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Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is a mature B-cell neoplasm that typically follows an indolent clinical course. Amyloid deposition associated with MALT lymphoma is uncommon. We describe the clinical and pathologic features of 20 cases of MALT lymphoma and associated amyloid deposition across diverse primary sites. Frozen section immunofluorescence performed on 4 cases suggests that these deposits are a localized form of AL amyloid. Clinical follow-up was available for 15 patients. Amyloid deposits distant from the initial site occurred in 5 cases, always at sites also involved by the underlying lymphoma. No definitive evidence of systemic amyloidosis affecting the heart, kidneys, or liver was present in any patient. Given the generally indolent clinical behavior of MALT lymphomas with associated amyloid, we do not recommend extensive follow-up testing for systemic amyloidosis or more aggressive therapy than would be indicated for other MALT lymphomas of similar clinical stage. [ABSTRACT FROM AUTHOR]

Importance: Absolute neutrophil counts (ANCs) are used to determine cancer clinical trial (CCT) eligibility and systemic anticancer therapy (SACT) dose modifications. Duffy null-associated ANC (DANC) is a nonpathologic phenotype associated with lower ANC and most frequently seen in individuals with African and Middle Eastern ancestry. It is unclear whether CCTs exclude or SACT regimens modify doses for individuals with ANC within the DANC reference range., Objective: To investigate CCT exclusions and SACT dose modifications for ANC within the DANC reference range., Design, Setting, and Participants: This cross-sectional study of contemporary CCTs and SACT regimens included adult, interventional, phase 3 CCTs for the 5 most prevalent cancers in the US and United Kingdom (prostate, breast, melanoma, colorectal, and lung cancers) testing SACTs with start dates between November 1, 2021, and November 1, 2023, and that were registered on ClinicalTrials.gov. Preferred curative-intent SACT regimens were listed in National Comprehensive Cancer Network guidelines., Exposure: Cancer clinical trial exclusions and SACT regimen modifications., Main Outcome and Measures: Proportions of CCTs that exclude and SACT regimens that modify doses for individuals with an ANC within the DANC reference range., Results: For CCTs, 289 of 382 trials (75.7%) were eligible, of which 221 (76.5% [95% CI, 71.1%-81.2%]) excluded patients with ANC values within the DANC reference range. Colorectal CCTs had the highest (38 of 44 [86.4% (95% CI, 72.6%-94.8%)]) and prostate CCTs had the lowest (11 of 23 [47.8% (95% CI, 26.8%-69.4%)]) proportions of exclusions. Of CCTs testing cytotoxic chemotherapy, 116 of 142 (81.7% [95% CI, 74.3%-87.7%]) had exclusions; 93 of 123 (75.6% [95% CI, 67.0%-82.9%]) CCTs testing targeted therapies alone and 12 of 24 (50.0% [95% CI, 29.1%-70.9%]) testing hormonal therapies alone had exclusions. Among the 113 US- and UK-based trials, exclusions were present in 89 (78.8% [95% CI, 70.1%-85.9%]). Of 71 SACT regimens, 38 (53.5% [95% CI, 41.3%-65.5%]) included dose modifications for ANC values within the DANC reference range. Lung cancer regimens had the highest (23 of 31 [74.2% (95% CI, 55.4%-88.1%)]) and prostate cancer had the lowest (0 of 12 [0 (95% CI, 0%-26.4%)]) proportions of modifications. Regimens including chemotherapy had modifications in 32 of 44 (72.7% [95% CI, 57.2%-85.0%]); 11 of 20 (55.0% [95% CI, 31.5%-76.9%]) of targeted therapy regimens and 0 of 16 (0% [95% CI, 0%-20.6%]) of hormonal therapy regimens had modifications. Among regimens including chemotherapy and/or targeted therapy, modifications were present in 38 of 55 (69.1% [95% CI, 49.7%-73.2%])., Conclusions and Relevance: In this cross-sectional study, substantial proportions of CCTs excluded and SACT regimens modified doses for patients with ANCs in the DANC reference range. These practices structurally discriminate against patients of African and Middle Eastern ancestry. While determining optimal SACT dose modifications requires further study, CCT exclusion criteria should be revised.

