Treatment of primary plasma cell leukaemia with carfilzomib and lenalidomide-based therapy (EMN12/HOVON-129): final analysis of a non-randomised, multicentre, phase 2 study.

BACKGROUND: Primary plasma cell leukaemia is a rare and aggressive plasma cell disorder with a poor prognosis. The aim of the EMN12/HOVON-129 study was to improve the outcomes of patients with primary plasma cell leukaemia by incorporating carfilzomib and lenalidomide in induction, consolidation, and maintenance therapy. METHODS: The EMN12/HOVON-129 study is a non-randomised, phase 2, multicentre study conducted at 19 academic centres and hospitals in seven European countries (Belgium, Czech Republic, Denmark, Italy, Norway, The Netherlands, and the UK) for previously untreated patients with primary plasma cell leukaemia aged 18 years or older. Inclusion criteria were newly diagnosed primary plasma cell leukaemia (defined as >2 ×109 cells per L circulating monoclonal plasma cells or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Patients aged 18-65 years (younger patients) and 66 years or older (older patients) were treated in age-specific cohorts and were analysed separately. Younger patients were treated with four 28-day cycles of carfilzomib (36 mg/m2 intravenously on days 1, 2, 8, 9, 15, and 16), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 8, 9, 15, 16, 22, and 23). Carfilzomib-lenalidomide-dexamethasone (KRd) induction was followed by double autologous haematopoietic stem-cell transplantation (HSCT), four cycles of KRd consolidation, and then maintenance with carfilzomib (27 mg/m2 intravenously on days 1, 2, 15, and 16 for the first 12 28-day cycles, and then 56 mg/m2 on days 1 and 15 in all subsequent cycles) and lenalidomide (10 mg orally on days 1-21) until progression. Patients who were eligible for allogeneic HSCT, could also receive a single autologous HSCT followed by reduced-intensity conditioning allogeneic HSCT and then carfilzomib-lenalidomide maintenance. Older patients received eight cycles of KRd induction followed by maintenance therapy with carfilzomib and lenalidomide until progression. The primary endpoint was progression-free survival. The primary analysis population was the intention-to-treat population, irrespective of the actual treatment received. Data from all participants who received any study drug were included in the safety analyses. The trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR5350; recruitment is complete and this is the final analysis. FINDINGS: Between Oct 23, 2015, and Aug 5, 2021, 61 patients were enrolled and received KRd induction treatment (36 patients aged 18-65 years [20 (56%) were male and 16 (44%) female], and 25 aged ≥66 years [12 (48%) were male and 13 (52%) female]). With a median follow-up of 43·5 months (IQR 27·7-67·8), the median progression-free survival was 15·5 months (95% CI 9·4-38·4) for younger patients. For older patients, median follow-up was 32·0 months (IQR 24·7-34·6), and median progression-free survival was 13·8 months (95% CI 9·2-35·5). Adverse events were most frequently observed directly after treatment initiation, with infections (two of 36 (6%) younger patients and eight of 25 (32%) older patients) and respiratory events (two of 36 [6%] younger patients and four of 25 [16%] older patients) being the most common grade 3 or greater events during the first four KRd cycles. Treatment-related serious adverse events were reported in 26 (72%) of 36 younger patients and in 19 (76%) of 25 older patients, with infections being the most common. Treatment-related deaths were reported in none of the younger patients and three (12%) of the older patients (two infections and one unknown cause of death). INTERPRETATION: Carfilzomib and lenalidomide-based therapy provides improved progression-free survival compared with previously published data. However, results remain inferior in primary plasma cell leukaemia compared with multiple myeloma, highlighting the need for new studies incorporating novel immunotherapies. FUNDING: Dutch Cancer Society, Celgene (a BMS company), and AMGEN.

Neurofilament light chain, a biomarker for polyneuropathy in systemic amyloidosis.

