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1.
Semin Hematol ; 60(2): 107-112, 2023 03.
Article in English | MEDLINE | ID: mdl-37099029

ABSTRACT

Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11; held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2; thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for preexposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Coadministration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza, and S. pneumoniae.


Subject(s)
COVID-19 , Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/drug therapy , Waldenstrom Macroglobulinemia/prevention & control , Waldenstrom Macroglobulinemia/diagnosis , COVID-19 Vaccines , Consensus , SARS-CoV-2 , Antiviral Agents/therapeutic use
2.
Semin Hematol ; 60(2): 118-124, 2023 03.
Article in English | MEDLINE | ID: mdl-37099031

ABSTRACT

Recent advances in the understanding of Waldenström macroglobulinemia (WM) biology have impacted the development of effective novel agents and improved our knowledge of how the genomic background of WM may influence selection of therapy. Consensus Panel 7 (CP7) of the 11th International Workshop on WM was convened to examine the current generation of completed and ongoing clinical trials involving novel agents, consider updated data on WM genomics, and make recommendations on the design and prioritization of future clinical trials. CP7 considers limited duration and novel-novel agent combinations to be the priority for the next generation of clinical trials. Evaluation of MYD88, CXCR4 and TP53 at baseline in the context of clinical trials is crucial. The common chemoimmunotherapy backbones, bendamustine-rituximab (BR) and dexamethasone, rituximab and cyclophosphamide (DRC), may be considered standard-of-care for the frontline comparative studies. Key unanswered questions include the definition of frailty in WM; the importance of attaining a very good partial response or better (≥VGPR), within stipulated time frame, in determining survival outcomes; and the optimal treatment of WM populations with special needs.


Subject(s)
Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/drug therapy , Waldenstrom Macroglobulinemia/genetics , Rituximab/therapeutic use , Consensus , Cyclophosphamide/therapeutic use , Bendamustine Hydrochloride/therapeutic use
3.
Ann Oncol ; 17(8): 1275-82, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16788002

ABSTRACT

Bone marrow (BM) mast cells (MC) are commonly found in association with lymphoplasmacytic cells (LPC) in patients with Waldenström's macroglobulinemia (WM). We therefore sought to clarify the role of MC in WM. Co-culture of sublethally irradiated HMC-1 MC, KU812 basophilic cells, or autologous BM MC along with BM LPC from WM patients resulted in MC dose-dependent tumor colony formation and/or proliferation as assessed by 3H-thymidine uptake studies. Furthermore, by immunohistochemistry, multicolor flow cytometry and/or RT-PCR analysis, CD40 ligand (CD154), a potent inducer of B-cell expansion, was expressed on BM MC from 32 of 34 (94%), 11 of 13 (85%), and 7 of 9 (78%) patients, respectively. In contrast, MC from five healthy donors did not express CD154. By multicolor flow cytometry, CD154 was expressed on BM LPC from 35 of 38 (92%) patients and functionality was confirmed by CD154 and CD40 agonistic antibody stimulation, which induced proliferation, support survival and/or pERK phosphorylation of LPC. Moreover, MC induced expansion of LPC from 3 of 5 patients was blocked in a dose dependent manner by use of a CD154 blocking protein. These studies demonstrate that in WM, MC may support tumor cell expansion through constitutive CD154-CD40 signaling and therefore provide the framework for therapeutic targeting of MC and MC-WM cell interactions in WM.


Subject(s)
Bone Marrow Cells/pathology , CD40 Ligand/metabolism , Mast Cells/pathology , Waldenstrom Macroglobulinemia/pathology , B-Lymphocytes/chemistry , B-Lymphocytes/pathology , Bone Marrow Cells/chemistry , CD40 Ligand/analysis , CD40 Ligand/antagonists & inhibitors , Cell Proliferation/drug effects , Coculture Techniques , Humans , Mast Cells/chemistry , Mast Cells/drug effects , Recombinant Fusion Proteins/pharmacology , Signal Transduction , Tumor Cells, Cultured , Waldenstrom Macroglobulinemia/metabolism
4.
Ann Oncol ; 17(3): 488-94, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16357024

ABSTRACT

BACKGROUND: Familial clustering of B-cell disorders among Waldenström's macroglobulinemia (WM) patients has been reported, though the frequency and any differences in disease manifestation for familial patients remain to be defined. PATIENTS AND METHODS: We therefore analyzed clinicopathological data from 257 consecutive and unrelated WM patients. Forty-eight (18.7%) patients had at least one first-degree relative with either WM (n = 13, 5.1%), or another B-cell disorder including non-Hodgkin's lymphoma (n = 9, 3.5%), myeloma (n = 8, 3.1%), chronic lymphocytic leukemia (n = 7, 2.7%), monoclonal gammopathy of unknown significance (n = 5, 1.9%), acute lymphocytic leukemia (n = 3, 1.2%) and Hodgkin's disease (n = 3, 1.2%). Patients with a familial history of WM or a plasma cell disorder (PCD) were diagnosed at a younger age and with greater bone marrow involvement. RESULTS: Deletions in 6q represented the only recurrent structural chromosomal abnormality and were found in 13% of patients, all non-familial cases. Interphase FISH analysis demonstrated deletions in 6q21-22.1 in nearly half of patients, irrespective of familial background. CONCLUSIONS: The above results suggest a high degree of clustering for B-cell disorders among first-degree relatives of patients with WM, along with distinct clinical features at presentation based on familial disease cluster patterns. Genomic studies to delineate genetic predisposition to WM are underway.


