bluuebunny/crossref_metadata_2025 huggingface dataset:
Toxicity burden in older patients with chronic lymphocytic leukemia (CLL) receiving bendamustine with rituximab (BR) or ibrutinib (IB) regimens: Alliance A041202.
Authors: Ruppert Amy S. , Mandrekar Sumithra J. , Booth Allison M. , Ding Wei , Bartlett Nancy L. , Brander Danielle M. , Coutre Steve E. , Brown Jennifer R. , Nattam Sreenivasa R. , Larson Richard A. , Erba Harry Paul , Litzow Mark Robert , Owen Carolyn , Kuzma Charles S. , Abramson Jeremy S. , Little Richard F. , Smith Scott E. , Stone Richard M. , Byrd John C. , Woyach Jennifer Ann
Published: May 2020

e20004

Background: IB is a Bruton’s tyrosine kinase inhibitor that showed superior progression-free survival compared with BR in CLL patients (pts) 65 years or older in a randomized phase 3 trial (Woyach et al, NEJM 2018). Pts receiving IB had higher rates of atrial fibrillation (AFIB) and hypertension (HTN); BR pts had higher rates of hematologic toxicity. Differences in treatment duration for BR (6 cycles) and IB (until progression) complicated adverse event (AE) comparisons. Here we use an exploratory approach to compare toxicity burden between arms and provide assessment of AFIB, HTN and infections (INF). Methods: AEs were reported for each of cycles 1-6 and then every 3 cycles until progression or nonprotocol CLL therapy. Only grade (gr) 3-4 AEs were reported thereafter until death. A simple global AE score was calculated for each pt by summing grades of all gr 1-4 AEs and dividing by the number of cycles over which AEs were submitted. Results: 537 pts began therapy (176 BR, 361 IB). 68% on BR completed all 6 cycles. At a median follow-up of 38 months, 64% remained on IB. Treatment discontinuation for AE occurred in 10% and 14% of BR and IB pts. Overall, median AE score was 1.8 (interquartile range (IQR) 0.9-3.3) and 3.8 (IQR 2.3-5.9) in BR and IB arms (p < 0.01). For cycles 1-6, median AE score was 6.2 (IQR 3.8-9.0) and 4.8 (IQR 3.0-7.2) in BR and IB arms (p < 0.01). In the IB arm, median AE score post 6 cycles decreased significantly to 3.4 (IQR 1.9-5.6) (p < 0.01). Gr 3 or higher cumulative rates of AFIB, HTN, and INF over time appear in the table. 100 pts (26/176 BR, 74/361 IB) had 137 severe INF (39% respiratory: 16 BR, 37 IB; 25% skin: 3 BR, 31 IB; 12% GU: 3 BR, 13 IB; 25% other: 12 BR, 22 IB). There were 7 gr 5 INF (3 BR, 4 IB), none confirmed fungal. Conclusions: There was no difference in treatment discontinuation rates for AE. Overall toxicity burden was significantly higher for IB, although IB toxicity burden decreased after 6 cycles. Toxicity burden was significantly higher in cycles 1-6 for pts receiving BR. Risk of severe AFIB, HTN, and INF is highest in the first year of IB. A simple AE score provides valuable information, especially when evaluating regimens of varying length. Clinical trial information: NCT01886872 . Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Pharmacyclics; ClinicalTrials.gov Identifier: NCT01886872. [Table: see text]
The association between tonsillectomy and Hodgkin’s lymphoma: A systematic review and meta-analysis.
Authors: Albawaliz Anas , Fatima Zainab , Abonofal Abdulrahman , Abumoawad Abdelrhman , Al Momani Laith , Shrestha Anuj
Published: May 2020

e20015

Background: Several observational studies have evaluated tonsillectomy as a predisposing factor for developing Hodgkin’s lymphoma (HL) with contradicting results. The true association is unknown. We sought to systematically review the literature and perform the first meta-analysis to study the association between a history of tonsillectomy and the development of HL. Methods: A systematic review was conducted in Pubmed, and Cochrane databases from inception through January 2020 to identify the studies which explored the association between history of tonsillectomy and HL. Effect estimates from the individual studies were extracted and combined using the random effect, generic inverse variance method of DerSimonian and Laird and a pooled odds ratio (OR) was calculated. A forest plot was generated, and publication bias was assessed for using conventional techniques. Results: Twenty studies with a total of 17931 patients were included in our analysis. 6231 of the patients were diagnosed with HL. The pooled OR for the development of HL in patients with history of tonsillectomy was 1.237 (CI 1.075-1.424, P = 0.003, I2= 45.073%) compared to patients without a history of tonsillectomy. Conclusions: Our analysis shows a statistically significant association between a history of tonsillectomy and the development of HL. As all the studies included in our meta-analysis were observational, we need prospective studies to better understand this important association.
Causes of death in nodular lymphocyte predominant Hodgkin's lymphoma.
Authors: Saad Anas M , Afifi Ahmed , Gad Mohamed , Al-Husseini Muneer J. , Baidoun Firas , Hilal Talal
Published: May 2020

