Background: Acute Lymphoblastic Leukemia (ALL) outcomes have significantly improved over time with multi-agent chemotherapy, and the addition of asparaginase (ASP) has demonstrated the ability to ...prolong overall survival. ASP has multiple toxicities, and it remains a challenge to manage them safely, particularly coagulopathy and thrombosis (30-40% based on historical studies). The best prophylactic anticoagulation strategy in patients with acute leukemias, particularly ALL with asparaginase use, remains unclear due to severe coexisting thrombocytopenia and coagulopathy. Though the current guidelines recommend using Antithrombin (AT) replacement or low molecular weight heparin (LMWH) for thrombosis prophylaxis, the evidence is weak with concerns of thrombosis (Blood (2020) 136 (3): 328-338) with the use of fibrinogen concentrates(cryoprecipitate) and limited efficacy data with AT replacement and unfractionated heparin (UFH) for thrombosis prophylaxis. Due to potential “resistance” to LMWH and UFH from acquired AT deficiency with ASP use, our institution in 2017 has adopted the use of the direct Xa inhibitor, Apixaban for thrombosis prophyalxis. We report the safety and effectiveness of Apixaban for thrombosis prophylaxis with ASP.
Methods: In this retrospective study, we reviewed the data on 20 patients treated with ASP between 2017-2020. Thrombosis prophylaxis was instituted with Apixaban 2.5 mg PO Q 12 hourly for three weeks along with cryoprecipitate as needed for bleeding or fibrinogen levels <100 mg/dL (normal 160-450 mg/dL) to balance the risk of bleeding. Apixaban was held if platelet count <20,000/µL and for invasive procedures or clinically significant bleeding events. We evaluated demographic data, ALL risk category, type of ASP use, laboratory data (Table 1 & 2) for four weeks following ASP, amount of cryoprecipitate used, major bleeding, clinically relevant non-major bleeding (CRNMB), and thrombosis incidence. The medians of pertinent laboratory data were plotted on a graph. Descriptive statistics with medians, quartiles, frequencies, and percentages are reported.
Results: Among the 20 patients treated during this period, 18 (90%) had ALL, and 2(10%) had NK/T cell lymphoma. Of the patients with ALL, 67% had high risk and 33% with standard-risk ALL. The median age of this cohort was 29.5 years (range: 19-63 years), 80% were males, 70% white, 30% were Latino or Hispanic, median body mass index-BMI of 30.2 kg/m 2(19.4-40.7 kg/m 2) and 65% were non-smokers. The median baseline AT activity was 107% (79-221%), 95% used concurrent corticosteroids (65%- Prednisone, and 30% used Dexamethasone). The most common induction treatment was CALGB 10403 (55%). Of the total, 95% received pegylated ASP, and only one patient received Erwinia ASP due to prior history of anaphylaxis. The major toxicities attributed to ASP included 5% grade II and 15% grade III-IV aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, 20% had bilirubin elevation, 10% developed grade III-IV acute pancreatitis, and 5% developed severe hypertriglyceridemia needing aphaeresis. Two patients (10%) developed thrombosis catheter associated deep venous thrombosis (DVT) and one patient with lower extremity proximal DVT within 4 weeks of use of ASP, with one of the two patients (5%) developing (lower extremity proximal DVT) while on being off anticoagulation due to bleeding. Major bleeding or CRNMB developed in 5% (spontaneous splenic rupture from ALL leading to hemorrhagic shock). The median number of cryoprecipitate units used per patient during weeks 1,2,3, and 4 was 5(0-35), 5(0-40), 5(0-15), 7.5(0-15), respectively; No patients received fresh frozen plasma or AT concentrates.
Conclusions: With the use of Apixaban prophylaxis, the incidence of thrombosis was 10% within four weeks from ASP and 5% while on anticoagulation. The incidence of major bleeding or CRNMB was 5%. Hypofibrinogenemia, acquired AT deficiency due to ASP, was seen between days 7-21 after using ASP (figure 1 & 2) and recovered subsequently. This study demonstrates initial evidence of the safety and efficacy of Apixaban for thrombosis prophylaxis and cryoprecipitate infusions in patients treated with ASP.
