Lymphoplasmacytic lymphoma/Waldenström Macroglobulinemia Research Articles

Clonal Relationship and Mutation Analysis in Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia Associated With Diffuse Large B-cell Lymphoma

Patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) occasionally develop diffuse large B-cell lymphoma (DLBCL). This mostly results from LPL/WM transformation, although clonally unrelated DLBCL can also arise. LPL/WM is characterized by activating MYD88 L265P (>95%) and CXCR4 mutations (~30%), but the genetic drivers of transformation remain to be identified. Here, in thirteen LPL/WM patients who developed DLBCL, the clonal relationship of LPL and DLBCL together with mutations contributing to transformation were investigated. In 2 LPL/WM patients (15%), high-throughput sequencing of immunoglobulin gene rearrangements showed evidence of >1 clonal B-cell population in LPL tissue biopsies. In the majority of LPL/WM patients, DLBCL presentations were clonally related to the dominant clone in LPL, providing evidence of transformation. However, in 3 patients (23%), DLBCL was clonally unrelated to the major malignant B-cell clone in LPL, of which 2 patients developed de novo DLBCL. In this study cohort, LPL displayed MYD88 L265P mutation in 8 out of eleven patients analyzed (73%), while CXCR4 mutations were observed in 6 cases (55%). MYD88 WT LPL biopsies present in 3 patients (27%) were characterized by CD79B and TNFAIP3 mutations. Upon transformation, DLBCL acquired novel mutations targeting BTG1, BTG2, CD79B, CARD11, TP53, and PIM1. Together, we demonstrate variable clonal B-cell dynamics in LPL/WM patients developing DLBCL, and the occurrence of clonally unrelated DLBCL in about one-quarter of LPL/WM patients. Moreover, we identified commonly mutated genes upon DLBCL transformation, which together with preserved mutations already present in LPL characterize the mutational landscape of DLBCL occurrences in LPL/WM patients.

Lymphoplasmacytic lymphoma: a clinicopathological and prognostic analysis of 27 cases

Objective: To study the clinical manifestations, pathologic features, diagnosis and differential diagnosis, treatment and prognosis of lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM). Methods: Twenty-seven cases of LPL from January 2016 to December 2020 at Guangdong Provincial People's Hospital were collected. The clinical data, histomorphology, immunophenotype, MYD88 L265P mutation, treatment and prognosis were analyzed retrospectively. Results: There were 19 males and 8 female patients, with median age of 63 years. The most common initial symptoms were fatigue related to anemia. Bone marrow was involved in all cases, lymphadenopathy was seen in 11 cases and splenomegaly in 10 cases. Monoclonal IgM type protein was detected in 25 cases, meeting the diagnostic criteria of WM. Microscopically, bone marrow and lymph nodes were infiltrated by small lymphocytes, plasmacytoid lymphocytes or plasma cells. The cells expressed pan B-cell markers and showed immunoglobulin light chain restriction. There was no expression of CD5, and low expression of CD23 and CD10; Ki-67 index was usually low. The positive rate of MYD88 L265P mutation was 73.9% (17/23). Most of the patients were treated with rituximab combined with alkylating agents, nucleoside analogues or immunomodulators, and the few patients with relapse or progression were treated with Ibutinib. During the 3-168 months' follow-up period, recurrence or progression were seen in nine cases. Thrombocytopenia, elevated β2-microglobulin and high-risk group were associated with recurrence or progression of the disease (P<0.05). The overall survival (OS) and progression-free survival (PFS) of the high-risk patients were significantly lower than those of the low-medium risk patients (P<0.05). Conclusions: LPL/WM is an exclusive diagnosis; the detection of MYD88 L265P mutation has high diagnostic value, but it is not specific. These cases should be assessed comprehensively for their clinical manifestation, serum IgM protein level and immunophenotype. The overall prognosis of LPL/WM is good, but there are still a small number of high-risk patients with rapid progress, and so the symptomatic patients should be diagnosed accurately and treated in a timely manner.

The Landscape of Immunoglobulin Heavy Chain Gene Repertoire in Lymphoplasmacytic Lymphoma / Waldenström Macroglobulinemia