e20016

Background: Nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHL) accounts for 5% of all cases of HL. The outcomes of patients with NLPHL is generally regarded as better than those with classical HL. However, causes of death (COD) of patients with NLPHL have not been previously described. Methods: The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program was used to identify all patients with NLPHL diagnosed between 1990 and 2015. Patient characteristics and disease stage, using the Ann-Arbor system, was extracted and tabulated. COD were identified and proportions were calculated for deaths within 5 years and after 5 years of diagnosis for patients with early and late stage NLPHL. Results: We identified 1,937 cases of NLPHL. The majority were younger than 65 years (86%), white (70%), male (67%), and diagnosed between 2001-2015 (85%), when rituximab was introduced. Of all cases, 1336 (69%) were classified as early stage. At a median follow-up of 91 months (IQR 41, 152) for early stage disease, and 73 months (IQR 30-123) for late stage disease, the median cancer-specific or overall survival were not reached. The estimated 5-year survival was 92% and 81% for early stage and late stage disease, respectively. Of all patients with early stage NLPHL, 186 (14%) died by the end of 2015, and 87 (46%) deaths occurred within 5 years of diagnosis. During the first 5 years after diagnosis, COD was NLPHL in 30 (35%). Beyond 5 years from diagnosis, NLPHL was the COD in 27% followed by other cancers (23%), and cardiovascular disease (18%). Of all patients with late stage NLPHL, 107 (21%) died, and 75 (70%) of deaths occurred within 5 years of diagnosis. During the first 5 years after diagnosis, COD was NLPHL in 44 (59%). Beyond 5 years from diagnosis, cardiovascular disease was the COD in 25%, followed by NLPHL (22%). Conclusions: The prognosis of NLPHL is excellent. Of all patients with NLPHL, those with advanced stage disease are more likely to die of their disease within 5 years of diagnosis. Patients with early and advanced stage disease beyond 5 years of diagnosis are more likely to die of causes other than NLPHL.
The Hodgkin lymphoma international study for individual care (HoLISTIC): Enhancing decision making in pediatric and adult Hodgkin lymphoma (HL).
Authors: Parsons Susan K. , Rodday Angie Mae , Scharman Carlton , André Marc , Federico Massimo , Friedberg Jonathan W. , Friedman Debra L. , Gallamini Andrea , Hay Annette E. , Hoskin Peter , Johnson Peter , Kahl Brad S. , Keller Frank G. , Kelly Kara M. , Meyer Ralph M. , Radford John A. , Raemaekers John , Zinzani Pier Luigi , Cohen Joshua T. , Evens Andrew M. ,   on behalf of the HoLISTIC Consortium
Published: May 2020

e20019

Background: Decision making in HL is complicated by clinical trial results that differ, a growing range of treatment options, and the absence of ideal, objective information on long term outcomes from modern therapy. Methods: We formed an international consortium, HoLISTIC, consisting of 50+ pediatric & adult HL providers, decision scientists, statisticians, epidemiologists, and patient (pt) advocates and are creating a data repository of individual pt data (IPD) from 16 contemporary, pediatric & adult clinical trials for newly diagnosed pts with HL, and 6 large HL registries/survivorship cohorts, the latter enriched with LE data (Table). We will enhance our prior decision model (DM) from group-level data (Parsons S et al. B J Haem 2018) to establish a dynamic HL DM from IPD. Using statistical and simulation modeling of IPD, the enhanced DM will project outcomes of interest, including quality-adjusted life years (QALYs), reflecting both mortality and morbidity. Results will be validated and calibrated against prominent external cohorts (e.g., St. Jude LIFE Cohort, Dutch HL registry). The DM then will be converted to a web-based platform that we will test and evaluate among HL providers and pts at the point of care. Results: To date, we have harmonized IPD from 10 trials (~8,000 HL pts), ranging in size from 165-1925 pts. At diagnosis, median age was 26 y (IQR 18-38); 51.5% were male. 43% had B symptoms, 34% had mediastinal bulk, and 79% had nodular sclerosis histology. Median follow up was 5.0 y (IQR 3.5-7.4). IPD harmonization is ongoing, which will be followed by creation of the enhanced DM. Conclusions: HoLISTIC capitalizes on a multidisciplinary pediatric & adult oncology collaborative, harmonizing extensive IPD by linking data from clinical trials and real world registries/survivorship cohorts. This work will inform questions about the influence of Tx options on both acute and potential long term events and how those options align with pt values and preferences. [Table: see text]
Brentuximab vedotin with chemotherapy for advanced stage untreated classic Hodgkin’s lymphoma in a real-world setting.
Authors: Steiner Raphael , Cramer Frederick M , Singh Prachee , Becnel Melody , Alcedo Pedro E , Chin Collin K , Cuglievan Branko , Strati Paolo , Ahmed Sairah , Samaniego Felipe , Nair Ranjit , Gunther Jillian Rebecca , Pinnix Chelsea Camille , Fang Penny , Dabaja Bouthaina Shbib , Feng Lei , Lee Hun Ju
Published: May 2020

e20020

Background: In the pivotal phase III study ECHELON-1, Brentuximab Vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A+AVD) demonstrated superior efficacy but more hematological and neurological toxicity than bleomycin+AVD (ABVD) as therapy of advanced-stage untreated classic Hodgkin’s lymphoma (ucHL) (Straus et al Blood 2020). It is unknown if A+AVD in a real world setting shows the same efficacy and safety profile. Methods: After obtaining institutional research approval, we retrospectively reviewed the characteristics and outcomes of 41 stage III and IV ucHL patients treated per physician preference with A+AVD as standard of care between 3/2010 and 12/2019. Treatment consisted of 1.2 mg/kg of BV and standard dose AVD, intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. All patients received support with granulocyte colony stimulating factor. Results: At time of treatment with A+AVD, median age was 38 (range 18-54 years) and IPS was 0-3 in 56% of patients. Overall, 95.1% of patients received 6 cycles of A+AVD, with a range of 3-6 cycles. During therapy, 19.5% of patients developed febrile neutropenia, 68.3% had at least one emergency department visit (median 2 visits, range 1-7), and 58.5% were hospitalized at least once (median hospital stay of 3 days, range 1-23). Furthermore, 4.9% of patients presented with grade ≥3 elevation of lipase, 4.9% grade ≥3 elevation of alanine aminotransferase, 9.8% deep vein thrombosis and 7.3% pulmonary embolism. Peripheral neuropathy (PN) occurred in 78% of patients, including grade ≥3 in 12.2%. Due to various toxicities, 22% of patients required at least one dose reduction of BV (median 5 reductions, range 2-7) and 46.3% had a least one dose omission of BV (median 4 omissions, range 1-10). At a median follow-up (FU) of 12.65 months (range: 5.91-85.97), 87.5% of patients had partial or complete improvement of their PN. The median delay of completion of 6 cycles of A+AVD was 8 days (range -1 to 35). The end-of-therapy PET/CT showed Deauville score of 1-3 in 85.3% of patients, 4 in 2.4% and 5 in 12.2%. However, only one patient relapsed 5 months after completion of 4 cycles of A+AVD and another relapsed 6 months after completion of 6 cycles. Both patients were still alive at last FU. The median PFS was not reached and 12-months PFS was 96.0% (95% confidence interval [CI], 88.6-100). Conclusions: In real-world experience, A+AVD is a highly effective treatment strategy for patients with advanced-stage ucHL. In light of its toxicity profile, strategies aimed at improving its safety are needed.
Simultaneous occurrence of Hodgkin disease and tuberculosis in children and adolescents.
Authors: Veron David A. , Obando Patricia , Castellanos Mauricio , Fernandez Karen S.
Published: May 2020

