scholarly journals Bendamustine-Rituximab (BR) Combination in Low Grade B-Cell Lymphoproliferative Disorders (LPD): A Community Oncology Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5454-5454
Author(s):  
Aarish Shahab ◽  
Janet Chin ◽  
Saadia Yunus
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Treatment Delays ◽  
Community Oncology ◽  
Number Of Patients ◽  
Duration Of Response ◽  
Dose Modifications

Abstract Introduction: Low-grade B-Cell LPDs are indolent Non-Hodgkin’s Lymphoma (NHL) that are incurable with current therapeutic options. BR chemoimmunotherapy has demonstrated remarkable effectiveness in these patients. Here we report our experience with BR in low-grade B Cell LPD subtypes. Method: Between October 2011 and May 2014, we treated 25 patients with a diagnosis of low-grade B-Cell LPD with a planned BR regimen of 6 cycles. The median age was 64 years (range 41-91), 15/10 M/F – a ratio of 3:2. LPD subtype included Chronic Lymphocytic Leukemia (CLL) 5, Small Lymphocytic Lymphoma (SLL) 3, Follicular Lymphoma (FL) 6, Marginal Zone Lymphoma (MZL) 2, Mantle Cell Lymphoma (MCL) 2, Mucosa-associated Lymphoid Tissue (MALT) 3, and Lymphoplasmacytic Lymphoma (LPL) 4. Twenty two (88%) were stages III or IV. Ten had received prior treatments. 15 had BR as first treatment. The regimen consisted of Bendamustine (B) 90 mg/m2 (on days 1&2 and Rituximab (R) 375 mg/m2 on day1 given every 28 days. Results: Seventeen (68%) completed the entire 6 planned cycles. 14 (56%) required treatment delays due to various toxicities. In 5 (20%) chemo was discontinued early for toxicity. The most common non-hematologic toxicity was fatigue 11 (44%), and skin rash 5 (20%). The grade III/IV hematologic toxicity was as follows neutropenia (3) anemia (9) and thrombocytopenia (2). The overall response rate (ORR) was 92% (23 pts) with 18 (72%) Partial Responses (PR), and 5 (20%) Complete Responses (CR). Twenty four (96%) continued to have remission with no progression noted during follow-up. One patient with 17p del CLL progressed after 3 months with Richters transformation to diffuse large B cell NHL. The median duration of response was 17 months, with a range from 2 months – 38 months. Conclusion: In all LPD subtypes, despite the observed toxicities requiring treatment delays and dose modifications, 96% patients attained significantly long lasting remissions. Although this review included a comparatively small number of patients, our experience shows that BR is a highly effective chemo immunotherapy in all subtypes of Low-Grade B-Cell LPD – suggestive of altering the natural biology of this disease. For more definitive results, the study should be inclusive of a larger number of patients and prolonged follow-ups. Disclosures No relevant conflicts of interest to declare.

Abbreviated, Dose Dense Fludarabine and Rituximab for Elderly Patients with Indolent B Cell Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4796-4796
Author(s):  
Gabriela Ballester ◽  
Lisa Frazer ◽  
Maria Tirona ◽  
Oscar F Ballester
Keyword(s):  
B Cell ◽  
Drug Exposure ◽  
Conflicts Of Interest ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Number Of Patients ◽  
Histological Transformation ◽  
Dose Dense