Introduction Immunoglobulin heavy-chain variable genes (IGHV) is critical for the defining epitope binding affinityand B cell differentiation. Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is a heterogeneous diseasewhose role of IGHV usage remains unknown. Besides, the clinical relevance of IGHV repertoire for LPL/WM remain largely unexplored. The aim of our study is to explore the IGH repertoire of LPL/WM in by far the largest series, and to evaluate the correlation between IGH rearrangements and genetic aberrations and clinical characteristics of LPL/WM patients.Methods A total of 162 patients with a diagnosis of LPL/WM were included in this study. Polymerase chain reaction (PCR)amplification of IGHV-IGHD-IGHJ was performed on genomic DNA or cDNA samples using the IGH Somatic Hypermutation Assay v2.0 (Invivoscribe, Technologies, San Diego, US). Sequences were aligned to IMGT (http://www.imgt.org/IMGT_vquest/vquest) and IGBLAST (https://www.ncbi.nlm.nih.gov/igblast/) databases. IGH gene repertoires, mutation status, IGHV CDR3 characteristics, genetic aberrations, MYD88 mutation status and clinical characteristics were collected to evaluate the relevance.Results Productive IGHV-D-J rearrangements were obtained in 136 out of 162 patients (84.0%). The IGHV gene repertoire was remarkably biased in LPL/WM. IGHV3-23 (15.4%), IGHV4-34 (10.3%), IGHV3-7 (8.1%), IGHV3-30 (7.4%) and IGHV3-74 (7.4%) were significantly overrepresented in LPL/WM(Figure 1). Among the 134 IGHD data, the most frequent segment was IGHD3-10 (21/134, 15.7%), followed by IGHD6-13 (18/134, 13.4%) (Figure 2). Among the 134 IGHJ data, IGHJ4 segment was selected in more than half of these rearrangements (70/136; 51.5%), followed by IGHJ6 (23/136; 16.9%) and IGHJ5 (21/136; 15.4%) (Figure 3). Most of the cases were mutated (97.0%) using a 98% IGHV germline homology cutoff. IGHV3-30 was associated with long heavy chain CDR3, indicating the specific antigen selection in LPL/WM. Patients with IGHV3-7 were significantly more likely to harbor 6q deletion (p<0.001)(Figure 4) and abnormal karyotype (p=0.004)(Figure 5).The IGHV hypermutation rate in patients with MYD88 L265P mutation was significantly higher than in wild-type patients (7.3% vs5.6%, p=0.009). IGHV3-23 and IGHV3-74 segments were more frequently detected in MYD88 mutated LPL/WM patients (25.7% vs. 4.3%, p=0.025). IGHV3-7 and IGHV4-59 were represented more in MYD88 wildtype patients (30.4% vs. 8.9%，p=0.005). Moreover, Patients with IGHV4 especially IGHV4-34 had higher level of LDH. IGHV4 was a prognostic marker of shorter progression-free-survival (Figure 6).Conclusion LPL/WM appears to be composed ofdifferent subgroups based on the IGHV repertoire. The mutational status and the IGHV CDR3 length indicated the role for antigenselection in LPL/WM development. The presence of IGHV4 genes proved to be a potential risk factor associated with outcome which deserved further study.These results showed for the first time that IGHV repertoire had clinical relevance in LPL/WM. [Display omitted] DisclosuresWang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

The Cytogenetic Aberrations and Their Prognostic Value in 181 Untreated Patients with Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia in China

Background: lymphoplasmacytic lymphoma/ Waldenström macroglobulinemia (LPL/WM) is a rare B cell proliferative malignancy characterized by immunoglobulin M monoclonal gammopathy and /or bone marrow infiltration by lymphoplasmacytic cells. Cytogenetic aberrations are now the main prognostic predicators in some B-NHLs such as CLL. However, their prognostic valve in LPL/WM remains controversial and recurrently chromosomal abnormalities have rarely been reported. Furthermore, the genetic basis of LPL/WM in China is also unclear.Methods: A panel of DNA probes was used to detect cytogenetic aberrations by fluorescence in situ hybridization (FISH), including RB1/D13S25 at 13q14, ATM at 11q22, TP 53 at 17p13, CEP12 and IGH translocation at 14q32, MYB at 6q23. Chromosomes were identified by G-banding and karyotypes were described according to the International System for Human Cytogenetics Nomenclature (ISCN, 1995). Totally, 181 untreated LPL/WM patients were enrolled in this study.Results: The median age of 181 patients was 61 years (range 32-87). The male to female ratio was 2.75 (133/48). 90% and 15.7% patients showed an elevated serumβ2 microglobulin and LDH. The percentage of hepatomegaly, splenomegaly, lymphadenopathy and B symptom were 15.3%, 35.2%, 50% and 27.3%, respectively. Almost half patients were in the high risk ISSWM group. The chromosomal karyotypes were successful in 153/181 (84.5%) cases, of which 15 patients showed clonal abnormalities. 8 of the 15 patients with abnormal chromosome were complex. The main aberrations of chromosomal karyotypes were 6q deletion (3/15, 20%), and loss of sex chromosomes (3/15, 20%). The other abnormalities include trisomy 12, trisomy 4, trisomy 3, 20q deletion, 17p deletion and so on. All the 6q deletions patients were in the complex karyotype group. Moreover, the trisomy 12 detected by FISH were always accompanied with chromosomal karyotypes abnormalities. Of 181 patients, 139 patients had FISH detection, of which 25 patients (18%) had FISH abnormalities. The most common aberrations were 6q deletion (6/28, 21.4%), trisomy 12 (5/59, 8.5%), 17p deletion (8/131, 6.1%). 13q deletion, gain 1q21and 11qdeletion were 4.6% (6/130) and 2.8% (3/36) and 2% (2/99), respectively. About 5.4% (7/130) patients had IGH gene translocation. Although it was higher in our study, this aberration always accompanied with other clones. Besides, 17p deletion was also more frequent in complex clone group, while trisomy 12 was more common in the single clone group. In LPL/WM, the chromosomal abnormities was an adverse predictor for both progress-free survival (PFS) and overall survival (OS). The median PFS and OS for patients with this abnormity was 62 months (62m vs 69m, p=0.022) and 75 months (75m vs 109m, p=0.033), which was significantly higher than normal patients. In different FISH groups, only TP 53 deletion had a poor effect on both PFS and OS in LPL/WM patients. The median PFS and OS were significantly shorter than those without the abnormality (median PFS 34m vs 77m, p=0.008; median OS 34m vs 135m, p=0.006). However, the 6q deletion and trisomy 12 did not significantly influence both PFS and OS. In addition, we found that the number of different clones had an effect on the survival of patients. The complex clone group showed shorter PFS and OS than the single clone group (p<0.05).Conclusion: Although the detection of cytogenetic aberration is rare in Chinese patients, it plays an essential role in diagnosis and prognostication. DisclosuresNo relevant conflicts of interest to declare.