e20022

Background: The simultaneous co-existence (TB) and Hodgkin lymphoma (HL) is a rare entity is a rare entity. The similarities in signs and symptoms of both diseases: cough, fever, weight loss, night sweats, cervical or hiliar adenopathy can lead to delays in the diagnosis of either two entities. In addition, HL treatment with immunosupressors could lead to reactivation or worsening of TB imposing challenges on the initiation of HL treatment. Methods: Retrospective review of HL patients in Guatemala and Argentina from 2010 – 2019. Results: Ten patients with TB-HL were identified. Eight patients were from Guatemala and, 2 from Argentina. There were 4 females and 6 males. Age ranged from 4 – 17 years (mean 10.5 years, media 9 years). Eight patients were suspected to have TB by the referring physician and were found to have TB-HL upon histological and microbial testing of the same lymph node. Two patients were found to have TB-HL by tissue culture at the time of relapse. Initial systemic symptoms included fever (n = 7), weight loss (n = 5), and night sweats (n = 5). Two patients had no systemic symptoms but lymphadenopathy alone. Time for referral to oncology center ranged from 0.5 to 6 months. Histology consisted of nodular sclerosis (n = 5), mixed cellularity (n = 2), lymphocyte predominant (n = 1), lymphocyte depleted (n = 1), unknown (n = 1). Eight patients had advanced disease (stage IIB, IIIB and IVB) and, two stage IIA. HL treatment was given according to the institutional standards depending on stage and risk stratification with ABVD, OEPA/COPDac +/- Radiation therapy, and ICE for relapse. Five patients started anti TB treatment simultaneously with chemotherapy, and five others after completing 1 or 2 cycles of chemotherapy. TB treatment consisted of Isoniazid, Rifampin, Pyrazinamide +/- Ethambutol for 2 months followed by Isoniazid and rifampin for 30-52 weeks. Eight patients have been followed for 3 – 8 years and are alive without evidence of recurrence of TB or HL. One patient died during therapy, another died for causes not related to TB or HL having achieved remission for both. Conclusions: These small case series demonstrates that TB therapy can be given simultaneously with chemotherapy without risking worsening TB infection. Coexistence of TB and HL appears to correlate with advanced disease (higher stage and systemic symptoms) although it does not appear to affect outcomes. In areas were TB is endemic or the prevalence of TB is high, microbiology investigations of biopsy specimen should considered as part of the examination of tissue specimen that is considered to have HL.
Primary extranodal non-Hodgkin lymphoma: Clinical characteristics and outcome.
Authors: Rajendran Tara , Prasad Krishna
Published: May 2020

e20027

Background: According to the National Cancer Registry Program, the Indian Council of Medical Research reports that the estimated Incidence rate of Non-Hodgkins Lymphoma in India is 2-3 per 100,000 people. The incidence rate of extranodal Non-Hodgkins Lymphoma (NHL) in Asia is higher than that of the United States. We illustrate a single center review of the clinical characteristics of all the primary extranodal NHL. Methods: We retrospectively identified patients diagnosed with primary extranodal NHL out of 269 NHL patients diagnosed at the department of medical oncology, Kasturba Medical College hospital, Mangalore, India from August 1999 and September 2015. Results: A total of 43 patients(15.9%) with primary extranodal NHL were identified out of which 25 patients (58%) were male with a median age of 49 years (5-92). 11patients (25%) had tonsil as the extranodal location and 10 patients (23%) had musculoskeletal involvement. Lung, thyroid, ovary, nasopharynx, gastrointestinal, paranasal sinuses and central nervous system were the other sites. 17 patients (39.5%) were presented at stage 4. The most common subtype was diffuse large B cell Lymphoma (DLBCL)-25 patients (58%). 2 patients had HIV infection. Some CD 20+ patients could not afford the cost of Rituximab and hence resorted to the CHOP regimen for 6 cycles. Rest received RCHOP 6-8 cycles depending on the stage and response. Follicular Lymphoma patient received 6 cycles of RCHOP and Rituximab maintenance for 12 cycles once in 2 months. Burkitts lymphoma patient received MCP 842. 3 patients denied treatment. 6 patients had recurrence who received DHAP +/- Rituximab or ICE +/- Rituximab. 1 patient-reported progression treated with supportive care. 6 patients (14%) died and 22 (55%) patients attained complete remission. Conclusions: In our cohort, DLBCL was the most common subtype and tonsil, the most involved site. The prognosis was impacted by the stage at which the patient was presented, HIV infections and the higher cost of Rituximab. Primary extranodal NHL must be considered in the differential diagnosis as the current treatments can achieve complete remission.
Symptomatic delayed seromas vs incidental findings on MR, and likelihood of BIA-ALCL in women with textured implants.
Authors: Ghione Paola , Sutton Elizabeth J. , Hu Qunying , Galasso Natasha , Ganesan Nivetha , Tyagi Neelam , Martinez Danny Francisco , Dogan Ahmet , Morris Elizabeth Anne , Horwitz Steven M. , Cordeiro Peter G.
Published: May 2020

