Lymphoplasmacytic lymphoma/Waldenstrom's Macroglobulinemia Research Articles

Treatment Selection and Clinical Outcomes in Lymphoplasmacytic Lymphoma/Waldenstrom Macroglobulinemia (LPL/WM) - a Single Center Analysis

Introduction: Lymphoplasmacytic lymphoma (LPL) is as an indolent neoplasm of B-lymphocytes with plasmacytic differentiation causing bone marrow infiltration along with variable involvement of lymph nodes/or spleen. Most common subtype of LPL, Waldenstrom Macroglobulinemia (WM) involves IgM monoclonal gammopathy of any concentration. Due to widespread availability of targeted therapy drugs (BTKi), the treatment landscape of LPL is changing. The aim of this study is to analyze disease characteristics, patterns of real-world treatment selection and its impact on clinical outcomes (Objective response rate (ORR), Progression free survival (PFS) and Overall survival (OS). Methods: A retrospective analysis of patients (age ≥18 years) with diagnosis of LPL/WM between January 1, 2003, to March 31, 2023, seen in consultation at Roswell Park Comprehensive Cancer Center was performed. ORR (CR, VGPR, PR and MR) was calculated according to response criteria at 6 th International Workshop for WM. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). OS and PFS were reported using standard Kaplan-Meier methods. Multivariate cox regression modeling was used to assess associations between first line regimen and survival outcomes (OS / PFS). Predictor variables, namely age at diagnosis, gender, Charlson Comorbidity Index (CCI) score, and rIPSS (revised International Prognostic Score System) were included in multivariable models. Results: A total of 127 patients were included in this study. The median age at diagnosis was 68 years (range 41 to 88), of which 75 (59.1%) were men. Majority of the population was White (n=112, 88.2%) and had ECOG of 0 (n=70, 67.3%). Monoclonal gammopathy of IgM subtype was present in 114 (94.2%), IgG in 3 (2.5%) and IgA in 1 (0.8%) patient. MYD88 mutation testing was positive in 69.8%, negative in 14% and unknown in 16.3% patients. Two out of 10 patients tested for CXCR4 mutation were positive. Sixteen (28.1%) patients had hyperviscosity symptoms and underwent plasmapheresis with first line treatment. These patients had a mean IgM level of 6249.5 mg/dL and mean M-spike of 4.53 g/dL. Of 121 patients with data on treatment strategy, 20 (16.5%) were monitored with observation alone. The most common treatment modality used in first line was chemo-immunotherapy (C-I) in 61 (50.4%) patients followed by Rituximab immunotherapy (R-I) in 20 (16.5%) patients and BTK inhibitors in 12 (9.9%) patients. ORR was highest 90.7% (39/43) in chemoimmunotherapy group, 87.5% (7/8) in BTKi group and 71.4% (10/14) in Immunotherapy group. Bendamustine-Rituximab was the most common used treatment regimen (n=42), with resultant CR in 20% and VGPR in 23.3% patients. At median follow-up duration of 36.9 months, median OS was 113.9 months in R-I, 159.8 months in C-I and not reached (NR) in BTKi group. The median PFS was 50.2 months in R-I, 61.2 in C-I and 23 months in BTKi group. Although Multivariate Cox Regression analysis failed to show statistically significant difference in PFS, there is tendency towards improved OS in C-I group (p=0.08) among all the groups when adjusted for age, sex, CCI. Conclusion: In our single center experience, chemoimmunotherapy combination with Bendamustine-Rituximab is the most used treatment choice in first line settings followed by single agent anti-CD20 therapy and BTKi. Although Multivariate Cox Regression analysis failed to show statistically significant difference in PFS, there is a tendency towards improved OS in the chemoimmunotherapy subgroup (p=0.08). The shorter PFS in BTKi group is likely due to toxicity of targeted therapy leading to treatment interruption and change of therapy.