The Cytogenetic Aberrations of Lymphoplasmacytic Lymphoma/ Waldenström’s Macroglobulinemia in China

Object:Lymphoplasmacytic lymphoma/ Waldenström's macroglobulinemia (LPL/WM) is a rare B-cell proliferative malignancy characterized by immunoglobulin M monoclonal gammopathy and /or bone marrow infiltration by lymphoplasmacytic cells. Recently, there are no large-scale studies to detect the clinical features, genetic background in patients with LPL/WM in China even Asia. The aim of this study is to explore the clinical and genetic differences, observe the impact of cytogenetic abnormalities on survival and prognosis in Chinese patients. Methods:305 patients with LPL/WM admitted in our hospital from June 1998 to December 2018 were retrospectively analyzed. Baseline characteristics, laboratory detection and therapy were compared using Chi-square test and Kaplan-Meier methodology was undertaken for survival analysis. Results:The median age of 305 patients in the study was 62 years (range 32-87) and male to female ratio was 2.45:1(216/89). The most common symptoms at diagnosis were fatigue (64.9%) and bleeding (14.1%).The patients in low, intermediate and high risk group of the international prognostic scoring system for WM (ISSWM) was 17.6%, 36.5% and 45.9%,respectively.The median hemoglobin was 8.5g/dl(range 2.4-18.7). About 41.3% patients had IgM higher than 4000mg/dl. The cytogenetic abnormalities were uncommon in LPL/WM patients. The chromosomal karyotypes were successful in 194 cases, of which 20 patients showed clonal abnormalities. 12 patients had two or more chromosome abnormalities. The most common chromosome abnormalities were deletion 6/6q(25%) and Y chromosome loss (20%). The median progression-free survival (PFS) and overall survival (OS) in patients with normal and abnormal chromosome karyotypes were similar. 194 patients had FISH detection, of which 33 patients (17%) had FISH abnormalities, 9 (4.6%) patients had two kind of abnormalities. The patients with more than one cytogenetic abnormality had lower survival than just had one abnormality or normal patients. The most common aberrations were 6q deletion and trisomy 12. 17p deletion was detected in 11 patients (11/184,6.0%) and it was a poor prognostic marker of PFS and OS. Single 13q14 deletion had not impact on PFS or OS, but when companied with other cytogenetic aberration, it could worsen the PFS and OS . Besides related to survival, cytogenetic abnormal was also related to the clinical features. Conclusions:Despite the low incidence and abnormal cytogenetic detection rate of LPL/WM, the clinical and genetic features are unique in Chinese patients. The cytogenetic aberrations play an important role in predicting prognosis. Disclosures No relevant conflicts of interest to declare.

The Real-Word Treatment Outcome of Symptomatic Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia in Chinese Patients

