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Rituximab (Mabthera)

Web Resources: Rituximab (Mabthera)
Latest Research Publications

Web Resources: Rituximab (Mabthera) (6 links)

Latest Research Publications

Shanafelt TD, Wang XV, Kay NE, et al.
Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia.
N Engl J Med. 2019; 381(5):432-443 [PubMed] Related Publications
BACKGROUND: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.
METHODS: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.
RESULTS: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (
CONCLUSIONS: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).

Pirozzi A, Riccardi F, Arpino G, et al.
Occurrence of second primary malignancies in patients with neuroendocrine tumors of the digestive tract: A case report.
Medicine (Baltimore). 2019; 98(29):e16508 [PubMed] Related Publications
RATIONALE: There is an association between the presence of neuroendocrine neoplasms and incremented risk to develop second primary malignancies. This risk is estimated to be 17%. The most common secondary neoplasms were found in the Gastrointestinal and Genitourinary tracts.
PATIENT CONCERNS: A 74-year-old Caucasian patient with melaena came to our observation in June 2015. The Esophago-gastro-duodenoscopy exam found a polypoid formation in the duodenal bulb. Histopathological examination showed a well-differentiated neuroendocrine neoplasm (G1).
DIAGNOSIS: During the follow up for the neuroendocrine neoplasm, a CT scan was performed in August 2016 describing infiltration of the right renal sinus and the third proximal ureter segment with heterogeneous enhancement of vascular structure. An US-guided biopsy was conclusive for a Diffuse Large B Cell Lymphoma. In October 2016, a colonoscopy showed a neoplastic lesion at 20 cm from the anal orifice. The Histology exam was positive for an adenocarcinoma with a desmoplastic stroma infiltration.
INTERVENTIONS: In November 2016, the patient underwent a left hemicolectomy: the pathologic staging described a G2 adenocarcinoma pT3N1b. In May 2018, the Octreotide scan was negative. In the same month, the patient started a treatment based on 6 cycles of Rituximab, Oxaliplatin, and Capecitabine due to the persistence of lymphomatous disease and hepatic metastases. In July 2018, other 3 cycles of the same treatment were scheduled.
OUTCOMES: In January 2019, due to an increase in liver metastases' size, it was decided to start a new regimen for the colon cancer with FOLFIRI+Cetuximab. The patient is still in treatment with this regimen in April 2019.
LESSONS: The risk of a second primary tumor is increased among patients older than 70. Therefore, it is necessary to follow them using total body CT scan and endoscopic techniques of gastrointestinal and genitourinary tracts, not only for the evaluation of the neuroendocrine tumor but also for the higher risk to develop other neoplastic diseases.

Barrenetxea Lekue C, Grasso Cicala S, Leppä S, et al.
Pixantrone beyond monotherapy: a review.
Ann Hematol. 2019; 98(9):2025-2033 [PubMed] Free Access to Full Article Related Publications
Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL.

Kim MS, Park JH, Kim JY, et al.
Upper gastrointestinal bleeding caused by direct invasion of diffuse large B-cell lymphoma into the stomach in a patient with HIV infection: A case report.
Medicine (Baltimore). 2019; 98(28):e16363 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Diffuse large B-cell lymphoma (DLBCL) is the most frequent human immunodeficiency virus (HIV)-related Non-Hodgkin's Lymphoma of the stomach. Although gastrointestinal (GI) bleeding due to primary gastric lymphoma has been previously reported in the literature, there have been no reports of stomach wall involvement of intra-abdominal lymphoma presenting as GI bleeding.
PATIENT CONCERNS: We present a rare case of direct invasion of DLBCL to the stomach wall that presented as upper GI bleeding in a patient with HIV.
DIAGNOSIS: Upper endoscopy showed a large ulcerofungating mass in the lesser curvature of upper stomach body. The computed tomography scan showed an about 22 × 12 cm sized huge mass that invades into the stomach wall in the abdominal cavity. A diagnosis of DLBCL was established after histological examination.
INTERVENTION: The patient was treated with 6 courses of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).
OUTCOMES: The patient achieved a complete response with 6 courses of R-CHOP treatment. No recurrence was observed during the 4-month follow-up period.
LESSONS: Because of the high incidence of lymphoma in patients with HIV, if such patients complain of dyspepsia, epigastric soreness, or melena, malignant tumors, such as lymphomas or stomach cancers, should be suspected. As in this patient, doctors should be aware that intra-abdominal lymphoma can invade into the stomach wall and cause bleeding.