Clinical Features and Outcomes of the Patients with B-Cell Chronic Lymphoproliferative Disease in the New Drug Era

To analyze the clinical characteristics of the patients with B-cell chronic lymphoproliferative disease（B-CLPD） in the new drug era and the effect of new drug treatment on efficacy and survival. The clinical and laboratory data of 200 cases B-CLPD patients diagnosed between April 2015 and August 2021 were analyzed retrospectively. The clinical efficacy and survival of the patients under different treatments including Bruton tyrosine kinase（BTK） inhibitors， rituximab， and chemotherapy alone were analyzed. The prognostic factors affecting the survival of patients were analyzed by univarite analysis and multivariate analysis. There were 119 male（59.5％） and 81 female（40.5%） in 200 cases B-CLPD patients， the sex ratio(male/female) was 1.5∶1 with median age of 61（30- 91） years old. The distribution of subtypes were as fallows: 51 cases (25.5%) of chronic lymphocytic leukemia/small lymphocytic lymphoma（CLL/SLL）， 64（32.0%） cases of follicular lymphoma（FL）， 40（20.0%） cases mantle cell lymphoma（MCL）， 30（15.0%） cases of marginal zone lymphoma（MZL）， 10（5%） cases of lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia（LPL/WM）， 5（2.5%） cases of B cell chronic lymphoproliferative disorders unclassified（B-CLPD-U） . The main clinical manifestation of 102 patients was lymph node enlargement, 32 cases were complicated with B symptoms. Among CLL/SLL patients， there were 12（23.5%） cases in Binet A and 39（76.5%） cases in Binet B/C. There were 29 patients（20.9%） in Ann Arbor or Lugano stage I-II and 110 cases（79.1%） in stage III-IV of other subtypes. The complete remission（CR） rate was 43.1%（25/58）， 40.2%（39/97）， 7.1%（1/14）， and overaIl response rate（ORR） was 87.9%（51/58）， 62.9%（61/97）， 28.6%（4/14） in the groups of BTK inhibitors， rituximab-based therapy， and chemotherapy alone. The 3-year OS rate and PFS rate in all patients was 79.2% and 72.4% respectively. The 3-year OS rate of patient with MZL, CLL/SLL, FL,WM was 94.7%, 87.7%, 86.8% and 83.3% respectively, while the 3-year OS rate of MCL was only 40.6%, which was significantly lower than other subtypes. The median OS of patients treated with BTK inhibitors and rituximab-based therapy was 20.5 and 18.5 months respectively， and the 3-year OS rate was 97.4% and 90.7%. However， the median PFS of patients receiving chemotherapy alone was 4 months， and the 1-year OS rate was 52.7%， which was statistically significant compared with the other two groups（P<0.05）. Univarite analysis showed that anemia， elevated lactate dehydrogenase， elevated β2-microglobulin， and splenomegaly were the poor prognostic factors for OS（P<0.05）， elevated lactate dehydrogenase was also poor prognostic factors for PFS（P<0.05）. Multifactor analysis showed that anemia and elevated lactate dehydrogenase were the independent poor prognostic factors for survival（P<0.05）. The clinical features of B-CLPD was various， anemia and elevated lactate dehydrogenase are the prognostic factors for poor survival. BTK inhibitors and new immunotherapy can improve the survival and prognosis of patients in the new drug era.

Comparative efficacy of triple combination therapies containing either bortezomib or rituximab in treatment naïve patients with lymphoplasmacytic lymphoma Waldenstrom macroglobulinemia

Purpose: To evaluate the comparative efficacy of triple combination therapies of cyclophosphamide/dexamethasone containing either bortezomib or rituximab in treatment-naïve patients diagnosed with lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia, LPL/WM). Methods: Symptomatic, untreated patients with LPL/WM diagnosed in the First Affiliated Hospital of Soochow University were enrolled in this study and divided into two groups (BCD and RCD). Group BCD consisted of 16 patients administered bortezomib/cyclophosphamide/dexamethasone, while group RCD (15 patients) received rituximab/cyclophosphamide/dexamethasone. The efficacy of the two therapies and the Kaplan-Meier survival curve of the groups were evaluated. Results: With regard to overall response rate (ORR) and minimal response rate (MRR), there was no statistically significant difference between the 2 groups (100 vs 86.6 %, p = 0.226, and 81.25 vs 60.0 %, p = 0.252, respectively). The median time to minimal response (MR) in the BCD group was 1.3 months, which was shorter compared with that of RCD group (3.5 months, p = 0.026). Treatment-related toxicities (grade&gt;2) were leukopenia, neutropenia, hypohepatia and pneumonia. With a median study follow-up of 27 months, disease in 18 patients (8 vs 10) progressed while 4 patients died (all in RCD group). The estimated median progression free survival (PFS) was 43 and 35 months in groups BCD and RCD, respectively, but the overall survival (OS) rate in 25 months significantly differed between the 2 groups (100 % vs 66.1 %，p = 0.033). Conclusion: The two regimens are active, produced responses and are safe as primary therapies for patients with LPL/WM. However, the response median time was much shorter in group BCD patients, and thus might have better survival benefits.

