BACKGROUND.Late antibody-mediated rejection (AMR) is a major cause of transplant failure. Potential therapeutic targets are plasma cells (PC) and/or natural killer (NK) cells, both expressing high ...levels of CD38.
METHODS.Here, we report the use of CD38 monoclonal antibody daratumumab (9-month course) in a kidney allograft recipient diagnosed with smoldering myeloma and anti-HLA class II donor-specific antibody (DSA)-positive chronic active AMR 13 years after transplantation. Patient monitoring included serial HLA single antigen testing, peripheral blood immune cell phenotyping, as well as follow-up allograft and bone marrow biopsies at 3 and 9 months, including analyses of rejection-related gene expression patterns.
RESULTS.Daratumumab led to persistent CD138 cell depletion in the bone marrow and blood, and substantially decreased NK cells counts in blood and graft tissue. At the same time, DSA in serum disappeared, and in vitro alloantibody production by CD138 cells enriched from bone marrow aspirates was abrogated. A 3-month follow-up biopsy revealed a complete resolution of microcirculation inflammation (g+ptc3 to 0) and molecular AMR activity (AMR score0.79 to <0.2). The same biopsy showed (subclinical) tubulo-interstitial inflammation, which prompted steroid treatment. Over an observation period of 12 months, graft function stabilized.
CONCLUSIONS.Targeting CD38 for PC and NK cell depletion may be an effective strategy to counteract AMR. Our results may encourage the design of future trials to clarify the role of this innovative treatment concept in organ transplantation.
The constitutively active BCR-ABL tyrosine kinase is the cause of chronic myeloid leukemia. Imatinib is the first small synthetic molecular inhibitor of the BCR-ABL tyrosine kinase with clinical ...activity in chronic-phase myeloid leukemia. This 5-year follow-up of patients with the disease who began continuous treatment with imatinib reports that the drug can induce durable hematologic and cytogenetic responses in a high proportion of patients.
This 5-year follow-up of patients with chronic myeloid leukemia who began continuous treatment with imatinib reports that the drug can induce durable hematologic and cytogenetic responses in a high proportion of patients.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the expansion of a clone of hematopoietic cells that carries the Philadelphia chromosome (Ph).
1
The Ph chromosome results from a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11).
2
The molecular consequence of this translocation is a novel fusion gene,
BCR-ABL,
which encodes a constitutively active protein, tyrosine kinase.
3
–
5
Imatinib (Gleevec, Novartis; formerly called STI571) is a relatively specific inhibitor of the BCR-ABL tyrosine kinase and has efficacy in CML.
6
–
11
Before the availability of imatinib, interferon alfa plus cytarabine was considered standard therapy for patients . . .
Treatment of patients with Mayo stage IIIb light chain (AL) amyloidosis is still challenging, and the prognosis remains very poor. Mayo stage IIIb patients were excluded from the pivotal trial ...leading to the approval of daratumumab in combination with bortezomib-cyclophosphamide-dexamethasone. This retrospective, multicenter study evaluates the addition of daratumumab to first-line therapy in patients with newly diagnosed stage IIIb AL amyloidosis. In total, data from 119 consecutive patients were analyzed, 27 patients received an upfront treatment including daratumumab, 63 a bortezomibbased regimen without daratumumab, eight received therapies other than daratumumab or bortezomib and 21 pretreated patients or deceased prior to treatment were excluded. In the daratumumab group, median overall survival was not reached after a median follow-up time of 14.5 months, while it was significantly worse in the bortezomib- and the otherwise treated group (6.6 and 2.2 months, respectively) (P=0.002). Overall hematologic response rate at 2 and 6 months was better in the daratumumab group compared to the bortezomib group (59% vs. 37%, P=0.12, 67% vs. 41%, P=0.04, respectively). Landmark survival analyses revealed a significantly improved overall survival in patients with partial hematologic response or better, compared to non-responders. Cardiac response at 6 months was 46%, 21%, 0% in the daratumumab-, bortezomib- and otherwise treated groups, respectively (P=0.04). A landmark survival analysis revealed markedly improved overall survival in patients with cardiac very good partial response vs. cardiac non-responders (P=0.002). This study demonstrates for the first time the superiority of an upfront treatment with daratumumab over standard-of-care in stage IIIb AL amyloidosis.
Background
Pericardial and pleural effusion are common findings in patients with cardiac amyloidosis (CA). It is not known, whether effusions correlate with right ventricular (RV) function in these ...patients. Furthermore, data on the prognostic significance of pleural and pericardial effusion in CA is scarce.
