Predictors of treatment response and survival outcomes in patients with advanced cardiac AL amyloidosis.

Patients with advanced cardiac immunoglobulin light chain (AL) amyloidosis have a poor prognosis. Early hematologic and cardiac responses can prolong survival, but predictors of these outcomes have yet to be clarified. We report on 142 patients with newly diagnosed stage IIIb AL amyloidosis. After a median follow-up of 60 months, the median overall survival (OS) was 9 months. Independent baseline factors associated with shorter OS were symptom onset to diagnosis >6 months (hazard ratio [HR], 1.94; P = .003); bone marrow plasmacytosis ≥ 10% (HR, 1.98; P = .01); troponin I > 0.635 ng/mL (HR, 1.62; P = .04); New York Heart Association class III or IV (HR, 1.67; P = .04); and 6-minute walk test distance < 200 m (HR, 1.85; P = .01). Early hematologic (within 1 month) and cardiac (within 3 months) responses were significantly associated with longer survival. In a 1-month landmark analysis, patients with a hematologic very good partial response, partial response, and no response had a median OS of 47, 25, and 5 months, respectively (P < .0001). Patients with cardiac response at 3 months had significantly longer OS (47 vs 11 months; P < .0001). On multivariable modeling, bortezomib use was associated with early hematologic and cardiac responses and longer OS. Symptom onset to diagnosis duration of >6 months and difference between the involved and uninvolved free light chain > 350 mg/L were independently associated with lower odds of an early cardiac response. This study identified factors predictive of treatment outcomes and survival in advanced cardiac AL amyloidosis.

Dose reductions in patients with Waldenström macroglobulinaemia treated with ibrutinib.

Waldenström macroglobulinaemia (WM) is characterized by the presence of a MYD88L265P mutation. This mutation promotes growth and survival of malignant cells through Bruton tyrosine kinase (BTK) activation. Ibrutinib was the first BTK inhibitor approved for WM. Intolerance to ibrutinib frequently leads to dose reductions, though the impact of reducing ibrutinib dosing has not been systematically studied. We performed a retrospective study to determine the frequency and impact of reducing ibrutinib dosing in WM patients. With a median treatment time of 64 months, 96 (27%) of 353 WM patients required a dose reduction due to adverse events such as musculoskeletal symptoms, cardiac events, dermatologic symptoms, cytopenias, and gastrointestinal symptoms. The median time to initial dose reduction was 9.3 months (range, 0.5-74). Dose reductions were more common in those 65 years of age or older versus under 65 [hazard ratio (HR) 2.46, 95% confidence interval (CI) 1.55-3.90; p < 0.001], and in females versus males (HR 2.20, 95% CI 1.41-3.28, p < 0.001). Most patients (65%) had improvement or resolution of adverse effects after initial dose reduction. With a median follow-up of three years from dose reduction, hematologic response sustained or deepened in 79% of patients. These data suggest that dose reduction of ibrutinib is a reasonable treatment approach for patients with intolerable side effects.

Predictors of hematologic response and survival with stem cell transplantation in AL amyloidosis: A 25-year longitudinal study.

High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis.

Response and survival predictors in a cohort of 319 patients with Waldenström macroglobulinemia treated with ibrutinib monotherapy.

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4 mutations were associated with lower odds of major (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.1-0.5; P < .001) and deep response (OR, 0.3; 95% CI, 0.2-0.6; P = .001). CXCR4 mutations (hazard ratio [HR], 2.0; 95% CI, 1.2-3.4; P = .01) and platelet count 100 K/uL or less (HR, 2.5; 95% CI, 1.3-4.9; P = .007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these 2 factors. The median PFS for patients with 0, 1, and 2 risk factors were not reached, 5 years and 3 years (P < .001). Patients with 2 risk factors had HR 2.2 (95% CI, 1.3-3.8; P = .004) compared with 1 factor, and patients with 1 factor had HR 2.3 (95% CI, 1.1-5.1; P = .03) compared with 0 factors. Age ≥65 years was the only factor associated with overall survival (HR, 3.2; 95% CI, 1.4-7.0; P = .005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4 mutations in patients with WM treated with ibrutinib monotherapy.

Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia.

Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.

Natural history of Waldenström macroglobulinemia following acquired resistance to ibrutinib monotherapy.

Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.4-6.5 years). Following discontinuation of ibrutinib, a rapid increase in serum immunoglobulin M level was observed in 60% (29/48) of evaluable patients, of whom ten acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% confidence interval [CI]: 13-27). The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI: 34-not reached). Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (odds ratio [OR] 0.20, 95% CI: 0.05-0.73) and salvage therapy ≤7 days after discontinuing ibrutinib (OR 4.12, 95% CI: 1.07- 18.9) were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44% (95% CI: 26-75). Response to salvage therapy was associated with better OS after ibrutinib (hazard ratio 0.08, 95% CI: 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTK C481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.