Venous thromboembolism (VTE) risk is increased in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A key question was whether increased intensity of anticoagulation would help prevent VTE and improve patient outcomes, including transfer to the intensive care unit (ICU) and mortality. At the start of the coronavirus disease-19 (COVID-19) pandemic, our institution, Boston Medical Center, instituted a VTE risk stratification protocol based on patients' initial D-dimer levels, medical history, and presence of thrombosis to determine whether they should receive standard-dose prophylaxis, high-dose prophylaxis, or therapeutic anticoagulation. We performed a retrospective observational cohort study examining the association of degree of anticoagulation with outcomes in 915 hospitalized COVID-19 patients hospitalized initially on the general inpatient wards between March 1, , 2020, and June 1, 2020. Patients directly hospitalized in the ICU were excluded. Most, 813 patients (89%), in our cohort were on standard-dose prophylaxis; 32 patients (3.5%) received high-dose prophylaxis; 70 patients (7.7%), were treated with therapeutic anticoagulation. VTE occurred in 45 patients (4.9%), and the overall in-hospital mortality rate was 5.4% (49 deaths). On multivariable analysis of clinical outcomes in relation to type of anticoagulation, in the high-dose prophylaxis group, there was a trend towards increased in-hospital mortality (odds ratio 2.4 (0.8-7.5, 95% CI)) and increased ICU transfer (odds ratio 2.2 (0.9-5.7, 95% CI)). Our results suggest that patients receiving high-dose prophylaxis had more severe disease that was not mitigated by intermediate-dose anticoagulation., Competing Interests: Rena Zheng, Alexandra Solomon, Iniya Rajendran, Vrushali Dhongade, Michael A. Garcia, and Robert T. Eberhardt have no relevant conflicts of interest. Madeline DiLorenzo previously held stocks in Abbvie, Amgen Inc., Becton Dickinson, Biogen Inc., Bristol Myers and Squibb, CVS Health, Elevance Health, Gilead, Henry Schein, Hologic Inc., Jazz Pharmaceuticals, Laboratory Corp., Merck and Co., Quest Diagnostics, Teladoc Health, Vertex Pharmaceuticals, and West Pharmaceuticals. All of this stock was sold during or prior to January 2023. John Mark Sloan has membership on board or directors or advisory committees for Astra Zeneca and Pharmacosmo and received honoraria for Stemline and Abbvie. Janice Weinberg is a current holder of individual stocks at Merck and Co and served on data safety monitoring boards for Janssen Pharmaceuticals. Elizabeth S. Klings is funded by NIH/NHLBI 1UG3 HL143192-01A1, NCATS 2UL1TR001430-05A1, and HRSA U1EMC27864‐08‐00. E.S.K. received research support from Novartis, FORMA Therapeutics, Bayer, and United Therapeutics. She received royalties for 3 topic cards in UpToDate. She is a consultant for CSL Behring for sickle cell disease-related clinical trials and was a member of an advisory board for Vertex Pharmaceuticals, Pfizer, and FORMA Therapeutics and has no conflicts with the present work., (Copyright © 2024 Rena Zheng et al.)

