Methotrexate is a commonly used agent in the treatment of many malignancies and rheumatologic/inflammatory diseases. Working by inhibiting dihydrofolate reductase and thereby preventing eventual ...formation of tetrahydrofolate, methotrexate inhibits synthesis of purines and thymidylate, therefore disabling a malignant cell’s ability to replicate. While it is able to effectively do this, methotrexate also holds potential for significant toxicity. Therefore, serum methotrexate monitoring is of utmost importance when administering the drug, particularly when high doses are used. Although there are several different measurement systems, the immunoassay is a commonly used monitoring system that may be prone to interference when using agents with similar carbon backbone as methotrexate, including folinic acid (leucovorin) at high doses, as well as in the setting of glucarpidase use and consequent methotrexate breakdown. However, adjusting leucovorin dosing policy and being aware of the potential of the immunoassay to be “confused” by similar molecules have allowed for the efficient and effective use of the immunoassay while preventing prolonged hospital stays at our institution.
Patients with double-hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of ...baseline clinical factors, induction therapy, and stem cell transplant (SCT) on the outcomes of 311 patients with previously untreated DHL. At median follow-up of 23 months, the median progression-free survival (PFS) and overall survival (OS) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (P = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the upper limit of normal were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high-, intermediate-, and low-risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.
•A subset of DHL patients may be cured, and some patients may benefit from intensive induction.•Further investigations into the roles of SCT and novel agents are needed.
Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort ...analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated
, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.
Summary
Bing‐Neel syndrome (BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic lymphoma cells colonize the central nervous system. In ...this retrospective multi‐centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3‐year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological and/or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 × 109/l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi‐institutional collaboration is warranted to improve treatment and outcomes in patients with BNS.
Ibrutinib is a Bruton tyrosine kinase inhibitor that is approved by the FDA for the treatment of mantle cell lymphoma and other hematological malignancies. Bruton tyrosine kinases promote platelet ...aggregation, and, therefore, bleeding is a common side effect of ibrutinib. At least half of patients taking ibrutinib experience a bleeding event, and up to 10% may experience major bleeding. Patient-specific factors that predict bleeding events remain unknown. This report describes a case of diffuse alveolar hemorrhage in a 67-year-old male taking ibrutinib for refractory mantle cell lymphoma. He was initially admitted to the hospital for recurrence of mantle cell lymphoma and evidence of tumor lysis syndrome, including acute kidney injury and hyperuricemia. He was taking aspirin prior to being hospitalized and was thrombocytopenic. A deep vein thrombosis was noted following admission, and the patient was started on enoxaparin. Two days after starting ibrutinib as an inpatient, the patient developed diffuse alveolar hemorrhage, which was ultimately fatal. Bronchoscopy with bronchoalveolar lavage ruled out infectious and other etiologies. To our knowledge, this is the first case of diffuse alveolar hemorrhage associated with ibrutinib. Based on the available literature, it is unclear if the patient’s recent aspirin use, concurrent enoxaparin, or thrombocytopenia was contributory. Further studies are necessary to clarify these patient-specific risks.
Background
Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued ...owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy.
Materials and Methods
Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post‐CBT treatment using the Lugano criteria. Secondary aims included progression‐free survival (PFS), duration of response, and overall survival (OS).
Results
Eighty‐one patients were included. Seventy‐two percent had stage III–IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post‐CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post‐CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post‐CBT regimen.
Conclusion
In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post‐CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials.
Implications for Practice
Novel, life‐prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment‐related toxicity and thus improve patient quality of life.
This study investigated the outcome of checkpoint blockade therapy on subsequent treatment for patients with relapsed and refractory Hodgkin lymphoma in a large, multicenter, retrospective analysis.
Intravascular large B-cell lymphoma (IVLBCL) is a subtype of diffuse large B-cell lymphoma, where the neoplastic lymphoid proliferation resides predominantly within the lumens of blood vessels but ...with no or few circulating neoplastic cells in the peripheral circulation. Focal or subtle involvement in some cases can cause the diagnosis to be misinterpreted or even overlooked, delaying the initiation of appropriate treatment. Our report focuses on a 78-year-old woman with a progressively enlarging thyroid mass, verified by ultrasound. She underwent a hemithyroidectomy, and microscopic evaluation demonstrated nodular thyroid parenchyma with atypical large cells in an intravascular distribution pattern identified on high magnification. Thorough evaluation showed that the large intravascular cells were positive CD20, PAX-5, and Ki-67 by immunoperoxidase staining, which lead to the diagnosis of IVLBCL. This case emphasizes the subtle appearance of IVLBCL, which may be missed on low-power light microscopy, and the need for careful evaluation of thyroid resection specimens.