Prognostic Role of Revised International Prognostic Score for Waldenstrom Macroglobulinemia (rIPSSWM) in Newly Diagnosed Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma: A Report from the NF10 International, Prospective, Observational Study of the Fondazione Italiana Linfomi

Background: Revised international prognostic score for Waldenstrom macroglobulinemia (rIPSSWM) has been recently validated for symptomatic WM patients in need of treatment and was built on the independent prognostic role of Age, LDH, Serum Albumin and Beta2microglobulin. In 2010 the NF10 study was started by the Fondazione Italiana Linfomi as a prospective registry specifically devised for investigating the prognosis of, Indolent non follicular B-Cell Lymphomas (INFL) including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) and marginal zone lymphomas (MZL). Methods: We aimed to assess the prognostic role of RIPSSWM (ref) on an unselected population of treatment naïve patients with LPL/WM enrolled in the NF10 registry. Main study endpoint was Overall Survival. Secondary endpoint was treatment free survival (TFS). Results: From July 2010 to January 2020, 1535 INFL cases were registered and 1328 validated. Three hundred and seventeen cases were LPL/WM. Median age was 69 years (range 60-76); 6% had ECOG performance status > 1, median hemoglobin concentration was 12 g/dl (IQR 10 - 13.6), median serum albumin was 4 g/dl (IQR 3.6 - 4.3); serum CM was present in 254 patients with median concentration of 1.6 g/dl (IQR 0.74 - 2.4). Lactate dehydrogenase and b2-microglobulin were elevated in 21% and 59% of cases, respectively. Overall, 191 patient received systemic therapy. Immediate systemic therapy was planned in 133 (42%) patients. Additionally 58 patients required systemic treatment due to progressive disease from watch and wait. Median time to treatment for WW patients was 18 months (95% CI 15 to 28). When systemic therapy was prescribed rituximab (R) was used in 82% and was combined with cytotoxic therapy in 76% of cases. Regarding immunochemotherapy regimens, R was combined with bendamustine in 34%, alkylating agents in 30%, fludarabine in 8%, and CHOP like in 4%. With 58 months of median follow up (1 - 114), 5-year overall survival (OS) was 83% (95%CI: 78-88). In univariate analysis of OS, Age (>75years), elevated LDH, elevated B2M, and low serum albumin (<3.5) were associated with a different risk of death; the initial choice of deferring therapy did not impact on OS. Revised IPSSWM score could be calculated for 228 patients: 34(15%), 55(24%), 63(28%), 60(26%), and 16(7%) patients had 0,1,2,3, or 4-5 risk factors, respectively. Five-year OS was 100%, 98%, 79%, 83%, and 29% by risk group (p<0.001; c-Harrel 0.792: Figure1). The risk of dying due to lymphoma progression or due to other causes was similarly low for low risk patients (0-1 risk factors). Intermediate (2-3 RF) and high risk patients (4-5 RF) had a three-fold higher risk of dying due to causes unrelated to lymphoma compared to lymphoma related deaths. rIPSSWM was also correlated with a different TFS among patients initially observed (Figure 1: median TFS not reached for 0 RF, vs 15 months for 1-3 RF, vs 1.5 months for 4-5 RF p <0.001). Conclusions: We were able to validate the prognostic role of rIPSSWM in an unselected population of newly diagnosed patients with LPL/WM thus extending the usefulness of this score to asymptomatic patients. The rIPSSWM was particularly able to identify a small group of patients at very high risk of death within few months from the diagnosis. Moreover the rIPSSWM was also able to predict the time to initial treatment for patients who were initially observed. The NF10 study confirms that a web-based world-wide cooperation allows the collection of a relevant and complete data set, providing a platform for future prognostic and pathobiological studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Uncommon Presentation of a Common Leukemia (Chronic Lymphocytic Leukemia): Case Report

The association of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with usually low level of serum IgM monoclonal paraprotein is well recognized. We describe a rare case of a patient who developed overt IgM-related hyperviscosity syndrome after treatment for a diagnosis of CLL that was unresponsive to immunochemotherapy and to targeted therapies. Hyperviscosity syndrome, related to CLL-associated IgM paraprotein, is a very rare finding. High levels (> 3 g/dl) of serum IgM are mostly found in lymphoplasmacytic lymphoma-Waldenstrom macroglobulinemia (LPL/WM). In this patient, LPL was ruled out and diagnostic findings were consistent with only one clonal B cell population: CLL. It could be interesting understanding if ibrutinib therapy triggered IgM increase.

