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Context Tisagenlecleucel demonstrated durable responses and manageable safety in adult patients with r/r diffuse large B-cell lymphoma. Objective Determine the efficacy and safety of tisagenlecleucel in adult patients with r/r FL. Design ELARA (NCT03568461) is an international, multicenter, single-arm, phase 2 trial of tisagenlecleucel treatment. Patients or Other Participants Adult (≥18 years) patients with r/r FL (grades 1–3A) after ≥2 lines of therapy or whose disease relapsed after autologous stem cell transplant were eligible. As of September 28, 2020, 98 patients were enrolled. Interventions Bridging therapy was permitted, and disease status was reassessed prior to infusion. Patients received tisagenlecleucel (0.6–6×10 8 CAR+ viable T-cells) after lymphodepleting chemotherapy. Main Outcomes Measures Primary endpoint was complete response rate (CRR) by central review (Lugano 2014 criteria). Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and cellular kinetics. Results Ninety-seven patients received tisagenlecleucel (median follow-up, 10.6 months). Median age at study entry was 57 years (range, 29-73), 85% had stage III–IV disease, 60% had a FLIPI score ≥3, 65% had bulky disease, and 42% had LDH > upper limit of normal. Median number of prior therapies was 4 (range, 2–13); 78% of patients were refractory to their last treatment, and 60% progressed ≤2 years of initial anti-CD20-containing treatment. Among 94 patients evaluable for efficacy, CRR was 66% (95% CI, 56%–75%), and ORR was 86% (95% CI, 78%–92%). Estimated DOR (CR) and PFS rates at 6 months were 94% (95% CI, 82%–98%) and 76% (95% CI, 65%–84%), respectively. Of 97 patients evaluable for safety, 65% experienced grade ≥3 adverse events ≤8 weeks post-infusion, most commonly neutropenia (28%) and anemia (13%). Any-grade cytokine release syndrome (Lee scale) occurred in 49% of patients. Any-grade neurological events (per CTCAE v4.03) occurred in 9% of patients. Three patients died from disease progression. C(max) and AUC(0–28d) for tisagenlecleucel were similar between responders and nonresponders. C(max) was achieved at a median of 10 days in responders and 12.9 days in nonresponders. Conclusions Tisagenlecleucel demonstrated efficacy and a favorable safety profile in patients with r/r FL. The study was funded by Novartis.

Background: From 1999, Norwegian guidelines recommend two escalated (esc) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) followed by six standard (s) BEACOPP for patients with advanced-stage classical Hodgkin lymphoma (HL) with an international prognostic score (IPS) ‡4. We evaluated retrospectively the experience with this recommendation at the Norwegian Radium Hospital, also including all IPS 3 patients treated with the same regimen. Patients and methods: Forty-seven patients were treated between June 1999 and December 2008. IPS was 3 in 10 patients and ‡4 in 37. Results: Thirty-five patients received eight cycles of BEACOPP, 12 patients received one to six cycles only, mainly due to toxicity. Sixty percent of patients had dose reductions. With median follow-up of survivors of 89 months, 5-year progression-free and overall survival are 84% [95% confidence interval (CI) 73% to 95%] and 91% (95% CI 82% to 100%), respectively. Toxicity was considerable with grade 3 or more infections/febrile neutropenia in 66% of patients, including one death and three cases of Pneumocystis jiroveci pneumonia. Of note, 10 patients (21%) experienced symptomatic aseptic osteonecrosis, of whom 3 have had hip replacement surgery after treatment. Conclusion: Two escBEACOPP plus six sBEACOPP is efficacious in advanced-stage high-risk HL. We document a high incidence of aseptic bone necrosis, possibly related to prednisolone.

