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Journal of Clinical Oncology : Official... Jan 2020Patients with transplantation-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) fare poorly, with limited treatment options. The antibody-drug... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Patients with transplantation-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) fare poorly, with limited treatment options. The antibody-drug conjugate polatuzumab vedotin targets CD79b, a B-cell receptor component.
METHODS
Safety and efficacy of polatuzumab vedotin with bendamustine and obinutuzumab (pola-BG) was evaluated in a single-arm cohort. Polatuzumab vedotin combined with bendamustine and rituximab (pola-BR) was compared with bendamustine and rituximab (BR) in a randomly assigned cohort of patients with transplantation-ineligible R/R DLBCL (primary end point: independent review committee [IRC] assessed complete response [CR] rate at the end of treatment). Duration of response, progression-free survival (PFS), and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression methods.
RESULTS
Pola-BG and pola-BR had a tolerable safety profile. The phase Ib/II pola-BG cohort (n = 27) had a CR rate of 29.6% and a median OS of 10.8 months (median follow-up, 27.0 months). In the randomly assigned cohort (n = 80; 40 per arm), pola-BR patients had a significantly higher IRC-assessed CR rate (40.0% 17.5%; = .026) and longer IRC-assessed PFS (median, 9.5 3.7 months; hazard ratio [HR], 0.36, 95% CI, 0.21 to 0.63; < .001) and OS (median, 12.4 4.7 months; HR, 0.42; 95% CI, 0.24 to 0.75; = .002; median follow-up, 22.3 months). Pola-BR patients had higher rates of grade 3-4 neutropenia (46.2% 33.3%), anemia (28.2% 17.9%), and thrombocytopenia (41% 23.1%), but similar grade 3-4 infections (23.1% 20.5%), versus the BR group. Peripheral neuropathy associated with polatuzumab vedotin (43.6% of patients) was grade 1-2 and resolved in most patients.
CONCLUSION
Polatuzumab vedotin combined with BR resulted in a significantly higher CR rate and reduced the risk of death by 58% compared with BR in patients with transplantation-ineligible R/R DLBCL.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Biomarkers, Tumor; Female; Humans; Immunoconjugates; Immunohistochemistry; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Progression-Free Survival; Survival Rate
PubMed: 31693429
DOI: 10.1200/JCO.19.00172 -
American Family Physician Jan 2020Lymphoma is a group of malignant neoplasms of lymphocytes with more than 90 subtypes. It is traditionally classified broadly as non-Hodgkin or Hodgkin lymphoma.... (Review)
Review
Lymphoma is a group of malignant neoplasms of lymphocytes with more than 90 subtypes. It is traditionally classified broadly as non-Hodgkin or Hodgkin lymphoma. Approximately 82,000 new U.S. patients are diagnosed with lymphoma annually. Any tobacco use and obesity are major modifiable risk factors, with genetic, infectious, and inflammatory etiologies also contributing. Lymphoma typically presents as painless adenopathy, with systemic symptoms of fever, unexplained weight loss, and night sweats occurring in more advanced stages of the disease. An open lymph node biopsy is preferred for diagnosis. The Lugano classification system incorporates symptoms and the extent of the disease as shown on positron emission tomography/computed tomography to stage lymphoma, which is then used to determine treatment. Chemotherapy treatment plans differ between the main subtypes of lymphoma. Non-Hodgkin lymphoma is treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab (R-CHOP), bendamustine, and lenalidomide. Hodgkin lymphoma is treated with combined chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), Stanford V (a chemotherapy regimen consisting of mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone), or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) with radiotherapy. Subsequent chemotherapy toxicities include neuropathy, cardiotoxicity, and secondary cancers such as lung and breast, and should be considered in the shared decision-making process to select a treatment regimen. Once remission is achieved, patients need routine surveillance to monitor for complications and relapse, in addition to age-appropriate screenings recommended by the U.S. Preventive Services Task Force. Patients should receive a 13-valent pneumococcal conjugate vaccine followed by a 23-valent pneumococcal polysaccharide vaccine at least eight weeks later with additional age-appropriate vaccinations because lymphoma is an immunosuppressive condition. Household contacts should also be current with their immunizations.