Methods
Patients with transthyretin (ATTR) and light chain (AL) CA were included in a clinical registry. All patients underwent transthoracic echocardiography at baseline. The presence of pericardial and pleural effusion was determined in every patient. The clinical endpoint was defined as cardiac death or heart failure hospitalization.
Results
In total, 143 patients were analysed. Of these, 85 patients were diagnosed with ATTR and 58 patients with AL. Twenty-four patients presented with isolated pericardial effusion and 35 with isolated pleural effusion. In 19 patients, both pericardial and pleural effusion were found and in 65 patients no effusion was present at baseline. The presence of pleural effusion correlated well with poor RV function, measured by global RV free-wall strain (
p
= 0.007) in patients with AL, but not in ATTR. No such correlation could be found for pericardial effusion in either amyloidosis subtype. Patients with AL presenting with pleural effusion had worse outcomes compared to patients with pericardial effusion alone or no effusion at baseline. In the ATTR group, there was no difference in outcomes according to presence and type of effusion.
Conclusion
More than 50% of patients with CA presented with pleural and/or pericardial effusions. While pleural effusion was clearly associated with poor RV function in AL, we were not able to detect this association with pericardial effusion.
The treatment landscape for relapsed multiple myeloma (RRMM) has experienced an unprecedented wave of innovation. Implementation of numerous new substances and drug classes with different modes of ...action is made possible in routine clinical practice. Next generation proteasome inhibitors, monoclonal antibodies, as well as first in class agents such as selinexor and venetoclax have widened the therapeutic spectrum. This has led to an increase in progression-free and overall survival. Consequently, new challenges for treating physicians in choosing the right treatment at the right stage of the disease have been generated. Several trials support the use of novel agents in the frontline treatment of newly diagnosed multiple myeloma. The use of lenalidomide or bortezomib as a backbone in the first-line setting, requires strategies for treatment once these patients relapse and are refractory to these drugs. Despite the variety of options, selecting the optimal treatment strategy is difficult, since multiple factors have to be considered: patient-specific factors such as age and co-morbidities, as well as myeloma/tumor specific factors such as cytogenetics and relapse kinetics. This review intends to summarize the existing data and guidelines regarding the optimal sequencing of treatments of RRMM using already approved agents as well as agents under investigation.
Abstract
Aims
Cardiac amyloidosis (CA) leads to signs and symptoms of heart failure (HF). The mechanisms of biventricular dysfunction and their impact on outcome in subtypes of CA are poorly ...understood. Our aim was to compare right ventricular (RV) and left ventricular (LV) parameters in patients with light chain (AL) and wild-type transthyretin amyloidosis (ATTRw) and evaluate their ability to predict cardiac outcome.
Methods and results
We included patients with CA into a prospective registry. Baseline assessment included biventricular 2D speckle tracking imaging parameters. Patients were followed-up in regular intervals. The composite endpoint was defined as cardiovascular death, heart transplantation or ventricular assist device implantation, and HF hospitalization. We included 122 patients with CA. Sixty-two of these patients (50.8%) were diagnosed with ATTRw and 60 (49.2%) with AL. In ATTRw, parameters of RV size and function correlated well with symptom severity and only morphological and functional parameters of the RV predicted outcome. RV free wall strain was the only independent predictor of outcome with a hazard ratio (HR) of 1.185 95% confidence interval (CI) 1.047–1.342, P = 0.007. In AL on the other hand, RV function correlated well with symptoms but was not associated with outcome. In contrast, global longitudinal strain of the LV (LV-GLS) was predictive for outcome. After adjusting in a multivariable model, LV-GLS remained predictive with a HR of 1.180 (95% CI 1.032–1.348, P = 0.015).
Conclusion
Our data suggest that mechanisms underlying HF differ between ATTRw and AL. This may have substantial implications in particular in light of emerging therapies for both subtypes of CA.
Cast nephropathy (CN) is the leading cause of acute kidney injury (AKI) in multiple myeloma (MM). Since it is sparsely documented why some patients with CN do achieve a renal response while others do ...not, we describe a single-center cohort of patients with multiple myeloma and biopsy-confirmed CN to evaluate potential markers of renal response.
The data was collected as a retrospective, single-center analysis of CN-patients treated at the Medical University Vienna between 01/01/2004 and 01/01/2022. Baseline parameters and clinical outcome was compared between renal responders and non-responders.
Among 28 patients with CN,
= 23 were assessed for renal response (14 responders; 9 non-responders). Renal responders were younger (median age: 61 years; 77 years,
= 0.039), showed higher overall survival (153months; 58months,
= 0.044) and achieved hematologic response (≥PR) to first-line therapy (
= 0.029), and complete hematologic response (CR) at any time (
= 0.025) significantly more often. Further, we could show that rapid initiation of anti-myeloma therapy after initial presentation correlated significantly with renal response (median 9 days; 27 days,
= 0.016). Analyses of kidney biopsy specimens revealed that patients with a high IF/TA score showed end stage renal disease (dialysis ≥ 3 months) significantly more often (
= <0.001).