Purpose 177Lu-lilotomab satetraxetan is an antibody-radionuclide conjugate therapy for non–Hodgkin lymphoma, which is currently in a phase 1/2-study. The primary toxicity is transient myelosuppression. The aim of this work was to determine if a linear model including red marrow absorbed dose and various clinical factors can be used to predict myelosuppression. Methods Patient characteristics and dosimetric data for 17 patients were included. All patients had no or minor bone marrow infiltration. The percentage reduction of neutrophils and platelets at nadir compared to baseline was used as to indicate myelosuppression. Platelets and neutrophils were analysed separately. The Common Terminology Criteria version 4.0 were used to grade thrombocytopenia and neutropenia. A total of six factors believed to affect bone marrow reserve were tested: Red marrow absorbed dose, age at treatment, baseline cell-counts, history of prior external beam radiation therapy, total number of previous chemotherapy treatments (including rituximab) and elapsed time since the last chemotherapy treatment. Predictors were found using ordinary least square fitting, testing all possible subsets of variables. A significance level of 0.05 was used. A leave 1-out analysis was used to validate the final model. Results The typical patient, as described by the mean and standard deviation, was 69 (+/−10) years of age at treatment, had previously been treated 2.8 (+/−1.8) times with chemotherapy and might have previously received external beam radiation therapy (5/17 patients). Elapsed time since the last chemotherapy was 20.9 (+/−17.2) months. Mean red marrow absorbed dose was 1.45 (+/−0.45) Gy. Of the sub-sets of predictors investigated, only a model consisting solely of the red marrow absorbed dose was significant (p = 0.048 for platelets and 0.027 for neutrophils). Model coefficients indicate total loss of both platelets and neutrophils at 3 Gy. The leave-1 out analysis resulted in correct prediction of CTCAE-grading +/−1 grade for 76.5 % (13/17) and 88.2 % (15/17) of the patients for thrombocytopenia and neutropenia, respectively. Conclusions A linear model with red marrow absorbed dose as the only parameter predicted myelosuppression in 177Lu-lilotomab satetraxetan treated patients.

Background: A graft-versus-lymphoma effect against diffuse large B-cell lymphoma (DLBCL) is inferred by sustained relapse-free survival after allogeneic stem-cell transplantation; however, there are limited data on a direct graft-versus-lymphoma effect against DLBCL following immunotherapeutic intervention by either withdrawal of immunosuppression or donor lymphocyte infusion (DLI). Materials and methods: An analysis was carried out to determine whether a direct graft-versus-lymphoma effect exists against DLBCL. The analysis was restricted to patients with DLBCL, who were either not in complete remission at day +100 after allogeneic stem-cell transplantation or subsequently relapsed beyond this time point. Results: Fifteen patients were identified as either not in complete remission (n = 13) at their day +100 evaluation or subsequently relapsed (n = 2) and were assessed for subsequent responses after withdrawal of immunosuppression or DLI. Eleven patients were treated with either withdrawal of immunosuppression (n = 10) or a DLI (n = 1) alone; four patients received chemotherapy with DLI to reduce tumor bulk. Nine (60%) patients subsequently responded (complete = 8, partial = 1). Six responses occurred after withdrawal of immunosuppression alone. Six patients are alive (range 42–83+ months) in complete remission without further treatment. Conclusion: The demonstration of sustained complete remission following immunotherapeutic intervention provides direct evidence of a graft-versus-lymphoma effect against DLBCL.

This study reports on oncology professionals' knowledge and attitude toward complementary and alternative medicines (CAM), classified according to their primary application as complementary or alternative methods. In June 2002, we conducted a national, multicentre survey of 828 Norwegian oncologists, nurses, clerks and therapeutic radiographers. A response rate of 61% was achieved. Only a few physicians (4%) described their reactions to alternative medicine as positive compared with nurses (33%), therapeutic radiographers (32%) and clerks (55%) (P