e20028

Background: Breast Implant Associated Anaplastic Large Cell Lymphoma (BIA-ALCL), a subtype of ALCL, arises as a seroma in the space between the implant and the capsule, or as an adjacent mass. BIA-ALCL appears to be related to textured-surface implants, after 7-10 years of exposure. We conducted two large cohort studies. The 1st, a retrospective series (Sutton, 2019) assessed the incidental findings of masses or seromas in 1070 women with breast implants undergoing MR for FDA recommended screening for silent ruptures of silicone implants. Incidental finding of seromas or breast masses on MRI were found in 18/1070 (1.7%) women, of which 1/15 had BIA-ALCL, and was symptomatic at the time of MRI. The 2nd, a prospective study (Cordeiro, 2020) defined the incidence of BIA-ALCL (1/355) in a cohort of 3546 women with textured implants followed long term. Within this cohort, there were 28 clinically relevant delayed seromas (0.79%), 8 of which were BIA-ALCL (28.5%). We hypothesize that combining these databases will inform whether asymptomatic women with textured implants may benefit from MR to r/o BIA-ALCL. Methods: The two IRB approved databases were merged. Patients with incidental findings of seroma on MRI were identified. A majority of the MRIs in this merged cohort were performed to follow the FDA recommended screening for silent ruptures. We identified all clinically relevant late seromas sent to hematopathology to r/o BIA-ALCL by cross checking pathology reports containing the words “lymphoma” or “anaplastic” or “ALCL”. Results: 572 women were included in both studies: followed long term and received an MRI after a median time of 7.4 years after breast reconstruction. 8 of 572 women had an incidental finding of seroma on random MRI, and 2 had capsular masses. None of these 10 asymptomatic women have developed BIA-ALCL to date (median follow-up 9 years). 11 of 572 women had a symptomatic seroma or mass, 4 of which later developed BIA-ALCL, a fifth patient was found to have BIA-ALCL on a PET/CT + lymph node, despite being asymptomatic. Median time from last MR to lymphoma was 5 years (3-8 years). Conclusions: In this merged cohort of patients with textured breast implants, incidence of BIA-ALCL in patients with symptomatic late seromas is around 30%, while seromas found incidentally on MR of asymptomatic patients were negative for BIA-ALCL.
Examination of necrosis in tumors treated with AVM0703 compared to chemotherapy.
Authors: Deisher Theresa
Published: May 2020

e20029

Background: AVM0703 should be the first choice for no-option cancer patients. AVM0703 is a fast-acting formulation that lympho-ablates while sparing HSCs, MSCs, platelets, and RBCs. Its transient and manageable side effects reduce the need for additional maintenance treatments while improving quality of life. AVM0703 induces a novel NKT that induces tumor-killing activity without causing GvHD or CRS. AVM0703 is a versatile formulation that can be safely redosed or given in combination with known chemotherapeutics. It is predicted to be safe for previously neglected patient populations. Methods: Mice were monitored over the course of 13 weeks or endpoint criteria. Body weights and tumor measurements were taken 3x per week. Both group and individual growth was tracked. Tumors were dissected from the right flank on takedown and fixed for 24 hours in 4% paraformaldehyde, then stored in 70% ethanol. For analysis, tumors were sent to HistoTox Labs, embedded in paraffin blocks, then sliced and stained for H&E. In a separate study, mice with subcutaneous A20 were treated with increasing concentrations of AVM0703 and allowed to go to endpoint. Tumors were dissected and stained for H&E, CD3, NKp46, and AC3. Finally, tumor bearing mice were treated with high doses of AVM0703 48 hours before takedown. Tumors were dissected and sent to HistoTox for embedding, slicing and staining for H&E, NKp46, CD3, CD49b, AC3, CD31, B220, Ly6G, Sca-1, and PSR. Results: Mice treated with repeat doses of AVM0703 did not display significant loss of body weight or worsening of condition, which was observed in mice treated with chemotherapy. All combination mice displayed significantly higher tumor necrosis and resorption compared to all other treatment groups. Significant necrosis was observed in tumors in as little as 48 hours post dosing. At endpoint, apoptosis was slightly increased at all doses compared to placebo. CD3 and CD49b were decreased in doses above 18 mg/kg, indicating activation of NKT cells in comparison to placebo and low dose AVM0703. There was also an increase in NKp46 staining along the border of large necrotic regions within the tumor. While necrosis was prevalent within the tumor, there was only a slight increase in apoptosis staining. Conclusions: AVM0703 can be repeatedly dosed without significant signs of toxicity. A single dose after 48 hours displays large regions of necrosis within the tumor, indicating that AVM0703 is a fast-acting formulation. AVM0703 is able to replace a dose of Cy/Flu in mice with similar efficacy and increased tumor killing in comparison to Cy/Flu alone with less toxicity.
Economic assessment of diagnostic revision in peripheral T-cell lymphoma.
Authors: Lisano Julie M. , Liu Nicholas , Yu-Isenberg Kristina , Singh Deepak , Campbell David , Su Wayne
Published: May 2020