Abstract Abstract 4796 Introduction Therapy for indolent B cell malignancies is primarily palliative. Therefore limiting toxicities by reducing drug exposure is desirable, particularly in elderly individuals. The combination of fludarabine and rituximab has been extensively used in patients with these disorders. We sought to decrease the number of fludarabine cycles, attempting to maintain the high response rates of this combination by increasing the doses of rituximab and the dose density. Patients and Methods We designed an abbreviated, but dose dense regimen (addFR) consisting of fludarabine 25 mg/m2/d for 5 days on weeks 1, 6 and 11 plus rituximab at 375mg/m2 on weeks 2-5 and 7-10. Maintenance was offered to responding patients with rituximab for 4 weekly doses every 6 months (for 2 years). This schema represents a 50% decrease in the dosage on fludarabine with a 33% increase in the dosage of rituximab compared to the standard regimen. Twelve patients with a median age of 70 years, (range 43 to 85, 9 of the 12 patient are older than 65 years of age) have been treated. Nine patients had chronic lymphocytic leukemia (CLL, n= 5) or small lymphocytic lymphoma (SLL, n= 4). Three patients had marginal zone lymphoma (MZL). Three patients had received prior therapy. Responses were assessed by standard criteria 4 weeks after completion of the planned 11 weeks of therapy. Results Two patients are still completing their 11 weeks of therapy. Ten patients have completed the 11 weeks of addFR. They are evaluable for toxicity and responses. Hematological toxicities included neutropenia Grade >III in 2 patients with a single episode of neutropenic fevers requiring hospitalization. One patient with refractory disease was shown to have histological transformation from SLL to a diffuse large B cell lymphoma. All of the remaining 9 patients achieved a complete clinical remission, including 8 patients with CLL/SLL and 1 patient with MZL. With a median follow up of 13 months (range 10 to 23 months); these 9 patients have remained free of disease progression. Conclusions addFR seems to be well tolerated and effective even in patients older than 65 years of age. Experience with a larger number of patients and longer follow up is needed. Disclosures: No relevant conflicts of interest to declare.

The Composition of the B Cell Receptor Repertoire In 7428 Cases of Chronic Lymphocytic Leukemia: One Third Stereotyped, Two Thirds Heterogeneous - What Does This Mean?

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 43-43 ◽  
Author(s):  
Andreas Agathaggelidis ◽  
Nikos Darzentas ◽  
Anastasia Hadzidimitriou ◽  
Xavier Brochet ◽  
Fiona Murray ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Critical Mass ◽  
Relative Size ◽  
Ground Level ◽  
Lymphocytic Leukemia ◽  
Cluster Assignment ◽  
Number Of Patients

