Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses.

Outcomes are poor in triple-class-exposed (TCE) relapsed/refractory multiple myeloma (RRMM). In the phase 3 KarMMa-3 (clinicaltrials.gov; NCT03651128) trial, patients with TCE RRMM and 2-4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary endpoint; 13.3 vs 4.4 months; P<.0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median (95% CI) was 41.4 (30.9-not reached [NR]) vs 37.9 (23.4-NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE RRMM. NCT03651128.

[Chronic graft-versus-host disease]. / Kronisk transplantat-mot-vert-sykdom.

Chronic graft-versus-host disease is a late complication of allogeneic stem cell transplantation and leads to chronic inflammation and fibrosis in various organs due to dysregulation of donor immune cells. The disease can occur in all organs, but is most frequently seen in the skin, eyes, oral cavity, gastrointestinal tract, genitalia, lungs, muscles, fascia and joints. Chronic graft-versus-host disease is associated with considerable morbidity and mortality, and treatment requires close collaboration between different parts of the specialist health services. This article provides a clinical review of chronic graft-versus-host disease based on a non-systematic literature search and the authors' own clinical experience.

Allogeneic stem cell transplantation in adults 2015-21. / Allogen stamcelletransplantasjon hos voksne 2015­21.

BACKGROUND: Allogeneic stem cell transplantation is the only curative treatment for several malignant and non-malignant haematological diseases, and is associated with a risk of serious complications. In recent years, several changes have been introduced with the aim of reducing treatment-related complications. This retrospective study reviews quality indicators for patients who underwent transplantation in the period 2015-21. MATERIAL AND METHOD: The study included 589 adult patients who were treated with allogeneic stem cell transplantation for the first time at Oslo University Hospital in the period May 2015 to May 2021. Three two-year periods are compared using descriptive methods. RESULTS: In the period 2015-2021, the number of first-time transplant patients per year increased from 85 to 113. One-year survival increased from 68 % in the first two-year period to 74 % in the second period and 82 % in the last period. Both acute and chronic GVHD were reduced, and one-year GVHD-free and relapse-free survival increased from 42 % to 60 % during the study period. INTERPRETATION: Since 2015, the number of transplants has increased, while survival has improved and the risk of complications is lower.

Allogeneic stem cell transplant recipients surviving at least 2 years without relapse: outcome and risk factors.

Outcomes of 2-year survivours undergoing allo-haematopoietic stem cell transplantation at Oslo University Hospital were retrospectively assessed with the objectives of identification of risk factors for late death as possible means for precautionary measures and interventions to improve long-term survival. 421 patients with haematological malignancy, transplanted between 2005 and 2019, alive and free of disease after 2 years were included with data reported from The OUS-HSCT registry. Median follow-up was 6.2 years (2.016.1), and 232 patients (55%) were observed for minimum 5 years. The probability of being alive 5 and 10 years after HSCT was 86% and 76%. Primary risk factors for late death included initial diagnosis of age ≥ 60 years, chronic lymphocytic leukaemia (CLL), previous blood stream- or invasive fungal infection (BSI, IFI), and chronic graft-versus-host disease (cGVHD). Transplant-related mortality (TRM) and relapse at 5 years were 9.0% and 7.7%, respectively. Two factors were associated with the latter: cytomegalovirus (CMV) seronegative donor and CLL. Compared with the age- and gender-matched Norwegian general population, life expectancy was lower for each disease, except for CML. The prospect for the long-term survival is good for 2-year survivors of the allogeneic hematopoietic stem cell transplantation. However, life expectancy remains inferior to the age- and gender-matched general population. Optimising prophylaxis and treatment for chronic GVHD, BSI and IFI are needed along with the improved adherence to guidelines for early detection of secondary malignancies. Measures to improve immune reconstitution, possibly the microbiota, and the use of CMV seropositive donors regardless of recipient sero-status may be warranted and should be addressed in further studies.

T cells raised against allogeneic HLA-A2/CD20 kill primary follicular lymphoma and acute lymphoblastic leukemia cells.