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Gundabolu: Samus Therapeutics: Research Funding; Pfizer: Research Funding; BioMarin Pharmaceuticals: Consultancy; Bristol-Myers Squibb Company: Consultancy; Blueprint Medicines: Consultancy. Bhatt: Jazz: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; National Marrow Donor Program: Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Partnership for health analytic research, LLC: Consultancy; Servier Pharmaceuticals LLC: Consultancy; Rigel: Consultancy. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Lunning: Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Kyowa Kirin: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Novartis: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Legend: Consultancy; Kite, a Gilead Company: Consultancy; Verastem: Consultancy; Acrotech: Consultancy; Karyopharm: Consultancy; Spectrum: Consultancy; Beigene: Consultancy; Morphosys: Consultancy. Baljevic: BMS/Celgene: Consultancy; Oncopeptides: Other: Advisory Board; Janssen Research: Other: Advisory Board; Karyopharm: Other: Advisory Board; BMS/Celgene: Other: Advisory Board; Amgen: Research Funding; Exelixis: Research Funding. Ganti: Merck: Research Funding; Apexigen: Research Funding; Nektar: Research Funding; Top Alliance Biosceinces: Research Funding; Lovance: Research Funding; Novartis: Research Funding; WindMil Therapeitucs: Research Funding; Takeda: Research Funding; Flagship Biosciences: Consultancy; AstraZeneca: Consultancy, Other: Advisory Board; Mirati Therapeutics: Consultancy, Other: Advisory Board; G1 Therapeutics: Consultancy, Other: Advisory Board; Blueprint Medicines: Consultancy, Other: Advisory Board; Cardinal Health: Consultancy, Other: Advisory Board; Roche: Consultancy, Other: Advisory Board; YMabS Therapeutics: Other: DSMC Chair.
Introduction: Treatment for relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) remains an unmet medical need despite the recent approval of chimeric antigen receptor T-cell ...(CAR-T) therapeutic constructs. Many patients will be “too sick to CAR-T” or may have logistical/financial challenges that will not allow this treatment. As a result, non-chemotherapy agents with activity in rel/ref DLBCL require further development to help fill this need. Umbralisib (UMB) is dual PI3K delta/CK-1ε inhibitor that has single agent activity in rel/ref DLBCL with an ORR of 31% Burris et al. 2018. Ibrutinib (IBR) is a Bruton Tyrosine kinase (BTK) inhibitor with activity seen in the activated B-cell (ABC) subtype of DLBCL with an ORR of 37% in this subtype Wilson et al. 2015. Pre-clinical data (not shown) demonstrated synergistic activity of UMB-IBR against cell lines of both germinal center B-cell (GCB) and non-GCB subtypes of DLBCL. We report results of phase IIa study of the combination of UMB-IBR in rel/ref DLBCL.
Methods: Eligible patients (pts) had relapsed or refractory DLBCL, ANC ≥1000 cells/mm3, platelets ≥100 K/mm3, and adequate organ function. The Hans algorithm defined cell of origin. UMB was dosed at 800 mg daily in AM and IBR 560 mg daily in PM. Treatment stratification was performed on a 1:1:1 design to Cohort A (UMB), B (IBR), or C (UMB+IBR) by consent to optional biopsies, which included optional pre-treatment and day 8 biopsies to assess pre-specified correlative flow cytometric analysis of the B-cell receptor (BCR) pathway. In cohorts A/B the combination was initiated at day 8. A cycle was 28 days. Pts received UMB-IBR for up to 1-year of therapy in the absence of progression disease (PD) or excess toxicity. The primary endpoint was monitoring for cumulative toxicity events (CTEs) occurring during cycles 1-4. A CTE was defined as grade (G) 4 neutropenia or thrombocytopenia, G3 neutropenia or thrombocytopenia last longer than 7 days, G3 non-hematologic toxicity, or any G adverse event which led to a drug hold > 7 days. Consecutive stopping rules for CTEs and efficacy were employed. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, progression-free survival (PFS), time to response (TTR), and duration of response (DOR).
Results: Thirteen pts with rel/ref DLBCL were enrolled. Median age was 71 years (range 27-81) and 9 were male. Median number of prior therapies was 2 range 1-7 with 8% having undergone prior autologous transplantation. Sixty-two percent were refractory to last therapy. DLBCL subtypes were GCB in 7 and non-GCB in 6 pts. The first 3 pts were enrolled to Cohort C regardless of optional biopsy consent. Cohorts A (n=1) and B (n=1) included pts that consented to optional biopsies. Cohort C (n=11) included the first 3 pts enrolled into the study and those thereafter that did not consent to optional biopsies. Two CTEs were seen: G3 rash and G3 Clostridium difficile (C. diff) diarrhea. No CTEs occurred during cycle 1. Notable serious or recurrent adverse events (SAEs or AEs) of interest occurring across all cycles regardless of attribution included elevated AST/ALT 0% G 3-4 (all G 31%), nausea 15% G 3-4 (all G 54%), and diarrhea 15% G 3-4 (all G 31%). The ORR of the UBR-IBR regimen was 23% with 2 PRs (both GCB) and 1 CR (non-GCB). The pt in CR remains on treatment at 7 months and recovered from a CTE during cycle 4 (C. diff). The median PFS was 3 months 95 % CI 0.85, 3.8. No patient was taken off study for toxicity and there were no dose reductions necessary.