Topics: Adult; Aged; Antineoplastic Agents; Biopsy; Evidence-Based Medicine; Female; Humans; Lymphoma; Male; Middle Aged; Neoplasm Staging; Risk Factors; United States
PubMed: 31894937
DOI: No ID Found -
Blood Advances Jan 2022Polatuzumab vedotin plus bendamustine and rituximab (pola + BR) received regulatory approvals for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) based on... (Randomized Controlled Trial)
Randomized Controlled Trial
Polatuzumab vedotin plus bendamustine and rituximab (pola + BR) received regulatory approvals for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) based on primary results from the randomized arms of the GO29365 study. After the randomized phase, 106 additional patients received pola + BR in a single-arm extension cohort. We report updated results from the randomized arms and results of the extension cohort. In this phase 1b/2 study, patients with R/R DLBCL who were transplant ineligible received up to six 21-day cycles of pola + BR or BR. The primary end point of the randomized arms was the complete response (CR) rate at end of treatment. Primary objectives of the extension cohort were safety, pharmacokinetic profile, and efficacy of pola + BR. As of 7 July 2020, a total of 192 patients with R/R DLBCL were enrolled in the pola + BR cohort (n = 152 [safety run-in, n = 6; randomized, n = 40; extension cohort, n = 106]) or the BR cohort (n = 40). Significant survival benefit with pola + BR vs BR persisted in the randomized arms (median progression-free survival, 9.2 vs 3.7 months [hazard ratio, 0.39; 95% confidence interval, 0.23-0.66]; median overall survival, 12.4 vs 4.7 months [hazard ratio, 0.42; 95% confidence interval, 0.24-0.72]). In the extension cohort, the independent review committee-assessed objective response rate was 41.5%, and the CR rate was 38.7%; median independent review committee-assessed progression-free survival and overall survival were 6.6 months and 12.5 months, respectively. No new safety signals with pola + BR were identified. Pola + BR is an effective treatment option for patients with R/R DLBCL, with a well-characterized and manageable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02257567.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Humans; Immunoconjugates; Rituximab
PubMed: 34749395
DOI: 10.1182/bloodadvances.2021005794 -
American Journal of Hematology Feb 2023Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia,...
DISEASE OVERVIEW
Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity.
DIAGNOSIS
Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS patients. MYD88 is not required for the diagnosis.
RISK STRATIFICATION
Age, hemoglobin level, platelet count, β microglobulin, LDH, and monoclonal IgM concentrations are characteristics that are predictive of outcomes.
RISK-ADAPTED THERAPY
Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or a BTK inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib.
MANAGEMENT OF REFRACTORY DISEASE
Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM's natural history, the reduction of therapy toxicity is an important part of treatment selection.
Topics: Humans; Waldenstrom Macroglobulinemia; Rituximab; Bendamustine Hydrochloride; Myeloid Differentiation Factor 88; Antibodies, Monoclonal; Paraproteins; Risk Assessment; Immunoglobulin M
PubMed: 36588395
DOI: 10.1002/ajh.26796 -
Blood Mar 2021The last decades have seen great progress in the treatment of cold agglutinin disease (CAD). Comparative trials are lacking, and recommendations must be based mainly on... (Review)
Review
The last decades have seen great progress in the treatment of cold agglutinin disease (CAD). Comparative trials are lacking, and recommendations must be based mainly on nonrandomized trials and will be influenced by personal experience. Herein, current treatment options are reviewed and linked to 3 cases, each addressing specific aspects of therapy. Two major steps in CAD pathogenesis are identified, clonal B-cell lymphoproliferation and complement-mediated hemolysis, each of which constitutes a target of therapy. Although drug treatment is not always indicated, patients with symptomatic anemia or other bothersome symptoms should be treated. The importance of avoiding ineffective therapies is underscored. Corticosteroids should not be used to treat CAD. Studies on safety and efficacy of relevant drugs and combinations are briefly described. The author recommends that B cell-directed approaches remain the first choice in most patients requiring treatment. The 4-cycle bendamustine plus rituximab combination is highly efficacious and sufficiently safe and induces durable responses in most patients, but the time to response can be many months. Rituximab monotherapy should be preferred in frail patients. The complement C1s inhibitor sutimlimab is an emerging option in the second line and may also find its place in the first line in specific situations.
Topics: Aged; Aged, 80 and over; Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bendamustine Hydrochloride; Complement Inactivating Agents; Disease Management; Female; Humans; Middle Aged; Rituximab; Thrombosis
PubMed: 33512410
DOI: 10.1182/blood.2019003809 -
American Journal of Hematology Feb 2021Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia,... (Review)
Review
DISEASE OVERVIEW
Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity.
DIAGNOSIS
Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in the majority of IgM MGUS patients.
RISK STRATIFICATION
Age, hemoglobin level, platelet count, β microglobulin, LDH and monoclonal IgM concentrations are characteristics that are predictive of outcomes.
RISK-ADAPTED THERAPY
Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogues are active but usage is declining in favor of less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine.
MANAGEMENT OF REFRACTORY DISEASE
Bortezomib, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection.
Topics: Age Factors; Humans; Immunoglobulin M; L-Lactate Dehydrogenase; Mutation, Missense; Myeloid Differentiation Factor 88; Platelet Count; Risk Assessment; Waldenstrom Macroglobulinemia
PubMed: 33368476
DOI: 10.1002/ajh.26082 -
Journal of Clinical Oncology : Official... Jan 2023Brexucabtagene autoleucel (KTE-X19) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is approved for the treatment of relapsed/refractory mantle cell...
PURPOSE
Brexucabtagene autoleucel (KTE-X19) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). Outcomes after a 3-year follow-up in the pivotal ZUMA-2 study of KTE-X19 in relapsed/refractory MCL are reported, including for subgroups by prior therapy (bendamustine and type of Bruton tyrosine kinase inhibitor [BTKi]) or high-risk characteristics.