Objective:lymphoplasmacytic lymphoma/Waldenström Macroglobulinemia(LPL/WM) is a rare and incurable lymphoid malignancy. The treatment outcomes in Chinese patients had never been studies. In this study, we systematically reviewed the treatment outcome in a consecutive cohort from a single center in the past 20 years to explore the efficacy of different treatment regimens in real word in China. Methods:The clinical data of 269 newly diagnosis patients with LPL/WM admitted to our hospital in the past 20 years (2000-2020) were retrospectively analyzed. Therapy efficacy and survival were compared between different groups. Results:The median age of 269 patients was 62 years (range 32-87) and the male to female ratio was 2.7(196/73). Nearly half patients were high risk group of ISSWM (48%). Of 269 patients,192 patients received combined chemotherapy.The most common symptoms for initial chemotherapy wereanemia(75.7%), thrombocytopenia (36.9%), followed by IgM-related (33.7%) and constitutional symptoms(21.2%).Of the 192 patients, 109 patients received the novel agents for first-line therapy,83 patients received traditional chemotherapy.180 of192 patients would evaluated. The overall response rate(ORR) and major response rate(MRR) in the novel agent group were significantly higher than the traditional group(ORR:81.7% vs 61.8%,P=0.003; MRR:68.3% vs 48.7%,P=0.008) .In the traditional group, 41 patients received oral alkylating agent-based therapy and 42 patients received conventional intravenous cytotoxicity agents-basedtherapy. The ORR and MRR in the intravenous group were higher than oral group(ORR:75% vs 47.2%,P=0.013;MRR:62.5% vs33.3%,P=0.011).With a median observation time of 36 months, the median overall survival (OS) and progression-free survival (PFS) were 60 months and not reached in the novel agent groups which were also significantly higher than traditional groups(PFS: 60 vs 42,P=0.009,OS:NR vs 89,P=0.000). Intriguingly, In the traditional group, the PFS and OS were no significantly differentbetween conventional intravenous and oralgroup(PFS oral vs intravenous: 42 vs 40,P=0.849,OS oral vs intravenous:62vs 114,P=0.260). In novel agent group, 36 patients had received RCHOP regiment,20 patients received DRC,21 patients received BCD,8 patients received BRD,16 patients received TCD and 8 patients received RFC regiment. Patients who received RCHOP,DRC,BCD,BDR or RFC had similar ORR (82%-87.5%)which were slightly higher than TCD (58.3%)regiment. The median PFS and OS in different subgroups were also similar. But BDR regiment showed a trend of better OS(5 year 100%) and TCD showed a worse OS(5 year 46.4%). For all the patients, 35 patients received maintenance therapy, including 16 patients with rituximab maintenance and 19 patients with thalidomide maintenance. Maintenance was associated with better PFS(60 vs 47,p=0.083) and OS(5 year OS were 96.3% and 64.8%,p=0.006) and patients who received rituximab maintenance had better survival than thalidomide maintenance. In novel agent subgroup, maintenance with rituximab also had a trend of better PFS and OS. But maintenance thalidomide had no significantly different with no maintenance group. Conclusion:Combined with novel agent can tremendously improve the short-term and long-term therapeutic effects in Chinese LPL/WM patients. Different novel agent regiment might had similar efficacy, BRD regiment had a trend of better survival. Maintenance with rituximab would further improve the effect even in novel agent age. Disclosures No relevant conflicts of interest to declare.

Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells

AbstractMYD88L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88WT) and MYD88L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma.

Oncogenic activity of human MYD88L265P mutation in mature B-cells in vivo

MYD88(L265P) is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although, inhibition of MYD88(L265P) activity has been shown to be toxic to LPL/WM and DLBCL cells, providing crucial insight for potential targeted therapies, these studies were conducted in the context of pre-quiescent tumor suppressor signaling and the results bear limited information on the role of MYD88(L265P) in tumor initiation, which remains uncertain.

Significance of urinary albumin excretion inpatients with cast nephropathy .

Background: This study was performed to determine whether the urinary albumin excretion rate (%UAE) could distinguish myeloma cast nephropathy (MCN) without glomerular amyloid deposition from MCN with glomerular amyloid deposition. Materials and methods: We retrospectively reviewed clinicopathological data on 16 patients with MCN diagnosed by renal biopsy at Toranomon Hospital from 2004 to 2014. Results: A total of 10 patients had pure MCN without glomerular amyloid deposition (group 1), and 6 patients had MCN with glomerular amyloid deposition (group 2). In all 10 patients from group 1, the underlying disease was multiple myeloma (MM), while 4 patients had MM, and 2 patients had lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) in group 2. Total protein did not show a significant difference between the two groups, but serum albumin was significantly higher in group 1 than group 2 (p = 0.0101). Serum-adjusted calcium did not show a significant difference between the groups, while serum creatinine (Cre) was significantly higher in group 1 than group 2 (p = 0.0343). Although urinary protein excretion did not differ significantly between the groups, the %UAE was significantly lower in group 1 than group 2 (p = 0.00198). In group 2, 3 of the 4 patients with MM died within 15 months of diagnosis, but the 2 patients with LPL/WM are alive after 32 months. In group 1, only 1 patient died (of unknown causes) within 15 months after diagnosis. Conclusion: In patients with MCN, %UAE may be a useful marker for the detection of coexistence of glomerular lesions, such as amyloidosis, which are associated with a poor outcome.

A predicting model of bone marrow malignant infiltration in 18F-FDG PET/CT images with increased diffuse bone marrow FDG uptake.

Purpose: To demonstrate the relationship between the etiologies of increased diffuse bone marrow (BM) 18F-FDG uptake and PET/CT imaging/clinical features, as well as to explore a predicting model of BM malignant infiltration (MI) based on decision tree.Methods: 84 patients with increased diffuse BM uptake were retrospectively enrolled. Their complete case record and PET/CT images were reviewed, with the maximal standardized uptake values of bone marrow (SUVmaxBM) and other imaging/clinical features were noted. At the same time, the differences in imaging/clinical features between bone marrow MI and non-MI groups were compared. The decision tree for predicting MI was established by C5.0 component of SPSS Clementine.Results: In patients with homogenously increased BM uptake, 21 patients had MI resulted from leukemia, lymphoma and small cell lung cancer (SCLC). MI group had higher SUVmaxBM than non-MI group (6.7±3.1 vs 4.2±0.9, p=0.001). However, a considerable proportion of MI patients had similar SUVmaxBM to non-MI patients, which were mainly seen in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM), chronic myeloid leukemia (CML) and multiple myeloma (MM). There were significant differences in other factors between the two groups. MI patients were highly associated with SUVmaxAP/AX≥1 (the ratio of SUVmaxBM of appendicular skeleton to that of axial skeleton), hepatosplenomegaly, older age and lower rate of fever. The decision tree combining SUVmaxBM, SUVmaxAP/AX, fever and hepatosplenomegaly achieved a sensitivity of 81.0%, a specificity of 98.4% and an accuracy of 94.0% for predicting MI.Conclusion: Increased diffuse BM 18F-FDG uptake can be attributed to both bone marrow MI and benign etiologies. A decision tree based on C5.0 algorithm, combining PET/CT imaging and clinical features, is of potential use in discriminating BM malignant infiltration from patients with increased diffuse BM uptake.