Conclusion: In this phase IIa study of rel/ref DLBCL, the non-chemotherapy regimen of UMB-IBR was well tolerated with only 2 CTEs and limited AEs. The evaluation of CTEs was limited by the rapid PD in many pts seen prior to 4 cycles of therapy. The ORR of the UMB-IBR was modest (23%) and of limited durability in this difficult to treat patient population. Based on limited activity and difficulty in obtaining biopsies for correlative analyses, this study was terminated prematurely.
Lunning:Portola: Consultancy; Spectrum: Consultancy; Genzyme: Consultancy; Genentech: Consultancy; Juno: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Kite: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Vose:Epizyme: Honoraria; Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Roche: Honoraria; Acerta Pharma: Research Funding; Abbvie: Honoraria; Kite Pharma: Research Funding; Legend Pharmaceuticals: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding.
Burkitt lymphoma is a unique B-cell malignancy with a high proliferation rate and characteristic genetic changes involving the c-myc oncogene. Burkitt lymphoma is common in children but also occurs ...in adults, where distinction from diffuse large B-cell lymphoma may pose a problem. The development of brief, very intensive chemotherapy regimens has led to a very high cure rate in children with Burkitt lymphoma. The use of these regimens in adults, often in combination with the antibody rituximab (Rituxan), has also made the cure of a majority of adults possible. Burkitt lymphoma in adults cannot be treated effectively with the common regimens used for diffuse large B-cell lymphoma such as CHOP-R (cyclophosphamide, doxorubicin HCl, vincristine Oncovin, prednisone, rituximab). Prompt diagnosis and initiation of appropriate therapy with attention to the possibility of tumor lysis syndrome are necessary for optimal results.
Introduction:
Outcomes for patients with NHL who are refractory to first line therapy as well as relapsed disease are poor. Lenalidomide, an immunomodulatory drug, stimulates T-cell proliferation, ...IL2, IL10 and IFN-gamma production. Ofatumumab, a monoclonal anti-CD20 antibody has shown to have activity as monotherapy in B-cell NHL. This phase I/II study evaluates the safety and clinical activity of the combination treatment of lenalidomide and ofatumumab for relapsed/refractory NHL.
Methods:
Patients with histologically confirmed diagnosis of CD20+ NHL, recurrent/ refractory to at least one prior therapy were eligible for the study. All the patients received 8 weekly infusions of ofatumumab 1000mg. Dose escalation of lenalidomide was done in three planned dose cohorts. Cohort 1 received 15mg per day, cohort 2 and 3 received 20mg and 25mg per day respectively on days 1-21 every 28 days. The study design involved a standard 3+3 approach. Dose reduction Cohort (-1) at 10mg/day was built into the protocol in the event of a dose limiting toxicity in cohort 1. Phase II evaluated lenalidomide at maximum tolerated dose (MTD) and ofatumumab in 36 patients. Flow analysis for total T-cells, sIL2r, IL12, VEGF, TNFa levels were checked at baseline, 6 months, 12 months on therapy and at the time of discontinuation of treatment.