Sakai R, Ohmachi K, Sano F, et al.
Bendamustine-120 plus rituximab therapy for relapsed or refractory follicular lymphoma: a multicenter phase II study.
Ann Hematol. 2019; 98(9):2131-2138 [PubMed] Related Publications
The optimal dose, schedule, and other aspects of bendamustine plus rituximab treatment remain unclear for patients with relapsed or refractory follicular lymphoma (FL). Herein, we analyzed the efficacy of bendamustine combined with rituximab (RB-120) treatment for Japanese patients with relapsed or refractory FL. This phase II clinical trial included patients with relapsed or refractory FL who received 375 mg/m

Budau L, Wilhelm C, Moll R, et al.
Low number of intrafollicular T cells may predict favourable response to rituximab-based immuno-chemotherapy in advanced follicular lymphoma: a secondary analysis of a randomized clinical trial.
J Cancer Res Clin Oncol. 2019; 145(8):2149-2156 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: First-line rituximab therapy together with chemotherapy is the standard care for patients with advanced follicular B-cell lymphoma, as rituximab together with chemotherapy prolongs progression-free and overall survival (Herold et al. 2007; Marcus et al. 2005). However, as not all patient subgroups benefit from combined immuno-chemotherapy, we asked whether the microenvironment may predict benefit from rituximab-based therapy.
DESIGN: To address this question, we performed a retrospective immunohistochemical analysis on pathological specimens of 18 patients recruited into a randomized clinical trial, where patients with advanced follicular lymphoma were randomized into either chemotherapy or immuno-chemotherapy with rituximab (Herold et al. 2007).
RESULTS: We show here that rituximab exerts beneficial effects, especially in the subgroup of follicular lymphoma patients with low intrafollicular CD3, CD5, CD8, and ZAP70 and high CD56 and CD68 expression.
CONCLUSION: Rituximab may overcome immune-dormancy in follicular lymphoma in cases with lower intrafollicular T-cell numbers and higher CD56 and CD68 cell counts. As this was a retrospective analysis on a small subgroup of patients, these data need to be corroborated in larger clinical trials.

Falini B, Tiacci E
New treatment options in hairy cell leukemia with focus on BRAF inhibitors.
Hematol Oncol. 2019; 37 Suppl 1:30-37 [PubMed] Related Publications
Hairy cell leukemia (HCL) responds initially very well to chemotherapy with purine analogues. However, up to 50% of patients relapse, often multiple times, and become progressively less sensitive to these myelotoxic and immune-suppressive drugs. At progression, viable therapeutic strategies include addition of rituximab to purine analogues, and treatment with the anti-CD22 immunotoxin moxetumomab pasudotox, which has been recently approved by the FDA in HCL patients after at least two prior therapies. Identification of the BRAF-V600E kinase mutation as the genetic cause of HCL has opened the way, in the relapsed/refractory experimental setting, to targeted and non-myelotoxic effective strategies that are based on inhibition of BRAF with vemurafenib, co-inhibition of BRAF and its target MEK with dabrafenib and trametinib, and BRAF inhibition with vemurafenib combined with anti-CD20 immunotherapy. In particular, vemurafenib plus rituximab is emerging as a short, safe, chemotherapy-free regimen able to induce deep complete remissions in most HCL patients refractory to, or relapsed multiple times, after chemo(immuno)therapy.

Bogeljić Patekar M, Milunović V, Mišura Jakobac K, et al.
Acta Clin Croat. 2018; 57(3):542-553 [PubMed] Free Access to Full Article Related Publications
- The aim of this review is to present data on bendamustine, a non-cross resistant alkylating agent, alone or in combination for treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Bendamustine is currently approved for rituximab-resistant indolent NHL and CLL in patients not fit for conventional chemotherapy. Recent studies have shown superiority of bendamustine combination with rituximab (B-R) in first line treatment of indolent NHLs and mantle cell lymphoma, suggesting a shift of the standard of care in this setting. B-R regimen has also shown efficacy in relapsed setting suggesting the possible treatment option for patients failing conventional chemotherapy. In rituximab-resistant NHL, the recent GADOLIN study exploring the addition of obinutuzumab to bendamustine has yielded impressive result changing the standard of care in this hard-to-treat population. Concerning CLL, despite inferiority to the standard of care in young fit patients, as defined in CLL10 study, B-R has yielded a more beneficial toxicity profile and its use in first line treatment should be decided individually. In relapsed setting, the addition of ibrutinib to B-R has shown superior results compared to B-R alone, possibly changing the paradigm of treatment of relapsed CLL. In conclusion, bendamustine as a single agent or in combinations has shown activity with acceptable toxic profile in the treatment of patients with indolent NHLs or CLL without del(17p) mutation.

