Comprehensive Review of AL amyloidosis: some practical recommendations

International audienceAmyloid light chain (AL) amyloidosis is among the more common and more severe of the amyloidoses usually involving the slow proliferation of a bone-marrow-residing plasma cell (PC) clone and the secretion of unstable immunoglobulin-free light chains (FLC) that infiltrate peripheral tissues and result in detrimental end-organ damage. Disease presentation is rather vague, and the hallmark of treatment is early diagnosis before irreversible end-organ damage. Once diagnosed, treatment decision is transplant-driven whereby ~20% of patients are eligible for autologous stem cell transplantation (ASCT) with or without bortezomib-based induction. In the setting of ASCT-ineligibility, bortezomib plays a central role in upfront treatment with the recent addition of daratumumab to the current emerging standard of care. In general, management of AL amyloidosis is aimed at achieving deep, durable responses with very close monitoring for early detection of relapse/refractory disease. This article provides a comprehensive review of the management of patients with AL amyloidosis including goals of therapy, current treatment guidelines in the setting of both ASCT-eligibility and ineligibility, treatment response monitoring recommendations, toxicity management, and treatment of relapse/refractory disease

Impact of Adding Antithymocyte Globulin to Posttransplantation Cyclophosphamide in Haploidentical Stem-Cell Transplantation

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Predictive Factors for Outcome of First Allogeneic Transplant for Elderly Patients With Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) in elderly patients is challenging, and while allogeneic stem cell transplantation (alloHCT) has established benefits in younger candidates, its use in the elderly can be difficult. We identified 84 ALL patients 70 years or older in the EBMT registry that underwent alloHCT. Our results demonstrate favorable outcome especially in those achieving first complete remission with >50% 2-year OS. AlloHCT appears feasible in select elderly ALL patients. Introduction/Background: The treatment of acute lymphoblastic leukemia (ALL) in patients older than 70 is extremely challenging with dismal outcome. Allogeneic stem cell transplantation (alloHCT) has seen many advancements in the last decades showing benefits in younger ALL patients, but this treatment modality is decreasingly used with increasing age due to high treatment-related mortality. Patients and Methods: We identified 84 ALL patients 70 to 84 years old allografted In 2002 to 2019 from a matched related (23%), unrelated (58%), haploidentical (17%), or cord blood (2%) donor at EBMT participating centers with a median follow-up of 23 months. Results: The 2-year relapse incidence (RI) and non-relapse mortality were 37% and 28%, respectively, and 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 35%, 39% and 23%, respectively. The strongest predictor of outcome was disease status at transplant whereby patients in first complete remission (CR1) had >50% 2-year OS, reflected in multivariate analysis (MVA) with significant improvement in RI, LFS, and GRFS (HR 0.23, 0.49, and 0.54, respectively). Furthermore, karnofsky score >= 90 reflective of good functional status positively influenced non-relapse mortality in both univariate and MVA (HR 0.37), and interestingly, donor CMV positivity appeared to negatively affect RI, LFS and OS in univariate analysis and RI in MVA (HR 2.87). Conclusion: Our data suggest that alloHCT is an option for elderly ALL patients, particularly those carefully selected and transplanted in CR1 especially if failed or without access to novel non-chemotherapy-based approaches. (C) 2021 Elsevier Inc. All rights reserved

Isocitrate dehydrogenase (IDH) 1 and 2 mutations predict better outcome in patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation:a study of the ALWP of the EBMT