T cells mediating a graft-versus-leukemia/lymphoma effects without causing graft-versus-host disease would greatly improve the safety and applicability of hematopoietic stem cell transplantation. We recently demonstrated that highly peptide- and HLA-specific T cells can readily be generated against allogeneic HLA-A*02:01 in complex with a peptide from the B cell-restricted protein CD20. Here, we show that such CD20-specific T cells can easily be induced from naïve precursors in cord blood, demonstrating that they do not represent cross-reactive memory cells. The cells displayed high avidity and mediated potent cytotoxic effects on cells from patients with the CD20(pos) B cell malignancies follicular lymphoma (FL) and acute lymphoblastic leukemia (ALL). However, the cytotoxicity was consistently lower for cells from two of the ALL patients. The ALL cells that were less efficiently killed did not display lower surface expression of CD20 or HLA-A*02:01, or mutations in the CD20 sequence. Peptide pulsing fully restored the levels of cytotoxicity, indicating that they are indeed susceptible to T cell-mediated killing. Adoptive transfer of CD20-specific T cells to an HLA-A*02:01(pos) patient requires an HLA-A*02:01(neg) , but otherwise HLA identical, donor. A search clarified that donors meeting these criteria can be readily identified even for patients with rare haplotypes. The results bear further promise for the clinical utility of CD20-specific T cells in B cell malignancies.

Case Report: Pure Red Cell Aplasia Caused by Refractory Parvovirus B19 Infection After Pancreas Transplantation Alone.

A multidisciplinary team of doctors is in charge or is involved in the follow-up of patients who undergo solid organ transplantation (SOT). Immunosuppressive drugs are required after SOT, some potential unwanted side effects can be difficult to detect, and physicians must be aware of potential pitfalls. We report a case of a recipient with brittle type 1 diabetes who experienced severe and refractory anemia after pancreas transplantation alone (PTA). Despite a broad diagnostic approach for anemia, the diagnosis was delayed. The patient had normocytic normochromic anemia with severe reticulocytopenia and marked reduction or absence of erythroid precursors in the bone marrow, compatible with pure red cell aplasia (PRCA). Analyses of serological parvovirus B19 anti-IgM and anti-IgG antibodies, including PCR, were initially inconclusive/negative. The diagnosis of parvovirus B19 infection was confirmed after bone marrow biopsy with immunohistochemical staining for parvovirus B19. A retrospective analysis revealed an early post-transplant primary parvovirus B19 infection. The patient was successfully treated with intravenous immunoglobulin (IVIg) therapy. There is a risk of diagnostic delay for the less common types of anemia following SOT. Parvovirus B19 infection-associated PRCA is curable in SOT recipients and should be actively considered in patients with persistent anemia and low reticulocytes.

Immune reconstitution after allogeneic stem cell transplantation: the impact of stem cell source and graft-versus-host disease.

BACKGROUND AND OBJECTIVES: Bone marrow (BM) and blood stem cell (BSC) allografts differ considerably with respect to their content of progenitor cells and progenitor cell subsets as well as mature lymphocytes. The aim of this prospective, randomized study was to determine whether these differences have an impact on early post-transplant immune recovery. DESIGN AND METHODS: In a prospective randomised study, we found enhanced immune recovery in recipients of BSC allografts compared to in recipients of BM allografts despite transplantation of a lower number of lymphoid progenitors, particularly B-cell progenitors. The large number of mature lymphocytes in BSC allografts is a plausible explanation for this observation. At the progenitor cell level, we found a comparable and very high proportion of progenitor cells involved in lymphopoiesis in both study groups. RESULTS: Patients with extensive chronic GVHD, irrespective of the allograft received, had low immunoglobulin (Ig) levels in serum, low B-cell counts in blood and low numbers of B-cell progenitors in the bone marrow. They also showed high T-cell counts, particularly CD3+CD8+ T-cell counts, which was paralleled by a high number of T-cell progenitors in the bone marrow. In patients with extensive chronic GVHD we found low natural killer (NK)-cell counts which has not been reported previously. INTERPRETATION AND CONCLUSIONS: Early immune recovery is enhanced following BSC allografting compared with BM allografting. This is plausibly explained by the large inoculum of mature lymphocytes in BSC allografts. Following allografting, a higher proportion of the BM progenitor cell compartment is involved in lymphopoiesis than it is in healthy adults. However, B-lymphopoiesis is inhibited in patients with extensive chronic GVHD resulting in impaired B-cell recovery. These patients also seem to show impaired NK-cell recovery.