Results:
The MTD for lenalidomide was 10mg. Six patients in phase 1 treated at the MTD and 34 patients enrolled on Phase II were eligible for evaluation. Data was analyzed for all patients treated at the MTD (n=40). Twelve (30%) patients had diffuse large B-cell lymphoma (DLBCL), 12 (30%) follicular lymphoma (FL), 6 (15%) mantle cell lymphoma (MCL), 6 (15%) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), 4(10%) other lymphomas. The median age was 64.5 years (35.5-80.7). Thirty one (78%) were male, 40 (100%) caucasians, 45% had stage IV disease. Number of lenalidomide cycles ranged from 1-63. In the phase I cohort, grade 3-4 adverse events included neutropenia (10%), thrombocytopenia (10%) and secondary malignancies (20%). Grade 3-4 adverse events on Phase II were neutropenia (42%), thrombocytopenia (8%), infusion reactions (8%) and secondary malignancies (17%). Overall response rate stable disease (SD), partial response (PR) + complete response CR was 67% (95% %CI:52%-80%) including 11 (92%) patients with FL, 5 (83%) MCL, 3 (25%) DLBCL and 4(66%) CLL/SLL. CR was noted in 3 patients which included DLBCL, FL and MCL. The durability of response in patients who achieved CR was 7.02 years (DLBCL), 2.89 years (FL) and 2.54 years (MCL). At 6 months, the mean change from baseline in sIL2r was 389.8 SD=421 p=0.002, CD3+T = -0.43 SD=0.77, p=0.04. The median change in sIL2r and CD3+CD4+G was lower for patients with CR when compared to patients with PR or SD sIL2r:-82.7 vs 543.5, p=0.02; CD3_CD4_G: -26.1 vs. -0.82, p=0.02. Median progression free survival (PFS) was 6.8 months (2.3-12.1). Median overall survival (OS) was 19.8 months (7.4-42.8). Estimated 1 year PFS was 38% and 2 years was 20%. Estimated 1 year OS was 56%, 2-year survival was 49%.
Conclusion:
The combination of lenalidomide at 10 mg for 21/28 days and ofatumumab has manageable toxicities and produces some durable response in patients with relapsed/refractory indolent NHL including FL, MCL, and CLL/SLL.
Lunning:Celgene: Consultancy; BMS: Consultancy; Genentech: Consultancy; Onyx: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy; Juno: Consultancy; Epizyme: Consultancy; Gilead: Consultancy; Spectrum: Consultancy; Pharmacyclics: Consultancy. Armitage:Tesario bio Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Consultancy; Conatus- IDMC: Consultancy. Vose:Incyte: Research Funding; Acerta: Research Funding; Allos Therapeutics: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Kite: Research Funding; Merck: Research Funding; Onyx: Research Funding; Seattle Genetics: Research Funding; US Biotest: Research Funding; Bristol-Myers Squibb: Research Funding.
Primary central nervous system (CNS) lymphoma, most frequently a diffuse large B-cell lymphoma, is a rare aggressive lymphoma confined to the CNS, thus requiring differentiation from other brain ...malignancies such as glioblastoma. Although stereotactic biopsy can confirm the diagnosis, this is invasive, not always feasible and can be inconclusive after steroid use. Hence, cranial magnetic resonance imaging (MRI) with contrast and cerebrospinal fluid analysis are frequently used to make a prompt diagnosis. We report a case of a woman with two brain masses who presented unique diagnostic challenge.
Introduction:
In the modern era, Rituximab (R) has been demonstrated to be a very effective therapy for patients with SMZL. Although there are no randomized controlled trials, historical data have ...demonstrated good outcomes with R alone, allowing patients to forego splenectomy as a treatment modality. Most recently however, a retrospective study from Vancouver showed superior outcomes with splenectomy as compared to chemotherapy in the front line setting. We aimed to determine the national trend in splenectomy rate for SMZL using a US population-based database.
Methods:
We utilized the SEER 18 database to identify all patients with SMZL between the years 1998-2012 using International Classifications of Disease for Oncology, 3rd edition (ICD-O-3) code 9689/3. Only cases with known age, race, stage, receipt of surgery and follow up information were included. Median Overall survival (OS) and 5-year OS were calculated using Kaplan Meier method. Using Poisson regression methods, we estimated the yearly splenectomy rate adjusting for age, gender and stage at diagnosis. Estimated annual percentage change (EAPC) was calculated as the antilog for the regression coefficient for year minus 1 times 100 i.e. EAPC = {exp(year of diagnosis) -1} x 100.Flexible but smooth rate was obtained with restricted cubic splines using Akaike's information criteria. All p-values were two-sided and the level of significance was chosen at 0.05.
Results:
A total of 1368 patients with SMZL met eligibility criteria. The median age was 69 years (range 25-96 years). The study population comprised of 53% females(n=721) and 90% whites (n=1236). A total of 70% (n=951) were stage IV at diagnosis. A total of 40% (n=540) received splenectomy, whereas only 16 patients (1.2%) received radiation therapy. The receipt of chemotherapy could not be analyzed. The adjusted rate in splenectomy declined sharply from 79.5% in 1998 to 24.7% in 2012 at an EAPC of -5.34 (95% CI -7.56 to -3.07; p<0.01). Figure 1 shows the restricted cubic spline graph showing a decline in adjusted splenectomy rate during the study time period. The median and 5-year OS was 101 months and 66% respectively.