Expression of serum monoclonal immunoglobulins in B-cell chronic lymphoproliferative disorders and their significances

Objective To investigate the incidence of serum monoclonal immunoglobulins (McIg) in B-cell chronic lymphoproliferative disorders (B-CLPD) and the clinical significance of McIg in B-CLPD and its possible sources. Methods A total of 1 147 patients with B-CLPD treated from May 2006 to May 2015 were enrolled into this retrospective study. The incidence of McIg and the relationship between McIg and prognostic factors in patients with B-CLPD were analyzed. Results Out of 1 147 B-CLPD patients, there were 164 patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM), and among them, McIg was detected in 140 cases (85.4%). In the remaining 983 patients with B-CLPD, monoclonal Ig was detected in 50 (5.1%) patients. Most of McIg in 2 groups were IgM paraprotein. The levels of IgM paraprotein of the LPL/WM group, non-LPL/WM group and McIg-negative patients were (48.88 ± 33.42) g/L, (27.9 ± 15.23) g/L and (2.75±1.21) g/L, respectively, the difference was statistical significance (P=0.000); the level of IgM paraprotein in LPL/WM group was significantly higher than that in non-LPL/WM group (P=0.000). The level of paraprotein decreased significantly when the patients got complete response after therapy (P=0.001, 0.048, respectively). The incidence of serum McIg was higher in the group with complex karyotype (P=0.016) and with high level of β2-microglobulin (β2-MG) (P=0.001). In the 47 non-LPL/WM patients with positive McIg, serum McIg in 38 (80.9%) patients were expressed in a pattern consistent with the distribution of tumor cells (P<0.005). Most of the light chain subtype of the McIg were consistent with the light chain subtype of the membrane immunoglobulin on the tumor cells. Conclusions Some non-LPL/WM B-CLPD patients also have serum McIg, and it could have certain relevance with the prognosis of B-CLPD. Moreover, the McIg may be secreted by tumor cells or those derived from the same progenitor cells with tumor cells. Key words: Lymphoproliferative disorders; Immunoglobulin; Prognosis

A Phase I Study of BKM120 (Buparlisib) and Rituximab in Patients with Relapsed or Refractory B-Cell Non-Hodgkins Lymphoma (NHL)