Patients with systemic light chain (AL) amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) may develop renal and cardiac toxicities potentially exacerbated by the co-solvent propylene glycol in conventional melphalan formulations. We investigated the safety and efficacy of propylene glycol-free melphalan (PGF-Mel) during HDM/SCT in patients with AL amyloidosis (ClinicalTrials.gov identifier NCT02994784). The primary objective of this phase II, open-label study was evaluation for renal dysfunction, new cardiac arrhythmias, and postural hypotension related to autonomic dysfunction. Secondary objectives included time to neutrophil and platelet engraftment, treatment-related mortality (TRM), overall hematologic response, organ response, and number of peritransplantation hospitalizations. Twenty-eight patients with AL amyloidosis enrolled, of whom 27 underwent HDM/SCT. PGF-Mel at 140 to 200 mg/m 2 was administered i.v. in 2 equally divided doses. Patients were monitored for up to 30 days after the last administration of PGF-Mel to assess for treatment-related toxicity. Patients were followed for 12 months from the time of treatment with HDM/SCT for evaluation of hematologic and organ responses. Kaplan-Meier analysis was used to estimate progression-free survival. Two patients (7%) developed renal dysfunction, 5 (19%) experienced new cardiac arrhythmias, and 3 (11%) developed orthostatic hypotension. All patients achieved neutrophil and platelet engraftment, at a median of 10 days and 17 days post-HDM/SCT, respectively. TRM on day +100 was 0%. Peritransplantation hospitalization was required for 23 patients (85%). The most common nonhematologic adverse events were diarrhea (93%), fatigue (82%), and nausea (74%). At 6 months post-HDM/SCT, hematologic complete response or very good partial response occurred in 66% of the patients. At 12 months post-HDM/SCT, renal response occurred in 12 of 23 (52%) patients with renal involvement, and cardiac response occurred in 3 of 11 (27%) patients with evaluable cardiac involvement. Our data indicate that PGF-Mel is safe and efficacious as a high-dose conditioning regimen for autologous SCT in patients with AL amyloidosis., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: There is limited guidance on the selection of tyrosine kinase inhibitors (TKIs) in patients with short bowel syndrome (SBS). Concerns regarding absorption, toxicity profiles, and drug interactions should be considered when selecting optimal TKI therapy., Case Report: A 57-year-old male with SBS was newly diagnosed with chronic myeloid leukemia (CML). A careful review of his surgical history, comorbidities, and concurrent medications led to a treatment decision to initiate dasatinib at 100 mg once daily., Management and Outcome: After initiation of therapy, the patient achieved a complete hematological response after two weeks and an early major molecular response on a three-month assessment. The therapy was tolerated well with no identified adverse effects., Discussion: Clinical rationale for selecting dasatinib in patients with SBS includes supporting literature regarding its pharmacokinetic absorption characteristics, its efficacy with lower doses in newly diagnosed patients with CML, and its side effect profile in comparison to other second-generation TKIs. The case discussed provides an example of successful therapy in a patient with SBS undergoing treatment for CML.

Background: Intraoperative inflammation may contribute to postoperative neurocognitive disorders after cardiac surgery requiring cardiopulmonary bypass (CPB). However, the relative contributions of general anesthesia (GA), surgical site injury, and CPB are unclear., Methods: In adult female sheep, we investigated (1) the temporal profile of proinflammatory and anti-inflammatory cytokines and (2) the extent of microglia activation across major cerebral cortical regions during GA and surgical trauma with and without CPB (N = 5/group). Sheep were studied while conscious, during GA and surgical trauma, with and without CPB., Results: Plasma tumor necrosis factor-alpha (mean [95% confidence intervals], 3.7 [2.5-4.9] vs 1.6 [0.8-2.3] ng/mL; P = .0004) and interleukin-6 levels (4.4 [3.0-5.8] vs 1.6 [0.8-2.3] ng/mL; P = .029) were significantly higher at 1.5 hours, with a further increase in interleukin-6 at 3 hours (7.0 [3.7-10.3] vs 1.8 [1.1-2.6] ng/mL; P < .0001) in animals undergoing CPB compared with those that