The new human-human hybridoma TrD3 secretes a cytotoxic IgM mAb, which reacted with 28 of a panel of 56 HLA-typed lymphoblastoid cells. All 28 TrD3+ cells expressed the HLA-B supertype Bw6, whereas 10 Bw6+ cells were not recognized by the mAb. None of the 17 Bw4 homozygous cells were positive with TrD3. Thus, TrD3 divided the Bw6+ HLA-B specificities of the cell lines into two subgroups, namely, Bw6+TrD3+ and Bw6+TrD3-, and therefore defines a new HLA-B supertype. TrD3 reacted strongly with some B8+ cell lines and weakly or not at all with others, suggesting a new split of HLA-B8. Compared with cell lines, TrD3 reacted more weakly with freshly isolated T cells from blood. The Bw6-specific rat mAb SFR8-B6 partially blocked the binding of 125I-labeled TrD3 to a Bw6+ cell line. By using cell lines transfected with hybrid genes between HLA-B7 (Bw6+) and HLA-B27 (Bw6-) as targets in flow cytometry, critical residues for the TrD3 epitope could be mapped to the amino acid region 24-62 of the HLA class-I alpha 1 domain. Comparison of deduced amino acid sequences of TrD3-positive and -negative cells indicated that a tryptophane residue at position 95 destroyed the TrD3 epitope, and that one or more of the residues in positions 24, 45, and 46 may be critical, suggesting that it is a discontinuous epitope. It is notable that none of these residues are located on alpha-helixes.(ABSTRACT TRUNCATED AT 250 WORDS)

pathways. Alloreactivity was mainly restricted to CIK bulk and CD56subset as confirmed by the Th1/Th2 cytokines released in the supernatant. Conclusion: In the contest of a clinical application, the immunomagnetic purging of the CD56cell fraction by the CIK bulk could limit the risk of Graft Versus Host Disease maintaining at the same time the antitumor effect restricted to the CD56+ cell subset.

We have constructed an IgG, k human-human hybridoma Ab(TrB12), which precipitates a molecule consisting of two polypeptides of about 33 and 27 kD in size. TrB12 reacted with; (1) 7 out of 10 DQw1-positive cell lines in IIF ∗ , and all 10 in a rosette-assay; (2) 5 out of 12 DQw3-positive cells, both in IIF and the rosette-assay; (3) none of 4 DQw2 homozygous cells. Detergent cell lysate of DQw1 homozygous cell lines contained antigens that cross-linked the mouse monoclonal antibody Genox 353 G2a-5 (anti-DQw1) and TrB12. TrB12 competed with the mouse DQw3-specific monoclonal antibody IVD-12 for binding to DQw3 homozygous cells. The data imply that the TrB12 epitope is associated with molecules that carry DQw1 and DQw3 serological specificities. By radioimmunoassay. TrB12 and the mouse monoclonal antibody IIB3 divided both DQw1- and DQw3- bearing cell lines into three phenotypic groups: (1) TrB12 + IIB3 bi∗ , (2) TrB12 − IIB3 lo , and (3) TrB12 − IIB3 − . For DQw1 the results suggest that the first two groups represent structural variants but the third group may reflect low expression of DQw1. For DQw3 the evidence suggests that all three phenotypes represent structural variants. DQw3 has previously been divided into two serologically defined alleles, TA10 + IIB3 − and TA10 − IIB3 + . The TrB12 + IIB3 bi and TrB12 − IIB3 lo variants of DQw3 described in this study probably represent novel subgroups of the TA10 − IIB3 + allele.

We here report two human-human hybridoma antibodies: TrB50 (IgG) and TrE11 (IgM), derived from the same donor. They displayed an identical reaction pattern with 76 Epstein-Barr virus-transformed cell lines. Of these, 29 lines were completely HLA-typed and both antibodies recognized all cells expressing DPwl (six lines), DPw3 (five lines), or DPw5 (three lines). In addition, they bound to one out of four DPw2+ cells and three out of four DPblank+ cells. This specificity correlated strikingly with a characteristic DP beta amino acid sequence (DEAV) at positions 84-87 that had been determined by others. Binding of 125I-labeled TrB50 to lymphoblastoid cells was inhibited by unlabeled IVA-12 (anti-DR + DP monomorphic) and by TrE11. Furthermore, antigens in lysates from TrB50+TrE11+ cells cross-linked TrB50 and TrE11 to the monomorphic anti-DP monoclonal antibody B7/21. Collectively the data provide strong evidence that the epitopes reside on DP molecules. TrE11 can be used to type for this DP beta supertypic specificity by microcytotoxicity using isolated blood B lymphocytes as targets or by a rosette assay directly on whole blood.