Abstract LB-236: Risk of tMDS/AML after chemotherapy for first primary lymphoid malignancy, 2000-2013

Abstract Previous studies have demonstrated elevated risks for tMDS/AML after chemotherapy for non-Hodgkin lymphoma, Hodgkin lymphoma, and plasma cell neoplasms, but current treatment practices have changed considerably. We utilized large-scale, population-based cancer registry data from the United States to quantify for the first time tMDS/AML risks after chemotherapy for lymphoid malignancies in the current treatment era, including analysis for specific non-Hodgkin lymphoma subtypes. In 17 registries, we identified 121,840 adults without HIV infection who survived ≥1 year following a first primary lymphoid malignancy diagnosis during 2000-2013 and were initially treated with chemotherapy. tMDS/AML risk was compared with that expected in the general population using SIRs. tMDS/AML risk was significantly increased 5- to 9-fold after chemotherapy for the most common lymphoid malignancies, including DLBCL, plasma cell neoplasms, follicular lymphoma, Hodgkin lymphoma, and CLL/SLL (Table 1). Approximately 5-fold increased risks were observed after chemotherapy for marginal zone lymphoma, LPL/WM, and other/unspecified lymphomas. In contrast, risks were strikingly elevated (&amp;gt;10-fold) after chemotherapy for precursor leukemia/lymphoma, Burkitt lymphoma/leukemia, peripheral T-cell lymphoma, and mantle cell lymphoma. Only chemotherapy for hairy cell leukemia was not associated with increased tMDS/AML risk (SIR=1.4), albeit based on small numbers. tMDS/AML risks were higher &amp;lt;5 years after diagnosis compared with ≥5 years for Hodgkin lymphoma, precursor leukemia/lymphoma, Burkitt lymphoma/leukemia, and peripheral T-cell lymphoma. In contrast risks were persistently elevated ≥5 years after diagnosis for other lymphoid malignancies. In summary, tMDS/AML risk remains elevated in the modern era following chemotherapy for nearly all lymphoid malignancies. With ongoing introduction of new treatment approaches, continued consideration of risks and benefits of specific agents (and combinations), doses, and duration of therapy is critical. By time since lymphoid neoplasm diagnosisOverall1.0-4.9 years≥5 yearsFirst primary lymphoid malignancyTotal (N)Mean age at diagnosis (y)NSIR(95%CI)NSIR(95%CI)NSIR(95%CI)Hodgkin lymphoma16,74840.3659.0(6.9, 11.4)4310.7(7.8, 14.5)226.8(4.3, 10.3)CLL/SLL8,47864.31129.4(7.7, 11.3)729.2(7.2, 11.6)409.8(7.0, 13.3)DLBCL31,69259.72045.6(4.8, 6.4)1265.6(4.7, 6.7)785.5(4.4, 6.9)Follicular lymphoma15,65659.51457.8(6.6, 9.2)867.9(6.3, 9.8)597.7(5.8, 9.9)Marginal zone lymphoma4,22362.8295.5(3.7, 7.8)195.7(3.4, 8.9)105.1(2.4, 9.4)Plasma cell neoplasms22,75363.21176.1(5.0, 7.3)795.4(4.3, 6.8)388.2(5.8, 11.2)Precursor leukemia/lymphoma3,53042.73237.3(25.5, 52.7)2852.6(35.0, 76.1)412.3(3.3, 31.4)Mantle cell lymphoma3,52163.44010.1(7.3, 13.8)279.9(6.5, 14.4)1310.7(5.7, 18.3)LPL/WM1,95466.0134.3(2.3, 7.3)105.0(2.4, 9.2)32.8(0.6, 8.2)Peripheral T-cell lymphoma3,15655.73012.7(8.6, 18.1)2315.5(9.8, 23.2)78.0(3.2, 16.5)Burkitt lymphoma/leukemia1,18048.41924.3(14.6, 37.9)1328.6(15.2, 48.9)618.3(6.7, 39.8)Hairy cell leukemia1,70554.631.4(0.3, 4.2)~~Other, unspecified7,24462.0535.7(4.3, 7.4)386.6(4.7, 9.1)154.2(2.3, 6.9) Abbreviations: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); confidence interval (CI); diffuse large B-cell lymphoma (DLBCL); lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM); standardized incidence ratio (SIR); Surveillance, Epidemiology, and End Results (SEER); treatment-related myelodysplastic syndrome/acute myeloid leukemia (tMDS/AML). Citation Format: Lindsay M. Morton, Graca M. Dores, Megan M. Herr, Martha S. Linet, Margaret A. Tucker, Rochelle E. Curtis. Risk of tMDS/AML after chemotherapy for first primary lymphoid malignancy, 2000-2013 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-236. doi:10.1158/1538-7445.AM2017-LB-236

Clinical case: idelalisib-induced immunoglobulin flare

IgM flare is a transient, treatment-induced, increase of monoclonal IgM levels in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) patients. Until recently this phenomenon was observed in patients treated with Cladribine and Rituximab. Here we report a case of a heavily pretreated chronic lymphocytic leukemia patient with an atypically high immunoglobulin production who developed clinically significant immunoglobulin flare following Idelalisib treatment.

