First-line high-dose therapy and autologous blood stem cell transplantation in patients with primary central nervous system non-Hodgkin lymphomas—a single-centre experience in 61 patients

Primary central nervous system non-Hodgkin lymphomas (PCNS-NHLs) are extranodal B-cell lymphomas with poor prognosis. The role of high-dose therapy (HDT) followed by autologous blood stem cell transplantation (ASCT) as first-line therapy is still not clear. We retrospectively collected long-term follow up data of 61 consecutive patients with PCNS-NHL at the University Hospital Düsseldorf from January 2004 to December 2016. Thirty-six patients were treated with conventional chemoimmunotherapy (cCIT) only (CT-group). Seventeen patients received an induction cCIT followed by HDT and ASCT. In the CT-group, the overall response rate (ORR) was 61% (CR 47%, PR 14%), and there were 8% treatment-related deaths (TRD). Progression-free survival (PFS) was 31.8 months, and overall survival (OS) was 57.3 months. In the HDT-group, the ORR was 88% (59% CR, 29% PR), and there were 6% TRD. Median PFS and OS were not reached at 5 years. The 5-year PFS and OS were 64.7%. After a median follow up of 71 months, 10 patients (59%) were still alive in CR/PR following HDT and ASCT, one patient was treated for progressive disease (PD), and 7 had died (41%, 6 PD, 1 TRD). All patients achieving CR prior to HDT achieved durable CR. In the CT-group, 8 patients (22%) were alive in CR/PR after a median follow-up of 100 months. Twenty-eight patients died (78%, 24 PD, 2 TRD, 2 deaths in remission). In the univariate analysis, the HDT-group patients had significantly better PFS (not reached vs 31.8 months, p = 0.004) and OS (not reached vs 57.3 months, p = 0.021). The multivariate analysis showed HDT was not predictive for survival. Treatment with HDT + ASCT is feasible and offers the chance for long-term survival with low treatment-related mortality in younger patients. In this analysis, ORR, PFS and OS were better with HDT than with conventional cCIT alone. This result was not confirmed in the multivariate analysis, and further studies need to be done to examine the role of HDT in PCNSL.

A Simplified Geriatric Assessment (sGA) Can Identify Older Patients with Relapse/Refractory (R/R) Aggressive Lymphoma Suitable for Autologous Stem Cell Transplantation (ASCT): Final Results of Recanz Multicentre Prospective Phase 2 Study By the Fondazione Italiana Linfomi (FIL)