Bone marrow involvement and subclonal diversity impairs detection of mutated CXCR4 by diagnostic next-generation sequencing in Waldenström macroglobulinaemia.

CXCR4 mutations impact disease presentation and treatment outcomes in Waldenström macroglobulinaemia (WM). Non-uniform testing for CXCR4 mutations may account for discordant findings in WM clinical trials. We compared two approaches used in these trials for detection of the most common CXCR4 (S338X) variant: targeted next-generation sequencing (NGS) using unselected bone marrow (BM) samples, and combined allele-specific polymerase chain reaction (AS-PCR) and Sanger sequencing with unselected and CD19-selected BM samples. Our findings showed that targeted NGS frequently yielded false-negative results. Both CD19 selection and AS-PCR markedly improved detection of CXCR4S338X mutations. Sensitivity was adversely impacted by low BM involvement and CXCR4 mutation clonality.

Immunopathology of Hyperinflammation in COVID-19.

The rapid spread of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), has resulted in an unprecedented public health crisis worldwide. Recent studies indicate that a hyperinflammatory syndrome induced by SARS-CoV-2 contributes to disease severity and mortality in COVID-19. In this review, an overview of the pathophysiology underlying the hyperinflammatory syndrome in severe COVID-19 is provided. The current evidence suggests that the hyperinflammatory syndrome results from a dysregulated host innate immune response. The gross and microscopic pathologic findings as well as the alterations in the cytokine milieu, macrophages/monocytes, natural killer cells, T cells, and neutrophils in severe COVID-19 are summarized. The data highlighted include the potential therapeutic approaches undergoing investigation to modulate the immune response and abrogate lung injury in severe COVID-19.

Partial response or better at six months is prognostic of superior progression-free survival in Waldenström macroglobulinaemia patients treated with ibrutinib.

Ibrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression-free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 81% and 57% respectively (P = 0·009). In the validation cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38; P = 0·01] and validation cohorts (HR 0·18; P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

Response and Survival Outcomes to Ibrutinib Monotherapy for Patients With Waldenström Macroglobulinemia on and off Clinical Trials.

Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The approval was based on a single, multicenter, phase II trial in previously treated WM patients. We sought to evaluate whether there were differences in clinical characteristics, response, and survival outcomes to ibrutinib monotherapy between WM patients treated on and off clinical trials. Treatment naïve and previously treated patients who received ibrutinib monotherapy at our institution and participated in two prospective studies (ON trial; n = 72) or a prospective database (OFF trial; n = 157) were included. The median times from WM diagnosis to ibrutinib initiation were 3.1 and 3.5 years for ON and OFF trial patients, respectively (p = 0.38). Similar rates of categorical response at 6, 12, and 24 months and at best response were also observed between ON trial and OFF trial patients. The 4-year PFS and OS rates for ON trial and OFF trial patients were 72% and 63%, respectively (log-rank p = 0.14) and 83% and 81%, respectively (log-rank p = 0.14). CXCR4 mutations impacted response and survival outcomes to ibrutinib monotherapy. The 4-year rates of ibrutinib discontinuation in ON and OFF trial patients were 36% and 44%, respectively (p = 0.11). Ibrutinib is effective in the routine clinical care of both treatment-naïve and previously treated WM patients. The findings of our study validate the efficacy of ibrutinib monotherapy reported in multiple phase II clinical trials.

A matched case-control study comparing features, treatment and outcomes between patients with non-IgM lymphoplasmacytic lymphoma and Waldenström macroglobulinemia.

Cases of non-IgM lymphoplasmacytic lymphoma (LPL) are rare. We performed a case-control study comparing features and outcomes of 31 non-IgM LPL cases and 93 Waldenström macroglobulinemia (WM) controls matched by age, sex, and year of diagnosis. Odds of MYD88 mutations were lower (odds ratio (OR) 0.22, p = .05), and median time to treatment was shorter in cases than in controls (4 vs. 32 months; p < .001). Odds of extramedullary disease were higher (OR 4.20, p = .01), while odds of neuropathy (OR 0.22, p = .25), and hyperviscosity (OR 0.26, p = .26) were lower in cases than in controls. Odds of using chemoimmunotherapy were higher (OR 2.62, p = .11) while odds of using proteasome inhibitors (OR 0.35, p = .15) and BTK inhibitors (OR 0.17, p = .21) were lower in cases than in controls. There were no differences in response and overall survival (OS) between cases and controls. Despite clinicopathological differences, response, and survival outcomes are similar between non-IgM LPL cases and WM controls.