did not. Although cerebral oxygen saturation was preserved throughout CPB, there was pronounced neuroinflammation as characterized by greater microglia circularity within the frontal cortex of sheep that underwent CPB compared with those that did not (0.34 [0.32-0.37] vs 0.30 [0.29-0.32]; P = .029). Moreover, microglia had fewer branches within the parietal (7.7 [6.5-8.9] vs 10.9 [9.4-12.5]; P = .001) and temporal (7.8 [7.2-8.3] vs 9.9 [8.2-11.7]; P = .020) cortices in sheep that underwent CPB compared with those that did not., Conclusions: CPB enhanced the release of proinflammatory cytokines beyond that initiated by GA and surgical trauma. This systemic inflammation was associated with microglial activation across 3 major cerebral cortical regions, with a phagocytic microglia phenotype within the frontal cortex, and an inflammatory microglia phenotype within the parietal and temporal cortices. These data provide direct histopathological evidence of CPB-induced neuroinflammation in a large animal model and provide further mechanistic data on how CPB-induced cerebral inflammation might drive postoperative neurocognitive disorders in humans., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Tillering and yield are linked in rice, with significant efforts being invested to understand the genetic basis of this phenomenon. However, in addition to genetic factors, tillering is also influenced by the environment. Exploiting experiments in which seedlings were first grown in elevated CO 2 (eCO 2 ) before transfer and further growth under ambient CO 2 (aCO 2 ) levels, we found that even moderate exposure times to eCO 2 were sufficient to induce tillering in seedlings, which was maintained in plants grown to maturity plants in controlled environment chambers. We then explored whether brief exposure to eCO 2 (eCO 2 priming) could be implemented to regulate tiller number and yield in the field. We designed a cost-effective growth system, using yeast to increase the CO 2 level for the first 24 days of growth, and grew these seedlings to maturity in semi-field conditions in Malaysia. The increased growth caused by eCO 2 priming translated into larger mature plants with increased tillering, panicle number, and improved grain filling and 1000 grain weight. In order to make the process more appealing to conventional rice farmers, we then developed a system in which fungal mycelium was used to generate the eCO 2 via respiration of sugars derived by growing the fungus on lignocellulosic waste. Not only does this provide a sustainable source of CO 2 , it also has the added financial benefit to farmers of generating economically valuable oyster mushrooms as an end-product of mycelium growth. Our experiments show that the system is capable of generating sufficient CO 2 to induce increased tillering in rice seedlings, leading eventually to 18% more tillers and panicles in mature paddy-grown crop. We discuss the potential of eCO 2 priming as a rapidly implementable, broadly applicable and sustainable system to increase tillering, and thus yield potential in rice., (© 2023. The Author(s).)

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light-chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m 2 ) is considered in older patients because of concerns regarding tolerability. Age does not predict frailty, and dose modification could compromise responses in an era where effective non-transplant regimens are available. We analyzed 43 patients ≥ 65 years with AL amyloidosis who underwent SCT at Boston University Amyloidosis Center between 2011 and 2020. Median age was 66 years (range 65-68) versus 69 years (range 65-76) in the HDM and mHDM groups, respectively. HR of ≥ very good partial response at 12 months was 66.7% versus 42.3% for patients treated with HDM versus mHDM. Median progression-free survival (PFS) from day 0 of SCT was not reached versus 12.0 months (P =.13); grade ≥ 3 non-hematologic transplant-related toxicities occurred in 87.5% versus 76.9%; and transplant-related mortality was 0% versus 2.3% in the HDM versus mHDM group, respectively. In carefully selected older patients with AL amyloidosis, HDM is well tolerated. Use of mHDM results in reduced HR and PFS; an important consideration with the advent of highly effective non-transplant therapies., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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., (© 2022 Wiley Periodicals LLC.)