Abstract Abstract 43 Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets (clusters) of cases with restricted, “stereotyped” immunoglobulin (IG) variable heavy complementarity-determining region 3 (VH CDR3) sequences within their B cell receptors (BcR), suggesting selection by common epitopes or classes of structurally similar epitopes. Emerging evidence indicates that the grouping of CLL cases into distinct clusters with “stereotyped” BcR is functionally and prognostically relevant. Further than that, several issues remain open: (i) the refinement of criteria for identification of BcR stereotypy and cluster assignment; (ii) the true frequency of BcR stereotypy; (iii) the total number of clusters and relative size of each; and, (iv) the identification of “CLL-biased” features in BcR stereotypes. To address these issues, we systematically examined VH CDR3 stereotypy in 7596 IGHV-D-J sequences from 7428 patients with CLL (168 cases, 2.2%, with two productive sequences), three times the size of the largest published series. Recent studies in both normal B cells and other (non-CLL) B cell malignancies along with accumulated experience in our group led to an advanced clustering bioinformatics algorithm applying more stringent criteria than before. A novel parameter was also included; the usage of IGHV genes, which takes into account the role of the germline-encoded specificities in (super)antigen recognition. The algorithm assigns sequences in a cluster only if exhibiting >50% amino acid identity and >70% amino acid VH CDR3 similarity and also carrying IGHV genes that share common ancestry and, thus, belong to the same IGHV phylogenetic clan. To increase the likelihood that cluster assignment reflects actual structural relatedness, we also required that each cluster consisted only of sequences with identical VH CDR3 length and identical offsets of common patterns. Following this new approach, 2308/7596 (30.4%) CLL sequences were assigned to 952 different ground-level clusters with shared patterns and unique characteristics, each containing 2 to 56 cases. Different types of VH CDR3 patterns were identified, independent of mutational status, as “mainly germline”, i.e. deriving from restricted associations of specific IGHD and IGHJ genes, and “junctional+germline”, i.e. extending over V-D and/or D-J junctions as well. In several clusters of mutated sequences, the cluster-defining features were ubiquitous junctional residues. Common sequences among ground-level clusters enabled grouping into clearly delineated, higher-order (HO) clusters that were considerably larger in size and displayed ‘CLL-biased’ features with regard to: IGHV gene usage, somatic hypermutation (for clusters with mutated sequences) and VH CDR3 pattern composition. As an example, the largest HO cluster, including 213 sequences (2.8% of the cohort), utilized the IGHV3-21 gene with an acidic residue at VH CDR3 position 107 (3 of 9), while the second-ranking HO cluster, including 184 sequences (2.1% of the cohort), utilized different IGHV genes of Clan I (e.g. IGHV1-2, 1–3, 1–8, 1–18, 5-a, 7-4-1) with a QWL motif at VH CDR3 positions 108–110 (4-6 of 13). Based on random set simulations (using the actual sequences) and starting from a critical mass of 2000 cases, each increase of the total set by a 1000 random cases resulted in an increase in the percentage of stereotypy to ∼2% (i.e. from 21% in 2000 cases to 25% in 3000 cases to 30% in 7000), though not proportional to the increase of the cohort. Perhaps most important, however, was the finding that the percentage of sequences in known major clusters was remarkably stable compared to previous studies on smaller series. These results strongly indicate that not all CLL belong to stereotyped subsets even if the cohort size is increased significantly, corroborating our previous hypothesis that CLL consists of two distinct categories, one with stereotyped and the other with heterogeneous BcR, likely of different ontogenetic origin. Furthermore, they demonstrate that the major clusters collectively represent a sizeable proportion of the cohort. Consequently, this deeper, more robust, compartmentalized examination of BcR structures in association with other biological and clinical information may eventually pave the way for the introduction of specialized treatment protocols applicable to a significant number of patients assigned to the same cluster. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD180 Expression in B-Cell Lymphomas: A Multicenter Geil Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1628-1628
Author(s):  
Caroline Mayeur-Rousse ◽  
Julien Guy ◽  
Laurent Miguet ◽  
Sabrina Bouyer ◽  
Franck Genevieve ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
University Hospital ◽  
Routine Practice ◽  
Similar Data ◽  
B Cell Lymphomas ◽  
Whitney Test ◽  
Mann Whitney Test

Abstract CD180 is a Toll-Like Receptor homolog strongly expressed on normal human B-cells and involved in innate immune responses. Previous proteomic analyses on microparticles derived from mature B-cell neoplasms allowed us to identify CD180 as a marker of marginal zone lymphomas (MZL)(Miguet, Leukemia, 2013). Using flow cytometry on blood samples we showed that this protein is lost or underexpressed at the plasma membrane for almost all B-cell lymphomas except MZL. In order to confirm its clinical relevance, we conducted a prospective multicenter flow cytometry study in 5 French University Hospital laboratories, on behalf of the GEIL. Blood or bone marrow samples from 236 patients were studied (20 normal controls ; 74 chronic lymphocytic leukemia (CLL); 21 mantle cell lymphoma (MCL); 42 lymphoplasmacytic lymphoma (LPL); 13 follicular lymphoma (FL) ; 58 MZL, 14 of which with numerous villous lymphocytes; 8 hairy cell leukemia (HCL)). Analyses were performed either on FACSCanto II (BD Biosciences, 3 centers) or on Navios (Beckman Coulter, 2 centers) instruments. Harmonization process was performed using Rainbow beads (Spherotech). For the CLL group, CD180 Median fluorescence (MdFI) in each center was not significantly different (Anova test, p>0.05). Instruments’ harmonization was therefore effective enough to obtain similar data from all centres. In the whole cohort, CD180 was significantly less expressed in the group of lymphomas -including CLL, MCL, LPL and FL- than in controls (Mann-Whitney test, p<0.05). Conversely, in the group of MZL and HCL, CD180 MdFI was not different from those of controls (Mann-Whitney test, p>0.05) but significantly higher than in CLL, MCL, LPL and FL (Mann-Whitney test, p<0.0001). Distinction between MZL and lymphomas with numerous villous lymphocytes was possible (Mann-Whitney test, p=0.0012) but not between MZL and HCL. ROC curve analysis determined a CD180 MdFI threshold of 1800 which allow the positive diagnosis of MZL with a sensitivity of 77% and specificity of 92%. These results underline the efficiency of CD180 as a single positive and robust marker for MZL diagnosis, and confirm that between centers and between instruments harmonization is largely feasible in routine practice as published recently (Solly F et al. Cytomery part A, 2013). It should be emphasized that among the group of lymphomas with intense expression of CD180, all interestingly originating from the spleen, those with numerous villous lymphocytes display the highest expression. We described for the first time in this study the strong positivity of CD180 in HCL. Anti-CD180 antibody may be included in diagnosis combination markers in order to improve the diagnosis of chronic B-cell malignancies Disclosures No relevant conflicts of interest to declare.