e20039

Background: Peripheral T-cell lymphoma (PTCL) is a rare disease that is challenging to diagnose. A retrospective claims analysis and parallel electronic health records analysis estimated the rate of PTCL diagnostic revision (DR) either to or from other lymphomas at 29.3%, with significantly higher costs for DR than non-DR patients during follow-up. The current study used data from this analysis to estimate the cost of DR in PTCL to US health plans and quantify the potential impact of reducing DR in this population. Methods: A cost calculator was developed using pharmacy and medical costs for adult patients in the IBM MarketScan Commercial and Medicare Supplemental Databases with a PTCL diagnosis from 01/10-06/17, with or without DR (≥1 medical claim for a non-PTCL lymphoma in the year prior to or after the index PTCL diagnosis). Cost data were incorporated for non-DR, DR to PTCL, and DR from PTCL cohorts, and for the DR period (time from initial PTCL diagnosis to non-PTCL diagnosis or vice versa) and subsequent follow-up period. In the current scenario (based on the analysis of MarketScan data), rates of DR were 29.3%, of which 51.4% were DR to PTCL and 48.6% from PTCL. DR periods were 5.0 and 3.7 months, respectively, over a 1-year time horizon. A ‘new’ scenario was included that assumed a 50% reduction in the rate of DR to and from PTCL, and a 50% reduction in the length of DR period. Results: Total per patient per month (PPPM) costs for adults in a Medicare health plan diagnosed correctly or incorrectly with PTCL were estimated at $13,064 in the current scenario and $12,131 in the new scenario, representing a savings of $933 PPPM assuming a 50% reduction in both the rate of DR and the DR period. Savings were largely derived from reduced costs associated with other outpatient services ($385 PPPM) and inpatient services ($367 PPPM) in the new scenario (Table). In a hypothetical 1 million member Medicare plan, the estimated total plan savings annually in the new scenario would be $906,801, based on an estimated 81 PTCL patients among all plan members. Conclusions: Accurate and timely diagnosis of PTCL is essential to enable appropriate treatment. Interventions that reduce the rate of DR in PTCL are likely to result in potential cost-savings to US health plans. [Table: see text]
Effect of expression of ICOS in cutaneous T-cell lymphoma and its targeting on killing of malignant cells.
Authors: Amatore Florent , Ortonne Nicolas , Lopez Marc , Orlanducci Florence , Castellano Rémy , Ingen-Housz-Oro Saskia , Decroos Amandine , Gorvel Laurent , Goubard Armelle , Bouabdallah Reda , Bonnet Nathalie , Grob Jean-Jacques , Gaulard Philippe , Bagot Martine , Bensussan Armand , Berbis Philippe , Olive Daniel
Published: May 2020

e20040

Background: Advanced stage cutaneous T-cell lymphomas (CTCLs) remain an unmet medical need. Immunomodulatory agents such as mogamulizumab, anti-KIR3DL2 and brentuximab vedotin (BV), an anti-CD30 antibody–drug conjugate (ADC) coupled to monomethyl-auristatin-E (MMAE), provided encouraging results but new targeted therapies are needed. Inducible Co-Stimulator (ICOS), a T-cell costimulatory receptor involved in the development of CTCLs, arouses interest. Methods: We used immunohistochemistry to study ICOS expression in skin biopsies of 23 patients with early-stage mycosis fungoides (MF), 12 with transformed MF (TMF) and 17 with Sézary Syndrome (SS), at diagnosis or in relapse. ICOS expression by circulating Sézary cells and regulatory T cells (Tregs) in patients with SS was evaluated using flow cytometry, and compared to healthy donors (HD) lymphocytes. In 5 patients with SS, we also analyzed concomitant biopsies from involved nodes. Then, we investigated the efficacy of anti-ICOS ADCs generated by coupling murine anti-ICOS monoclonal antibodies with MMAE, in comparison to BV. We used ICOS+ CTCL cell lines (MyLa and MJ), murine xenograft models with MyLa and ICOS+ Patient Derived Xenografts (PDXs) from patients with SS and angioimmunoblastic T-cell lymphoma (AITL). Results: ICOS was highly expressed by the cutaneous atypical lymphocytic infiltrates in respectively 61%, 75% and 88% of patients with early-stage MF, TMF and SS, such as in the 5 patients with node involvement. ICOS expression by circulating Sézary cells was strong: 69±7.3% versus 38.8±7.1% of non-tumoral CD4+ cells ( p< 0.009; CI95%: 8.7-51.6); and 31±3.2% of CD4+ cells in HD ( p< 0.0001; CI95%:20.3-46.3). Percentages of ICOS+ Tregs were significantly higher in patients with SS than in HD. In CTCL cell lines, we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS ADCs. In a mouse xenograft model (MyLa), anti-ICOS ADCs provided a longer overall survival (OS) than BV (HR = 15.2;CI95%:3.2-71.1; p< 0.0006). Finally, in ICOS+ PDXs anti-ICOS ADCs significantly improved OS, and reduced the number of tumor cells in the blood, bone marrow and spleen. No evidence of ADC toxicity was observed in treated mice. Conclusions: All together our results show that ICOS is a therapeutic target of interest in CTCLs and provide the preliminary basis for a therapeutic trial
Characterization of cytokine release syndrome (CRS) and neurological events (NEs) in the phase I TRANSCEND NHL 001 trial of lisocabtagene maraleucel (liso-cel) for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL).
Authors: Abramson Jeremy S. , Siddiqi Tanya , Gordon Leo I. , Lunning Matthew Alexander , Wang Michael , Arnason Jon E. , Mehta Amitkumar N. , Purev Enkhee , Maloney David G. , Andreadis Charalambos , Sehgal Alison R. , Solomon Scott R. , Ghosh Nilanjan , Albertson Tina M. , Garcia Jacob , Kostic Ana , Li Daniel , Kim Yeonhee , Palomba Maria Lia
Published: May 2020