OBJECTIVE: To study serum neurofilament light chain (sNfL) in amyloid light chain (AL) amyloidosis patients with and without polyneuropathy (PNP) and to corroborate previous observations that sNfL is increased in hereditary transthyretin-related (ATTRv) amyloidosis patients with PNP. METHODS: sNfL levels were assessed retrospectively in patients with AL amyloidosis with and without PNP (AL/PNP+ and AL/PNP-, respectively), patients with ATTRv amyloidosis and PNP (ATTRv/PNP+), asymptomatic transthyretin (TTR) gene mutation carriers (TTRv carriers) and healthy controls. Healthy controls (HC) were age- and sex-matched to both AL/PNP- (HC/AL) and TTRv carriers (HC/TTRv). The single-molecule array (Simoa) assay was used to assess sNfL levels. RESULTS: sNfL levels were increased both in 10 AL/PNP+ patients (p < .001) and in 10 AL/PNP- patients (p < .005) compared to 10 HC/AL individuals. sNfL levels were higher in AL/PNP+ patients than in AL/PNP- patients (p < .005). sNfL levels were also increased in 15 ATTRv/PNP+ patients, compared to both 15 HC/TTRv (p < .0001) and 15 TTRv carriers (p < .0001). ATTRv/PNP+ patients with progressive PNP (PND-score > I) had the highest sNfL levels compared to patients with early PNP (PND-score I) (p = .05). sNfL levels did not differ between TTRv carriers and HC/TTRv individuals. In the group comprising all healthy controls and in the group of TTRv carriers, sNfL levels correlated with age. CONCLUSION: sNfL levels are increased in patients with PNP in both AL and ATTRv amyloidosis and are related to severity of PNP in ATTRv amyloidosis. sNfL is a promising biomarker to detect PNP, not only in ATTRv but also in AL amyloidosis.

A real-life cohort study of immunoglobulin light-chain (AL) amyloidosis patients ineligible for autologous stem cell transplantation due to severe cardiac involvement or advanced disease.

Objective: To study the outcome of patients with AL amyloidosis who were ineligible for high dose melphalan (HDM) and autologous stem cell transplantation (ASCT).Methods: A real-life retrospective observational cohort study of Dutch patients with AL amyloidosis ineligible for HDM and ASCT was performed at the University Medical Center Groningen from January 2001 until April 2017. Primary outcome measure was overall survival (OS). Secondary outcome measures were hematological response (HR), organ responses, and treatment toxicity.Results: Eighty-four patients were included. Ineligibility was due to NYHA class III/IV (n = 58), otherwise advanced disease (n = 11), advanced age (n = 14), or treatment refusal (n = 1). Early death (<3 months) rate was high (44%). Median OS improved from 4 months in period 2001-2009 (n = 36) to 8 months in period 2009-2017 (n = 48, p = .02). HR was seen in 29%, and 42% of the patients, respectively. Median OS was 36 months after induction treatment with bortezomib (n = 32) and 18 months with immunomodulatory imide drug (IMID) (n = 16), both higher than median OS (7 months) with other regimens (n = 27). Incidence of toxicity was high (51%).Conclusion: OS improved in this high-risk group over the years, especially after introduction of new treatment modalities. However, early death rate remains high, illustrating the need for more effective treatment.

Thrombocytopenia affects plasmatic coagulation as measured by thrombelastography.

Thrombelastography (TEG) is used as a point-of-care test of hemostasis. Different components of the test tracing are considered to reflect various parts of the hemostatic system and to distinguish low platelet count, platelet dysfunction or both from lack of plasmatic coagulation factors. To analyze the influence of one single element of the coagulation system, namely the platelet count, we used TEG serially in patients with well documented transient thrombocytopenia. A total of 189 TEG analyses were performed from 16 patients with a hematological malignancy in remission, receiving consolidation courses of chemotherapy. TEG outcomes using unmanipulated and citrated blood samples at a median of 11 times (range 1-17) in the same patients during the decrease of platelet count in response to chemotherapy were compared with outcomes in 120 healthy adults from various age categories. We found a correlation (r = 0.7, P < 0.001) between TEG clot strength (maximum amplitude) and platelet count. Moreover, platelet count was correlated respectively with the initial rate of clot formation (reaction time and clotting time), the rate of clot growth (alpha angle), and also with maximum thrombus generation, time to maximum thrombus generation and total thrombus generation. We conclude that platelet count not only affects the strength of clot formation, as was expected, but also all other phases of plasmatic coagulation. Citration of the blood sample, aiming at easy storage of the material, masked some of the important biological parameters of coagulation.

In normal controls, both age and gender affect coagulability as measured by thrombelastography.