Deepening of response after completing rituximab-containing therapy in patients with Waldenstrom macroglobulinemia.

Rituximab-containing regimens are commonly used for frontline therapy in patients with symptomatic Waldenström macroglobulinemia (WM). We had observed that a portion of WM patients experienced deepening of response months to years after therapy completion. We carried a retrospective study aimed at describing this phenomenon. We gathered baseline data, and responses at end of induction, end of maintenance and best response. Deepening of response was defined as ≥25% decrease in serum IgM achieved at a later time from therapy completion. Of 178 patients included, 116 (65%) received maintenance therapy and 62 (35%) were observed. In patients who received maintenance, 44 (38%) had ≥25% decrease in serum IgM level after the end of maintenance with a median time from end of maintenance to lowest IgM level of 1.6 years (range 0.1-7.9 years). In patients who were observed, 19 (31%) had ≥25% decrease in serum IgM level after the end of induction with a median time from end of induction to lowest IgM level of 1.6 years (range 0.2-5.1 years). Baseline hemoglobin <11.5 g/dL, bone marrow involvement ≥50%, CXCR4 mutations and serum IgM ≥4000 mg/dL were associated with lower odds of deepening of response after therapy completion. Deepening of response was associated with better progression-free survival (PFS; HR 0.46, 95% CI 0.26-0.80; P = .006) and better survival after frontline treatment initiation (SAFTI; HR 0.21, 95% CI 0.06-0.73; P = .01). In conclusion, deepening of response occurs in one third of WM patients after completing rituximab-containing regimens and was associated with better PFS and SAFTI.

CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenström macroglobulinaemia treated with ibrutinib.

Ibrutinib is associated with response rate of 90% and median progression-free survival (PFS) in excess of 5 years in Waldenström macroglobulinaemia (WM) patients. CXCR4 mutations are detected in 30-40% of patients with WM and associate with lower rates of response and shorter PFS to ibrutinib therapy. Both frameshift (CXCR4FS ) and nonsense (CXCR4NS ) CXCR4 mutations have been described. The impact of these mutations on outcomes to ibrutinib have not been evaluated in WM patients. We studied consecutive patients with a diagnosis of WM, on ibrutinib therapy, for the presence of CXCR4FS and CXCR4NS mutations and evaluated the differences in response and PFS between groups. Of 180 patients, 68 patients (38%) had CXCR4 mutations; 49 (27%) had CXCR4NS and 19 (11%) had CXCR4FS mutations. In multivariate models, patients with CXCR4NS had lower odds of major response (Odds ratio 0·25, 95% confidence interval [CI] 0·12-0·53; P < 0·001) and worse PFS (Hazard ratio 4·02, 95% CI 1·95-8·26; P < 0·001) than patients without CXCR4 mutations. CXCR4FS was not associated with worse major response or PFS rates than patients without CXCR4 mutations. Our results suggest different response and PFS rates to ibrutinib for WM patients with CXCR4NS and CXCR4FS , and advocate in favour of CXCR4 mutational testing as well as CXCR4-directed therapy.

Cell Wall Hydrolytic Enzymes Enhance Antimicrobial Drug Activity Against Mycobacterium.

Cell wall hydrolases are enzymes that cleave bacterial cell walls by hydrolyzing specific bonds within peptidoglycan and other portions of the envelope. Two major sources of hydrolases in nature are from hosts and microbes. This study specifically investigated whether cell wall hydrolytic enzymes could be employed as exogenous reagents to augment the efficacy of antimicrobial agents against mycobacteria. Mycobacterium smegmatis cultures were treated with ten conventional antibiotics and six anti-tuberculosis drugs-alone or in combination with cell wall hydrolases. Culture turbidity, colony-forming units (CFUs), vital staining, and oxygen consumption were all monitored. The majority of antimicrobial agents tested alone only had minimal inhibitory effects on bacterial growth. However, the combination of cell wall hydrolases and most of the antimicrobial agents tested, revealed a synergistic effect that resulted in significant enhancement of bactericidal activity. Vital staining showed increased cellular damage when M. smegmatis and Mycobacterium bovis bacillus Calmette-Guérin (M. bovis BCG) were treated with both drug and lysozyme. Respiration analysis revealed stress responses when cells were treated with lysozyme and drugs individually, and an acute increase in oxygen consumption when treated with both drug and lysozyme. Similar trends were also observed for the other three enzymes (hydrolase-30, RipA-His6 and RpfE-His6) evaluated. These findings demonstrated that cell wall hydrolytic enzymes, as a group of biological agents, have the capability to improve the potency of many current antimicrobial drugs and render ineffective antibiotics effective in killing mycobacteria. This combinatorial approach may represent an important strategy to eliminate drug-resistant bacteria.