Background: Patients with cancer undergoing cytotoxic chemotherapy face an elevated risk of developing serious infection as a consequence of their treatment, which lowers their white blood cell count and, more specifically, their absolute neutrophil count. This condition is known as neutropenia. Neutropenia accompanied by a fever is referred to as febrile neutropenia, a common side effect of chemotherapy with a high mortality rate. The timely detection of severe neutropenia (<500 absolute neutrophil count/μL) is critical in detecting and managing febrile neutropenia. Current methods rely on blood draws, which limit them to clinical settings and do not allow frequent or portable monitoring. In this study, we demonstrated the usability of PointCheck, a noninvasive device for neutropenia screening, in a simulated home environment without clinical supervision. PointCheck automatically performs microscopy through the skin of the finger to image the blood flowing through superficial microcapillaries and enables the remote monitoring of neutropenia status, without requiring venipuncture., Objective: This study aimed to evaluate the usability of PointCheck, a noninvasive optical technology for screening severe neutropenia, with the goal of identifying potential user interface, functionality, and design issues from the perspective of untrained users., Methods: We conducted a multicenter study using quantitative and qualitative approaches to evaluate the usability of PointCheck across 154 untrained participants. We used a mixed method approach to gather usability data through user testing observations, a short-answer qualitative questionnaire, and a standardized quantitative System Usability Scale (SUS) survey to assess perceived usability and satisfaction., Results: Of the 154 participants, we found that 108 (70.1%) scored above 80.8 on the SUS across all sites, with a mean SUS score of 86.1 across all sites. Furthermore, the SUS results indicated that, out of the 151 users who completed the SUS survey, 145 (96%) found that they learned how to use PointCheck very quickly, and 141 (93.4%) felt very confident when using the device., Conclusions: We have shown that PointCheck, a novel technology for noninvasive, home-based neutropenia detection, can be safely and effectively operated by first-time users. In a simulated home environment, these users found it easy to use, with a mean SUS score of 86.1, indicating an excellent perception of usability and placing this device within the top tenth percentile of systems evaluated for usability by the SUS., Trial Registration: ClinicalTrials.gov NCT04448314; https://clinicaltrials.gov/ct2/show/NCT04448314 (Hospital Universitario 12 de Octubre registration) and NCT04448301; https://clinicaltrials.gov/ct2/show/NCT04448301 (Boston Medical Center registration)., (©Ganimete Lamaj, Alberto Pablo-Trinidad, Ian Butterworth, Nolan Bell, Ryan Benasutti, Aurelien Bourquard, Alvaro Sanchez-Ferro, Carlos Castro-Gonzalez, Ana Jiménez-Ubieto, Tycho Baumann, Antonia Rodriguez-Izquierdo, Elizabeth Pottier, Anthony Shelton, Joaquin Martinez-Lopez, John Mark Sloan. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 09.08.2022.)

Human T cell lymphotropic virus types 1 and 2 (HTLV-1/2) are delta retroviruses. HTLV-1 may lead to complications, including adult T cell leukemia-lymphoma (ATLL) and HTLV-1-associated myelopathy. Immunosuppression may result in progression from an asymptomatic carrier state to ATLL. Data on the safety of stem cell transplantation (SCT) in patients with HTLV-1/2 infection are lacking. The Center for International Blood and Marrow Transplant Research database was queried for patients who tested positive for HTLV infection in the pretransplantation workup and underwent either autologous SCT (autoSCT) or allogeneic SCT (alloSCT). Patients were excluded if they underwent SCT for ATLL. The primary outcome was overall survival (OS) at 3 years and 4 years post-SCT. In those who underwent autoSCT, 54 patients were HTLV-positive and 9836 were HTLV-negative. In those who underwent alloSCT, 105 patients were HTLV-positive and 18,077 were HTLV-negative. No difference in OS was noted between the HTLV-positive and HTLV-negative patients at 3 years post-autoSCT (76% versus 77%; P = .916). Inferior OS (32% versus 46%; P = .017) and nonrelapse mortality (35% versus 27%; P = .030) were observed in HTLV-positive patients at 4 years post-alloSCT. Future work should examine the mechanism by which HTLV-1/2 impact survival in alloSCT recipients., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Adverse events affecting Black patients, including skin hyperpigmentation, may be overlooked using existing clinical trial data on lenalidomide. The objective of this systematic review is to characterize the representation of Black participants and rate of skin hyperpigmentation in clinical