Illésy L, Szabó RP, Kovács DÁ, et al.
Non-Hodgkin Lymphoma in a Kidney Transplant Patient: A Case Report.
Transplant Proc. 2019; 51(4):1286-1288 [PubMed] Related Publications
Post-transplant lymphoproliferative disorders are a possible complication of kidney transplant due to chronic immunosuppressive therapy, and they can elevate the mortality rate. Furthermore, the type of clinical appearance has a wide range. We describe a case of a 38-year-old male recipient who developed post-transplant lymphoproliferative disorders and received successful treatment. The recipient had received a kidney with 1 HLA-B and 1 HLA-DR match, and the deceased donor allotransplant was performed successfully on December 9, 2012. The cause of kidney failure was membranoproliferative-glomerulonephritis proved by biopsy results. The induction therapy was antithymocyte globulin; the basic immunosuppressive therapy consisted of tacrolimus, steroid, and mycophenolate mofetil. After 2 months the patient had elevated serum creatinine level, and biopsy results revealed cellular rejection (Banff grade I). We applied steroid bolus therapy. After that the graft worked properly for 5 years, and the patient had no symptoms or complaints; then he had right lower abdomen pain. After urgent procedures (laboratory diagnostics, abdominal ultrasonography, computed tomography), we operated on the patient in a short time, and after a few weeks the fluorescence in situ hybridization confirmed the translocation of region C-myc; the diagnosis was diffuse large B-cell lymphoma. With the assistance of hematologists, the patient received adequate therapy. He was asymptomatic half a year after the rituximab with cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, and high-dose cytarabine protocol therapy; the lymphoma is in remission. Our case is worth presenting because immunosuppressive drugs can modify the clinical picture, complicating the diagnosis and delaying treatment.

Hou R, Wu J, He D, et al.
Anti-N-methyl-D-aspartate receptor encephalitis associated with reactivated Epstein-Barr virus infection in pediatric patients: Three case reports.
Medicine (Baltimore). 2019; 98(20):e15726 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent autoimmune encephalitis in children, and its presentation is various. The disease can be triggered by various infections.
PATIENT CONCERNS: Case 1 was a 7-year-old female with the presentation of seizure, repeated fever, language disorder, and decreased muscle strength of the right limbs; Case 2 was a 7-year-old male with the manifestation of repeated emesis, headache, involuntary movement, altered personality, seizures, and cognitive impairment; Case 3 was a 2-year-old female with repeated fever, emesis, seizures, coma, and decreased muscle strength of limbs. Anti-NMDAR antibody was identified in cerebrospinal fluid (CSF) in the 3 cases, confirming the diagnosis of anti-NMDAR encephalitis. Pathogenic examinations revealed positive serum Epstein-Barr virus (EBV)-nuclear antigen and EBV-capsid antigen (CA)-IgG antibodies in the 3 cases, as well as positive EBV-early antigen (EA)-IgG antibody in CSF. Case 1 also had positive EBV-CA-IgA antibody; Case 3 also had positive EBV-CA-IgA and EBV-CA-IgG antibodies.
DIAGNOSES: Anti-NMDAR antibody and EBV-EA-IgG antibody in CSF were tested positive in the 3 cases. Thus, they were diagnosed as anti-NMDAR encephalitis associated with reactivated EBV infection.
INTERVENTIONS: All of the 3 cases received immunoglobulin, corticosteroid, and ganciclovir treatment. Cases 2 and 3 also received antiepileptic drugs due to repeated seizures. In addition, Case 3 also received assistant respiration, plasma exchange, and rituximab.
OUTCOMES: The 3 cases were substantially recovered after treatment. Repeat CSF analysis showed decreased titer of the anti-NMDAR antibody.
LESSONS: Reactivated EBV infection may trigger anti-NMDAR encephalitis in children, which has not been reported previously. Related possible virology tests should be completed while diagnosing the disease.

Tang H, Zhou H, Wei J, et al.
Clinicopathologic significance and therapeutic implication of de novo CD5+ diffuse large B-cell lymphoma.
Hematology. 2019; 24(1):446-454 [PubMed] Related Publications
BACKGROUND: Various subsets of diffuse large B-cell lymphoma(DLBCL) are distinguished based on molecular and immunohistochemical features. As we know, CD5 is a pan-T-cell surface marker and is seldom expressed in DLBCL. Large-scale studies of de novo CD5+ DLBCL are lacking in Chinese patients.
METHOD: A total of 139 patients with DLBCL (30 CD5+ DLBCL and 109 CD5- DLBCL) who were immunophenotyped and treated with chemotherapy were subjected to this analysis. There were 85 males and 54 females. Their age ranged from 17 to 84 years old, and the median age was 58 years old.
RESULTS: In this study CD5+ DLBCL was associated with higher IPI scores (>2), bone marrow involvement, higher probability of >1 ECOG performance status, non-germinal center B-cell like(non-GCB), BCL2 overexpression, whereas seldom expressed CD10 or BCL6, and unconspicuous higher expression of Ki67. With standard chemotherapy, CD5+ DLBCL patients had significantly worse overall survival (OS, median, 29.5 months vs. not reached, P = 0.0004) and progression-free survival (PFS, median, 18.0 months vs. not reached, P = 0.0002) than CD5- DLBCL patients, which had independent prognostic significance of the International Prognostic Index (IPI), and subtype of the non-GCB DLBCL. For CD5+ DLBCL, the addition of rituximab to chemotherapy may not significantly improve the OS (median, 14 months vs. 29.5 months, P = 0.72) and PFS (median, 10 months vs. 12 months, P = 0.92).
CONCLUSION: CD5+ DLBCL patients have the distinctive clinical and biological features, they should be provided with clinic individualized treatment and important pathways with therapeutic implications should be underscored.