Bendamustine and rituximab (BR) has been established as a superior frontline therapy over R-CHOP in the treatment of follicular lymphoma (FL). Yttrium-90 Ibritumomab tiuxetan (
YIT) is an effective ...consolidation strategy after chemotherapy induction. This prospective, single-arm, multicenter, phase II trial evaluated the response rate, progression-free survival (PFS), and tolerability of BR followed by consolidation with
YIT in patients with untreated FL.
The study included grade 1 to 3a FL patients aged ≥18 years, chemotherapy-naïve, and requiring treatment for stage II-IV disease. Study treatment included an initial rituximab treatment, followed by four cycles of BR. Patients were eligible for consolidation with
YIT, 6 to 12 weeks after BR, if they obtained at least a partial response after induction had adequate count recovery and bone marrow infiltration < 25%.
Thirty-nine patients were treated. Eighty-two percent had an intermediate or high-risk Follicular Lymphoma International Prognostic Index score, and 6 of 39 (15%) were grade 3a. The response rate was 94.8%, and the complete response(CR)/CR unconfirmed (CRu) rate was 77% in the intention-to-treat analysis. The conversion rate from PR to CR/Cru after
YIT was 81%. After median follow-up of 45 months, the PFS was 0.71 (95% confidence interval, 0.57-0.89).
This report demonstrates that four cycles of BR followed by consolidation with
YIT achieve high response rates that are durable. In addition, consolidation with
YIT results in a high conversion rate of PR to CR/CRu. A short course of BR followed by
YIT is a safe and effective regimen for frontline treatment of FL.
Follicular lymphoma (FL) patients treated with firstline R‐CHOP who experience progression of disease (POD) within 2 years have a shorter survival than those who do not have POD within 2 years. ...Whether this observation holds for patients treated initially with biologic immunotherapy alone is unknown. We performed a retrospective analysis of 174 patients pooled from three frontline rituximab (R)‐based nonchemotherapy doublet trials: R‐galiximab (Anti‐CD80, CALGB 50402), R‐epratuzumab (Anti‐CD22, CALGB 50701), and R‐lenalidomide (CALGB 50803) to determine outcomes of early progressors and risk factors for early POD, defined as progression within 24 months from study entry. Twenty‐eight percent (48/174) of patients had early POD. After adjusting for the Follicular Lymphoma International Prognostic Index (FLIPI), patients with early POD from study entry had a worse OS compared with patients who did not progress within 2 years (HR = 4.33 (95% CI 1.50‐12.5), P = 0.007). For early POD, the 2‐year survival was 80% vs 99% for nonearly POD, and the 5‐year survival was 74% vs 90%, respectively. These findings suggest that the adverse survival of patients with early POD may be independent of initial treatment modality.
In this combined analysis of three CALGB clinical trials, patients with early progression of follicular lymphoma following frontline immunotherapy doublets are at increased risk of death. PFS24 is a prognostic marker for overall survival in patients treated with rituximab‐containing immunotherapy.
Metabolic dysfunctions enabling increased nucleotide biosynthesis are necessary for supporting malignant proliferation. Our investigations indicate that upregulation of fatty acid synthase (FASN) and ...de novo lipogenesis, commonly observed in many cancers, are associated with nucleotide metabolic dysfunction in lymphoma. The results from our experiments showed that ribonucleotide and deoxyribonucleotide pool depletion, suppression of global RNA/DNA synthesis, and cell cycle inhibition occurred in the presence of FASN inhibition. Subsequently, we observed that FASN inhibition caused metabolic blockade in the rate-limiting step of the oxidative branch of the pentose phosphate pathway (oxPPP) catalyzed by phosphogluconate dehydrogenase (PGDH). Furthermore, we determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. Through cell-free enzyme assays consisting of FASN and PGDH, we delineated that the PGDH-catalyzed ribulose-5-phosphate synthesis is enhanced in the presence of FASN and is suppressed by increasing concentrations of NADPH. Additionally, we observed that FASN and PGDH were colocalized in the cytosol. The results from these experiments led us to conclude that NADP–NADPH turnover and the reciprocal stimulation of FASN and PGDH catalysis are involved in promoting oxPPP and nucleotide biosynthesis in lymphoma. Finally, a transcriptomic analysis of non-Hodgkin’s lymphoma (n = 624) revealed the increased expression of genes associated with metabolic functions interlinked with oxPPP, while the expression of genes participating in oxPPP remained unaltered. Together we conclude that FASN–PGDH enzymatic interactions are involved in enabling oxPPP and nucleotide metabolic dysfunction in lymphoma tumors.
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