, Celgene, and Janssen. K.C.W. received consultancy honoraria from Amgen, Takeda, and BMS, as well as honoraria from Novartis, research funding from Janssen and Celgene, and consultancy honoraria from Onyx. H.G. received consultancy honoraria and research funding from Janssen, Celgene, and Novartis, as well as consultancy honoraria from Onyx and Millenium and fees outside this work from BMS. J.H. received speakers honoraria from Celgene, acts on advisory boards for Janssen, BMS, and Amgen, and received consultancy honoraria from Janssen, Novartis, and Amgen as well as research funding from Sanofi. The remaining authors declare no competing financial interests.

To investigate cytogenetic evolution after upfront autologous stem cell transplantation for newly diagnosed myeloma we retrospectively analyzed fluorescence in situ hybridization results of 128 patients with paired bone marrow samples from the time of primary diagnosis and at relapse. High-risk cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more frequently after relapse (odds ratio: 6.33; 95% confidence interval: 1.86-33.42; P <0.001). No significant changes were observed for defined IGH translocations [t(4;14); t(11;14); t(14;16)] or hyperdiploid karyotypes between primary diagnosis and relapse. IGH translocations with unknown partners occurred more frequently at relapse. New deletion 17p and/or gain 1q21 were associated with cytogenetic heterogeneity, since some de novo lesions with different copy numbers were present only in subclones. No distinct baseline characteristics were associated with the occurrence of new high-risk cytogenetic abnormalities after progression. Patients who relapsed after novel agent-based induction therapy had an increased risk of developing high-risk aberrations (odds ratio 10.82; 95% confidence interval: 1.65-127.66; P =0.03) compared to those who were treated with conventional chemotherapy. Survival analysis revealed dismal outcomes regardless of whether high-risk aberrations were present at baseline (hazard ratio, 3.53; 95% confidence interval: 1.53-8.14; P =0.003) or developed at relapse only (hazard ratio, 3.06; 95% confidence interval: 1.09-8.59; P =0.03). Our results demonstrate cytogenetic evolution towards high-risk disease after autologous transplantation and underline the importance of repeated genetic testing in relapsed myeloma (EudraCT number of the HD4 trial: 2004-000944-26)., (Copyright© 2017 Ferrata Storti Foundation.)

Objective: Analysis of the efficiency and toxicity of cyclophosphamide-based stem cell mobilization in patients with relapsed multiple myeloma (RMM)., Methods: Peripheral blood stem cells (PBSCs) were mobilized with high dose cyclophosphamide (2 g/m 2 daily on days 1 and 2) and G-CSF plus pre-emptive/rescue plerixafor in RMM patients (first to third relapse) treated within the ReLApsE trial of the German-Speaking Myeloma Multicenter Group (GMMG)., Results: Mobilization was initiated with high-dose cyclophosphamide (HD-CY) and G-CSF in 30 patients. Fifteen patients received additional pre-emptive/rescue administration of plerixafor. Stem cell collection was successful (≥2×10 6 CD34+ cells per kg bw) in 77% (23/30 patients). Patients with prior high-dose melphalan collected a significantly lower median total number of PBSCs than patients without prior high-dose melphalan (3.3×10 6 vs 17×10 6 CD34+ cells/kg bw). Toxicity of HD-CY was frequent with 12 serious adverse events (SAE) in 37% of patients (11/30 patients). Infections accounted for the majority of SAE reports. In two patients, SAEs were lethal (septic shock)., Conclusions: These data proof feasibility of PBSC collection at relapse but emphasize the importance of collection and storage of additional PBSC transplants during first-line treatment when mobilization is more efficient and less toxic., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients., Methods/design: ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS., Discussion: This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients., Trial Registration: ISRCTN16345835 (date of registration 2010-08-24).

Background: Gene expression profiling (GEP) has significantly contributed to the elucidation of the molecular heterogeneity of multiple myeloma plasma cells (MMPC) and only recently it has been recommended for risk stratification. Prior to GEP MMPC need to be enriched resulting in an inability to immediately freeze bone marrow aspirates or use RNA stabilization reagents. As a result in multi-center MM trials sample processing delay due to shipping may be an important confounder of molecular analyses and risk stratification based on GEP data., Results: We compared GEP data of 145 in-house and 246 shipped samples and detected 3301 down-regulated and 3501 up-regulated genes in shipped samples. For 3994 genes we confirmed differential expression in an independent set of 85 in-house and 97 shipped samples. Differentially expressed genes were enriched in processes like ribosome biogenesis, cell cycle, and apoptosis. Among GEP based risk predictors the IFM-15 seemed to underestimate high risk in shipped samples, whereas the GEP70 and the EMC-92 gene signatures were more robust. In order to provide a tool to assess the "shipping effect" in public repositories, we generated a 17-gene predictor for shipped samples with a 10-fold cross validation error rate of 0.06 for the training set and an error rate of 0.15 for the validation set., Conclusion: Sample processing delay significantly influences GEP of MMPC, implying it should be avoided if samples were used for risk stratification.

We investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide, and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on data from relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients had been enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates of grade 2 or more peripheral neuropathy were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, P=0.001). Overall response rates were similar in patients treated intravenously or subcutaneously. The presence of International Staging System stage III disease, renal impairment or adverse cytogenetic abnormalities did not have a negative impact on overall response rates in either group. To our knowledge this is the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at eudract.ema.europa.eu as n. 2010-019173-16., (Copyright© Ferrata Storti Foundation.)