Opat S, Dickinson M, Cheah CY, et al.
Management of patients with follicular lymphoma treated first line with obinutuzumab.
Asia Pac J Clin Oncol. 2019; 15 Suppl 3:3-11 [PubMed] Related Publications
Recently, obinutuzumab was included in the Australian Pharmaceutical Benefits Scheme for use in first line, advanced or bulky stage 2, follicular lymphoma, providing more immunochemotherapy treatment options available than ever before. Rituximab with chemotherapy has been the standard of care since reimbursement in the late 1990s; however, obinutuzumab-based regimens have shown superior progression-free survival in comparison to rituximab-based options, albeit at an increased risk of grade ≥3 adverse events. As median overall survival approaches 20 years or more, the long-term effects and sequencing of any strategy should be considered. Here we discuss the considerations for selection of front-line therapy, based on evidence and local Australian clinician experience, in the management of first line follicular lymphoma.

Lavezzi SM, de Jong J, Neyens M, et al.
Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial.
Pharm Res. 2019; 36(7):93 [PubMed] Related Publications
INTRODUCTION: In the HELIOS trial, bendamustine/rituximab (BR) plus ibrutinib (BR-I) improved disease outcomes versus BR plus placebo in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Here, we describe the pharmacokinetic (PK) observations, along with modeling to further explore the interaction between ibrutinib and rituximab.
METHODS: 578 subjects were randomized to ibrutinib or placebo with BR (6 cycles). Ibrutinib PK samples and tumor measurements were obtained from all subjects; a subset was evaluated for bendamustine and rituximab PK. Population rituximab PK was assessed using nonlinear mixed-effects modeling.
RESULTS: Dose-normalized plasma concentration-time bendamustine data were comparable between the arms. Systemic rituximab exposure was higher with BR-I versus BR; mean trough serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher subsequently. No relevant safety differences were observed. In the modeling, including treatment arm as a categorical covariate and tumor burden as a continuous time-varying covariate on overall rituximab clearance significantly improved fitting of the data.
CONCLUSIONS: BR-I led to higher dose-normalized systemic rituximab exposure versus BR and more rapid steady-state achievement. The modeling data suggest that rituximab disposition is, at least in part, target mediated. Determining the clinical significance of these findings requires further assessments.
TRIAL REGISTRATION: This study is registered at https://clinicaltrials.gov/ct2/show/NCT01611090 .

Hao S, Sun Y, Hu C, et al.
Primary nasal diffuse large B-cell lymphoma with synchronous pulmonary involvement: A case report.
Medicine (Baltimore). 2019; 98(17):e15439 [PubMed] Related Publications
RATIONALE: Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring type of non-Hodgkin's lymphoma, which may be found at various extranodal sites. The nose is not a common site for DLBCL as compared with natural killer/T-cell lymphoma, and synchronous pulmonary involvement is even rarer. We report a case of primary nasal DLBCL who presented with a mass in the left lower lobe, mimicking primary lung carcinoma.
PATIENT CONCERNS: A 62-year-old Chinese female visited the Ear-Nose-Throat Department of our hospital with nasal congestion and rhinorrhea for 2 months.
DIAGNOSIS: Computed tomography scan revealed a mass with soft tissue density in the left vestibule and nasal cavity. Histopathological examination revealed a large number of lymphoma cells, and immunohistochemistry confirmed the diagnosis of DLBCL.
INTERVENTIONS: The patient was treated with 6 cycles of R-CHOP (cyclophosphamide, adriamycin, vincristine, prednisone, and rituximab).
OUTCOMES: The treatment was well tolerated and led to complete remission for the patient. There was no sign of relapse over the 3-year close follow-up LESSONS:: DLBCL can be present at various extranodal sites and clinicians irrespective of their specialty must be vigilant for the synchronous mode of presentation of such lesions. Immunohistochemical techniques play a vital role in the diagnosis, because clinical characteristics may be misleading.

Yonezawa A, Otani Y, Kitano T, et al.
Concentration and Glycoform of Rituximab in Plasma of Patients with B Cell Non-Hodgkin's Lymphoma.
Pharm Res. 2019; 36(6):82 [PubMed] Related Publications
PURPOSE: Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients.
METHODS: Twenty B cell non-Hodgkin's lymphoma patients who were treated with rituximab for the first time or after more than one year's abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined.
RESULTS: Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different.
CONCLUSION: Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.

Korycka-Wolowiec A, Wolowiec D, Kubiak-Mlonka A, Robak T
Venetoclax in the treatment of chronic lymphocytic leukemia.
Expert Opin Drug Metab Toxicol. 2019; 15(5):353-366 [PubMed] Related Publications
INTRODUCTION: Venetoclax, an antagonist of BCL-2 protein plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). It has been approved by the FDA for the treatment of relapsed/refractory CLL with del17p, and by the EMA for patients with del17p/TP53 mutation who have failed a BCR inhibitor, or in patients without those aberrations who have failed previous therapy, regardless of their genetic/molecular profile. Venetoclax in combination with rituximab has been also approved for the treatment of CLL after at least 1 prior therapy, regardless of del17p. Areas covered: This article reviews the chemical structure, mechanisms of action, pharmacokinetic, and the clinical applications of venetoclax in monotherapy and in combined treatment of CLL. Publications dated 2010 through March 2019 were obtained from the MEDLINE database. The proceedings of the American Society of Hematology held during the last five years were also included. Expert opinion: Venetoclax shows high efficacy, a favorable toxicity profile, and a high rate of minimal residual disease negativity, which is thought to have an impact on overall survival. It is efficient in patients with del17p/TP53 mutations, the incidence of which increases during clonal CLL evolution, and after the failure of BCR pathway inhibitors.