Introduction: BKM120 is a potent and highly specific oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor. Several PI3K inhibitors have single agent activity in relapsed or refractory B-cell NHL. We are conducting a phase I trial of the combination of BKM120 and rituximab to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), tolerability and preliminary efficacy in patients with relapsed or refractory NHL. Methods: Patients ≥ 18 years with relapsed or refractory B-cell NHL including follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma/waldenstrom's macroglobulinemia (LPL/WM), mantle cell lymphoma (MCL), and activated B cell subtype diffuse large B cell lymphoma (ABC DLBCL) who have received at least one prior therapy were eligible. Additional eligibility included ECOG Performance Status 0-2, adequate renal and liver function, absolute neutrophil count (ANC) ≥ 750/mm3, platelets ≥ 50,000/mm3, INR ≤ 2.0, and fasting glucose &lt; 120 mg/dL. Prior autologous or allogeneic transplant was allowed if patient did not require immunosuppressive therapy for GVHD. Prior treatment with a pan-selective PI3K inhibitor was not allowed but prior therapy with a selective PI3K inhibitor, Bruton's tyrosine kinase inhibitor or other B-cell receptor targeting agent was allowed. Patients with active moderate or severe major mood or psychiatric disorders were excluded given mood-associated toxicities. Treatment consisted of escalating doses of BKM120 (mg/day) days 1-28 and standard rituximab dosing at 375 mg/m2 days 2, 8, 15, and 22 of cycle 1 and then day 1 of cycles 3, 5, 7, 9, 11 for 28-day cycles. A standard 3+3 dose escalation schema was followed. DLT was defined during cycle 1 and included: treatment delays &gt; 28 days for toxicity; grade 5 toxicity: grade 3 febrile neutropenia &gt; 7 days; grade 4 febrile neutropenia or infection; grade 3 or 4 somnolence, cognitive changes, altered mood, anxiety, or confusion; grade 2 somnolence, cognitive changes, altered mood, anxiety, or confusion that does not resolve to ≤ grade 1 within 14 days; other grade 3 or 4 non-hematologic toxicity with the exception of grade 3 nausea, vomiting, diarrhea, or electrolyte abnormalities that are reversible within 72 hours of holding treatment. Patients without toxicity were allowed to continue treatment until disease progression. To further evaluate safety, preliminary efficacy and correlatives, an expansion cohort of an additional 12 patients to be treated at the MTD was planned, 6 patients with indolent NHL or MCL and 6 patients with ABC DLBCL. Response was assessed by CT or PET/CT after cycles 2, 4, 6, and then every 3 months while on therapy. Results: From August 2014 until July 2015, seven patients were enrolled in this trial. The median age was 67 (range 52-71). Histologies included FL (n=5) and MZL (n=2). Three patients were treated at dose level (DL) 1 (BKM120 80 mg/day). No DLT's occurred. Four patients have been treated at DL2 (BKM120 100 mg/day). One patient experienced a DLT consisting of grade 3 maculopapular rash. The rash occurred cycle 1 day 15 and resolved with interruption of therapy which was continued on day 22 at a reduced dose of BKM120 at 80 mg without any recurrence. The rash was confounded by the simultaneous initiation of allopurinol. Grade 3 toxicities occurred in 2/7 (29%) patients, including grade 3 maculopapular rash in one patient (DLT) and grade 3 hyperglycemia in one patient. Patients have received a median 3 cycles of therapy to date (range 1-9) and six remain on therapy. At DL1, two patients with FL achieved a partial response (PR). At DL2, one patient with FL achieved a PR. Overall response rate for the 5 evaluable patients is 60%. The other two evaluable patients had best response of stable disease. One patient discontinued study to pursue alternative therapy. Conclusions: Combined therapy with the pan-PI3 kinase inhibitor BKM and rituximab in patients with relapsed or refractory B-NHL has been well tolerated, with only one DLT of maculopapular rash that resolved with therapy interruption and did not recur at a lower dose. Patients continue to enroll at the current and final dose level of BKM120 mg administered at 100 mg daily with standard rituximab dosing, with a planned expansion cohort at the MTD. While the number of patients treated has been small, preliminary efficacy has been observed including all enrolled FL patients assessable for response achieving a PR. Disclosures Maddocks: Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Cohen:BMS, Janssen: Research Funding; Celgene, Pharmacyclics, Millennium, Seattle Genetics: Consultancy. Christian:Seattle Genetics: Consultancy, Research Funding; Novartis: Other: IDSM; Celgene: Consultancy; Pharmacyclics: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding. Blum:Janssen: Research Funding; Pharmacyclics: Research Funding; cephalon: Research Funding; Celgene: Research Funding.

Lymphoplasmacytic non-Hodgkin lymphoma/Waldenström's macroglobulinemia with CD5+, CD23+, and CD10-

Lymphoplasmacytic non-Hodgkin lymphoma/Waldenström's macroglobulinemia with CD5+, CD23+, and CD10-

Indolent B-Cell Lymphomas Treated Upfront with Antiviral Therapy: a Series of 13 Patients