The Clinical Features and Prognosis of Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia: A Large Series Analysis from a Single Center

Background: Lymphoplasmacytic Lymphoma/Waldenströmmacroglobulinemia (LPL/WM) is a rare B-cell proliferative malignancy characterized by immunoglobulin M monoclonal gammopathy and /or bone marrow infiltration by lymphocyte, lymphoplasmacytic and/or plasma cells. The clinical features and prognosis of WM/LPL have less been investigated in Chinese patients. Moreover, few studies had reported the prognostic value of cytogenetic aberrations in Chinese WM/LPL patients.Methods: We systematically reviewed the records of 233 LPL/WM patients, who had been diagnosed at institute of Hematology&Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College.Results: The median age of 233 patients was 62 years (range 32-87) and the male to female ratio was 2.76 (171/62). The most common symptoms at diagnosis were fatigue (59.1%) and bleeding (11.2%). The patients in low, intermediate and higher risk group of the international prognostic scoring system for WM (ISSWM) occupied 14.9%, 32.6% and 52.6%, respectively. 90.4% and 16% patients showed an elevated serum β2-microglobulinand LDH. The percentages of hepatomegaly, splenomegaly, peripheral lymphadenopathy, B symptom were 14.9%, 34.5%, 43% and 29.3%, respectively. The degree of splenomegaly was always mild or moderate, only 19.1% patients with giant spleen. The karyotypes abnormalities were not common in LPL/WM patients. Only 8.9% (14/157) patients had abnormal chromosome karyotypes. The most common cytogenetic aberration detected by fluorescence in situ hybridization (FISH) were deletion of 17q13 (9/120, 7.5%), trisomy 12(5/58, 8.6%). Other aberrations include 13q14 deletion in 3 of 128 patients (2.3%), 11q22 deletion in2 of 90 patients (2.2%). Univariate analysis showed that age>62 years, leukocytopenia, thrombocytopenia, anemia, cytopenias ≥ 2, elevated LDH, abnormal chromosome karyotypes, P53 deletion and high risk of ISSWM were adverse risk factors for OS. But only clinical effect not reaching partial response (p=0.006), elevated LDH (p=0.049) and leukocytopenia (p=0.048) were the independent prognostic factors at multivariate analysis.Conclusion: Distinct characteristics exist in WM in China compared with the Western country. Elevated LDH and leukocytopenia were the independent adviser factors for OS in this series patient. DisclosuresNo relevant conflicts of interest to declare.

Different Prognostic Significance of a Panel Cytogenetic Aberrations Between Chronic Lymphocytic Leukemia and Other B-Cell Chronic Lymphoproliferative Disorders