Felemban AA, Rashidi ZA, Almatrafi MH, Alsahabi JA
Autoimmune hemolytic anemia and ovarian dermoid cysts in pregnancy.
Saudi Med J. 2019; 40(4):397-400 [PubMed] Free Access to Full Article Related Publications
Ovarian teratoma is a rare cause of autoimmune hemolytic anemia (AIHA) by warm antibodies, resistant to corticosteroid therapy. This also implies that ovarian teratoma should be included in the differential diagnosis of AIHA, whether or not associated with pregnancy. We present a case of a primigravida who presented with ovarian dermoid cysts and AIHA at 24 weeks of gestation. The patient received corticosteroids, intravenous immunoglobulin, rituximab, and multiple blood transfusions, with no significant improvement. Hemoglobin levels returned to normal only after laparoscopic ovarian cystectomy. Autoimmune hemolytic anemia caused by dermoid cyst is a rare condition especially in pregnancy. However, in light of similar case reports and review of the existing literature, we conclude that surgical excision should be considered when AIHA and ovarian teratoma coexist.

Canepa C
Waldenstrom-associated anti-MAG paraprotein polyneuropathy with neurogenic tremor.
BMJ Case Rep. 2019; 12(3) [PubMed] Related Publications
A 71-year-old female patient presented with a 14-year history of slowly progressive distal limb numbness, paraesthesia and reduced vibration perception, ataxic gait and intentional tremor. Examination revealed with a length-dependent sensory neuropathy. Nerve conduction studies showed a chronic sensorimotor inflammatory demyelinating polyneuropathy. Intravenous immunoglobulin treatment (on two occasions) proved ineffective. Serum electrophoresis showed increased monoclonal IgM with kappa light chains. Anti-myelin-associated glycoprotein (MAG) levels were extremely elevated, >70 000 BTU. Bone marrow biopsy revealed 15%-20% small B cells and positive MYD88 mutation, indicative of Waldenstrom macroglobulinaemia. A diagnosis of Waldenstrom-associated anti-MAG paraprotein neuropathy with intentional (neurogenic) tremor was made. Repeat nerve conduction study showed a severe sensory demyelinating neuropathy with no axonal lesion. Treatment with rituximab was given for 1 month with minimal improvement. Repeat anti-MAG levels dropped to 53 670 BTU, with minimal clinical improvement.

Morschhauser F, Flinn IW, Advani R, et al.
Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS).
Lancet Haematol. 2019; 6(5):e254-e265 [PubMed] Related Publications
BACKGROUND: Antibody-drug conjugates (ADCs) polatuzumab vedotin (pola) and pinatuzumab vedotin (pina) showed clinical activity and tolerability in phase 1 trials. The aim of this multicentre, open-label, phase 2 study was to compare rituximab plus pola (R-pola) or pina (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma.
METHODS: In this phase 2 randomised study at 39 investigational sites in six countries, patients were randomly assigned (1:1), by use of a dynamic hierarchical randomisation scheme, to receive R-pola or R-pina (375 mg/m
FINDINGS: 81 patients with diffuse large B-cell lymphoma and 42 with follicular lymphoma were recruited between Sept 27, 2012, and Oct 10, 2013, and were assigned to treatment. 81 patients with diffuse large B-cell lymphoma and 41 patients with follicular lymphoma were eligible for analysis. Of the 42 patients with diffuse large B-cell lymphoma who received R-pina, 25 (60%, 95% CI 43-74) achieved an objective response and 11 (26%, 95% CI 14-42) achieved a complete response. Of the 39 patients in this cohort who received R-pola, 21 (54%, 95% CI 37-70) achieved an objective response, and eight (21%, 95% CI 9-36) achieved a complete response. Of the 21 patients in the follicular lymphoma cohort who received R-pina, 13 (62%, 95% CI 38-82) achieved an objective response, and one (5%, 95% CI 0·1-24) achieved a complete response. Of the 20 patients in this cohort who received R-pola, 14 (70%, 95% CI 46-88) achieved an objective response, and nine (45%, 95% CI 23-68) achieved a complete response. In the diffuse large B-cell lymphoma cohort, grade 3-5 adverse events occurred in 33 (79%) of 42 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [10%]; nine [21%] grade 5 adverse events, five of which were infection-related), and in 30 (77%) of 39 patients receiving R-pola (most common were neutropenia [23%], anaemia [8%] and diarrhoea [8%]; no grade 5 adverse events). In the follicular lymphoma cohort, grade 3-5 adverse events occurred in 13 (62%) of 21 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [14%]; no grade 5 adverse events) and in ten (50%) of 20 patients receiving R-pola (most common were neutropenia [15%] and diarrhoea [10%]; one grade 5 adverse event).
INTERPRETATION: R-pina and R-pola are potential treatment options in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. Pola was selected by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response than pina, and an overall benefit-risk favouring R-pola.
FUNDING: F Hoffmann-La Roche.