e20046

Background: Clinical studies of liso-cel show low incidences of severe CRS and NEs. Pts with high tumor burden and inflammation are at higher risk of CRS and NEs (Borrega, Hemasphere 2019). Here, we characterize the presenting symptoms, timing, and management of CRS and NEs in pts with R/R LBCL treated with liso-cel in TRANSCEND NHL 001 (NCT02631044). A deeper understanding of CRS/NEs after liso-cel treatment may help clinicians identify and manage these toxicities. Methods: Pts with R/R LBCL and ≥2 lines of therapy received liso-cel after lymphodepletion (LD) with fludarabine and cyclophosphamide. Bridging therapy was allowed for pts with PET-positive disease before LD (Abramson, ASH 2019 #241). Investigators were educated on prospectively identifying liso-cel–related NEs and CRS, which were collected and graded per NCI CTCAE v4.03 (NEs) or 2014 Lee criteria (CRS). Timing and severity of individual CRS/NE symptoms and interventions were also collected. Results: The analysis included 269 pts (median age, 63 y): 38% had sum of perpendicular diameters ≥50 cm2 or lactate dehydrogenase ≥500 U/L, and 59% received bridging therapy. CRS and NEs had delayed onset (median, 5 and 9 d, respectively) and a low incidence of grade (Gr) ≥3 events (CRS 2%; NE 10%). CRS occurred before NEs in most pts and was Gr 1/2 at onset in all but 2 pts (Table). The most common CRS symptoms were pyrexia (40%), hypotension (20%), and tachycardia (18%). Overall, 20% of pts received tocilizumab and/or corticosteroids for CRS (10% tocilizumab only; 2% corticosteroids only; 8% both); 3% received vasopressors. The most common NE symptoms were confusional state (11%), tremor (9%), and aphasia (8%); most were low grade. A total of 17% of pts received tocilizumab and/or corticosteroids for NEs (13% corticosteroids only; < 1% tocilizumab only; 3% both); < 1% received vasopressors. Overall, 4% of pts were admitted to the ICU for CRS and/or NEs. Additional analyses on timing of intervention and type/severity of initial symptoms will be presented. Conclusions: In pts with high-risk, aggressive R/R LBCL, liso-cel treatment was associated with a low incidence of severe CRS/NEs, late onset of mostly low-grade events at presentation, and low use of tocilizumab/corticosteroids. Clinical trial information: NCT02631044 . [Table: see text]
Factors influencing infusion-related reactions following dosing of reference rituximab (RTX) and PF-05280586, a RTX biosimilar.
Authors: Courville Jocelyn , Nastoupil Loretta J. , Kaila Nitin , Kelton John M. , Nava-Parada Pilar , Parsad Sandeep , Zhang Jeffrey , Alcasid Ann , Lee Peter
Published: May 2020

e20049

Background: Rituximab (RTX) is an effective therapy for some patients with CD20 positive (CD20+), B-cell malignancies. Infusion-related reactions (IRRs) are the most common adverse event (AE) associated with infusion of RTX. The objective of this analysis was to assess if IRRs were correlated with infusion rates of the first dose of the RTX biosimilar PF-05280586 (RTX-PF) or reference RTX sourced from the EU (RTX-EU). Methods: This analysis incorporates data from a randomized, double-blind comparative trial of 394 patients (RTX-PF, n = 196; RTX-EU, n = 198) with low tumor burden follicular lymphoma. RTX was administered at a dose of 375 mg/m2 on days 1, 8, 15 and 22 (one cycle), with a follow-up period through 52 weeks. Logistic regression analysis was performed with infusion rate and treatment or maximum serum concentration (Cmax) as independent variables. Treatment or Cmax was excluded from the model if not significant. Descriptive statistics of baseline CD20+ B-cell level, baseline anti-drug antibody (ADA) status and baseline tumor burden (Ann Arbor stage and bone marrow biopsy lymphoma results) were summarized by occurrence of IRR (yes/no). Results: The median RTX infusion duration on day 1 was 3.50 h for each of the two treatments. There was a significant positive correlation between infusion rate and all-grade IRR AEs occurring within 24 h after infusion (p < 0.0001). The estimated probability of developing an IRR was 0.16 and 0.29 at infusion rates of 189 mg/h and 227 mg/h, respectively. The estimated odds ratio with an increase in rate of 100 mg/h was 7.7. Treatment (RTX-PF or RTX-EU) was not a significant covariate and was excluded from the model. There was a non-significant trend between Cmax of RTX and developing an IRR; the estimated probability of developing an IRR was 0.26 at the median Cmax (196.5 μg/mL) of RTX. Patients who developed IRRs had a higher median baseline CD20+ B-cell level. The trough plasma concentration (Ctrough), collected before the second dose, and baseline tumor burden did not correlate with increased IRR incidence. Baseline ADA status did not predict IRR outcome. Conclusions: The results of this analysis suggest that higher infusion rates of RTX, administered as RTX-PF or RTX-EU, are positively correlated with IRR after the first dose. Clinical trial information: NCT02213263 .
Zanubrutinib monotherapy for patients with relapsed or refractory non-germinal center diffuse large B-cell lymphoma: Results from a phase II, single-arm, multicenter, study.
Authors: Yang Haiyan , Xiang Bing , Song Yuqin , Zhang Huilai , Zhao Weili , Zou Dehui , Lv Fangfang , Bai Ou , Liu Aichun , Li Caixia , Tan Ziwen , Wang Weige , Guo Haiyi , Novotny William , Huang Jane E. , Li Yufu
Published: May 2020