Background: B-cell chronic lymphoproliferative disorders (B-CLPD) comprise several entities with similar clinical manifestations, within which chronic lymphocytic leukemia (CLL) account for the majority, others including follicular lymphoma (FL), hairy cell leukemia (HCL), splenic marginal zone lymphoma (SMZL),nodal marginal zone lymphoma (NMZL), gastric mucosa-associated lymphoid tissue (MALT) lymphoma, lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM), and other unclassified subtypes. Cytogenetic aberrations are now the main prognostic predicators in CLL, with deletion of TP53 or ATM as the adverse predicators, while sole deletion of 13q14 as the favorable one, trisomy 12 and IGH translocation as the neutral factors. The prognostic role of this cytogenetic aberrations panel has not been well established in other B-CLPD excluding CLL.Patients and methods: A panel of DNA probes were used to detect cytogenetic aberrations by fluorescence in situ hybridization (FISH), including RB1/D13S25 at 13q14, ATM at 11q22, TP 53 at 17p13, CEP12 and IGH translocation at 14q32. Totally, 870 patients were enrolled in this study, including 459 CLL patients, 41 SMZL patients, 24 HCL patients, 96 LPL/WM patients, 24 NMZL patients with bone marrows involvement (BMI) ,59 FL patients with BMI and 161 patients without definite subtype classification.Results: The incidence of each cytogenetic aberration in CLL is as follow: 38.0%(169/445) for del 13q14, 11.5% (46/400) for del 11q22, 14.5% (66/455) for del 17p13 , 23.8% (68/286) for +12, and 21.9% (97/443) for t(14q32). While in other B-CLPD excluding CLL is as follow: 10.3% (36/351) for del 13q14, 3.6% (11/305) for del 11q22, 7.9% (30/380) for del 17p13, 12.3% (23/ 187) for +12 and 24.1% (93/386) for t(14q32). The incidence of del 13q14 (p=.000), del 11q22 (p=.000), del17p13 (p=.003) and +12 (p=.002) were higher in CLL than in other B-CLPD. With a median follow-up of 46.0 months (2.0-288.0) in CLL and 39 months (3.0-239.0) in other B-CLPD, the median estimated progress-free survival (PFS) and overall survival (OS) in CLL were 80.0 months (95% CI 67.2-92.7) and 129 months (95% CI 111.5-146.5) respectively, while in other B-CLPD were 84 months (95% CI 71.8-96.1) and 135 months respectively.In CLL, the del 13q (p=.046), del 11q (p=.002) and del 17p (p<.001) were the adverse predictors for the PFS with only del 17p (p<.001) for the OS. There were no significant difference between patients with or without del 13q in aspect of OS (129.0 vs 110.5 months, p=.207). while sole del 13q was the favorable predictor for both PFS (p<.001) and OS (p=.001). Del 11q also indicated poor OS without statistical significance (p=.112). The median PFS for patients with or without +12 was 90 months (95% CI 60.5-119.5) and 93.0 months (95% CI 73.3-112.7) (p=.273), and the median OS was also similar (131.0 months vs. 129.0, p=.921). IGH translocation did not significantly influence both PFS (p=.198) and OS (p=.648).In other B-CLPD except CLL, the del 13q, del 17p and t (14q32) had no impact on both PFS (p=.983, p=.910 and p=.675 respectively) and OS (p=.171, p=.401 and p=.453 respectively). But patients with trisomy 12 had poor PFS (69.0 vs.86.0months, p=.094) and OS (69.0 vs.135.0months, p=.006) compared with those without. Del 11q also adversely impacted the OS (75.0 months vs. not reached, p=.059) but not PFS (62.0 vs. 84.0 months, p=.735).Conclusions: Del 11q and del 17p had the adverse prognostic impact in CLL. However, trisomy 12 was the predictor of poor survival in other B-CLPD which indicated neutral prognostic role in CLL. These results may imply different role of the same cytogenetic aberration in the pathology between CLL and other B-CLPD. DisclosuresNo relevant conflicts of interest to declare.

Medical history, lifestyle, family history, and occupational risk factors for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM), a rare non-Hodgkin lymphoma subtype, shows strong familial aggregation and a positive association with chronic immune stimulation, but evidence regarding other risk factors is very limited. The International Lymphoma Epidemiology Consortium (InterLymph) pooled data from 11 predominantly population-based case-control studies from North America, Europe, and Australia to examine medical history, lifestyle, family history, and occupational risk factors for LPL/WM. Age-, sex-, race/ethnicity-, and study-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for a total of 374 LPL/WM cases and 23 096 controls. In multivariate analysis including all putative risk factors, LPL/WM risk was associated with history of Sjögren's syndrome (OR = 14.0, 95% CI = 3.60 to 54.6), systemic lupus erythematosus (OR = 8.23, 95% CI = 2.69 to 25.2), hay fever (OR = 0.73, 95% CI = 0.54 to 0.99), positive hepatitis C serology (OR = 2.51, 95% CI = 1.03 to 6.17), hematologic malignancy in a first-degree relative (OR = 1.64, 95% CI = 1.02 to 2.64), adult weight (OR = 0.61, 95% CI = 0.44 to 0.85 for highest vs. lowest quartile), duration of cigarette smoking (OR = 1.46, 95% CI = 1.04 to 2.05 for ≥ 40 years vs. nonsmokers), and occupation as a medical doctor (OR = 5.54, 95% CI = 2.19 to 14.0). There was no association with other medical conditions, lifestyle factors, or occupations. This pooled analysis confirmed associations with immune conditions and family history of hematologic malignancy, and identified new associations with hay fever, weight, smoking, and occupation, and no association with other lifestyle factors. These findings offer clues to LPL/WM biology and prevention.

Incidence of lymphoplasmacytic lymphoma/Waldenström's macroglobulinaemia in Japan and Taiwan population‐based cancer registries, 1996–2003

Few studies have investigated the incidence rate of lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM) in Asian populations. We assessed the incidence of LPL/WM using data from 13 population-based cancer registries in Japan and data from the Taiwan National Cancer registry. During 1996-2003, a total of 280 new cases of LPL/WM were recorded in Japan and 56 were recorded in Taiwan, with the median age at diagnosis being 73 and 67 years, respectively. The incidence of LPL/WM showed male predominance in both countries. Crude age-specific incidence rates increased sharply with age in both countries, especially in people >65 years. Age-standardized (to the World standard population) incidence rates per 100,000 person-years were 0.043 (0.071 for men and 0.023 for women) and 0.031 (0.041 for men and 0.020 for women) in Japan and Taiwan, respectively. Age-standardized (to the 2,000 US standard population) incidence rates in Japan and Taiwan were lower than rates reported in the literature for Asians living in the United State. A significant increasing trend was observed in the incidence over the period from 1996 to 2003 in Japan alone. This report suggests that both environmental and/or genetic factors may be involved in LPL/WM development.