AbstractAbstract 2876 Background:HCV infection has been demonstrated to be involved in clonal B cell proliferation and in the subsequent development of non-Hodgkin's lymphoma (NHL). The regression of NHL after antiviral treatment is considered an indirect evidence of this pathogenetic relationship. Aim:to evaluate clinical course of patients affected by HCV infection (serology and HCV RNA positive) and low grade B-cell NHL (LG-NHL), not needing immediate treatment (absence of B symptoms, bulky disease or symptomatic tumor mass and lymphocyte doubling time less than 6 months) and treated upfront with antiviral therapy alone. Method:From 2006 to 2010, 13 patients, affected by LG- NHL at diagnosis have been treated with pegylated interferon (PegIFNa2a, 100–180 mcg weekly) and ribavirin (Rbv, 800–1200 mg daily) for a median treatment period of 6 months (6-18 months). Two patients are still in treatment. M/F ratio was 1.6 and median age was 59 years (range 51–73). The study included 9 marginal zone lymphomas (MZL: 2 splenic MZL, 7 extranodal non gastric MZL), 3 LG-NHL NOS and 1 lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LPL). Cryoglobulin were present in five patients. 7 pts had genotype 2, 5 pts genotype 1b, one not assessed; HCV infection was detected before lymphoma diagnosis in 9 pts and at lymphoma onset in 4 pts. Only 2 patients have previously received other combinations of antiviral therapy. Virologic response was assessed monthly by HCV-RNA polymerase chain reaction (PCR) and hematologic response was evaluated according to International Working Group response criteria (Cheson et al. J Clin Oncol. 2007) at the end of antiviral therapy. Results:Eleven patients completed the planned treatment course. Sustained virologic response (SVR) was achieved in 9 patients (6 with genotype 2); viremia clearance was achieved in a median period of 2 months (1-6). Among patients that gained a SVR, 5 achieved a complete response (CR) (3 genotype 2, 1 1b, one not assessed), one (genotype 2) partial response (PR), and 3 (2 genotype 2 and one genotype 1b) presented stable disease (SD). The remaining patients obtained only a reduction of viremia: one presented a SD and one was in PR. The treatment was well tolerated without any WHO grade III-IV toxicity. Among patients that completed treatment program, more frequent toxicity was haematological (one patient developed a WHO grade 1 anemia and one patients developed WHO grade 1 anemia and grade 2 neutropenia). After a median follow up of 17 months from the end of therapy (range 3–44), considering the 9 patients in SVR, only 2 (1 CR and 1 PR) progressed, maintaining SVR and one lost SVR maintaining SD. Patients that obtained only a reduction of viremia, maintained their hematologic status. Conclusion:We described a high CR rate in patients that obtained SVR after antiviral therapy (55%); the relationship between hematologic and viral response during follow up is not always stringent. We confirm that antiviral therapy could be considered as frontline therapeutic option in cases of HCV-related LG-NHL not requiring immediately immunochemotherapy. Disclosures:No relevant conflicts of interest to declare.

Expression of inhibitor of apoptosis proteins in B‐cell non‐Hodgkin and Hodgkin lymphomas

Inhibitor of apoptosis proteins (IAPs) inhibit apoptosis by binding specific caspases, and possibly by other mechanisms. Eight IAPs have been identified in humans, of which cIAP1, cIAP2, and XIAP are well known. IAPs are being investigated as potential treatment targets in cancer patients. cIAP1, cIAP2, and XIAP were assessed in lymphoma cell lines, 240 B-cell non-Hodgkin lymphoma (NHL) tumors, and 40 Hodgkin lymphoma (HL) tumors. All IAPs were expressed in most NHL and all HL cell lines. In NHL tumors, cIAP1 was expressed in 174 (73%), cIAP2 in 115 (48%), and XIAP in 37 (15%). cIAP1 was positive in all precursor B-cell lymphoblastic lymphoma/leukemia (LBL) and nodal marginal zone B-cell lymphoma (MZL), over 90% of follicular lymphoma and diffuse large B-cell lymphoma (DLBCL), and approximately 50% to 60% of myeloma, Burkitt lymphoma (BL), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM), small lymphocytic lymphoma/ chronic lymphocytic leukemia (SLL/CLL), extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT-lymphoma), splenic MZL, and mantle cell lymphoma. cIAP2 was positive in all MALT-lymphoma, over 90% of precursor B-cell LBL (94%), most BL (75%), LPL/WM (71%), and SLL/CLL (67%), and approximately 40% to 60% of follicular lymphoma, myeloma, and DLBCL. XIAP was positive most cases of precursor B-cell LBL (57%) and approximately 30% to 40% of nodal MZL, BL, and DLBCL. In HL tumors, cIAP1 was positive in 30 (75%), cIAP2 in 27 (68%), and XIAP in 23 (58%), and did not correlate with histologic type. Differential expression of IAPs in B-cell lymphomas suggests differences in pathogenesis that may have implications for novel treatment strategies targeting IAPs.

Targeted Overexpression of the Transcription Factor XBP-1 in B Cells Promotes Plasma Cell and Lymphoplasmacytic Neoplasms in Transgenic Mice.