scholarly journals Anlotinib Shows Potent Antileukemia Effects in B-Cell Acute Lymphocytic Leukemia through the Blockage of Angiogenic Related Pathways

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 49-49
Author(s):  
Qiuling Chen ◽  
Yuelong Jiang ◽  
Qinwei Chen ◽  
Long Liu ◽  
Bing Xu
Keyword(s):  
B Cell ◽  
Solid Tumors ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Unmet Need ◽  
Lymphocytic Leukemia ◽  
Advanced Lung Cancer ◽  
Antitumor Effects

Acute lymphoblastic leukemia (ALL) derives from the malignant transformation of lymphoid progenitor cells with ~85% being originated from B-cell progenitors (B-ALL). Despite fairly good prognoses for most pediatric B-ALL patients, the outcome is fatal in over 50% of adult patients who have a recurrent or progressive disease and lack of effective therapeutic approaches. Therefore, novel treatment strategies with high efficacy and low toxicity are an unmet need for B-ALL patients, especially those with relapsed or refractory status. Angiogenesis is a process of new vessel formation that requires the participation of multiple proangiogenic factors (e.g., VEGF, PDGF, and FGF) and their corresponding receptors (e.g., VEGFR, PDGFR, and FGFR). Angiogenesis, a well-established feature of solid tumors, also contributes to leukemia progression and correlates with the involvement of specific sanctuary sites in ALL, highlighting that the perturbation of angiogenesis would be an attractive approach for ALL treatment. Anlotinib is an oral tyrosine kinase (TKI) inhibitor with a broad range of antitumor effects via the suppression of VEGFR, PDGFR and FGFR. Of importance, anlotinib has been approved for the treatment of advanced lung cancer in China. Here, we evaluated the antileukemia activity of anlotinib in preclinical B-ALL models and its underlying molecular mechanisms. In this study, we observed that anlotinib significantly blunted the capability of cell proliferation and arrested cell cycle at G2 phase in B-ALL cell lines. Subsequently, we found that anlotinib resulted in remarkably enhanced apoptosis in B-ALL in vitro. To assess the in vivo antileukemia potential, we established a B-ALL patient-derived xenograft (PDX) mouse model and then treated the B-ALL PDX model with anlotinib. As a result, oral administration of anlotinib pronouncedly delayed in vivo B-ALL cell growth and reduced leukemia burden with acceptable safety profiles in this model. As for the mechanism of action, the antileukemia effect of anlotinib was associated with the disruption of the role of VEGFR2, PDGFRb, and FGFR3. Moreover, we revealed that this drug blocked the PI3K/AKT/mTOR/ signaling, a pathway that is linked with angiogenesis and its proangiogenic regulators, including VEGFR2, PDGFRb, and FGFR3. In aggregate, these results indicate that anlotinib is a potent antitumor agent for the treatment of B-ALL via the inhibition of angiogenic relevant pathways, which provide a novel potential treatment intervention for patients with B-ALL who have little effective therapy options. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Anlotinib originally designed by China is a novel orally active multitarget inhibitor that is evaluating in clinical trials against multiple solid tumors.