Conclusion:
Our population-based study demonstratesa steady decline in the rate of splenectomy for SMZL between 1998-2012. This declining rate is likely reflective of increasing use of R or R based chemotherapy regimens for the treatment of patients with SMZL. It also likely reflects to some extent improved pathologic characterization of this entity based on bone marrow evaluation alone, decreasing the need for a diagnostic splenectomy.
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Armitage:Ziopharm: Consultancy; Conatus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tesaro Bio, Inc: Membership on an entity's Board of Directors or advisory committees; Spectrum: Consultancy; Roche: Consultancy; Celgene: Consultancy; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Micro-Abstract Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T-cell/histiocyte-rich large B-cell lymphoma (THR-LBCL) share histologic features but require different therapies. We report ...clinical and functional imaging characteristics of twelve patients with either NLPHL or THR-LBCL. Earlier stage disease and less avid PET/CT findings were more characteristic of NLPHL and may influence patient management when histology alone makes distinguishing NLPHL from THR-LBCL difficult.
Anthracycline-based chemotherapy is widely used in a variety of regimens for Hodgkin's Lymphoma (HL) and Non-Hodgkin's Lymphoma (NHL). Unfortunately this agent is associated with cardiotoxicity, ...especially in larger cumulative doses. Doxorubicin cardiotoxicity is characterized by a dose-dependent decline in mitochondrial oxidative phosphorylation. Reactive oxygen species, generated by the interaction of doxorubicin with iron, can then damage the myocytes causing myofibrillar loss, cytoplasmic vacuolization, and apoptosis.
Current NCCN guidelines for HL and NHL state that left ventricle function is recommended in patients who will receive such chemotherapy. Subsequent evaluations are recommended at a cumulative dose of doxorubicin of at least 300 mg/m² and periodically thereafter during the course of therapy. Despite these recommendations, there is little literature about the usefulness of this approach, the rate of abnormal findings, and whether routine testing changes management.
A list of patients with HL or NHL treated with anthracycline-based chemotherapy from the University of Nebraska Medical Center from August 2004-May 2012 was obtained from our Lymphoma Registry.
Baseline characteristics of age, disease diagnosis, gender, and prior history of cardiac diagnosis were collected. Prior cardiac diagnosis specified as patients with a past history of atrial fibrillation/flutter, supraventricular tachycardia, heart block requiring pacemaker implantation, coronary artery disease, valvular disease, pulmonary hypertension, or cardiomyopathy.
Charts were reviewed for pre-chemotherapy evaluation of left ventricular function and the method of evaluation (echocardiogram, nuclear, cardiac MRI were included). Additionally, post treatment evaluation of cardiac function was evaluated for any change.
The individual therapy for each patient was reviewed to determine if findings from the cardiac evaluation modified treatment regimens.
A left ventricular function less than 50% was considered abnormal. Echocardiogram findings of moderate to severe valvular disease, diastolic dysfunction (grade 1-3), and moderate or severe pulmonary hypertension (moderate = pulmonary artery systolic pressure of 45-60, severe = pulmonary artery systolic pressure of > 60) were collected.
We identified 309 patients from the UNMC lymphoma database. Of these 219 (71%) had an echocardiogram performed prior to therapy and documented in the patient record. Their mean age was 54.2 years of age with 53% of them being male and 47% female.
188 of the 219 (86%) had no prior cardiac diagnosis as defined previously. From this group 22 of the 188 (10%) had a pre-chemotherapy echocardiogram that demonstrated one of the following: moderate-severe valvular disease, diastolic dysfunction, moderate-severe pulmonary hypertension or abnormal EF (<50%). However, none of these findings altered the chemotherapy regimen for the 22 patients.
31 of the 219 patients with echocardiograms carried a prior cardiac diagnosis. 4 of the 31 had an alteration in their chemotherapy regimen as a result. Post therapy echocardiograms showed no change in cardiac function.
5 of the 219 patients were diagnosed with adriamycin induced cardiomyopathy following treatment. All 5 patients had no prior cardiac history and pre-chemotherapy echocardiograms were normal.
These finding suggest that current methods of evaluating cardiac function prior to chemotherapy and risk stratifying patients are inadequate and do not alter patient outcomes.
No relevant conflicts of interest to declare.
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