trials. In this systematic review and pooled analysis of 21 clinical trials comprising 4539 participants, the proportion of Black participants in trials (6.9%, n = 315) was significantly less than the multiple myeloma population (p < 0.001). The rate of skin hyperpigmentation (0.066%, n = 3) and all skin changes (6.4%, n = 291) was significantly less compared to a 40.8% incidence in a recent retrospective study (p. <0.001). Among participants undergoing treatment with lenalidomide for multiple myeloma, Black patients were underrepresented and the adverse event of skin hyperpigmentation was underreported. Fair representation of Black patients in clinical trials is needed to better describe this adverse event and other events that may be underreported., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Daratumumab as a single agent (sDARA) or in combination with chemotherapies (cDARA) leads to impressive hematologic and organ responses in AL amyloidosis. However, predictive factors associated with outcomes, and optimal duration of therapy remain unclear. We analyzed 107 patients with AL amyloidosis treated with daratumumab between 2017 and 2020. The median overall survival (OS) was not reached while the median major organ deterioration progression free survival (MOD-PFS) was 36 months in the sDARA cohort and not reached in the cDARA cohort, respectively. Hematologic response > VGPR was achieved in 81% of patients receiving sDARA and 86% of patients treated with cDARA. Several predictive factors were identified on a univariate analysis, including NTproBNP >8500 pg/mL but only achievement of at least VGPR and presence of 1q21 gain were independently associated with MOD-PFS and OS on a multivariate analysis. Finally, patients receiving > 12 cycles had significantly longer MOD-PFS (30 vs.13 months; (p = .0018) and OS (NR vs. 15 months; p < .0001). NTproBNP > 8500 pg/mL, presence of 1q21 gain and shorter duration of therapy (≤ 12 cycles) are strong negative predictive factors for outcomes with daratumumab therapy in AL amyloidosis., (© 2021 Wiley Periodicals LLC.)

The proteasome inhibitor, bortezomib, has become a backbone for the first line treatment of patients with AL amyloidosis who are not eligible for high dose melphalan and stem cell transplantation. The presence of t(11;14), seen in up to 40-60% of patients with AL amyloidosis, may be associated with poorer response when treated with bortezomib based regimens. This remains a critical distinction in light of recent evidence demonstrating favourable responses to BCL-2 inhibition with venetoclax in patients with t(11;14) in multiple myeloma. We report on 135 patients with newly diagnosed AL amyloidosis treated with a bortezomib-based regimen as first line therapy between 2013 and 2017. Treatment outcomes were compared between a cohort of patients with t(11;14) and those without the translocation. Forty-four patients had the presence of t(11;14). Five-year overall survival was 46% for those with t(11;14) and 72% in patients without this translocation ( p  = .026). The median haematologic event free survival was 17 months for patients with t(11;14) compared to 34 months without ( p  = .068). Haematologic response of VGPR or better was achieved in 41% of patients with t(11;14) vs 66% without t(11;14) ( p  = .012). Cardiac and renal responses to first line treatment with bortezomib-based regimens were also higher in patients without t(11;14). In conclusion, patients with AL amyloidosis and the presence of t(11;14) have inferior outcomes with respect to survival, as well as haematologic and organ responses, when treated with bortezomib-based regimens as first line therapy.

Objectives: A subset of coronavirus disease 2019 (COVID-19) patients exhibit clinical features of cytokine storm. However, clinicopathologic features diagnostic of hemophagocytic lymphohistiocytosis (HLH) have not been reported. We studied the reticuloendothelial organs of 4 consecutive patients who died of COVID-19 and correlated with clinical and laboratory parameters to detect HLH., Methods: Autopsies were performed on 4 patients who died of COVID-19. Routine H&E staining and immunohistochemical staining for CD163 were performed to detect hemophagocytosis. Clinical and laboratory results from premortem blood samples were used to calculate H-scores., Results: All 4 cases demonstrated diffuse alveolar damage within the lungs. Three of the 4 cases had histologic evidence of hemophagocytosis within pulmonary lymph nodes. One case showed hemophagocytosis in the spleen but none showed hemophagocytosis in liver or bone marrow. Lymphophagocytosis was the predominant form of hemophagocytosis observed. One patient showed diagnostic features of HLH with an H-score of 217, while a second patient likely had HLH with a partial H-score of 145 due to a missing triglyceride level. The remaining 2 patients had