Introduction: We recently demonstrated in a large multicentre study that sGA can identify fit older patients with aggressive lymphoma able to tolerate first-line intensive treatment with curative intent and to obtain similar results than younger people (Merli at al JCO 2021). Regardless of age, about 40% of patients with aggressive lymphoma are either refractory or will eventually relapse after treatment with curative intent. Salvage platinum-based regimens followed by ASCT in responsive disease is a standard of care to obtain longer second remission. However, in many case series, patients over 65 years are excluded from the transplant approach because of potential severe toxicities of high-dose therapy in older patients. This study was designed to evaluate the feasibility and activity of high-dose treatment followed by ASCT in older FIT patients with R/R aggressive lymphoma selected with a sGA. Methods: Patients with R/R aggressive lymphoma after one line of treatment, aged between 65 and 75, and FIT to sGA were eligible for the study. Salvage treatment could be chosen between R-DHAP, R-ICE or other platinum or gemcitabine-containing regimens and stem cells were mobilized after 1 or 2 cycles. Patients achieving at least partial response after 3 courses and who remained FIT to sGA evaluation were eligible for ASCT and were conditioned with either BEAM or FEAM. Results: From May 2014 to August 2019, seventy-five patients from 16 FIL centres were enrolled and 70 were eligible for the study. Sixty-six of them had a diffuse large B-cell lymphoma, one had follicular 3b, 2 mantle cell and 1 Burkitt histology. Salvage treatment was R-DHAP in 48 patients, R-ICE in seven and gemcitabine or oxalyplatinum containing regimens in the remaining ones. Overall response rate after three courses was 44% (21 complete and 10 partial remission). Among the 39 unresponsive patients, 29 had progressive and 4 stable disease, 2 patients died of septic shock and heart failure during salvage and 4 patients withdrew their consent to ASCT. Four patients relapsed soon after response achievement before undergoing the transplant. ASCT was performed in 27 patients with a median of 5.6 x 10 6 CD34/Kg reinfused. No differences emerged in demographic and clinical characteristics between patients reaching the ASCT timepoint or not (Tab 1a). By intention to treat analysis, 2-y overall survival (OS) and PFS of the entire intention-to-treat population were 65% (95%CI: 50-76%) and 34% (95%CI: 22-46%) respectively, without differences according to age (Tab 1b). After a median of 27 months, 2-y OS was 79% (95CI: 51-86%) and EFS 56% (95CI: 32-75%). Twenty-four patients obtained a complete remission (CR) and 20 of them are in continuous CR after more than 12 months. Three patients progressed 1-8 months after ASCT and died. Most common non-hematologic grade 3-4 adverse events were gastrointestinal (10%) and infectious (8%). Conclusion: This study shows that sGA can identify older patients with R/R aggressive lymphoma who are able to tolerate and can benefit from high-dose therapy and ASCT. The poor response to second-line immunochemotherapy remains the major drawback of this approach since less than 50% of patients could actually receive ASCT. Nevertheless the 2-y survival of 65% in the intention to treat population is remarkable and sets the stage for the evaluation of new approaches such as CAR-T or bispecific antibodies also in older patients. A next step should be to explore the usefulness of sGA in the selection of candidates to these innovative treatments. Figure 1 Figure 1. Disclosures Tucci: Takeda: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau; Takeda: Other: travel expenses, accommodation. Merli: EUSA Pharma: Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses. Marcheselli: sandoz: Membership on an entity's Board of Directors or advisory committees. Rossi: Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees.

Selinexor in Combination with R-GDP for Patients with Relapsed/Refractory B-Cell Lymphoma: Results of the Selinda Phase Ib Lysa Study

Background: Salvage chemotherapy followed by high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) is the standard treatment of young patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). A complete remission before ASCT is the most important prognosis factor for a better outcome. Selinexor is a first-in-class, oral selective inhibitor of nuclear export compound, an exportin 1 [XPO1] inhibitor, which, through XPO1 blockade, causes nuclear accumulation and activation of tumor suppressor proteins, reduction in oncoproteins and cancer cell apoptosis. Selinexor has been approved by the US Food and Drug Administration for the treatment of R/R DLBCL, de novo or transformed from follicular lymphoma (FL) pts after ≥2 therapies. The phase Ib SELINDA (EUDRACT 2015-005612-15) study assessed safety and efficacy of selinexor, in combination with R-GDP for pts with R/R B-cell lymphoma. Patients & methods: Eligible pts < 70 years with R/R B-cell lymphoma after first or second treatment failure received every 21 days (d) 3 cycles of rituximab 375 mg/m² on d1, dexamethasone 40 mg on d1 to 4, cisplatin 75 mg/m² d1 and gemcitabine 1 gr/m² on d1 and 8 (R-GDP) in combination with escalating doses of selinexor. The starting dose (dose level 1, DL1) 40 mg was given on days 1, 3, 8, 10 (Cohort A), and from December 2017 on days 1, 8 and 15 (Cohort B). The dose-variation scheme followed a traditional "3+3" design (DL1: 40 mg; DL2: 60 mg). The primary endpoint of SELINDA was the determination of the recommended phase 2 dose of selinexor in combination with R-GDP. Secondary and exploratory endpoints were safety, efficacy, and feasibility of ASCT after selinexor-R-GDP. Results: The R2PD for selinexor in combination with R-GDP was established as 40 mg on days 1, 8, and 15 (Maerevoet, IMCL 2021#176). Between January 2017 and January 2021, 32 pts received selinexor-R-GDP. We focused on the 18 pts who received the R2PD: 15 had DLBCL, 2 FL, 1 marginal zone lymphoma. In this cohort, median age was 61 years (range 44-69); 14 pts (78%) has stage III/IV. Thirteen pts received 1 previous line before inclusion, 5 pts received 2 previous lines. At inclusion, 6 pts had refractory disease and 12 relapsed. Four pts prematurely discontinued treatment: 2 for thrombocytopenia, 1 for COVID, 1 for progression. Major adverse events (AEs) in >10% of pts were reversible neutropenia (50%), thrombocytopenia (39%), and nausea (22%). No AEs leading to death were observed. Seven pts (39%) achieved a complete metabolic response (CMR), 5 pts (28%) partial metabolic response (PMR). Overall response rate (CMR+PMR) assessed at the end of treatment according to Lugano classification was 67% (12 of 18). Nine of the 15 pts (60 %) with DLBCL had metabolic response (CMR:4, PMR:5). Per protocol, peripheral stem cell collection and ASCT were optional, 4 pts of this RP2D cohort proceeded to high dose therapy (BEAM) and ASCT. Conclusion: This study established the safety profile of weekly 40mg of Selinexor in combination with R-GDP for R/R B cell lymphoma with an ORR of 67%. Reversible AEs are expected for platinum-based regimen. An ongoing randomized phase 2 study comparing R-GDP and R-GDP plus selinexor in pts with R/R DLBCL will now establish the safety and efficacy of the combination. Disclosures Casasnovas: Janssen: Consultancy; BMS: Consultancy; Gilead/Kite: Consultancy, Research Funding; TAKEDA: Consultancy, Research Funding; ROCHE: Consultancy, Research Funding; Amgen: Consultancy. Morschhauser: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Genentech, Inc.: Consultancy; Chugai: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees. Thieblemont: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Feugier: Amgen: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astrazeneca: Consultancy, Honoraria.

