Aggressive non-Hodgkin Lymphoma Patients Research Articles

The Experience of Timisoara Hematology Clinic on the Management of Aggressive Non-Hodgkin Lymphoma Patients

Objectives. One of the most prevalent types of malignant lymphoproliferative disorders is non-Hodgkin lymphoma (NHL), which has shown an increased frequency worldwide of roughly 168% since 1975, coinciding with a decline in the age at diagnosis. Despite a ten-year improvement in overall survival, NHL accounts for approximately 3% of all cancer-related deaths. Delays in diagnosis and the emergence of related comorbidities are caused by the diverse symptomatology and symptoms associated with NHL. Thus, the purpose of this study was to assess patients treated at Timisoara's Clinical Emergency Municipal Hospital who had been diagnosed with aggressive HNL. Material and methods. This cross-sectional study comprised 76 patients diagnosed with aggressive NHL between January 2020 and June 2023 who were admitted to Timisoara's Clinical Emergency Municipal Hospital. Biopsy along with histopathologic examination served as the basis for the diagnosis. As part of the first assessment, bone marrow biopsy and imaging studies (PET/CT) were carried out in addition to laboratory tests. The NHL was staged using the Ann Arbour classification. The present protocols were followed in the establishment of the treatment. PET/CT was used to assess the response to treatment. Results. In this study cohort 72% were stage 4 of NHL at the diagnosis, 16% were stage 3, 5% were stage 2, while only 2% were stage 1. B symptoms were present in 69% of cases. In patients with 4th stage of NHL, bone marrow represents the most frequent extranodal site. 57 patients finished minimum a complete chemotherapy line, from which 90% of the patients had complete (63%) or partial (24%) remission after first-line treatment. Conclusion. The importance of this study was to emphasize the heterogeneity of NHL and to evaluate the treatment response and survivance of aggressive NHL patients.

Long-Term Results of IFRT vs. ISRT in Infradiaphragmal Fields in Aggressive Non-Hodgkins’s Lymphoma Patients—A Single Centre Experience

(1) Background: This study aimed to examine the difference in efficacy and toxicity of involved-field (IFRT) and involved-site radiotherapy (ISRT) fields in infradiaphragmal aggressive non-Hodgkin lymphoma patients. (2) Methods: In total, 140 patients with infradiaphragmal lymphoma treated between 2003 and 2020 were retrospectively evaluated. There were 69 patients (49%) treated with IFRT, and 71 (51%) patients treated with ISRT. The median dose in the IFRT group was 36 Gy, (range 4–50.4 Gy), and in the ISRT group, it was 30 Gy (range 4–48 Gy). (3) Results: The median follow-up in the IFRT group was 133 months (95% CI 109–158), and in the ISRT group, it was 48 months (95% CI 39–57). In the IFRT group, locoregional control was 67%, and in the ISRT group, 73%. The 2- and 5-year overall survival (OS) in the IFRT and ISRT groups were 79% and 69% vs. 80% and 70%, respectively (p = 0.711). The 2- and 5-year event-free survival (EFS) in the IFRT and ISRT groups were 73% and 68% vs. 77% and 70%, respectively (p = 0.575). Acute side effects occurred in 43 (31%) patients, which is more frequent in the IFRT group, 34 (39%) patients, than in the ISRT group, 9 (13%) patients, p > 0.01. Late toxicities occurred more often in the IFRT group of patients, (10/53) 19%, than in the ISRT group of patients, (2/37) 5%, (p = 0.026). (4) Conclusions: By reducing the radiotherapy volume and the doses in the treatment of infradiaphragmatic fields, treatment with significantly fewer acute and long-term side effects is possible. At the same time, efficiency and local disease control are not compromised.

Ultra-Hypofractionated Involved Site Radiation Therapy (ISRT) As Salvage or Bridging Therapy in Aggressive Non-Hodgkin Lymphomas