IVAC +/- R for Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas: Real-World Experience in the Modern Era

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Michael J Buege ◽  
Phuong H Dao ◽  
Esther Drill ◽  
Andréa C LeVoir ◽  
Terry Pak ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Advisory Committees ◽  
Prophylactic Measures ◽  
Grade 3

Introduction Part B of the modified Magrath regimen (ifosfamide, etoposide, and cytarabine; IVAC) with or without rituximab (R) is utilized as a standalone regimen in the management of relapsed/refractory Burkitt lymphoma and other non-Hodgkin lymphomas (NHL). There are no comparative or prospective data and a paucity of retrospective, non-comparative data to support use of this regimen. A small retrospective study described second-line IVAC use without R in a mixed cohort of patients with diffuse large B-cell lymphoma (DLBCL) or peripheral T-cell lymphoma, suggesting utility as a bridge to hematopoietic cell transplantation (HCT) (Pereira J, et al. Leuk Res. 2006 Jun;30(6):681-5). The activity of this regimen in B-cell NHL, particularly in conjunction with R, and its toxicity remain incompletely described. In this study, we describe our institutional experience with IVAC +/- R in relapsed/refractory B-cell NHL. Methods We reviewed all patients with relapsed/refractory B-cell NHL treated with IVAC +/- R between 1 January 2004 and 30 September 2019 at Memorial Sloan Kettering Cancer Center to assess efficacy and toxicity. Patients who received IVAC as part of sequential or alternating chemotherapy were excluded. Standard dosing consisted of ifosfamide 1500mg/m2 IV over 60min days 1-5, etoposide 60mg/m2 IV over 60min days 1-5, cytarabine 2000mg/m2 IV over 3 hours every 12 hours days 1-2, with or without rituximab 375mg/m2 IV day 0 or 1 in 21- to 28-day cycles (Lacasce A, et al. Leuk Lymphoma. 2004 Apr;45(4):761-7). Results Cohort and treatment characteristics are described in Table 1. Among 54 eligible patients (median age 51 years), 76% had DLBCL; 30% had lymphomatous central nervous system involvement at the time of initiating IVAC. Patients had received median 2 prior lines of therapy, with the last dose of the most recent line of therapy administered a median of 3 weeks prior to initiating IVAC. Patients received median 2 cycles of IVAC +/- R; 48% received IVAC-R. Prophylactic antimicrobials with cycle 1 were utilized in 94%. Most patients received herpesvirus- (81%) and Pneumocystis- (80%) directed prophylaxis; broad-spectrum prophylaxis with a fluoroquinolone was less common (24%). Primary granulocyte colony stimulating factor (GCSF) was utilized in 93% of patients with cycle 1; primary or secondary GCSF was utilized in 94% of cycles. Efficacy outcomes are described in Table 1. Objective response rate (ORR) among 46 evaluated patients was 48%; 17% achieved CR. ORR did not vary significantly between patients who did or did not receive R (58% vs 42%; p = 0.5) but was associated with number of IVAC cycles administered (among responders, 69% received 3-4 cycles while 31% received 1-2 cycles; p &lt; 0.001). At median follow-up of 22 months, median progression-free survival (PFS) and overall survival (OS) were 3.1 months and 4.9 months, respectively (Figure). In Cox proportional hazard regression analysis of survival, patients who received R with every cycle (p = 0.025) and received 3 or more cycles (p &lt; 0.001) experienced significantly longer PFS. Patients who achieved CR (p &lt; 0.001) or PR (p = 0.003), received R with every cycle (p &lt; 0.001), received 3 or more cycles (p &lt; 0.001), or underwent subsequent HCT or CAR-T cell therapy (p = 0.001) experienced significantly longer OS. Toxicity outcomes are described in Table 2. Grade ≥ 3 anemia (93%), neutropenia (94%), and thrombocytopenia (100%; all grade 4) were common, regardless of number of cycles received. Febrile neutropenia (FN) occurred in 65% of patients and complicated 47% of cycles; documented infection occurred in 44%. Risk of FN and infection did not appear to be influenced by use of antimicrobial or GCSF prophylaxis. Grade ≥ 3 elevations in AST/ALT or total bilirubin were uncommon (5.6% and 9.3%, respectively). Neurotoxicity attributed to cytarabine or ifosfamide occurred in 17% of patients and was usually low-grade; hemorrhagic cystitis occurred in one patient. In patients for whom cause of death was documented (n = 37), mortality was attributed to a treatment-related complication in 19%. Conclusion IVAC-R may be a useful bridging therapy for patients with relapsed/refractory B-cell NHL who are planned for HCT. However, its potential for profound hematologic toxicity and life-threatening complications despite prophylactic measures requires careful consideration of less toxic alternatives. Disclosures Straus: Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Speakers Bureau; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals P54 Pneumocystis jirovecii prophylaxis in patients on rituximab