Tanaka Y, Ishihara M, Miyoshi H, et al.
Spontaneous regression of diffuse large B-cell lymphoma in the small intestine with multiple lymphadenopathy.
J Clin Exp Hematop. 2019; 59(1):17-21 [PubMed] Free Access to Full Article Related Publications
Diffuse large B cell lymphoma (DLBCL) is classified as an aggressive lymphoma due to its poor prognosis regardless of the treatment. Almost all cases of DLBCL are treated using rituximab-combination chemotherapy, but spontaneous regression without any therapeutic modalities may rarely occur. A 35-year-old man complained of abdominal pain and discomfort. Positron emission tomography-computed tomography (PET-CT) demonstrated abnormal accumulation of fluorodeoxyglucose in the thickened wall of the small intestine and multiple lymphadenopathy. Laparoscopic lymph node biopsy was performed, and the diagnosis of DLBCL was made based on the biopsy findings. Soon after the laparoscopic biopsy, the patient felt free from any symptoms. Approximately three months later, no abnormal accumulation of fluorodeoxyglucose in the entire body was found on PET-CT. He has remained in complete metabolic remission for over three years according to PET-CT. We discuss the mechanism of this rare phenomenon.

Nicholson MC, Pavenski K, Trinkaus M
A case for consideration by apheresis practitioners: Melanoma and PD-1 inhibitor treatment in a patient with multiple relapses of immune thrombotic thrombocytopenic purpura.
Transfus Apher Sci. 2019; 58(2):123-124 [PubMed] Related Publications
Thrombotic Thrombocytopenic Purpura (TTP) is a rare life-threatening disease caused by ADAMTS-13 deficiency. Up to forty percent of patients with TTP relapse, and most relapse within eight years of their first presentation. This case report describes a patient with an aggressive course of TTP who subsequently developed metastatic melanoma while receiving prophylactic rituximab. Limited data exists regarding the potential for malignancy in patients receiving Rituximab for benign conditions. This is the first published case of melanoma in a TTP patient treated with rituximab. Melanoma treatment with PD-1 inhibitors is also associated with worsening of pre-existing autoimmune conditions. In this case, a splenectomy resulted in a durable remission despite treatment with PD-1 inhibitor.

Sahin O, Albayrak M, Yıldız A, et al.
Refractory Thrombotic Thrombocytopenic Purpura in a patient with Kaposi sarcoma.
Transfus Apher Sci. 2019; 58(2):187-189 [PubMed] Related Publications
The case is here presented of a 70-year old male patient with rare coexistence of Kaposi Sarcoma and resistant Thrombotic Thrombocytopenic Purpura (TTP). The Kaposi lesions were determined before the diagnosis of TTP and were exacerbated after receiving TTP-associated immunosuppressive therapy, in particular associated with rituximab. TTP in this case was resistant to conventional therapies such as steroid and plasma exchange and current immunosuppressive (rituximab, cyclophosphamide, vincristin) treatments. Novel treatment agents consisting of bortezomib and eculizumab given to the patient were also ineffective. To the best of our knowledge, this case presents the first case of coexistence of TTP and Kaposi sarcoma from Turkey and the challenge of refractory TTP management.