The transcription factor X-box binding protein-1 (XBP-1) plays critical roles in the unfolded protein response (UPR), the differentiation of plasma cells, and the regulation of growth factor signaling pathways. XBP-1 is subject to regulation by alternative RNA processing producing XBP-1-spliced (S) and -unspliced (U) mRNAs encoding proteins with identical DNA-binding and bZIP domains yet distinct C-terminal transactivation domains. The weaker transactivation potential of XBP-1(U) has prompted speculation that it may influence XBP-1(S) activity as a transdominant mutant. While elevated XBP-1 expression has been reported in transformed cells, the relative ratios of these XBP-1 isoforms and associated physiological relevance in cancer are uncertain. Here, we assessed the differential impact of enforced XBP-1(S) versus XBP-1(U) transgene expression in the B cell lineage. Both transgenes elicited early onset antibody-dependent autoimmune disease characterized by elevated levels of serum immunoglobulin (Ig) and IL-6 production, increased numbers of marginal zone and mature follicular B cells in the spleen, and expanded mature B cell populations in the bone marrow. Notably, aged XBP-1(S) mice developed clonal plasma cell expansions, culminating in the human-equivalent of Monoclonal Gammopathy of Undetermined Significance (MGUS) or Multiple Myeloma (MM). Conversely, XBP-1(U) mice develop multi-organ lymphoplasmacytic infiltrates and, with advancing age, succumb to neoplasms resembling human Lymphoplasmacytic Lymphoma/Waldenstrom's Macroglobulinemia (LPL/WM). These unanticipated genetic observations in the mouse were translated to human disease with documentation of elevated levels of XBP-1(S) in MM and XBP-1(U) in LPL/WM. Together, these results indicate that imbalances in XBP-1(S) and XBP-1(U) alters B cell lineage homeostasis and can drive two distinct types of lymphoplasmacytic neoplasms in vivo. The findings of this study, together with the known capacity of XBP-1 to regulate various cancer-relevant growth factor signaling pathways, predicts that epigenetic dysregulation of alternate XBP-1 RNA processing can promote age-associated B cell malignancies in humans.

Lymphoplasmacytic Lymphoma/Waldenstrom Macroglobulinemia

The concept of Waldenstrom macroglobulinemia has evolved from the original description of a clinical syndrome to its more recent designation as a distinct clinicopathologic entity, that is, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM), in the World Health Organization (WHO) classification and by the participants of consensus meetings on WM. The diagnosis of LPL/WM, however, remains a challenge in daily practice. Distinguishing LPL/WM from other B-cell lymphomas, especially marginal zone B-cell lymphomas, which share overlapping morphologic features, is difficult. The traditional practice of separating LPL/WM from other lymphomas by an arbitrary level of serum IgM is no longer considered valid. The characteristic immunophenotype described for LPL/WM by the WHO classification, that is, CD5(-)CD10(-)CD23-, is observed in 60-80% of neoplasms, but variations from this pattern of antigen expression are common, with CD23 being detected in up to 40% of cases. Lack of a distinct molecular genetic hallmark complicates the distinction of LPL/WM from other B-cell lymphomas. Although the t(9;14) is stated to be present in 50% of cases in the WHO classification, translocations involving the Ig heavy chain including the t(9;14) are actually rare in LPL/WM. Deletion of 6q21-q23, a nonspecific finding, is the most common aberration reported in 40-70% of patients. At the molecular level, the neoplastic clone in most cases has undergone Ig variable gene mutation, but not isotype switching, and the clone retains the capability of plasmacytic differentiation. Currently, the diagnosis of LPL/WM can only be established by incorporating clinical and pathologic findings and excluding alternative diagnoses. In some cases, in our opinion, distinguishing LPL/WM from marginal zone B-cell lymphomas seems arbitrary using currently recommended criteria.

Diffuse Large B-Cell Lymphoma Occurring in Patients With Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

Of 92 patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) treated at our institution, diffuse large B-cell lymphoma (DLBCL) also developed in 12 (13%). In 10 patients, DLBCL developed 12 to 128 months (median, 44 months) after the diagnosis of LPL/WM. Two patients had LPL/WM and DLBCL simultaneously. Clinicopathologic features at diagnosis of LPL/WM did not predict the risk of DLBCL. Onset of DLBCL was characterized by worsening constitutional symptoms, profound cytopenias, extramedullary disease, and organomegaly. Immunoglobulin light chain expression was identical in both LPL/WM and DLBCL. In situ hybridization for Epstein-Barr virus (EBV) in 8 cases of DLBCL was negative. Of 11 patients with clinical follow-up information available, 8 (73%) died within 10 months of diagnosis of DLBCL. DLBCL, most likely as a result of histologic transformation, occurs in a subset of patients with LPL/WM and is associated with aggressive clinical course and poor outcome. EBV is unlikely to be involved in transformation.