In summary, our data suggests, that a rapid start with systemic hematologic treatment in patients with MM and CN is crucial and achieving an early hematologic response is important for renal recovery. Moreover, achieving a deep hematologic response and subsequent renal recovery improves clinical outcome as reflected by an overall survival benefit.
Systemic light-chain (AL) amyloidosis is a rare and debilitating disease. Advances have been made in new treatments in recent years, yet real-world data on the management of the disease are scarce. ...EMN23 is a retrospective, observational study of patients who initiated first-line treatment in 2004-2018 in Europe, presenting the demographics, clinical characteristics, treatment patterns, and outcomes, from 4480 patients. Regimens based on bortezomib were the most frequently used as first-line therapy; only 6.2% of the patients received autologous stem cell transplant. Hematologic responses improved post-2010 (67.1% vs 55.6% pre-2010). The median overall survival (OS) was 48.8 (45.2-51.7) months; 51.4 (47.3-57.7) months pre-2010 and 46.7 (41.3-52.2) months post-2010. Early mortality was 13.4% and did not improve (11.4% vs 14.4% pre- and post-2010); furthermore, it remained high in patients with advanced cardiac disease (over 39% for stage IIIb). There was a significant improvement for stage IIIa (14.2 vs 30.7 months, p = 0.0170) but no improvement for stage IIIb patients (5.0 vs 4.5 months). This European real-world study of AL-amyloidosis emphasizes the unmet needs of early diagnosis, and the lack of improvement in survival outcomes of the frail stage IIIb population, despite the introduction of new therapies in recent years.
Multiple myeloma (MM) is characterized by serial relapses, necessitating the application of sequential lines of therapy (LoT). Reports on attrition rates (ARs) vary widely. The present study analysed ...ARs from the Austrian Myeloma Registry. Attrition was defined as being either deceased, progressive without having received another LoT, or lack of follow-up for ≥5 years. A total of 571 patients diagnosed between January 2009 and August 2021 were included (median age: 72 years; median follow-up: 50.8 months). Some 507 patients received at least one LoT. Of the total, 43.6% underwent autologous stem cell transplantation (SCT, transplant eligible = TE)) with primarily VRd (Bortezomib/Lenalidomide/Dexamethasone) given as induction (26.5%), followed by lenalidomide maintenance in 55.7% of cases. Transplant-ineligible (NTE) patients were predominantly treated with Vd (Bortezomib/Dexamethasone, 21.6%), receiving maintenance in 27.1%. A total of 37.5% received a second LoT. ARs across one to five LoTs were 16.7-27%. Frontline induction/ SCT followed by maintenance reduced ARs associated with age and achievement of deep remission in the frontline. Deep remission prolongs follow-up and time-to-next-treatment (TTNT), while high-risk-cyctogenetics negatively affected these outcomes. Our results demonstrate considerably lower ARs for MM patients within the AMR data versus other healthcare systems. Young age and the achievement of significant remissions after optimal frontline therapy resulted in particularly low ARs. These promising results support a key role for the ease of drug access and reimbursement policies in governing long-term MM patient outcomes.
Renal impairment (RI) is a negative prognostic factor in Multiple Myeloma (MM) and affected patients are often excluded from autologous stem cell transplantation (ASCT). However, it remains unclear ...whether historically inferior outcome data still hold true.
From a total of 475 eligible MM patients who had undergone ASCT between 1998 and 2016, 374 were included in this multi-centric retrospective cohort study. Renal function was determined both at the time of MM diagnosis and ASCT by estimated glomerular filtration rate (eGFR according to the MDRD formula, RI defined as eGFR < 60 ml/min/1.73m
). Patients were categorized into 3 groups: A) no RI diagnosis and ASCT, B) RI at diagnosis with normalization before ASCT and C) RI both at the time of diagnosis and ASCT. Log-rank testing was used for overall and progression-free survival (OS, PFS) analysis.
While severe RI at MM diagnosis confers a risk of shorter OS, MM progression after ASCT is not affected by any stage of renal failure. It can be concluded that ASCT can be safely carried out in MM patients with mild to moderate RI and should be pro-actively considered in those with severe RI.
When comparing all groups, no difference in OS and PFS was found (p = 0.319 and p = 0.904). After further stratification according to the degree of RI at the time of diagnosis, an OS disadvantage was detected for patients with an eGFR < 45 ml/min/m
. PFS was not affected by any RI stage.
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