Subject(s)
Waldenstrom Macroglobulinemia/diagnosis , Humans , In Situ Hybridization, Fluorescence , Incidence , Interphase , Karyotyping , Waldenstrom Macroglobulinemia/genetics , Waldenstrom Macroglobulinemia/physiopathology
5.
Ann Oncol ; 16(1): 132-8, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15598950

ABSTRACT

BACKGROUND: Waldenström's macroglobulinemia (WM) is a CD20 expressing B-cell malignancy represented by the pathological diagnosis of IgM secreting lymphoplasmacytic lymphoma. Major response rates of 30% have been reported in most studies with standard dose rituximab, i.e. 4 weekly infusions at 375 mg/m(2)/week. METHODS: In an effort to increase rituximab activity in WM, an extended dose schedule employing two sets of four (375 mg/m(2)/week) infusions at weeks 1-4 and 12-16 was evaluated. Expression of the complement resistance antigens CD46, CD55 and CD59 was also evaluated on tumor cells pre- and post-therapy to determine impact on response. RESULTS: Twenty-nine patients were enrolled and 26 patients completed the intended therapy. On an intent to treat analysis, 14 (48.3%) patients achieved a partial response, and 5 (17.2%) patients achieved a minor response. Responses were observed in 18/24 (75%) patients with a serum IgM level of <6000 mg/dl, and only 1 of 5 (20%) patients with a level of >6000 mg/dl (P=0.03). The median time to best response was 17 months, and only 2 of 19 responding patients progressed with a median follow-up of 29 months. No differences in baseline expression of the complement resistance antigens CD46, CD55 and CD59 were observed among responding and non-responding patients, although post-therapy CD55 expression was higher in non-responding patients (P=0.002). CONCLUSIONS: These data show that extended rituximab therapy is active and may lead to more major responses over standard dose rituximab in WM. WM patients with serum IgM levels of <6000 mg/dl are more likely to benefit from extended rituximab therapy.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Waldenstrom Macroglobulinemia/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Murine-Derived , Antigens, CD/analysis , Antigens, CD/biosynthesis , Antineoplastic Agents/administration & dosage , CD55 Antigens/analysis , CD55 Antigens/biosynthesis , CD59 Antigens/analysis , CD59 Antigens/biosynthesis , Drug Administration Schedule , Female , Humans , Immunoglobulin M/analysis , Immunohistochemistry , Male , Membrane Cofactor Protein , Membrane Glycoproteins/analysis , Membrane Glycoproteins/biosynthesis , Middle Aged , Rituximab , Treatment Outcome , Waldenstrom Macroglobulinemia/immunology , Waldenstrom Macroglobulinemia/pathology
6.
Ann Oncol ; 15(10): 1481-3, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15367407

ABSTRACT

BACKGROUND: The anti-CD20 monoclonal antibody rituximab is an important therapeutic in Waldenstrom's macroglobulinemia (WM), producing response rates of 50-70%. Responses, which are based on serum IgM levels, have typically been evaluated at 12 weeks. Paradoxically, we have observed that serum IgM levels can abruptly rise following rituximab therapy in patients with WM, and can often lead to morbidity on the basis of hyperviscosity. PATIENTS AND METHODS: Eleven WM patients with CD20+ tumor cells who received rituximab at our Institution and had serum IgM levels measured within a 12-week period following start of therapy were evaluated. Therapy consisted of four weekly infusions of rituximab at 375 mg/m(2). Pre- and post-therapy serum IgM levels were determined by nephelometry and corresponding serum viscosity levels were determined by viscometry. RESULTS: Ten of the 11 patients demonstrated an abrupt rise in serum IgM levels, with a >25% increase occurring in eight (73%) patients. Mean serum IgM levels for all 10 spiking patients rose from 4370 (range, 655-7940) to a peak of 5865 (range, 872-11 800) mg/dl (P=0.004), which occurred at a mean of 4 (range, 1-8) weeks following initiation of therapy. Mean serum viscosity levels also increased from 3.5 to 5.6 centipoise (CP) (P=0.09) in eight patients for whom pre- and post-therapy studies were obtained. A subdural hemorrhage occurred in one patient when serum IgM levels rose from 7530 to 11 800 mg/dl, and serum viscosity increased from 3.9 to 10.1 CP. Two other spiking patients with pre-therapy IgM levels of >5000 mg/dl experienced worsening headaches and/or epistaxis attributed to increasing serum viscosity. CONCLUSIONS: Abrupt increases in serum IgM levels commonly occur following rituximab therapy in WM. Careful clinical and laboratory monitoring is warranted, particularly if patients have pre-therapy serum IgM levels of >5000 mg/dl. The mechanism of this effect is under active investigation, and may be related to CD20 signaling triggered by rituximab.


Subject(s)
Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Blood Viscosity/drug effects , Immunoglobulin M/blood , Waldenstrom Macroglobulinemia/blood , Waldenstrom Macroglobulinemia/drug therapy , Antibodies, Monoclonal, Murine-Derived , Antigens, CD20/analysis , Flow Cytometry , Humans , Rituximab
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