A randomized phase 3 trial of auto vs. allo transplantation as part of first-line therapy in poor-risk peripheral T-NHL

Standard first-line therapy for younger patients with peripheral T-cell lymphoma consists of six courses of CHOP or CHOEP consolidated by high-dose therapy and autologous stem cell transplantation (AutoSCT). We hypothesized that consolidative allogeneic transplantation (AlloSCT) could improve outcome. 104 patients with nodal peripheral T-cell lymphoma except ALK+ ALCL, 18 to 60 years of age, all stages and IPI scores except stage 1 and aaIPI 0, were randomized to receive 4 x CHOEP and 1 x DHAP followed by high-dose therapy and AutoSCT or myeloablative conditioning and AlloSCT. The primary endpoint was event-free survival (EFS) at three years. After a median follow-up of 42 months, 3-year EFS of patients undergoing AlloSCT was 43% (95% confidence interval [CI]: 29%; 57%) as compared to 38% (95% CI: 25%; 52%) after AutoSCT. Overall survival at 3 years was 57% (95% CI: 43%; 71%) versus 70% (95% CI: 57%; 82%) after AlloSCT or AutoSCT, without significant differences between treatment arms. None of 21 responding patients proceeding to AlloSCT as opposed to 13 of 36 patients (36%) proceeding to AutoSCT relapsed. Eight of 26 patients (31%) and none of 41 patients died due to transplant-related toxicity after allogeneic and autologous transplantation, respectively. In younger patients with T-cell lymphoma standard chemotherapy consolidated by autologous or allogeneic transplantation results in comparable survival. The strong graft-versus-lymphoma effect after AlloSCT was counterbalanced by transplant-related mortality. CHO(E)P followed by AutoSCT remains the preferred treatment option for transplant-eligible patients. AlloSCT is the treatment of choice for relapsing patients also after AutoSCT.

A complex of methods of radiation diagnostics in a patient with multiple myeloma (clinical case)

The article presents the possibilities of the complex application of methods of radiation diagnostics: bone x-ray, dual-energy X-ray absorptiometry, computed tomography, positron emission tomography combined with computed tomography using fluorodeoxyglucose labeled with 18-fluorine (PET/CT with 18F-FDG) in a patient with multiple myeloma, which was treated in the amount of high-dose therapy with autologous transplantation of hematopoietic stem cells. The diagnosis was established immunohistochemically. The use of these methods allowed us to dynamically assess the pathological changes characteristic of multiple myeloma.