Introduction: Conventional fractionated radiation treatment (RT) to a total dose of 40-50 Gy in 20-25 fractions is typically recommended in the ‘definitive’ intent treatment of aggressive chemorefractory non-Hodgkin lymphoma. However, during the time of COVID-19, recommendations for hypofractionated courses (5-13 fractions) arose (Yahalom et al Blood 2020) as modern radiation techniques should allow similar total doses to be delivered safely in far fewer fractions. Our aim is to evaluate the outcomes and toxicities of ultra-hypofractionated (</=5 fractions) ‘definitive’ ISRT in aggressive non-Hodgkin lymphomas to see if this may be an acceptable alternate recommendation beyond COVID-19. Methods: We conducted an IRB-approved, retrospective review of all aggressive non-Hodgkin lymphoma patients treated at our institution with ‘definitive’ intent (40-50 Gy EQD2 with an α/β of 10) ultra-hypofractionated ISRT between April 2020 and July 2023. Demographic, disease-specific, and treatment-related variables were collected. Primary outcomes include objective response rate (ORR), defined as complete (CR) or partial response (PR) on post-RT positron emission tomography (PET) scans using the Lugano classification, local failure (LF), and radiation-related toxicity per CTCAE v5. Secondary outcomes include overall disease control and survival. Results: 26 ultra-hypofractionated radiation treatments were identified from 23 unique patients who were treated with ‘definitive’ intent ISRT (39.1% salvage, 30.4% early-salvage post CAR-T, and 30.4% bridging to SCT or CAR-T). The most common dose was 30 Gy in 5 fractions (96%); all patients were treated with IMRT with SBRT-type immobilization and image guidance as clinically indicated. The most common diagnosis was DLBCL (91%). 10/23 (43%) patients were female, the majority (82%) were ECOG 0-1 performance status, and the average age at time of RT was 68.9 years. 39% had all FDG-avid sites at the time of radiation treated. The median follow-up was 8.3 months (range 0.3-27.9 months). 26% of patients had acute radiation related toxicities, which were all grade 1-2 with the most common being fatigue (30%). There were no grade 3-4 toxicities, and no subacute or long-term toxicities. Initial local ORR was 20/21, or 95% (86% CR and 10% PR), while initial overall ORR was 12/21, or 57% (52% CR and 5% PR). At time of last follow up, only 1/24 (4%) of irradiated sites had local failure (2 data points N/A), with a TTLF of 1.5 months. 62% of patients had disease progression, with median time to disease progression of 1.5 months. At time of last follow up, 48% were dead, with a median time to death of 6.6 months. Conclusions: Ultra-hypofractionated ISRT in the ‘definitive’ intent treatment of aggressive non-Hodgkin lymphomas has excellent local tumor control and appears to be safe with minimal acute and subacute toxicities. In addition to patient convenience and cost effectiveness, short-course ISRT allows patients to quickly move on to next-line therapy when indicated. Prospective studies and long-term follow up are needed to further validate this as an alternative radiation treatment option.

290P Use of PEG G-CSF is associated with decreased myelotoxicity in dexrazoxane-used aggressive non-Hodgkin lymphoma patients

Dexrazoxane (DXZ) is indicated as a cardioprotective agent for elderly aggressive lymphoma receiving doxorubicin. Several studies reported an apparent increase in the severity of myelosuppression when dexrazoxane was used. Prophylactic use of pegylated granulocyte colony stimulating factor (PEG G-CSF) is known to reduce the incidence of both neutropenia and febrile neutropenia. We conducted a retrospective study to evaluate prophylactic effect of PEG G-CSF in elderly aggressive lymphoma treated with CHOP-based regimen and cardioprotective dexrazoxane.

Impact of Age, Comorbidity, and Polypharmacy on Treatment and Survival for Aggressive Non-Hodgkin Lymphoma

Introduction: Non-Hodgkin's lymphoma (NHL) is the most prevalent hematologic malignancy, with most people diagnosed aged over 65 years (Alexander et. al. Int.J.Cancer 2007). Older populations have more comorbid health conditions, frailty, polypharmacy, and health resource use (Ogle et. al. Cancer 2000). The complex interplay of these factors may influence the prescription of curative therapy and prognosis. In trials evaluating NHL therapies, elderly patients are underrepresented, particularly those with frailty or comorbidity, resulting in knowledge gaps. We report a retrospective, population-based cohort study of aggressive NHL patients and examine the impact of age and its interaction with comorbidity and polypharmacy on treatment patterns and survival. Methods: Using the Manitoba Cancer Registry we identified patients aged over 18 years with NHL diagnosed from 2004-2015. We limited the cohort to aggressive NHL types using morphology codes. Data on demographics, stage, NHL type, comorbidities, polypharmacy, and chemotherapy were obtained from population-based provincial databases. Comorbidity was measured using Johns Hopkins ACG System software, which factored in all measured hospital-based and outpatient medical services utilized and collapsed them into one of six Resource Utilization Band (RUB) categories, from no use to very high user. Overall survival (OS) was calculated using Kaplan-Meier curves. Cox proportional hazards regression models were constructed to determine the interaction of age with a variety of factors. Multi-variable logistic regression was also used to examine the receipt of chemotherapy and the interaction with age. Results: In our cohort of 1,073 patients with aggressive NHL, 704 were treated with systemic chemotherapy. Treatment rates decreased with increasing age and medication count, while stage and comorbidity had little impact (Table 1). Median OS decreased with age among treated patients and was very short without chemotherapy (Table 1). Multivariate analyses found that individuals with increasing age, stage III, unknown stage, histology other than DLBCL, and higher medication counts were less likely to receive chemotherapy. For the receipt of chemotherapy, no age interactions were found. In addition, in patients who received chemotherapy, increased age and stage were associated with poorer survival, while more recent year of diagnosis improved survival. No age interactions with a substantial impact on survival were found. Conclusions: OS in aggressive NHL diminishes with increasing age, but is longer in those receiving chemotherapy across all age groups. Comorbidity and medication count influenced the receipt of chemotherapy and OS. Higher medication count was only independently associated with less likelihood of receiving chemotherapy, while comorbidity was not independent of other factors for either receipt of chemotherapy or OS. Disclosures Dawe: AstraZeneca Canada: Research Funding; AstraZeneca Canada: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Merck Canada: Membership on an entity's Board of Directors or advisory committees.

