Bone marrow involvement by ATTR amyloid is common in cardiac amyloidosis patients and may signal advanced-stage disease

Abstract Introduction/Objective Amyloidosis encompasses a heterogeneous group of disorders characterized by abnormal deposition of misfolded proteins leading to progressive organ failure. Accurate amyloid typing is essential for proper patient management, as treatment regimens vary dramatically across different types. Bone marrow (BM) biopsy, in conjunction with fat pad aspiration/biopsy, is often the first step in patients with suspected amyloidosis. Although BM involvement by AL amyloid has been previously characterized, little is known about the incidence, morphology and clinical phenotype of non-AL amyloid in BM. Methods/Case Report We retrospectively identified 1469 BM biopsies by querying our reference laboratory database of 19,298 specimens from myriad anatomic sites typed by mass spectrometry-based proteomics (LC-MS/MS). These were reviewed for frequency of amyloid types (N=1469), distribution of amyloid deposits (N=139), and clinical phenotypes (N=345), with particular emphases on cardiac involvement. Results (if a Case Study enter NA) We identified the following amyloid types: AL (N=1172; 79.8%), ATTR (transthyretin) (N=240; 16.3%), AH (immunoglobulin heavy chain) (N=38; 2.6%), AA (serum amyloid A) (N=17; 1.2%), and Aβ2M (β2-microglobulin) (N=2; 0.1%). ATTR deposits showed striking predilection for periosteal soft tissue and/or periosteal vessels, and rarely involved BM stroma and/or interstitial vessels, while AL variably involved these compartments. AA primarily involved interstitial vessels. Both AL and ATTR cases commonly had a monoclonal gammopathy (AL: 92.9%; ATTR: 62.5%) with concomitant cardiac amyloidosis (AL: 91.6%; ATTR: 100%). Compared to AL, ATTR patients had higher stage cardiac amyloidosis and lower overall survival. Conclusion ATTR is common in BM, constituting16.3% of cases in our cohort. Rarer amyloid types, such as AA, AH and AB2M can also occur in BM. ATTR was frequently identified in patients with concomitant monoclonal gammopathy, in whom AL may have been suspected. Although ATTR deposits have distinctive morphologic distribution, primarily involving periosteal soft tissue and/or periosteal vessels and rarely involving BM stroma and/or interstitial vessels, there is considerable morphologic overlap with AL. Therefore, it is imperative to type BM amyloidosis, preferably by LC-MS/MS, to ensure proper patient management. Furthermore, BM involvement by ATTR may be a marker for advanced stage of disease.

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Prognostic factors in aggressive malignant lymphomas: description and validation of a prognostic index that could identify patients requiring a more intensive therapy. The Groupe d'Etudes des Lymphomes Agressifs.

Journal of Clinical Oncology ◽

10.1200/jco.1991.9.2.211 ◽

1991 ◽

Vol 9 (2) ◽

pp. 211-219 ◽

Cited By ~ 156

Author(s):

B Coiffier ◽

C Gisselbrecht ◽

J M Vose ◽

H Tilly ◽

R Herbrecht ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Prognostic Factors ◽