Immunohistochemical Phenotyping of Plasma Cells in Lymphoplasmacytic Lymphoma/Waldenström's Macroglobulinemia is Comparable to Flow Cytometric Techniques

Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM) can be difficult to distinguish from primary plasma cell neoplasms in bone marrow biopsies. Plasma cell immunophenotyping by flow cytometry can aid in this distinction as by this technique the plasma cells of LPL/WM express both CD19 and CD45 whereas primary plasma cell neoplasms are CD19 or CD45 negative. As immunophenotyping by flow cytometry has limitations, the comparative ability of immunohistochemistry to determine the plasma cell phenotype in WM/LPL was examined. The results indicate that immunohistochemistry yields results comparable to flow cytometry, and suggests that using both modalities in parallel compensates for the shortcomings of each.

Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia patients: a population-based study in Sweden

AbstractA role for genetic factors in the etiology of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is implicated based on prior findings from multiply affected families and small case-control and cohort studies. We identified 2144 LPL/WM patients (1539 WM [72%] and 605 LPL [28%]) diagnosed in Sweden, 8279 population-based matched controls, and linkable first-degree relatives of patients (n = 6177) and controls (n = 24 609). Using a marginal survival model, we calculated relative risks and 95% confidence intervals as measures of familial aggregation. We found first-degree relatives of LPL/WM patients to have 20-fold (4.1-98.4), 3.0-fold (2.0-4.4), 3.4-fold (1.7-6.6), and 5.0-fold (1.3-18.9) increased risks of developing LPL/WM, non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and monoclonal gammopathy of undetermined significance (MGUS), respectively. However, there was no evidence of an increased risk of developing multiple myeloma or Hodgkin lymphoma. In analyses stratified by type of first-degree relative (parent, sibling, offspring), age at diagnosis of the probands (greater or less than 70 years), and sex of the first-degree relative, we did not observe the risk estimates to be significantly different compared with the overall analyses. Our findings of highly increased risks of developing LPL/WM, NHL, CLL, and MGUS support the operation of shared susceptibility genes that predispose to LPL/WM and other lymphoproliferative disorders.

Association between the proliferative rate of neoplastic B cells, their maturation stage, and underlying cytogenetic abnormalities in B-cell chronic lymphoproliferative disorders: analysis of a series of 432 patients

AbstractLimited knowledge exists about the impact of specific genetic abnormalities on the proliferation of neoplastic B cells from chronic lymphoproliferative disorders (B-CLPDs). Here we analyze the impact of cytogenetic abnormalities on the proliferation of neoplastic B cells in 432 B-CLPD patients, grouped according to diagnosis and site of sampling, versus their normal counterparts. Overall, proliferation of neoplastic B cells highly varied among the different B-CLPD subtypes, the greatest numbers of proliferating cells being identified in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Compared with normal B cells, neoplastic B-CLPD cells showed significantly increased S + G2/M-phase values in mantle cell lymphoma (MCL), B-chronic lymphocytic leukemia (B-CLL), BL, and some DLBCL cases. Conversely, decreased proliferation was observed in follicular lymphoma, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM), and some DLBCL patients; hairy cell leukemia, splenic marginal zone, and MALT-lymphoma patients showed S + G2/M phase values similar to normal mature B lymphocytes from LN. Interestingly, in B-CLL and MCL significantly higher percentages of S + G2/M cells were detected in BM versus PB and in LN versus BM and PB samples, respectively. In turn, presence of 14q32.3 gene rearrangements and DNA aneuploidy, was associated with a higher percentage of S + G2/M-phase cells among LPL/WM and B-CLL cases, respectively.

Nuclear BCL-10 expression is common in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and does not correlate with p65 NF-κB activation

B-cell lymphoma 10 (BCL-10) is expressed in the cytoplasm of normal germinal center and marginal zone B-cells and is involved in lymphocyte development and activation. Aberrant nuclear expression of BCL-10 occurs in a subset of extranodal marginal zone B-cell lymphomas (MALT lymphomas), primarily those with the t(1;14)(p22;q32) or t(11;18)(q21;q21). Little is known about BCL-10 expression in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM). We assessed for BCL-10 in 51 bone marrow (BM) specimens involved by LPL/WM using immunohistochemical methods. All patients had monoclonal IgM in serum. Extent of BM involvement was assessed using PAX-5/BSAP and CD20 immunostains and the pattern and percentage of B-cells positive for BCL-10 was determined. The p65 subunit of nuclear factor-kappa B (NF-κB), a molecule downstream of BCL-10, was also assessed immunohistochemically. Nuclear BCL-10 staining was present in 28/51 (55%) specimens. BCL-10 expression correlated with greater extent of BM involvement (P=0.001), but did not correlate with serum IgM paraprotein levels, type of immunoglobulin light chain, or clinical variables. Nuclear expression of the p65 subunit of NF-κB was detected in 17/50 (34%) specimens, suggesting that NF-κB is active in a subset of LPL/WM. p65 NF-κB activation did not correlate with nuclear BCL-10 immunostaining. Cytogenetic analysis in 29 cases showed no evidence of the t(1;14) or t(11;18). These results indicate that nuclear BCL-10 expression is common in LPL/WM and does not correlate with MALT lymphoma-associated translocations or p65 NF-κB nuclear staining.