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations have uncertain prognostic implications in AML. We investigate the impact IDH1 and IDH2 mutations in AML patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). In total, 1515 adult patients were included, 15.91% (n = 241) carried IDH1 mutation (mIDH1), and 26.27% (n = 398) IDH2 mutation (mIDH2) and 57.82% (n = 876) had no-IDH mutation. NPM1 was frequently encountered with IDH1 mutation (no-IDH group, n = 217, 24.8%, mIDH1, n = 103, 42.7%, mIDH2, n = 111, 27.9%, p &lt; 0.0001). At day 180, the cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was significantly lower in mIDH1 and mIDH2 compared to no-IDH groups (Hazard ratio [HR] = 0.66 (95% CI 0.47–0.91), p = 0.011; HR = 0.73 (95% CI 0.56–0.96), p = 0.025, respectively). In the mIDH1 group, overall survival (OS) was improved compared to no-IDH (HR = 0.68 (95% CI 0.48–0.94), p = 0.021), whereas mIDH2 was associated with lower incidence of relapse (HR = 0.49 (95% CI 0.34–0.7), p &lt; 0.001), improved leukemia free survival (LFS) (HR = 0.7 (95% CI 0.55–0.9), p = 0.004) and OS (HR = 0.74 (95% CI 0.56–0.97), p = 0.027). In the subgroup of NPM1 wild type, only IDH2 was associated with improved outcomes. In conclusion, our data suggest that IDH1 and IDH2 mutations are associated with improved outcomes in patients with AML undergoing allo-HCT in CR1.</p

Allogeneic stem-cell transplantation with sequential conditioning in adult patients with refractory or relapsed acute lymphoblastic leukemia: a report from the EBMT Acute Leukemia Working Party

Treatment of relapsed/refractory acute lymphoblastic leukemia (RR-ALL) remains a clinical challenge with generally dismal prognosis. Allogeneic stem-cell transplantation using sequential conditioning (FLAMSA-like) has shown promising results in relapsed/refractory acute myeloid leukemia, but little is known about its efficacy in RR-ALL. We identified 115 patients (19-66 years) with relapsed (74%) or primary-refractory (26%) ALL allografted from matched related (31%), matched unrelated (58%), or haploidentical donor (11%). Median follow-up was 37 (13-111) months. At day 100, cumulative incidences of grade II-IV/III-IV acute graft-versus-host-disease (GVHD) were 30% and 17%, respectively. Two-year cumulative incidence of chronic GVHD was 25% with 11% extensive cases. Two-year relapse incidence (RI) was 45%, non-relapse mortality was 41%. Two-year leukemia free survival (LFS) was 14%, overall survival (OS) 17%, and GVHD relapse-free survival (GRFS) was 14%. In multivariable analysis, Karnofsky score <90 negatively affected RI, LFS, OS, and GRFS. Conditioning with chemotherapy alone, compared with total body irradiation (TBI) negatively affected RI (HR = 3.3; p = 0.008), LFS (HR = 1.94; p = 0.03), and OS (HR = 2.0; p = 0.03). These patients still face extremely poor outcomes, highlighting the importance of incorporating novel therapies (e.g., BITE antibodies, inotuzumab, CAR-T cells). Nevertheless, patients with RR-T-cell ALL remain with an unmet treatment need, for which TBI-based sequential conditioning could be one of few available options

Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party.

Allogeneic hematopoietic cell transplantation (alloHCT) is a complex, potentially fatal therapy featuring a myriad of complications. Triggering event(s) of such complications vary significantly, but often a so-called "multi-organ failure" (MOF) is reported as the leading cause of death. The identification of the exact trigger of MOF is critical towards early and disease-specific intervention to improve outcome. We examined data from 202 alloHCT patients reported to have died of MOF from the EBMT registry aiming to determine their exact cause of death focusing on veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) due to its life-threatening, often difficult to capture yet preventable nature. We identified a total of 70 patients (35%) for whom VOD/SOS could be considered as trigger for MOF and leading cause of death, among which 48 (69%) were previously undiagnosed. Multivariate analysis highlighted history of hepatic comorbidity or gentuzumab use and disease status beyond CR1 as the only significant factors predictive of VOD/SOS incidence (OR = 6.6; p = 0.001 and OR = 3.3; p = 0.004 respectively). VOD/SOS-related MOF was widely under-reported, accounting for 27% of deaths attributed to MOF of unknown origin without a previous VOD/SOS diagnosis. Our results suggest most missed cases developed late VOD/SOS beyond 21 days post-alloHCT, highlighting the importance of the newly revised EBMT criteria