e20051

Background: The non-germinal center (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) is associated with poor clinical outcomes. Inhibitors of Bruton’s tyrosine kinase (BTK) have established therapeutic activity in mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenstrom macroglobulinemia and have shown modest activity in DLBCL. Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 2 study in patients with relapsed or refractory (R/R) non-GCB DLBCL. Methods: The BGB-3111-207 study (NCT03145064) is a multicenter, single arm, phase 2 study in patients with R/R non-GCB DLBCL who were ineligible for intensive chemotherapy and bone marrow transplantation. Subjects received zanubrutinib 160 mg by mouth twice daily until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR) using the Lugano criteria. Secondary endpoints included progression free survival (PFS) and duration of response (DOR). Overall survival (OS) was the exploratory endpoint. Results: Forty-one patients were enrolled at 11 sites in China between June 2017 and May 2018. Patients were 61% male, with a median age of 62 years. The median number of prior therapies was 2. International Prognostic Index risk was high-intermediate or high for 48.8% of patients, and 56.1% of patients had extranodal disease at study entry. As of the data cutoff date of May 24, 2019, four patients were continuing treatment and 37 patients had discontinued. With a median follow-up time of 6.8 months, the ORR was 29.3% and the complete response rate was 17.1%. The median DOR was 4.5 months, the median PFS was 2.8 months, and the median OS was 8.4 months. Adverse events (AEs) leading to treatment discontinuation were reported in four patients. Grade 3 or higher AEs were reported in 48.8% of patients. Major hemorrhage, atrial fibrillation and/or flutter, second primary malignancy, and tumor lysis syndrome were not observed. Conclusions: In this study zanubrutinib demonstrated modest antitumor activity in non-GCB DLBCL, similar to other BTK inhibitors. The safety profile was tolerable and consistent with previous reports of zanubrutinib treatment. Future studies of zanubrutinib in R/R non-GCB DLBCL will focus on the development of mechanism-based treatment combinations and biomarker-driven patient selection. Clinical trial information: NCT03145064 .
Fatigue trajectories in long-term non-Hodgkin lymphoma survivors.
Authors: LeBlanc Matthew Roger , Zimmerman Sheryl , Kayle Mariam , LeBlanc Thomas William , Hudson Kathryn Elizabeth , Smith Sophia Kustas
Published: May 2020

e20053

Background: Fatigue is a common and distressing effect of cancer and its treatment. Prior research suggests fatigue persists long after diagnosis and treatment in non-Hodgkin lymphoma (NHL) survivors. This study aimed to identify distinct trajectories of fatigue in NHL survivors and predictors of trajectories that could inform clinical care. Methods: Our secondary analysis used data from a longitudinal study of NHL survivors (n = 886) at least 2 years post-diagnosis. Fatigue was measured using the SF-36 vitality subscale across three time points. Prior literature informed the selection of baseline demographic (e.g. age, gender, race) and disease characteristics [e.g. NHL type, comorbidities, post-traumatic stress disorder (PTSD)] explored as possible predictors of fatigue trajectories. We used group-based trajectory modeling to identify distinct groups of patients experiencing similar patterns of fatigue. Variables significant in bivariate analysis were included in a stepwise multinomial logistic regression to identify factors predictive of group membership. Results: We identified four distinct trajectories that suggest levels of fatigue persist unchanged over time. The Low Fatigue Group (15.6%) experienced less fatigue than the general population. The Population Norm Group (42.5%) experienced a similar level of fatigue to the general population mean. The Significant Fatigue Group (27.5%) experienced fatigue levels almost one standard deviation worse than the general population. The Worst Fatigue Group (14.3%) experienced fatigue almost two standard deviations worse than the population norm. PTSD symptoms and comorbidity scores were predictive of levels of fatigue over time. Greater age at diagnosis increases the odds survivors experienced worse fatigue than the population mean (Table). Conclusions: Levels of fatigue experienced early in an NHL patients’ disease trajectory may persist for many years. Higher levels of PTSD symptoms and comorbidities were predictive of worse fatigue over time. Early interventions addressing PTSD symptoms and comorbidities may improve long term fatigue outcomes. [Table: see text]
Prevalence and outcomes of pneumocystis pneumonia in patients with T-cell lymphoma.
Authors: Castillo Almeida Natalia , Gurram Pooja , Hwang Steven R , Benanni Nora N , Barreto Jason , Tosh Pritish , Wilson John W
Published: May 2020

e20057

Background: T-cell lymphomas (TCL) are a heterogeneous group of rare, but aggressive non-Hodgkin lymphomas. CD4+ and CD8+ T-cell function plays a vital role in the immunologic response to P.jirovecii infection. Our study aims to define the prevalence of Pneumocystis jirovecii pneumonia (PJP) in HIV-uninfected TCL patients. Methods: All patients at Mayo Clinic, Rochester MN diagnosed with TCL and a positive Pneumocystis PCR assay from either bronchoalveolar lavage (BAL) fluid or other respiratory specimens were identified from March 2005 until November 2019. Patients with TCL and a diagnosis of PJP made outside of our medical center were identified through Advanced Cohort Explorer, a query building tool. Results: A total of 922 patients with TCL were identified, and only 14 cases (1.5%) had confirmed PJP. In confirmed PJP cases, the median age of TCL diagnosis was 62 years (IQR 51-70 years), 79% were male, and the median number of chemotherapy lines was 1.5 (IQR of 1-3). Half of the cases (6/12) received CHOP as first-line of therapy, followed by CHOEP (25%, 3/12). The median time to PJP diagnosis relative to chemotherapy was 18 days (IQR 14-27 days). Peripheral TCL, not otherwise specified was the most common TCL, followed by angioimmunoblastic TCL, and CD30+ T-cell lymphoproliferative disorders (64%, 29% and 7%, respectively). The primary specimen type sampled for PJP diagnosis was BAL fluid (n = 9, 64%), followed by sputum (n = 3, 22%), induced sputum (n = 1, 7%), and transbronchial lung biopsy (n = 1, 7%). Three patients had a prior autologous stem cell transplant (ASCT), and all three cases had relapsed TCL one year after ASCT. 77% of cases received oral prednisone equivalents (median dose of 25 mg, IQR 20-40 mg) 30 days prior to PJP diagnosis. Two patients developed PJP despite anti- Pneumocystis prophylaxis with aerosolized pentamidine. At the time of PJP diagnosis, most patients had lymphopenia (88%, 8/9), and CD4+ T-cells measurement was obtained only in one patient (CD4+ of 100 cells/mL). 71% of the cases were treated with trimethoprim/sulfamethoxazole (TMP/SMX). After the initial PJP episode, 36% of the cases were transitioned to TMP/SMX for secondary prophylaxis. All cause 30-day and 90-day mortality was 7% and 29%, respectively. Mortality attributed to PJP was 7% (n = 1). Conclusions: In our TCL cohort, the occurrence of PJP was low. Primary prophylaxis should be individualized in this population.
A retrospective observational study on the efficacy and safety of pegylated recombinant human granulocyte-colony stimulating factor and recombinant human granulocyte-colony stimulating factor in patients with lymphoma.
Authors: Liu Lihong , Wu Lili , Huang Chen , Zhao Guimin , Ma Guangyu , Gao Yuhuan , Diao Lanping , Yao Yingzhen , Wu Xiaolin , Gao Zhe
Published: May 2020