Serum Albumin ◽

Serum Albumin Level ◽

Bone Marrow Involvement ◽

Prognostic Index ◽

Albumin Level ◽

Advanced Stage ◽

Low Serum

The objectives of this study were to determine prognostic factors for response to treatment, freedom-from-relapse (FFR) survival, and overall survival of 737 aggressive malignant lymphoma patients treated with the doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, methotrexate with leucovorin, ifosfamide, etoposide, asparaginase, and cytarabine (LNH-84) regimen; to construct a prognostic index with factors isolated by multivariate analyses; and to validate this prognostic index with another set of patients. Complete response (CR) was reached in 75% of LNH-84 patients, and 30% of them relapsed. With a median follow-up of 36 months, median FFR survival and median overall survival were not reached. Low serum albumin level, high tumoral mass, weight loss, bone marrow involvement, greater than or equal to 2 extranodal sites, and increased lactic dehydrogenase (LDH) level were associated with a low response rate. Advanced stage, increased LDH level, and nonlarge-cell histologic subtypes (diffuse mixed, lymphoblastic, and small non-cleaved) were statistically associated with a high relapse rate and short FFR survival. Increased LDH level, low serum albumin level, tumoral mass larger than 10 cm, greater than or equal to 2 extranodal sites, advanced stage, and age older than 65 years were statistically associated with short overall survival. Four of these parameters, namely, LDH level, stage, number of extranodal sites, and tumoral mass, were put together to construct a prognostic index. This index partitioned LNH-84 patients into three subgroups of good, intermediate, and poor prognosis (P less than .00001): CR rates of 93%, 83%, and 61%; relapse rates of 12%, 25%, and 45%; 3-year FFR survival of 87%, 73%, and 53%, and 3-year survival of 88%, 71%, and 41%, respectively. This prognostic index was applied to a test set of patients: 155 patients treated on protocols of the Nebraska Lymphoma Study Group. Using this index, these patients had 3-year FFR survival of 70%, 40%, and 22% (P = .0002) and 3-year survival of 79%, 52%, and 31% (P = .005). In patients with aggressive lymphomas, this simple prognostic index could distinguish between patients requiring intensive treatment such as autologous bone marrow transplantation in first complete remission and those who could be treated with standard regimens.

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Incidence and Risk Factors for Central Nervous System Manifestation in Elderly Patients with Aggressive Non-Hodgkin’s Lymphoma.

Blood ◽

10.1182/blood.v106.11.3333.3333 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3333-3333

Author(s):

E. Ösby ◽

H. Hagberg ◽

S. Kvalöy ◽

L. Teerenhovi ◽

H. Anderson ◽

...

Keyword(s):

Risk Factors ◽

Central Nervous System ◽

Bone Marrow ◽

Nervous System ◽

Elderly Patients ◽

Bone Marrow Involvement ◽

Hodgkin's Lymphoma ◽

Advanced Stage ◽

Cns Disease ◽

Non Hodgkin's Lymphoma

Abstract Introduction: Manifestation of central nervous system (CNS) disease in patients with aggressive non-Hodgkin’s lymphoma (NHL) during or after first line treatment is often a devastating condition, which is associated with a poor prognosis. There is today no general consensus regarding prophylactic treatment in this patient category, particularly in the elderly. The aim of this study was to define the incidence and risk factors for CNS manifestation in a large cohort of elderly (>60 years) patients with aggressive NHL and no CNS disease at diagnosis. Patients and methods: This Nordic study included a total of 455 previously untreated patients with advanced (stage II–IV) aggressive NHL without CNS involvement at diagnosis (Blood2003;101:3840). The vast majority had diffuse large B cell lymphoma. Patients (median age, 71 years; range, 60–86 years) were randomised to receive CHOP (doxorubicin 50 mg/m2) or CNOP (mitoxantrone 10 mg/m2) with or without G-CSF (5 microg/kg from day 2 until day 10–14 of each cycle every 3 weeks; 8 cycles). Intrathecal methotrexate was given as prophylaxis to patients with lymphoma bone marrow involvement and in patients with testicular, orbital, sinus and epidural sites of presentation. Results: At this time point information is available for 441/455 patients. After a median observation time of 113 months in surviving patients 30/441 (6.8%) developed CNS disease. Advanced stage (p=0.004) and a high age-adjusted International Prognostic Index (IPI; p=0.034) were associated with an increased risk of CNS disease. Age, sex, performance status, bone marrow involvement/extranodal disease, serum lactate dehydrogenase level, or treatment received were not related to the risk of CNS manifestation. All patients with CNS disease were dead at follow-up. Conclusion: A significant proportion of elderly patients with advanced aggressive NHL and no CNS manifestation at diagnosis develop CNS disease despite prophylactic measures in clinically defined high-risk patients. CNS occurrence is related to clinical stage and age-adjusted IPI. The prognosis of elderly aggressive NHL patients with CNS manifestation is poor.

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Prognostic Significance of Bone Marrow Involvement in Hodgkin Lymphoma

Blood ◽

10.1182/blood.v128.22.5370.5370 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5370-5370 ◽

Cited By ~ 1

Author(s):

Ankit Mangla ◽

Muhammad Umair Mushtaq ◽

Rohit Kumar ◽

Nikki Agarwal ◽

Sibgha Gull Chaudhary ◽

...

