The assessment of both thromboembolic and haemorrhagic risks and their management in systemic amyloidosis have been poorly emphasized so far. This narrative review summarizes main evidence from ...literature with clinical perspective.
The rate of thromboembolic events is as high as 5–10% amyloidosis patients, at least in patients with cardiac involvement, with deleterious impact on prognosis. The most known pro‐thrombotic factors are heart failure, atrial fibrillation, and atrial myopathy. Atrial fibrillation could occur in 20% to 75% of systemic amyloidosis patients. Cardiac thrombi are frequently observed in patients, particularly in immunoglobulin light chains (AL) amyloidosis, up to 30%, and it is advised to look for them systematically before cardioversion. In AL amyloidosis, nephrotic syndrome and the use of immunomodulatory drugs also favour thrombosis. On the other hand, the bleeding risk increases because of frequent amyloid digestive involvement as well as factor X deficiency, renal failure, and increased risk of dysautonomia‐related fall.
Chimeric antigen receptor T cells (CAR‐T) have provided promising results in multiple myeloma (MM). However, many patients still relapse, pointing toward the need of improving this therapy. Here, we ...analyzed peripheral blood T cells from MM patients at different stages of the disease and investigated their phenotype and capacity to generate functional CAR‐T directed against CS1 or B Cell Maturation antigen. We found a decrease in naive T cells and elevated frequencies of exhaustion markers in T cells from treated MM patients. Interestingly, individuals treated with daratumumab display elevated ratios of central memory T cells. CAR‐T derived from patients at relapse show reduced in vitro expansion and cytotoxic capacities in response to MM cells compared to those produced at diagnosis. Of note, CAR‐T from daratumumab treated patients display intermediate defects. Reduced anti‐myeloma activity of CAR T cells from treated patients was also observed in a mouse model. Our findings suggest that T cell defects in MM patients, specifically during relapse, have a major impact on their capacity to generate efficient therapeutic CAR‐T. Selecting naive or central memory T cell subsets to generate therapeutic T cells could improve the CAR‐T therapy for MM.
Summary
Waldenström's macroglobulinaemia (WM) is a B‐cell neoplasm resulting from bone marrow lymphoplasmacytic infiltration and monoclonal IgM secretion. Some patients present concomitant ...inflammatory syndrome attributed to the disease activity; we named this syndrome inflammatory WM (IWM). We retrospectively analysed all WM patients seen in a single tertiary referral centre from January 2007 to May 2021, and after excluding aetiologies for the inflammatory syndrome using a pertinent blood workup, including C‐reactive protein (CRP), and imaging, we identified 67 (28%) IWM, 166 (68%) non‐IWM, and nine (4%) WM with inflammatory syndrome of unknown origin. At treatment initiation, IWM patients had more severe anaemia (median Hb 90 vs 99 g/l; p < 0.01), higher platelet count (median 245 vs 196 × 109/l; p < 0.01) and comparable serum IgM level (median 24.9 vs 23.0 g/l; p = 0.28). A positive correlation was found between inflammatory and haematological responses (minimal response or better) (odds ratio 32.08; 95% confidence interval 8.80–98.03; p < 0.001). Overall survivals (OS) were similar (median OS: 17 vs 20 years; p = 0.11) but time to next treatment (TNT) was significantly shorter for IWM (TNT1: 1.6 vs 4.8 years, p < 0.0001). IWM mostly shared the same presentation and outcome as WM without inflammatory syndrome.
First line treatment of systemic non IgM AL amyloidosis is well defined in the recommendations of the French National Reference Center for AL amyloidosis. Melphalan or cyclophosphamide at standard ...dose with dexamethasone in combination with bortezomib are currently recommended. The objective is to rapidly obtain an hematological response, modulating treatment according to severity of heart involvement and hematologic response. At relapse there are no such precise guidelines. If the initial treatment has been effective, it may be chosen in case of late relapse occurring after at least one year. Combination of other drugs effective in plasma cell dyscrasias might be proposed, but studies on treatment in the relapse setting are scarce and a consensus remains to be established.