METHODS
Patients with relapsed/refractory MCL (one to five prior therapies, including prior BTKi exposure) received a single infusion of KTE-X19 (2 × 10 CAR T cells/kg).
RESULTS
After a median follow-up of 35.6 months, the objective response rate among all 68 treated patients was 91% (95% CI, 81.8 to 96.7) with 68% complete responses (95% CI, 55.2 to 78.5); medians for duration of response, progression-free survival, and overall survival were 28.2 months (95% CI, 13.5 to 47.1), 25.8 months (95% CI, 9.6 to 47.6), and 46.6 months (95% CI, 24.9 to not estimable), respectively. Post hoc analyses showed that objective response rates and ongoing response rates were consistent among prespecified subgroups by prior BTKi exposure or high-risk characteristics. In an exploratory analysis, patients with prior bendamustine benefited from KTE-X19, but showed a trend toward attenuated T-cell functionality, with more impact of bendamustine given within 6 versus 12 months of leukapheresis. Late-onset toxicities were infrequent; only 3% of treatment-emergent adverse events of interest in ZUMA-2 occurred during this longer follow-up period. Translational assessments revealed associations with long-term benefits of KTE-X19 including high-peak CAR T-cell expansion in responders and the predictive value of minimal residual disease for relapse.
CONCLUSION
These data, representing the longest follow-up of CAR T-cell therapy in patients with MCL to date, suggest that KTE-X19 induced durable long-term responses with manageable safety in patients with relapsed/refractory MCL and may also benefit those with high-risk characteristics.
Topics: Adult; Humans; Receptors, Chimeric Antigen; Lymphoma, Mantle-Cell; Immunotherapy, Adoptive; Follow-Up Studies; Bendamustine Hydrochloride; Neoplasm Recurrence, Local
PubMed: 35658525
DOI: 10.1200/JCO.21.02370 -
Cancer Treatment and Research... 2022Waldenström Macroglobulinemia (WM) is a unique, low grade, IgM lymphoplasmacytic lymphoma with a heterogeneous clinical course. A paucity of high-grade evidence from... (Review)
Review
Waldenström Macroglobulinemia (WM) is a unique, low grade, IgM lymphoplasmacytic lymphoma with a heterogeneous clinical course. A paucity of high-grade evidence from large phase 3 trials remains a major issue in the field despite a rapidly expanding therapeutic armamentarium against WM. Prior knowledge of the patients' MYD88 and CXCR4 mutation status aids in treatment decision making if Bruton's tyrosine kinase (BTK) inhibitor therapy is being considered. Head-to head comparative data to inform optimal approach are lacking, and a particularly vexing issue for the clinicians is choosing between fixed-duration bendamustine-rituximab (BR) therapy and an indefinite BTK inhibitor-based regimen, given that both approaches are well tolerated and effective, particularly for the patient population harboring MYD88 mutation. For the patients with MYD88 genotype, chemo-immunotherapy such as BR is preferred, although zanubrutinib, a potent second generation BTK inhibitor, with its reduced off target effects and greater BTK occupancy compared to its predecessor, ibrutinib, has also recently shown activity in MYD88 WM. This review summarizes the current literature pertaining to the diagnosis, prognosis, and the treatment of WM.
Topics: Humans; Molecular Targeted Therapy; Mutation; Myeloid Differentiation Factor 88; Rituximab; Waldenstrom Macroglobulinemia
PubMed: 35149375
DOI: 10.1016/j.ctarc.2022.100527 -
American Journal of Hematology Jun 2022Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in...
DISEASE OVERVIEW
Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include heart failure with preserved ejection fraction, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and "atypical smoldering multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS)."
DIAGNOSIS
Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for the diagnosis of AL amyloidosis. Invasive organ biopsy is not required in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy.
PROGNOSIS
N-terminal pro-brain natriuretic peptide (NT-proBNP or BNP), serum troponin T (or I), and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 73, 35, 15, and 5 months.
THERAPY
All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Current first-line therapy with the best outcome is daratumumab, bortezomib, cyclophosphamide, and dexamethasone. The goal of therapy is a complete response (CR). In patients failing to achieve this depth of response options for consolidation include pomalidomide, stem cell transplantation, venetoclax, and bendamustine.
FUTURE CHALLENGES
Delayed diagnosis remains a major obstacle to initiating effective therapy prior to the development of end-stage organ failure. Trials of antibodies to catabolize deposited fibrils are underway.
Topics: Amyloidosis; Bortezomib; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Prognosis
PubMed: 35429180
DOI: 10.1002/ajh.26569 -
Oncology (Williston Park, N.Y.) Feb 2022Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic... (Review)
Review
Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Benzamides; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Doxorubicin; Genetic Testing; Humans; Immune Checkpoint Inhibitors; Immunoconjugates; Immunotherapy, Adoptive; Lenalidomide; Lymphoma, Follicular; Maintenance Chemotherapy; Morpholines; Neoplasm Recurrence, Local; Phosphoinositide-3 Kinase Inhibitors; Prednisone; Pyridones; Rituximab; Sulfonamides; Vincristine
PubMed: 35180337
DOI: 10.46883/2022.25920946