Rheumatology ◽  
2019 ◽  
Vol 58 (Supplement_4) ◽  
Author(s):  
Kishore Warrier1 ◽  
Catherine Salvesani ◽  
Samundeeswari Deepak
Keyword(s):  
Risk Factors ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Pneumocystis Jirovecii ◽  
Current Evidence ◽  
Pneumocystis Jirovecii Pneumonia ◽  
Number Of Patients ◽  
Increased Risk

Abstract Background Rituximab is a chimeric monoclonal antibody that depletes the B cell population by targeting cells bearing the CD20 surface marker and is used widely in the management of paediatric rheumatological conditions like juvenile systemic lupus erythematosus (JSLE), juvenile dermatomyositis (JDM), mixed connective tissue disease (MCTD) and juvenile idiopathic arthritis (JIA). Pneumocystis jirovecii pneumonia (PCP) is a potentially fatal opportunistic infection associated with congenital and acquired defects in T cell–mediated immunity. Our guideline did not recommend prophylaxis against PCP for patients on rituximab, unlike patients on cyclophosphamide, who are on cotrimoxazole until three months after cessation of the treatment. Cyclophosphamide is an alkylating agent which affects both B and T lymphocytes. Following the death of 16 year-old girl with JSLE due to PCP, the team reviewed the possible contributing factors, undertook a review of literature and discussed this at multi-disciplinary meetings involving the microbiology and immunology teams. This patient was found to have other risk factors for PCP – low CD4 T cells, concomitant use of corticosteroids and hypogammaglobulinaemia (IgG 3.0g/L). Although there is limited evidence that rituximab on its own increases the risk of PCP, there is emerging data that B cells may have a role in the protection against pneumocystis. Following the review, it was concluded that children on rituximab and an additional immunosuppressant (including corticosteroids) should receive prophylactic cotrimoxazole to cover PCP. Methods Retrospective audit carried out by the team to look at adherence to the new guideline regarding the use of cotrimoxazole for PCP prophylaxis in patients who have had rituximab between August 2017 and May 2019. Results P54 Table 1 Total number of patients who had rituximab 10 Number of patients who had other immunosuppressants concomitantly / recently (within previous 3 months) 7 Number of patients on rituximab monotherapy 2 Number of patients who are 6 months post-treatment 1 Number of patients with other risk factors for PCP 1 (hypogammaglobulinaemia) Number of patients who are eligible for prophylaxis, as per the guideline 8 (7 for concomitant immunosuppression and 1 for hypogammaglobulinaemia) Number of patients on cotrimoxazole 7 (87.5%) - one of the patients is on methotrexate, which is advised not to combine with cotrimoxazole We achieved 87.5% compliance in prescribing cotrimoxazole for PCP prophylaxis to all rheumatology patients receiving rituximab alongside another immunosuppressant agent; the one patient who this was not adhered to was due to potential adverse drug pharmacodynamic interaction between cotrimoxazole and methotrexate. Conclusion Although the current evidence points to increased risk of PCP in patients with inherited and iatrogenic defect of T cell function, there is emerging evidence that B cells may have a role too. Hence more work is required to determine the risk of PCP in patients on B cell targeted therapy (BCTT) and the need for prophylaxis. Conflicts of Interest The authors declare no conflicts of interest.