H-scores of 131 and 96., Conclusions: This is the first report of severe acute respiratory syndrome coronavirus 2-associated HLH. Identification of HLH in a subset of patients with severe COVID-19 will inform clinical trials of therapeutic strategies., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hematologic complete response (hemCR) in AL amyloidosis requires absence of monoclonal protein by immunofixation electrophoreses (IFE) and normal serum free light chain ratio (FLCR). Recent literature suggests that an involved free light chain (iFLC) <20 mg/L or difference in free light chains (dFLC) <10 mg/L may more accurately predict outcomes after treatment. We evaluated overall survival in 340 patients treated with high-dose melphalan and stem cell transplantation (SCT). Of 305 patients evaluable 6 months after SCT, 90 (30%) achieved hemCR, 132 (43%) dFLC <10 mg/L, 118 (39%) iFLC <20 mg/L, and 176 (58%) normal FLCR. Of 215 patients without hemCR, 65 (30%) had dFLC <10 mg/L and 86 (40%) had normal FLCR. Overall survival (OS) in those achieving dFLC <10 mg/L or normal FLCR without hemCR was inferior to those achieving hemCR (p = 0.013 and p = 0.001). OS was not significantly different in patients achieving iFLC <20 mg/L without hemCR compared with hemCR (p = 0.243). Of those with hemCR, OS was not significantly improved if dFLC <10 mg/L was also achieved (p = 0.852), but OS was improved for those with hemCR who also attained iFLC <20 mg/L (p = 0.009). Multivariate analysis demonstrated absence of monoclonal protein in IFE and iFLC <20 mg/L as independent predictors of survival. Attainment of hemCR remains a treatment goal, although achieving iFLC <20 mg/L may also predict improved OS.

Daratumumab, a monoclonal CD38 antibody, is approved in the treatment of myeloma, but its efficacy and safety in light-chain (AL) amyloidosis has not been formally studied. This prospective phase 2 trial of daratumumab monotherapy for the treatment of AL amyloidosis was designed to determine the safety, tolerability, and hematologic and clinical response. Daratumumab 16 mg/kg was administered by IV infusion once weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, and every 4 weeks thereafter until progression or unacceptable toxicity, for up to 24 months. Twenty-two patients with previously treated AL amyloidosis were enrolled. The majority of the patients had received high-dose melphalan and stem cell transplantation and/or treatment with a proteasome inhibitor. The median time between prior therapy and trial enrollment was 9 months (range, 1-180 months). No grade 3-4 infusion-related reactions occurred. The most common grade ≥3 adverse events included respiratory infections (n = 4; 18%) and atrial fibrillation (n = 4, 18%). Hematologic complete and very-good-partial response occurred in 86% of patients. The median time to first and best hematologic response was 4 weeks and 3 months, respectively. Renal response occurred in 10 of 15 patients (67%) with renal involvement and cardiac response occurred in 7 of 14 patients (50%) with cardiac involvement. In summary, daratumumab is well tolerated in patients with relapsed AL amyloidosis and leads to rapid and deep hematologic responses and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT02841033.

Despite achieving a hematologic complete response after treatment, many patients with AL amyloidosis do not attain recovery of organ function and/or experience hematologic relapse. A persistent plasma cell clone producing amyloidogenic light chains at levels below the detection threshold of traditional serologic methods is hypothesized to impede organ response in some patients. Assessment of minimal residual disease (MRD) may therefore have clinical importance as a more stringent treatment response tool for patients in a hematologic complete response. We used 2-tube, 10-color combination multiparametric flow cytometry to assess for MRD at a minimum sensitivity of 1 in 105 nucleated cells. Of 65 patients in hematologic complete response, 36 (55%) were found to have a residual clonal plasma cell population in the bone marrow. Comparing the MRD-negative and MRD-positive groups, renal response was observed in 88% vs 64% (P = .06), cardiac response in 75% vs 59% (P = .45), and any organ response in 90% vs 75% (P = .20) of patients. Depth of organ response as measured by the percent decrease in 24-hour proteinuria and brain natriuretic peptide was 96% vs 91% (P = .16) and 55% vs 46% (P = .66), respectively. These data suggest a possible correlation between MRD negativity and higher probability of organ response after treatment in AL amyloidosis. Future prospective studies with a larger cohort are needed to determine the clinical relevance of these improvements. This trial was registered at www.clinicaltrials.gov as #NCT00898235., (© 2020 by The American Society of Hematology.)