Keyword(s):

Bone Marrow ◽

Hodgkin Lymphoma ◽

Bone Marrow Involvement ◽

Prognostic Significance ◽

Albumin Level ◽

Stage Iii ◽

Inverse Association ◽

Care Hospital ◽

Advanced Stage ◽

Histologic Subtype

Abstract Background: The utility of bone marrow biopsy (BMB) in patients with Hodgkin lymphoma (HL) has been a controversial topic. Clinical stage 4 (CS4) has been shown to be an independent poor prognostic marker and is also included in the International Prognostic Scoring (IPS) index for predicting both progression-free survival (PFS) and overall survival (OS). The current guidelines still recommend performing a BMB in patients with stage IIB (with unfavorable risk factors), III and IV HL, mainly for staging purposes. Though bone marrow involvement (BMI) upstages the HL to stage IV, the prognostic significance of BMI remains unclear. The study was aimed to determine the prognostic significance of BMI in underserved patients with HL and to determine the prognostic importance of other blood parameters. Methods: The study was conducted at John H. Stroger Hospital of Cook County, an inner city tertiary care hospital providing care to the underserved population of Chicago. Charts of 241 patients diagnosed with HL were screened from tumor registry. Patients with incomplete charts were not included in the study. Socio-demographic, clinical and pathologic factors were recorded at the time of diagnosis. For comparative purpose, CS4 disease did not include patients with BMI. Kaplan-Meier and bivariate analyses were performed. Cox regression analyses were conducted to explore predictors of OS and PFS. Hazard ratios (HR) with 95% confidence intervals (CI) were obtained. Results: The study included 192 patients of which 41% were Afro-Americans, 34% were Hispanics and 21% were Caucasians. Median age was 34 years with 25.5% patients being older than 45 years and 68% patients being women. Seventeen percent patients were positive for HIV. Nodular sclerosis was the most common histologic subtype (55%), bulky disease was recorded in 19% patients and 61.5% patients had B-symptoms. CS4 disease was seen in 12% patients while 28% patients were stage III, 47% were stage II and 13% were stage I. Single-site BMB was done in 96% patients. BMB was positive for involvement with HL in 19% patients (n=37). Out of these 37 patients, 84% (n=31) had advanced stage (III & IV) HL. BMI was seen in 5% patients with early-stage HL (stages I-II) and 41% patients with advanced-stage HL. Median IPS score was 2 (range 0-6). Median values for clinical factors were: hemoglobin-11.8 g/dL, platelets 314.5 x103/uL, leukocytes 8.3 x103/uL, neutrophils 6x103/uL, lymphocytes 1.2 x103/uL and albumin 3.7 g/dL. Mean OS was 143 months (95% CI 126-160) with 5-year OS of 89%. Significant correlates of OS included: age 45 years or older (HR 2.83, 95%CI 1.25-6.43, P =0.013), HIV (HR 2.80, 95%CI 1.19-6.61, P =0.019), nodular sclerosistype (HR 0.29, 95%CI 0.12-0.71, P =0.006), CS4 disease (HR 3.05, 95%CI 1.20-7.77, P =0.019), BM positive for involvement with HL (HR 5.76, 95%CI 2.56-12.98, P <0.001), IPS score (HR 1.57, 95%CI 1.20-2.06, P =0.001), hemoglobin <10.5 g/dL (HR 3.57, 95%CI 1.56-8.19, P =0.003), platelets <150 x103/uL (HR 5.32, 95%CI 2.19-12.96, P <0.001) and lymphocytes <0.6 x103/uL (HR 2.97, 95%CI 1.21-7.28, P =0.017). Gender, albumin level, leukocytosis (>15 x103/uL) and relative lymphopenia (<8%) did not have a significant association with OS. When adjusted for CS4 disease, BMI remained an independent predictor of OS (HR 2.17, 95%CI 1.04-4.55, P =0.039). Mean PFS was 105 months (95% CI 97-117) with 5-year PFS of 78%. BMI (HR 2.38, 95%CI 1.21-4.67, P =0.012), albumin level (HR 0.71, 95%CI 0.53-0.94, P =0.017) and albumin-globulin ratio (HR 0.41, 95%CI 0.18-0.93, P =0.032) predicted PFS. None of the other factors had a significant association with PFS. BMI had inverse association with OS (mean OS 97.5 months vs. 164 months, P <0.001; 5-year OS 70% vs. 93.5%, P<0.001) and PFS (mean PFS 74 months vs. 112 months, P = 0.004; 5-year PFS 65% vs. 81%, P=0.030). Conclusion: BMI in HL indicates disseminated disease. Our study shows that BMI in patients with HL has a significant inverse relation with OS and PFS, independent of stage. Our data indicates that in patients with HL important prognostic information can be achieved by demonstrating BMI and it should be considered for inclusion in the IPS score. The rate of BMI is higher in our cohort, for both early and advanced stage HL, when compared with literature and maybe a limitation of our retrospective study. However our results still warrant that long term prospective studies should be designed to explore the prognostic significance of BMI. Disclosures No relevant conflicts of interest to declare.