Here we report a multicenter retrospective study assessing treatment at relapse and evaluating their impact on hematologic response, progression-free survival (PFS), overall survival, organ responses and toxicity.
We included 84 patients who received, from 2006 to 2014, as first line treatment, a non-intensive chemotherapy in 15 French hospital centers. At diagnosis, 47 (56 %), 51 (61%) and 16 (19%) patients respectively presented with heart, kidney, and neurological involvement. Twenty three patients (27%) had a severe heart disease with a Mayo Clinic stage III. The median follow-up of the cohort was 58 months (9-135). The hematological response was assessed at 3 months based on free light chain measurement, according to the international consensus. At relapse, 29 patients (34,5%) received a bortezomib, cyclophosphamide and dexamethasone combination (VCD) resulting in 79% of very good partial response (VGPR) or better and 7% of partial response (PR), 18 patients (21%) had an organ response, and with a median follow up of 70,5 months (9,03-135) the estimated overall survival at 3 years was 79,4%. Twenty six patients (31%) experienced grade ≥ 3 toxicities that were peripheral neuropathy in 5 patients. Seventeen patients (21%) received a combination of lenalidomide and dexamethasone (RD), resulting in 17% of VGPR or better and 35% of PR, 12 % of organ response with an estimated overall survival at 3 years of 94% with a median follow up of 46,5 months (20,99-122,97). Four patients (23%) had a grade ≥ 3 toxicity, mainly hematologic. Five patients (6%) received a combination of bortezomib with lenalidomide and dexamethasone (VRD) resulting in VGPR or better in 4 patients and PR in 1 patients, 4 patients had an organ response with all patients being alive at 3 years. Grade ≥ 3 toxicity was observed in 1 patient. Regarding these 3 combinations, the median PFS were respectively 22 months for VCD, 8 months for RD (p = 0, 0012) and 17.3 months for VRD. At relapse 13 other therapeutic combinations were used. Other IMIDs (thalidomide or pomalidomide), melphalan, bendamustine or daratumumab were given to 4, 8, 6 and 5 patients respectively resulting in 1, 4, 3 and 1 of VGPR or better hematologic response. Bendamustine containing regimens were associated in grade ≥ 3 toxicity in 5 patients (83%). Sixty-seven patients (79%) were still alive at 3 years.
In conclusion, there is currently no consensus on the best treatment for AL amyloidosis patients in relapse. This study shows the different regimens used in France and their effectiveness in relapse. As usual in this disease the survival of relapsing patients is good with almost 80% of patients alive at 3 years. Bortezomib remains an important molecule in relapse. Lenalidomide alone with dexamethasone seems to be less effective to obtain a high rate of hematologic response. VRD has been used in few patients, we found no cumulative toxicity with the combination of proteasome inhibitor and lenalidomide with a very interesting response rate, PFS, OS and organ responses. VRD should be tested more systematically in relapsing or refractory patients. Finally, the role of daratumumab and new proteasome inhibitors remains to be defined.
Harel:janssen: Consultancy; takeda: Consultancy; amgen: Consultancy.
Al amyloidosis, from diagnosis to treatment. AL amyloidosis is a rare hemopathy characterized by immunoglobulin light chains deposits in almost all organs causing organ failure. The main issue is the ...early dia¬gnosis, which must be made in front of an unexplained non-specific symptomatology, especially cardiac or renal, in frequently elderly patients with monoclonal gammo¬pathy. Non-invasive biopsies should be made for histolo¬gical confirmation revealing positive congo red and birefringent yellow-green deposits in polarized light specific for amyloidosis. Severity is assessed by biologi¬cal markers of cardiac involvement. The treatment consists in eliminating the plasma or lympho-plasma cell dyscrasia secreting the amyloidogenic light chain, and in proposing supportive care specific to this pathology.
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