Cytokine-Release Syndrome in Patients With B-Cell Chronic Lymphocytic Leukemia and High Lymphocyte Counts After Treatment With an Anti-CD20 Monoclonal Antibody (Rituximab, IDEC-C2B8)

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2217-2224 ◽  
Author(s):  
U. Winkler ◽  
M. Jensen ◽  
O. Manzke ◽  
H. Schulz ◽  
V. Diehl ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Tumor Cells ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Anti Cd20 ◽  
Cell Chronic Lymphocytic Leukemia

Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin’s lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 × 109/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 × 109/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor- (TNF-) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin time. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 × 109/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 × 109/L peripheral tumor cells (P= .0017). Due to massive side effects in the first patient treated with 375 mg/m2 in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m2 dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 × 375 mg/m2 rituximab, efficacy in patients with relapsed fludarabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease, and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.

Pharmacokinetic Study of Single Doses of Oral Fludarabine Phosphate in Patients With “Low-Grade” Non-Hodgkin's Lymphoma and B-Cell Chronic Lymphocytic Leukemia

1999 ◽  
Vol 17 (5) ◽  
pp. 1574-1574 ◽  
Author(s):  
James M. Foran ◽  
David Oscier ◽  
Jennifer Orchard ◽  
Stephen A. Johnson ◽  
Mary Tighe ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Intravenous Administration ◽  
Pharmacokinetic Study ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Low Grade ◽  
Fludarabine Phosphate ◽  
Non Hodgkin's Lymphoma ◽  
Cell Chronic Lymphocytic Leukemia

PURPOSE: Fludarabine phosphate (F-AMP), a purine analog, requires daily intravenous administration. A pharmacokinetic study of an oral formulation (10 mg immediate-release tablet) was undertaken in patients with “low-grade” non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia. PATIENTS AND METHODS: Oral F-AMP was incorporated into the “conventional” treatment schedule. Single oral trial doses of 50, 70, and 90 mg of F-AMP were given on the first day of three cycles of treatment; a comparative 50-mg intravenous trial dose was given on the first day of the fourth cycle. Intravenous F-AMP (25 mg/m2) was given on days 2 to 5 at 4-week intervals. Pharmacokinetic samples taken after each trial dose were analyzed for plasma 2-fluoro-arabinofuranosyl-adenine (2F-ara-A) concentration (its main metabolite); area under the curve 0 to 24 hours (AUC(0-24h)) and maximum concentration (Cmax) were calculated. Eighteen patients received all three oral trial doses, and bioavailability was determined in 15 patients who completed four courses of therapy. RESULTS: Oral administration of F-AMP resulted in a dose-dependent increase in Cmax and AUC(0-24h) of 2F-ara-A and achieved an AUC(0-24h) similar to intravenous administration, although at a lower Cmax. The linear increase in mean AUC(0-24h) by factors of 1.36 ± 0.22 (mean ± SD) and 1.72 ± 0.31 corresponded well with the increase in oral dose from 50 to 70 mg (factor of 1.4) and 90 mg (factor of 1.8), respectively. Bioavailability (approximately 55%, with low intraindividual variation) and time to Cmax were dose independent. CONCLUSION: Oral doses of F-AMP can achieve an AUC(0-24h) of 2F-ara-A similar to intravenous administration, with dose-independent bioavailability. The tablet will greatly enhance the use of F-AMP in a palliative setting.

scholarly journals Radioimmunotherapy with iodine 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1259-1266 ◽  
Author(s):  
Mark S. Kaminski ◽  
Judith Estes ◽  
Kenneth R. Zasadny ◽  
Isaac R. Francis ◽  
Charles W. Ross ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
De Novo ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Cell Transplant ◽  
Non Hodgkin Lymphoma ◽  
Therapeutic Doses ◽  
131I Tositumomab