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The Prognostic Value of the Neutrophil to Lymphocyte Ratio in 209 Patients with Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.1675.1675 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1675-1675

Author(s):

Brady E Beltran ◽

Denisse Castro ◽

Julio C Chavez ◽

Eduardo M. Sotomayor ◽

Jorge J. Castillo

Keyword(s):

Bone Marrow ◽

T Cell ◽

Prognostic Value ◽

Cell Lymphoma ◽

Performance Status ◽

Bone Marrow Involvement ◽

T Cell Lymphoma ◽

Neutrophil To Lymphocyte Ratio ◽

Advanced Stage ◽

Lymphocyte Ratio

Abstract Introduction: Peripheral T-cell lymphomas (PTCL) are rare hematologic malignancies with a poor prognosis when treated with current standard therapies. Several factors have been developed to prognosticate survival in PTCL patients; however, more refined, easy to use and reliable prognostic tools are needed. The neutrophil to lymphocyte ratio (NLR) has been reported prognostic in patients with diffuse large B-cell lymphoma (Troppan et al. BJC 2014). We have investigated the prognostic value of the NLR in the overall survival (OS) of patients with untreated PTCL. Methods: We included patients with a pathological diagnosis of PTCL who were diagnosed and treated at our institution between 2001-2013. We excluded cases with primary cutaneous PTCL, CNS involvement, and patients with >50% incomplete data. IRB approval was obtained prior to research. Pathological samples were reviewed by expert hematopathologists to confirm a diagnosis of PTCL. Pertinent clinicopathological data such as age, sex, performance status, LDH levels, stage, bone marrow involvement, extranodal sites of disease, PTCL subtype, and absolute neutrophil and lymphocyte countswere collected through chart review, and are presented using descriptive statistics. The NLR was calculated by dividing the absolute neutrophil by the lymphocyte count, and dichotomized in NLR>=4 and NLR<4. The Prognostic Index for PTCL (PIT) was estimated using the clinical data above. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses were performed using Cox proportional-hazard regression models. Results: A total of 209 patients were included in our analysis from which 93 (44.5%) were PTCL, not otherwise specified (NOS), 83 (40%) were adult T-cell leukemia/lymphoma (ATLL), 22 (10.5%) were anaplastic large cell lymphoma (ALCL), 7 (3%) were extranodal NK/T-cell lymphoma (NKTCL), and 4 (2%) angioimmunoblastic T-cell lymphoma (AITL). The median age was 57 years (range 3-87 years) with equal distribution among men (52%) and women (48%). Poor performance status (ECOG >1) was seen in 85 (49%), elevated LDH levels in 116 (64%), >1 extranodal site in 31 (19%), bone marrow involvement in 64 (31%), and advanced stage (stage 3 and 4) in 151 (74%) of patients. Based on the NLR, 91 patients (59%) had NLR<4 and 62 (n=41%) had NLR>=4. Patients with NLR >=4 were more likely men (67% vs. 44%, p=0.005), and tended to present with elevated LDH (73% vs. 47%, p=0.002), advanced stage (87% vs. 61%, p=0.001) but lower bone marrow involvement (19% vs. 37%, p=0.02). There were no differences in age, performance status and number of extranodal sites. NLR>=4 was associated with a worse OS (HR 2.27, 95% CI 1.40-3.69; p=0.001). Specifically, NLR>=4 was associated with a worse OS in patients with non-ATLL PTCL (HR 2.99, 95% CI 1.67-5.37; p<0.001) but not in patients with ATLL (HR 1.16, 0.48-2.81; p=0.75). In the multivariate analysis, NLR>=4 was independently associated with worse OS when adjusting for the PIT score in non-ATLL PTCL patients (HR 2.12, 95% CI 1.06-4.26; p=0.03). Conclusion: The NLR appears as a novel and easy to use prognostic factor for OS in patients with untreated non-ATLL PTCL, independent of the PIT score. The NLR did not seem to be prognostic in ATLL patients. Our findings support the need for validation of the NLR in larger retrospective or prospective studies in patients with PTCL. Disclosures No relevant conflicts of interest to declare.