Pirozzi A, Cartenì G, Scagliarini S, et al.
Incidental finding of non-Hodgkin's lymphoma in a patient affected by castration-sensitive prostate cancer: A case report.
Medicine (Baltimore). 2019; 98(11):e14805 [PubMed] Free Access to Full Article Related Publications
RATIONALE: This article describes the case of a patient with 2 simultaneous malignant diseases: Follicular lymphoma and 'castration sensitive prostate cancer. Patients with multiple cancers are not easy to manage and it is difficult to find the appropriate approach and resources to use with them. We focused our attention on how to choose the correct strategy to face 2 different neoplasms and control the adverse reactions related to the corresponding treatments.
PATIENT CONCERNS: We present a case of a 71-year-old man who came to us complaining about an abnormal difficulty in urinating associated with an interrupted flow and excessive urination at night. Clinical examination detected multiple enlarged superior and inferior diaphragmatic lymph nodes.
DIAGNOSIS: Prostate biopsy revealed an acinar adenocarcinoma (Gleason 4+3, Grade group 3). Clinical staging by bone scan was negative but computed tomography scan (CT) detected multiple enlarged superior and inferior diaphragmatic, and inguinal lymph nodes. This type of lymph node involvement pattern is unusual for an acinar adenocarcinoma prostate cancer therefore we suspected the simultaneous presence of a lymphatic neoplasm. Fluorodeoxyglucose positron emission tomography scan. The exam showed one of the left inguinal lymph nodes had the highest standardized uptake value (13.0) so a biopsy was taken. The sample analysis confirmed the diagnosis of a follicular non-Hodgkin lymphoma of Grade 3a.
INTERVENTIONS: We used a multidisciplinary clinical approach based on Rituximab+CHOP administered every 21 days. Simultaneously, the patient underwent androgen deprivation therapy with triptorelin monthly and bicalutamide administered just during the first month of treatment. When we obtained a complete response for the lymphoma, the patient continued the therapy with Rituximab once every 2 months for the next 2 years. Then we added volumetric modulated arc therapy (VMAT) radiotherapy with simultaneous integrated boost (SIB) to androgen deprivation therapy for the duration of 1 month.
OUTCOMES: After 1 year and 6 months since the conclusion of therapy for prostate cancer and Follicular lymphoma, patient's conditions are good and he is in complete remission for both diseases. Gut toxicity is reduced with a mean number of 2 to 3 discharges daily and an increased body weight.
LESSONS: The presence of diffuse lymphadenopathy and urinary symptoms in the same patients must induce the suspect of 2 contemporary cancer diseases. Parallel treatments of follicular lymphoma and prostate cancer should consider the increased risk of severe adverse effects related to the treatment and their management. We describe our therapeutic strategy to highlight the importance to balance benefits and disadvantages to get the best possible response and maintain a good quality of life in this complex setting.

Liu Z, Markham M, Mandernach MW
Marginal zone lymphoma-associated antiphospholipid antibodies successfully treated with bendamustine rituximab.
BMJ Case Rep. 2019; 12(3) [PubMed] Related Publications
A 46-year-old man presented with splenomegaly, abdominal adenopathy and profoundly elevated prothrombin time and partial thromboplastin time. He was diagnosed with marginal zone lymphoma (MZL) and small lymphocytic lymphoma, and the abnormal coagulation studies were secondary to the presence of a lupus anticoagulant. Optimal upfront therapy for MZL has not been established, and the incidence of antiphospholipid antibodies (APLA) in this patient population is rare. Following treatment with six cycles of bendamustine and rituximab with 2 years of rituximab maintenance, our patient remained in remission and his coagulation studies normalised. This report describes a case of successful treatment of APLA associated with MZL that resolved after treatment of the lymphoma.

Gastwirt JP, Roschewski M
Management of adults with Burkitt lymphoma.
Clin Adv Hematol Oncol. 2018; 16(12):812-822 [PubMed] Related Publications
Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma characterized by marked tumor proliferation resulting from translocation of the MYC oncogene. Distinct clinical variants include endemic, sporadic, and immunodeficiency-associated cases. All variants are characterized by rapidly dividing tumor masses that quickly disseminate to extranodal sites, including the bone marrow and central nervous system (CNS). Although common in children, BL is rare in adults, mandating a high index of clinical suspicion for timely diagnosis. Prompt recognition and initiation of comprehensive supportive care are essential for prevention of early complications, such as tumor lysis syndrome and multisystem organ dysfunction. BL is highly sensitive to chemotherapy, and patients who tolerate highly intensive combination chemotherapy regimens are frequently cured. Most regimens were developed in children and young adults, however, and the treatment-related toxicities remain a major barrier for those with advanced age and/or comorbid conditions. Younger patients are less susceptible to acute toxicities but are more likely to experience long-term sequelae of treatment, including infertility and secondary malignancies. The infusional regimen of dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, and regular- or double-dose rituximab (DA-EPOCH-R or -RR) is less toxic than standard BL regimens, yet maintains high rates of cure across a diverse range of patients, including those with disseminated disease, advanced age, and HIV infection. Patients with low-risk BL can be cured with just 3 cycles of DA-EPOCH-RR. Still, patients with CNS involvement remain at high risk for early death, and prevention of late CNS relapses remains a priority. Future studies combining rational targeted agents with DA-EPOCH-R or -RR may further improve the cure rate.

Méndez M, Torrente M, Sánchez-Beato M, et al.
Transformed follicular lymphoma in the rituximab era: A report from the Spanish Lymphoma Oncology Group.
Hematol Oncol. 2019; 37(2):143-150 [PubMed] Related Publications
Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) subtype. The histological transformation (HT) of FL is an event considered frequent in the natural history of this tumor. We studied the transformation rates, predictive factors, and treatment characteristics that may impact in the survival of patients with FL and HT. A total of 1074 patients diagnosed with FL were prospectively enrolled from 1990 to 2016 in a Spanish registry. Sixty-four HTs were recorded based on clinical criteria (55%) or histological confirmation (45%). The cumulative incidence rate of transformation at 5 years is 7.3%. The 5-year overall survival (OS) without HT was 85% (95% confidence interval [CI], 70%-90%) vs 66% (95% CI, 51%-76%; P = 0.0012) with HT. Factors associated with HT were elevated lactate dehydrogenase (LDH) (odds ratio [OR] 1.83), intermediate-high Follicular lymphoma international prognostic index (FLIPI) (OR 2.16-OR 3.21), B symptoms (OR 2.46), or Eastern Cooperative Oncology Group (ECOG) 1 (OR 2.35). Treatment options related to HT were "watch and wait" or no rituximab or anthracyclines initially. A 5-year OS for patients treated with chemotherapy before HT was 55% (95% CI, 38%-69%) versus 81% (95% CI, 53%-93%; P = 0.009) for those who had not received it. The HT rate has decreased after the introduction of rituximab, as has been previously described. The timing of this treatment had an impact on the survival of these patients.