Introduction: Monoclonal Ig deposition disease (MIDD) frequently leads to kidney failure, and a large proportion of these patients would greatly benefit from kidney transplantation. However, data on kidney transplantation outcomes in MIDD are limited., Methods: This was a retrospective analysis of long-term renal outcomes of 23 patients with MIDD, including 6 patients who underwent kidney transplantation., Results: The 1-, 5-, and 10-year overall survival (OS) from diagnosis were 95%, 78%, and 65%, respectively. Approximately half of the patients (n = 12) progressed to end-stage renal disease (ESRD) with a median time from diagnosis to ESRD of 3.4 years. The 1-, 5-, and 10-year renal survival from diagnosis were 77%, 48%, and 29% respectively. Renal response was observed only in 5 patients (22%), all of them after achieving hematologic complete response. Median OS from diagnosis was significantly better for those who underwent kidney transplantation versus those who remained on dialysis (19.8 years vs. 8.3 years, P  = 0.016). Among patients who underwent kidney transplantation, the shortest survival from MIDD diagnosis was 13.7 years and the longest was 27.8 years. Of the 3 patients with kidney transplants who died, the time from the first kidney transplantation to death was 7.4, 18.8, and 20.4 years. Graft loss due to disease recurrence occurred at 4 months and 3.8 years after kidney transplantation in 2 patients who either were not treated or did not respond to treatment., Conclusion: As treatments for MIDD have dramatically improved, more patients are achieving sustained hematologic responses with longer patient and graft survival after kidney transplantation., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Light chain (AL) amyloidosis is a protein folding disorder that can affect many different organ systems, in addition to the coagulation pathway. D-dimer, a measurement of fibrin degradation, is commonly elevated in hematologic malignancies, but the prevalence and significance of D-dimer elevation in AL amyloidosis is unknown. We conducted an analysis of 921 patients with AL amyloidosis that presented to the Boston University Amyloidosis Center. Baseline characteristics and laboratory data of the 897 patients included in the final cohort were analyzed. Four hundred twenty three patients (47%) had an elevated D-dimer (>0.5 μg/mL). Multivariate analysis demonstrated that a normal D-dimer level of ≤0.5 μg/mL, and a level of >0.5 μg/mL but <1 μg/mL, conferred a lower risk of mortality (HR 0.49 and 0.59, respectively) when compared to a D-dimer level ≥ 1 μg/mL. The increased risk of mortality in patients with a D-dimer level ≥ 1 μg/mL was present in all cardiac stages. The median overall survival based on D-dimer range of ≤0.5, >0.5 but <1, and ≥ 1 μg/mL was 5.86, 4.04, and 2.08 years, respectively (P < .001). This retrospective analysis demonstrates the high prevalence of D-dimer elevation in AL amyloidosis and confirms that this laboratory finding is independently associated with decreased survival., (© 2019 Wiley Periodicals, Inc.)

Cardiac deposition of misfolded light chains is the leading cause of morbidity and mortality in patients with immunoglobulin (AL) amyloidosis. Cardiac defibrillators can be used in the management of patients with advanced cardiac amyloidosis, but data concerning the use of these devices in patients undergoing treatment with high-dose melphalan followed by autologous peripheral blood stem cell transplantation (HDM/SCT) is limited. Herein we describe a single-institution experience of HDM/SCT in 15 patients with cardiac defibrillators. During the peri-transplant period, five of these patients (33%) had detectable cardiac arrhythmias and two patients (13%) had implantable cardiac defibrillator (ICD) discharges. Thirteen of the 14 evaluable patients (93%) achieved at least a partial hematologic response. Transplant-related mortality was 6.7% and median overall survival was 40.8 months, with multiple patients achieving an overall survival of >10 years. These data highlight the feasibility of HDM/SCT in patients with an ICD due to advanced cardiac AL amyloidosis, but highlight the need for additional research to appropriately determine which patients will benefit from this aggressive therapy.