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A case of Schnitzler’s syndrome without monoclonal gammopathy successfully treated with canakinumab

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-04120-z ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yuya Fujita ◽

Tomoyuki Asano ◽

Akira Sakai ◽

Natsumi Norikawa ◽

Toshiyuki Yamamoto ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Urticaria ◽

Monoclonal Gammopathy ◽

Bone Pain ◽

Periodic Fever ◽

Interleukin 1 ◽

Clinical Manifestations ◽

Magnetic Resonance Imaging Examination ◽

Amyloid A ◽

Schnitzler’S Syndrome

Abstract Background Schnitzler’s syndrome (SchS) is a rare autoinflammatory syndrome with diagnostic challenge and be characterized by chronic urticaria, a monoclonal gammopath, periodic fever and bone pain. In addition to the monoclonal gammopathy, bone abnormalities are often found at the site of bone pain in patients with SchS. The remarkable efficacy of interleukin-1 (IL-1) inhibition was also demonstrated in this syndrome. Case presentation We describe a case of refractory chronic urticaria presenting with clinical manifestations consistent with SchS without monoclonal gammopathy. A 43-year-old female patient suffering from recurring of urticaria with periodic fever as well as bone pain for the past 4 years. The patient had leukocytosis and elevated levels of C-reactive protein (CRP) and serum amyloid A (SAA). PET/CT (positron emission tomography/computed tomography) and MRI (magnetic resonance imaging) examination revealed hyper-metabolism areas in both femoral bone marrow. Although bone marrow histology revealed no abnormality, urticarial skin lesions shows neutrophilic infiltrations without evidence of vasculitis. We could not exclude the possibility of SchS. The patient had been treated with antihistamines, steroids, omarizumab, colchicine and cyclosporine A, no therapeutic effect was observed. She was started on canakinumab 150 mg subcutaneous injection with 4 weeks interval. Within 48 h after the first injection, the urticarial rash disappeared, and febrile attack and bone pain had not recurred. Elevated levels of serum CRP and SAA were normalized within a week after the first injection of canakinumab. Conclusions The current case suggests an important role for IL-1 as a mediator in the pathophysiology of SchS-like refractory urticaria with bine pain. It had been presumed that monoclonal gammopathy may not always present in SchS. It is important to avoid delay in diagnosis and initiation of proper treatment in SchS or autoinflammatory conditions resembling SchS.

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Patients with Bone and Bone Marrow Involvement Had Better OS and PFS in Patients with Aggressive Non-Hodgkin Lymphoma Treated with CD19 CAR T Cells

Blood ◽

10.1182/blood-2019-130566 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5315-5315

Author(s):

Lili Zhou ◽

Liang Aibin ◽

Shaoguang Li ◽

Shiguang Ye ◽

Ping Li

Keyword(s):

Bone Marrow ◽

T Cells ◽

Soft Tissue ◽

Complete Remission ◽

Hodgkin Lymphoma ◽

Bone Marrow Involvement ◽

Car T Cells ◽

Non Hodgkin Lymphoma ◽

Soft Tissue Involvement ◽

Car T

Factors associated with complete remission and durable remission after CD19 chimeric antigen receptor (CAR)-modified T-cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors affecting response and progression-free survival (PFS) in patients with aggressive NHL treated with CD19 CAR T cells. The best overall response rate was 71%, with 32% of patients achieving complete remission. The median PFS and OS of patients with aggressive NHL who achieved complete remission were 11 months and 12 months. The median PFS and OS of patients with bone and bone marrow involvement without soft tissue involvement were 14 months and 18 months. The median PFS and OS of patients with soft tissue involvement were 1 months and 4 months. We report complete remission rates and long-term survival rates in patients with bone and bone marrow involvement were significantly higher than those in patients with soft tissue involvement. Figure Disclosures No relevant conflicts of interest to declare.

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