Belkacemi Y, Sio TT, Colson-Durand L, et al.
Primary extranodal lymphoma of the glands. Literature review and options for best practice in 2019.
Crit Rev Oncol Hematol. 2019; 135:8-19 [PubMed] Related Publications
Primary extranodal non-Hodgkin's lymphomas (EN-NHL) are a heterogeneous group of malignancies that involve numerous entities with significant difference in terms of tumor site locations, prognostic factors, biology expression, and therapeutic options. In the literature, many EN-NHL types were reported from limited series which only allowed narrow views for elucidating prognostic factors and defining the role of loco-regional therapies in the era of new systemic and biologically targeted therapies. The Rare Cancer Network (RCN), an international multidisciplinary consortium, has published a number of reports on several EN-NHL sites which included many gland locations. In this review, we will focus on the recent literature for a selected number of EN-NHL types in both exocrine and endocrine gland locations. We aim to provide renewed and clear messages for the best practice in 2019 for diagnosis, histopathology, treatments, and also their prognostic implications. We believe that better understanding of molecular and genetic characteristics of these particular diseases is crucial for an appropriate management in the era of personalized treatment developments.

Keskin AO, Tanburoglu A, Idiman E, Ozturk V
Anti-N-methyl-d-aspartate receptor encephalitis during pregnancy: A case report.
J Obstet Gynaecol Res. 2019; 45(4):935-937 [PubMed] Related Publications
Following a generalized tonic-clonic seizure, a previously healthy 27-year-old pregnant woman (18-week pregnancy) was admitted to our emergency department. She experienced lethargy, forgetfulness and persecutory hallucinations the day before hospitalization. Cerebrospinal fluid examination revealed moderate pleocytosis, and abdominal ultrasonography did not detect neoplasia. Orofacial dyskinesia, catatonia and central hypoventilation gradually developed despite medical intervention to ameliorate the symptoms. At 32 weeks of pregnancy, vaginal bleeding and hypotension occurred. Further, owing to septic shock due to fetal demise, the patient died. N-methyl-d-aspartate antibody test results obtained after the patient's death were positive (2++). Currently, no consensus exists on the appropriate treatment and follow-up for pregnant women with anti-N-methyl-d-aspartate receptor encephalitis; however, immunomodulators and teratoma resection may be helpful. Second line immunotherapy (rituximab, cyclophosphamide) and teratoma resection may be necessary in pregnant patients with high N-methyl-d-aspartate receptor antibody titers and inadequate response to first-line treatment.

Song L, Zhang W, Chen H, et al.
Apoptosis-promoting effect of rituximab-conjugated magnetic nanoprobes on malignant lymphoma cells with CD20 overexpression.
Int J Nanomedicine. 2019; 14:921-936 [PubMed] Free Access to Full Article Related Publications
Background: Cancer targeting nanoprobes with precisely designed physicochemical properties may show enhanced pharmacological targeting and therapeutic efficacy. As a widely used commercialized antibody, rituximab has been in clinical use for three decades and has lengthened or even saved thousands of lives. However, many people cannot benefit from rituximab treatment because of drug resistance or side effects.
Methods: In this study, a 13-nm rituximab-conjugated magnetic nanoparticle was developed as a therapeutic nanoprobe targeting CD20 overexpressing malignant lymphoma cells to enhance the treatment effects of rituximab. The magnetic cores (2,3-dimercaptosuccinicacid modified Fe
Results: Cell targeting experiments and magnetic resonance (MR) signal and T2 measurements showed that the Fe
Conclusion: These results indicate that Fe

Anis S, Regev K, Pittock SJ, et al.
Isolated recurrent myelitis in a persistent MOG positive patient.
Mult Scler Relat Disord. 2019; 30:163-164 [PubMed] Related Publications
MOG-Ab positive CNS demyelination typically involves the optic nerve and spinal cord. Recurrent episodes of myelitis without optic neuritis are very rare and according to current literature review represent about 3-5% of positive MOG-Ab cases. We report a 30-year-old woman with positive serum MOG-Ab suffering two discrete episodes of transverse myelitis without ophthalmic involvement. Repeated serum MOG-Ab test after the second relapse was positive, correlating with high likelihood of relapsing disease. Of note, our patient relapsed under Rituximab therapy, which does not seem to be uncommon for MOG-Ab patients. Patients with isolated or recurrent myelitis without optic involvement should be screened for anti MOG IgG as a part of their workup.

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