This study identifies and validates new criteria for response to first-line treatment in AL amyloidosis, based on their association with survival in large patient populations, and offers surrogate end points for clinical trials.

Key Points• A staging system based on proteinuria and glomerular filtration rate discriminates patients at different risk of progression to dialysis.• Changes in proteinuria and glomerular filtration rate allow early assessment of renal response to therapy.The kidney is involved in 70% of patients with immunoglobulin light-chain (AL) amyloidosis, but little is known on progression or reversibility of renal involvement, and criteria for renal response have never been validated. Newly diagnosed patients from the Pavia (n 5 461, testing cohort) and Heidelberg (n 5 271, validation cohort) centers were included. Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50 mL/min predicted progression to dialysis best. Proteinuria below and eGFR above the thresholds indicated low risk (0 and 4% at 3 years in the testing and validation cohorts, respectively). High proteinuria and low eGFR indicated high risk (60% and 85% at 3 years). At 6 months, a ‡25% eGFR decrease predicted poor renal survival in both cohorts and was adopted as criterion for renal progression. A decrease in proteinuria by ‡30% or below 0.5 g/24 h without renal progression was the criterion for renal response, being associated with longer renal survival in the testing and validation populations. Hematologic very good partial or complete remission at 6 months improved renal outcome in both populations. We identified and validated a staging system for renal involvement and criteria for early assessment of renal response and progression in AL amyloidosis that should be used in clinical practice and trial design. (Blood. 2014;124(15):2325-2332

In rheumatoid arthritis, peripheral blood T cells have age-inappropriate telomeric erosion. We examined whether HLA-DRB1*04 alleles, the major susceptibility genes for this disease, confer risk for T cell senescence. In healthy individuals, HLA-DRB1*04 alleles were associated with excessive loss of telomeres in CD4 ؉ T cells. Accelerated telomeric erosion occurred during the first two decades of life and was followed by reduced homeostatic T cell proliferation during adulthood. Premature telomeric loss also affected granulocytes, suggesting that the hematopoietic stem cell is the primary target. Telomeric repair mechanisms were intact in HLA-DRB1*04 ؉ donors. We propose that HLA-DRB1*04 alleles or genes in linkage disequilibrium regulate stem cell replication and contribute to the accumulation of senescent and autoreactive T cells in rheumatoid arthritis.

IntroductionDe novo T-cell generation requires a functional thymus. 1 The current paradigm is that the human T-cell repertoire is established during late fetal development and that, by the time of birth, thymectomy does not cause immediate immunodeficiency. 2,3 Thymic epithelial space-the component of the thymus relevant for T-cell production and selectioninvolutes rapidly after birth. Thymic involution starts at the age of 1 year and continues with a yearly loss of 3%. 4,5 The peripheral T-cell compartment is under homeostatic control 6 ; with the reduction in thymopoietic capacity, alternative mechanisms of T-cell generation are necessary to prevent lymphopenia. Autoproliferation of postthymic T cells, particularly those in the memory compartment, is now accepted as a mechanism of T-cell production. 7,8 With advancing age, a shift occurs from efficient thymic lymphopoiesis to T-cell generation through peripheral replication; however, both mechanisms likely coexist during adult life. Age-related loss of thymic function is not the only condition that necessitates alternative means of repopulating the T-cell compartment. A number of clinical conditions, including chemotherapy, bone marrow transplantation, and infection with human immunodeficiency virus, are associated with T-cell depletion and the subsequent need to regenerate T cells despite limited thymopoietic capability. Evidence shows that recovery of peripheral T-cell numbers after chemotherapy is from thymic sources in children younger than 18 years of age. 7 In adults, thymopoiesis may still contribute to some degree, but replication of peripheral T cells becomes the dominant mechanism of filling the pool. It is obvious that the proliferation of postthymic T cells, especially when not entirely random, can have profound consequences on the composition of the T-cell repertoire. 9,10 What precisely these consequences are for immunocompetence is not understood.Functionality of the immune system is tightly linked to the receptor diversity of the T-cell pool. 11,12 Obviously, a large spectrum of T-cell receptors (TCRs) increases the chances of recognizing invading microorganisms. Thymopoiesis, the single mechanism of creating novel T cells, should be the key factor in determining immunocompetence. Young adults carry approximately 2 ϫ 10 11 CD4 ϩ T cells and approximately 1 ϫ 10 11 CD8 ϩ T cells. 13,14 The highest degree of diversity would be obtained if each naive T cell in the pool had a unique TCR. However, such a high degree of diversity might not be advantageous because it would decrease the probability of antigen recognition at a given tissue site. Instead, a minimal clonal size for each naive T-cell specificity is required to increase the chance for a T cell to encounter antigen and to mount a defensive response. Generation of a minimal clonal size requires that T cells selected in the thymus undergo intrathymic or postthymic proliferation.Arstila et al 15 have estimated the clonal size of naive T cells in adult humans. They measured an average diversity ...

Key Points• Tandem autologous/reducedintensity allogeneic transplantation is superior to autologous transplantation alone in multiple myeloma.Long-term follow-up of prospective studies comparing allogeneic transplantation to autologous transplantation in multiple myeloma is few and controversial. This is an update at a median follow-up of 96 months of the European Group for Blood and Marrow Transplantation Non-Myeloablative Allogeneic stem cell transplantation in Multiple Myeloma (NMAM)2000 study that prospectively compares tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation alone (auto). There are 357 myeloma patients up to age 69 years enrolled. Patients with an HLA-identical sibling were allocated to auto/RICallo (n 5 108) and those without to auto alone (n 5 249). At 96 months progression-free survival (PFS) and overall survival (OS) were 22% and 49% vs 12% (P 5 .027) and 36% (P 5 .030) with auto/RICallo and auto respectively. The corresponding relapse/progression rate (RL) was 60% vs 82% (P 5 .0002). Non-relapse mortality at 36 months was 13% vs 3% (P 5 .0004). In patients with the del(13) abnormality corresponding PFS and OS were 21% and 47% vs 5% (P 5 .026), and 31% (P 5 .154). Long-term outcome in patients with multiple myeloma was better with auto/RICallo as compared with auto only and the auto/RICallo approach seemed to overcome the poor prognostic impact of del(13) observed after autologous transplantation. Follow up longer than 5 years is necessary for correct interpretation of the value of auto/RICallo in multiple myeloma. (Blood. 2013;121(25):5055-5063) Introduction Despite improvements in survival of patients with multiple myeloma by treatment with new drugs such as thalidomide, bortezomib, and lenalidomide, documented cures of the disease are lacking. Allogeneic hematopoietic stem cell transplantation has been studied, but results have been controversial. [1][2][3][4][5][6][7] Recently, we published the first results of a prospective Non-Myeloablative Allogeneic stem cell transplantation in Multiple Myeloma study (NMAM2000) comparing tandem autologous (auto)/reduced intensity conditioning allogeneic transplantation (RICallo) with autologous transplantation-single (auto) or tandem(auto/auto).8 Although superior progression-free survival (PFS), overall survival (OS), and relapse rate (RL) using the tandem auto/RICallo treatment modality was documented using appropriate tests for crossing curves, interpretation of the results has been controversial. This update of the study, after a median follow-up of 96 months, supports and strengthens the previous conclusion that the tandem auto/RICallo approach prolongs PFS and OS long term due to lower progression/relapse rate. This is true both using an intention to treat analysis and an analysis that compares only those patients who received treatment according to protocol. Considering this study started in the era predating "novel" agents, our results suggest that reports of the "death" ...