e20066

Background: To evaluate the efficacy and safety of pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) and recombinant human granulocyte-colony stimulating factor (rhG-CSF) in patients with lymphoma. Methods: This retrospective study included patients with newly diagnosed lymphoma who received CHOP ± R (cyclophosphamide, doxorubicin, vincristine, prednisone ± rituximab) between January 2014 to October 2018. PEG-rhG-CSF(brand name: jinyouli) was injected subcutaneously once 24-72 hours after chemotherapy as primary prevention. rhG-CSF was used as prevention or treatment. The primary endpoint was the incidence of febrile neutropenia (FN), and the secondary endpoints included the incidence of grade III/IV neutropenia, the incidence of chemotherapy dose adjustment, the incidence of chemotherapy delay, the rate of antibiotics application and safety. Results: 178 patients with lymphoma were included, of which 76 were in the PEG-rhG-CSF group (256 cycles) and 102 were in the rhG-CSF group (336 cycles). The incidence of FN was 1.17% (3/256) in the PEG-rhG-CSF group and 5.95% (20/336) in the rhG-CSF group, P= 0.003. The incidence of grade Ⅲ/Ⅳ neutropenia and chemotherapy delay in the PEG-rhG-CSF group were significantly lower than those in the rhG-CSF group (12.89%[33/256] vs 50.30%[169/336], P < 0.0001; 3.13%[8/256] vs 9.52% [32/336], P= 0.002). However, there was no significant difference between the two groups in the incidence of dose adjustment (6.25% vs 3.57%, P = 0.128) and the rate of antibiotics application (34.77% vs 33.33%, P= 0.715). And there was no significant difference in the incidence of fever, bone pain and fatigue between the two groups. Conclusions: Compared with rhG-CSF, prophylactic use of PEG-rhG-CSF can significantly reduce the incidence of FN, grade III/IV neutropenia and chemotherapy delay in patients with lymphoma with good safety.
Fostamatinib for the treatment of diffuse large B-cell lymphoma.
Authors: Arkenau Hendrik-Tobias , Patrikidou Anna , Flinn Ian , Hylton Jonas C. , Tong Sandra , Ardeshna Kirit
Published: May 2020

e20067

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and common form of non-Hodgkin’s lymphoma, characterized by marked genetic heterogeneity. The disease is difficult to treat, and patients with relapsed/refractory DLBCL often have poor outcomes. Some subsets of DLBCL have an increased reliance on B-cell receptor (BCR) activity. Spleen tyrosine kinase (SYK) is a signaling molecule essential for BCR activation. Fostamatinib, an oral SYK inhibitor, was evaluated for treatment of relapsed/refractory DLBCL in a phase 2 randomized, placebo-controlled trial1(NCT01499303), and 9 patients had clinical benefit (1 complete response, 1 partial response, and 7 stable disease). The patients with clinical benefit from fostamatinib treatment had DLBCL of germinal center B-cell (GCB) or intermediate cell of origin. We present the clinical outcomes of 2 patients from this trial who continued to benefit from fostamatinib treatment for over 6 years. Methods: Medical records for the 2 patients were retrospectively reviewed for dose regimen, clinical response, and safety data. Results: Patient A, a 63-year-old male patient with DLBCL of GCB origin, had been diagnosed with follicular lymphoma in 1996, transformation in 2002. He had undergone 1 line of treatment for follicular lymphoma and 5 treatments for DLBCL prior to fostamatinib treatment. He started fostamatinib at 100mg BID in Dec 2012, which was reduced to 100mg daily in Apr 2013, and patient continues at 100 mg QD. Patient A has maintained a complete response (CR) for > 5 years. An isolated infra-centimetric suspicious lesion was noted in Patient A in May 2019, which is stable as of January 2020 with a progressive decrease of metabolic activity. Patient B, a male with DLBCL of an intermediate cell of origin, was 69 years old at baseline with 2 DLBCL treatments prior to fostamatinib treatment since his diagnosis in Aug 2012. He started fostamatinib in May 2013 at 200 mg BID with no dose changes over the last 7 years. Patient B had a partial response (PR) per Chesson criteria since December 2014, with a sustained improved metabolic response continuing since ( > 6 years), with all but a single metastatic site no longer visible. The only serious adverse event in these 2 patients was a ventricular fibrillation and grade 4 cardiac arrest at Day 90 in Patient B, necessitating defibrillation insertion. This was deemed unrelated to treatment and resolved. Conclusions: Fostamatinib may provide durable benefit to a small subset of patients with relapsed/refractory DLBCL. 1. Flinn, I.W., et al., Eur J. Cancer 2016; 54:11-17