BACKGROUND: Our objective was to analyze the effects of age, gender, and the use of oral contraceptives (OCs) on coagulation using thrombelastography (TEG), a single test to analyze both plasma coagulation factors and cellular elements in whole blood. METHODS: TEG variables were measured in native whole blood and in recalcified citrated blood from 120 healthy adults (60 men and 60 women) with various ages and in an additional 29 healthy women using OCs. RESULTS: We observed hypercoagulability in women compared with men and in women using OCs compared with age-matched nonusers. Moreover, we found hypercoagulability with aging. Using the method of Bland and Altman (Lancet 1986;1:307-10), we demonstrated no correlation between TEG measurements in native and recalcified citrated blood. CONCLUSIONS: Aging, female gender, use of OCs, and low-normal hematocrit levels have significant procoagulant effects. TEG measurements in native and recalcified citrated blood are not interchangeable, as indicated by differences between the 2 measurements ranging from 20% in maximal amplitude to 246% in clotting time. Furthermore, the limits of agreement strongly exceeded clinical acceptability to conclude interchangeability.

Effects of red blood cells on hemostasis.

BACKGROUND: Currently there is no sensitive laboratory test to establish the influence of red blood cells (RBCs) on hemostasis. As thromboelastography (TEG) measures hemostasis in whole blood, taking into account the interactions of all cellular elements, we used this instrument to investigate the role that RBCs play in hemostasis. STUDY DESIGN AND METHODS: In 29 patients with chemotherapy-induced anemia we studied the effect of progressive anemia on the coagulation profile. In 24 patients with chronic anemia we studied the effect of transfusion of RBCs on coagulation. Finally, in 18 patients we evaluated whether storage time of RBCs has additional effects on hemostasis. RESULTS: We observed a significant negative correlation between hemoglobin and TEG variables related to both clot strength and elasticity (p < 0.05). Moreover, anemia was associated with a delay in the initiation of the coagulation cascade. Correction of anemia by RBC transfusion resulted in significant shortening of this initiation phase with now the opposite effect on clot strength and elasticity. The negative effects on clot quality were significantly worse when fresh RBCs were transfused compared to longer-stored RBCs. Furthermore, in contrast to the longer-stored RBCs, fresh RBCs did not enhance initial fibrin formation. CONCLUSIONS: In this study we found that anemia was associated with a delay in the initiation of the coagulation cascade with a finally formed clot with superior strength and viscoelastic properties. Transfusion of RBCs was associated with impaired clot quality, with even worse effects on the initial fibrin build-up and clot quality by fresh RBCs.

Assessment of hypolactasia and site-specific intestinal permeability by differential sugar absorption of raffinose, lactose, sucrose and mannitol.

The sugar absorption test is a non-invasive test for investigating intestinal permeability by simultaneous measurement of four probe sugars. In this study, we evaluated the utility of raffinose, lactose, sucrose and mannitol as probe sugars and calculated their urinary recovery as a percentage of ingested dose (mol/mol) and the recovery ratios of raffinose/mannitol, lactose/ raffinose and sucrose/raffinose. The reference ranges for these ratios, established from 39 healthy volunteers, are 0.005-0.015, 0.13-0.63 and 0.09-0.47, respectively. This sugar absorption test was performed in three patient groups. i) In 109 patients with aspecific gastrointestinal symptoms of whom intestinal histology was studied by duodenal biopsies: the urinary raffinose/mannitol recovery ratio highly correlated with gradation of duodenal damage; the sensitivity and specificity of the raffinose/mannitol ratio for detection of intestinal damage were 93% and 91%, respectively, using a cut-off level of 0.020. ii) In 70 patients in whom intestinal lactase activity was investigated by the lactose tolerance test: the urinary lactose/raffinose recovery ratio provided high diagnostic accuracy for hypolactasia (sensitivity 81% and specificity 89% at a cut-off level of 0.70). In analogy with the lactose/raffinose ratio, we suppose that the sucrose/raffinose ratio can be used as a marker of hyposucrasia. iii) In 40 patients with localized small intestinal damage, Crohn's disease of the ileum (n = 21) and celiac disease with histologically proven duodenal damage (n = 19): the raffinose/mannitol recovery ratio was increased in 100% of patients with celiac disease and in 81% of patients with Crohn's disease; increased lactose/raffinose recovery ratio (hypolactasia) and increased sucrose/raffinose (hyposucrasia) were present in 89% and 95% of celiac patients and 19% and 0% of Crohn's disease patients, respectively. The combination of the raffinose/mannitol ratio and sucrose/raffinose ratio appears to be an indication of the distribution of intestinal damage.