Abstract CD20-targeted radioimmunotherapy is a promising new treatment for B-cell non-Hodgkin lymphoma (NHL). We now provide updated and long-term data on 59 chemotherapy-relapsed/refractory patients treated with iodine 131I tositumomab in a phase I/II single-center study. Fifty-three patients received individualized therapeutic doses, delivering a specified total-body radiation dose (TBD) based on the clearance rate of a preceding dosimetric dose. Six patients received dosimetric doses only. Dose-escalations of TBD were conducted separately in patients who had or had not undergone a prior autologous stem cell transplant (ASCT) until a nonmyeloablative maximally tolerated TBD was established (non-ASCT = 75 cGy, post-ASCT = 45 cGy). Fourteen additional non-ASCT patients were treated with 75 cGy. Unlabeled antibody was given prior to labeled dosimetric and therapeutic doses to improve biodistribution. Forty-two (71%) of 59 patients responded; 20 (34%) had complete responses (CR). Thirty-five (83%) of 42 with low-grade or transformed NHL responded versus 7 (41%) of 17 with de novo intermediate-grade NHL (P = .005). For all 42 responders, the median progression-free survival was 12 months, 20.3 for those with CR. Seven patients remain in CR 3 to 5.7 years. Sixteen patients were re-treated after progression; 9 responded and 5 had a CR. Reversible hematologic toxicity was dose limiting. Only 10 patients (17%) had human anti-mouse antibodies detected. Long-term, 5 patients developed elevated thyroid-stimulating hormone levels, 5 were diagnosed with myelodysplasia and 3 with solid tumors. A single, well-tolerated treatment with iodine 131I tositumomab can, therefore, produce frequent and durable responses in NHL, especially low-grade or transformed NHL.

Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma.

1996 ◽  
Vol 14 (7) ◽  
pp. 1974-1981 ◽  
Author(s):  
M S Kaminski ◽  
K R Zasadny ◽  
I R Francis ◽  
M C Fenner ◽  
C W Ross ◽  
...  
Keyword(s):  
Complete Remission ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Rate ◽  
Whole Body ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Tracer Dose ◽  
Iodine 131

PURPOSE The CD20 B-lymphocyte surface antigen expressed by B-cell lymphomas is an attractive target for radioimmunotherapy, treatment using radiolabeled antibodies. We conducted a phase I dose-escalation trial to assess the toxicity, tumor targeting, and efficacy of nonmyeloablative doses of an anti-CD20 monoclonal antibody (anti-B1) labeled with iodine-131 (131I) in 34 patients with B-cell lymphoma who had failed chemotherapy. PATIENTS AND METHODS Patients were first given tracelabeled doses of 131I-labeled anti-B1 (15 to 20 mg, 5 mCi) to assess radiolabeled antibody biodistribution, and then a radioimmunotherapeutic dose (15 to 20 mg) labeled with a quantity of 131I that would deliver a specified centigray dose of whole-body radiation predicted by the tracer dose. Whole-body radiation doses were escalated from 25 to 85 cGy in sequential groups of patients in 10-cGy increments. To evaluate if radiolabeled antibody biodistribution could be optimized, initial patients were given one or two additional tracer doses on successive weeks, each dose preceded by an infusion of 135 mg of unlabeled anti-B1 one week and 685 mg the next. The unlabeled antibody dose resulting in the most optimal tracer biodistribution was also given before the radioimmunotherapeutic dose. Later patients were given a single tracer dose and radioimmunotherapeutic dose preceded by infusion of 685 mg of unlabeled anti-B1. RESULTS Treatment was well tolerated. Hematologic toxicity was dose-limiting, and 75 cGy was established as the maximally tolerated whole-body radiation dose. Twenty-eight patients received radioimmunotherapeutic doses of 34 to 161 mCi, resulting in complete remission in 14 patients and a partial response in eight. All 13 patients with low-grade lymphoma responded, and 10 achieved a complete remission. Six of eight patients with transformed lymphoma responded. Thirteen of 19 patients whose disease was resistant to their last course of chemotherapy and all patients with chemotherapy-sensitive disease responded. The median duration of complete remission exceeds 16.5 months. Six patients remain in complete remission 16 to 31 months after treatment. CONCLUSION Nonmyeloablative radioimmunotherapy with 131I-anti-B1 is associated with a high rate of durable remissions in patients with B-cell lymphoma refractory to chemotherapy.

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