Background: High-dose therapy (HDT) followed by transplantation of autologous haemopoietic stem cells is frequently done as part of first-line therapy in young patients with high-risk aggressive B-cell lymphoma. We investigated whether HDT with cytotoxic agents identical to those used for conventional therapy followed by autologous stem-cell transplantation (ASCT) improved survival outcome compared with conventional chemotherapy when rituximab was added to both modalities., Methods: We did an open-label, randomised trial comparing conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) and rituximab (R-CHOEP-14) with dose-escalated sequential HDT and rituximab (R-MegaCHOEP) followed by repetitive ASCT in high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) patients aged 18-60 years with aggressive B-cell lymphoma. Eligible patients received radiotherapy for bulky, extranodal disease, or both. Randomisation (1:1) used the Pocock minimisation algorithm; patients were stratified by age-adjusted IPI factors, bulky disease, and centre. The primary endpoint was event-free survival. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00129090., Findings: 136 patients were randomly assigned to R-CHOEP-14 and 139 to R-MegaCHOEP. 130 patients in the R-CHOEP-14 group and 132 in the R-MegaCHOEP group were included in the intention-to-treat population. After a median of 42 months (IQR 29-59), 3-year event-free survival was 69·5% (95% CI 61·3-77·7) in the R-CHOEP-14 group and 61·4% (52·8-70·0) in the R-MegaCHOEP group (p=0·14; hazard ratio 1·3, 95% CI 0·9-2·0). All 128 evaluable patients treated with R-MegaCHOEP had grade 4 leucopenia, as did 48 (58·5%) of 82 patients with documented blood counts in the R-CHOEP-14 group. All 128 evaluable patients in the R-MegaCHOEP group had grade 3-4 thrombocytopenia, as did 26 (33·8%) of 77 patients in the R-CHOEP-14 group with documented blood counts. The most important non-haematological grade 3 or 4 adverse event was infection, which occurred in 96 (75·0%) of 128 patients treated with R-MegaCHOEP and in 40 (31·3%) of 128 patients treated with R-CHOEP-14., Interpretation: In young patients with high-risk aggressive B-cell lymphoma, R-MegaCHOEP was not superior to conventional R-CHOEP therapy and was associated with significantly more toxic effects. R-CHOEP-14 with or without radiotherapy remains a treatment option for these patients, with encouraging efficacy., Funding: Deutsche Krebshilfe., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For allanalyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P < .0001) and OS (P < .0001) in arm A, whereas no statistically significant effect on PFS (P = .28) or OS (P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13).

Background: The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome in patients with aggressive non-Hodgkin's lymphoma. The intravenous administration of etoposide on three consecutive days represents a logistic problem and needs resources particular in the outpatient setting. This could be avoided by using etoposide capsules on days 2 and 3. However, the oral administration of cytotoxic agents is often affected by variable absorption and drug interactions., Patients and Methods: We investigated the pharmacokinetic equivalency of oral and intravenous etoposide in ten patients (male, n=7; female, n=3; median age 56 years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide 100 mg/m2 given intravenously on day 1, and 200 mg/m2 orally on days 3 and 4. Samples from blood and urine were taken on days 1 (i.v. study) and 3 (p.o. study) before and after etoposide administration. Etoposide levels were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated with the TOPFIT computer program., Results: Mean peak plasma level after intravenous etoposide was significantly higher compared to oral administration (16.3+/-3.7 vs. 12.0+/-4.2 microg/ml; P=0.015). The mean bioavailability of oral etoposide was 58+/-15% with an interpatient variability of 26%. Significant differences of bioavailability of oral etoposide between the used dose levels (350, 400 and 450 mg) were not observed. Mean AUC after a 100 mg/m2 intravenous and a 200 mg/m2 oral dose of etoposide were 74.0+/-18.3 and 84.9+/-29.6 microg h/ml (P=0.481). Interpatient variability of AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as percentage of administered dose was 39.4+/-10.6% after intravenous infusion versus 35.4+/-9.4% after oral intake (P=0.422). Renal clearance was also very similar with intravenous and oral route (18.5+/-7.4 vs. 16.7+/-6.6 ml/min; P=0.546)., Conclusion: The equivalency of AUC after 200 mg/m2 of oral and 100 mg/m2 of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.

Objective: To assess the outcome of intensive care unit (ICU) treatment in patients with hematological malignancies., Design and Setting: Retrospective cohort study in the medical ICU of a university hospital., Patients: 104 critically ill patients after receiving conventional chemotherapy or autologous hematopoietic stem cell transplantation., Interventions: We analyzed demographic data, underlying disease, intensity of antineoplastic regimen, cause of admission, need for mechanical ventilation, and hemofiltration, ICU survival, and survival after discharge, furthermore neutrophil count, C-reactive protein (150 mg/l), antithrombin III, prothrombin time, and SAPS II (50) at ICU admission. All recorded variables were evaluated for prognostic relevance by univariate and multivariate analyses., Measurements and Results: Overall ICU mortality was 44%, with significantly higher mortality in ventilated patients (74% vs. 12% in nonventilated patients, p<0.001). Overall survival for the entire group 6 months and 1 year after ICU admission was 33% and 29%, respectively. Multivariate analysis revealed mechanical ventilation and SAPS II as independent prognostic factors of both ICU mortality and long-term survival, while C-reactive protein predicted only ICU mortality., Conclusions: The outcome of patients not requiring ventilatory support in this study was encouraging, while invasive ventilation was again confirmed as predicting a dismal prognosis in this population. Efforts should be directed to avoiding this procedure by reducing the pulmonary toxicity of antineoplastic treatment and to making ventilatory support more tolerable.