EFS12 Is a Powerful Predictive Tool for Outcomes in Stage I Aggressive Non Hodgkin Lymphoma: A Report from Nationwide Registry in a Resource Limited Country Thai Lymphoma Study Group

Introduction: Stage I disease represents a minor subset of aggressive Non-Hodgkin Lymphoma (NHL) accounting around 10%. Overall prognosis is generally good but varied upon different histologic subtypes and topographic presentation. Herein, we describe an implication of event free survival at 12 months (EFS12) as a predictor for outcomes of stage I aggressive NHL including real-world data on clinical characteristics and treatment patterns of stage I aggressive NHL in a resource-limited country. Patients and methods: Thai lymphoma study group conducted the lymphoma registry which prospectively enrolled and systematically followed newly diagnosed lymphoma patients between 2007 and 2014 from 13 nationwide major University hospitals. We abstracted data of stage I aggressive NHL patients from the registry and obtained additional information from medical record. Clinical characteristics, treatment patterns and survival outcomes were described. EFS12 was a binary endpoint defined as whether patients developed events at 12 months after treatment initiation. Overall survival (OS) was defined as duration from a specific time-point either at the time of diagnosis, at EFS12 time-point to or at the event to death from any causes. Logistic regression model was used to evaluate the association between clinical characteristics and EFS12. Cox regression with EFS12 as a time-dependent co-variate and other clinical parameters were applied to evaluate association between EFS12 and OS. Results: Of 4,371 newly diagnosed lymphomas, there was a total of 636 stage I lymphoma patients (6.86%) including 590 NHL (519 B cell, 71 T/NK cell) and 46 HL. Among 590 stage 1 NHL, 435 were considered patients (356 diffuse large B cell lymphoma (DLBCL) and 8 Burkitt lymphoma (BL), 19 peripheral T cell lymphoma not otherwise specified (PTCL-NOS), 7 angioimmunoblastic T cell lymphoma (AITL), 11 anaplastic large cell lymphoma (ALCL), 1 other PTCL subtypes and 33 extranodal NK T cell lymphoma (ENKTL)). Table 1 summarizes baseline characteristics and treatment data of stage I aggressive NHL. At the time of analysis 61 patients relapsed and 146 patients had died. Major causes of death included infection related events (n=37, 25.3%), non-infectious related complication (n=21, 14.4%) and disease progression (n=60, 41.1%) respectively. With a median follow up of 47.3 months, both median event free survival (EFS) and overall survival (OS) were not reached with corresponding 4 years EFS and 4 years OS of 79.0% and 68.9% respectively (Figure 1A). Four-years OS of patients with aggressive B cell NHL, PTCL and ENKTL was 70.2%, 75.5% and 48.0% respectively. A total of 328 patients achieved EFS12 (No event within the first 12 months after first line treatment initiation). Patients who achieved EFS12 had significant better OS than patients who failed to achieve EFS12 (4-years OS 89.1% vs 7.1%, Hazard ratio 25.9, 95% Confidence Interval 17.7-37.9, P<0.001) (Figure 1C, 1D). Non-relapsed mortality and cumulative incidence of relapse was 15.1% and 19.0% respectively (Figure 1B). By using multivariable cox regression analysis, factors associated with favorable survival outcomes included absence of B symptoms, complete remission from therapy and achieving EFS12 (Table 2). Conclusion: Stage I disease represented a small proportion of aggressive NHL. Natural history and prognosis were highly varied depending upon histology. EFS12 was a power prognostic factor for stage I aggressive NHL and could be used as a clinical tool to stratify patients. Optimal treatment is to be defined to improve outcome and meanwhile minimize toxicities for stage I aggressive NHL patients. Disclosures No relevant conflicts of interest to declare.

Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas.

Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas.

Third line Treatment in Relapsed/Refractory Hodgkin's Lymphoma and Aggressive non-Hodgkin Lymphoma after 2nd line ESHAP or GEMOX

Background: Treatment after failure of 2nd line chemotherapy in patients with Hodgkin's lymphoma (HL) or aggressive non-Hodgkin’s lymphoma (NHL) is not well studied. Aim: To assess the value of 3rd line treatment in a cohort of HL and aggressive NHL patients. Methods: This was a retrospective study of patients with relapsed/refractory HL or aggressive NHL treated with 3rd line treatment based on physician choice. Response rate as well as overall survival (OS) and factors affecting it were assessed. Results: Fifteen (41%) out of 37 patients who failed 2nd line received 3rd line. The remaining 22 received single-agent palliative chemotherapy or best supportive care only. Third line treatment was IGEV (ifosfamide, gemcitabine, navelbine) in 7 (47%) patients, lenalidomide in 4 (26%), ESHAP (etoposide, methylprednisolone, cytosine arabinoside, cisplatin) in 2 (13%) and GEMOX (gemcitabine, oxaliplatin) in 2 (l3%). Four (27%) patients achieved complete remission (2 with IGEV and 2 with lenalidomide) and 3 of them underwent autologous stem cell transplantation. One (7%) patient achieved partial response and another one (7%) had stable disease. The median OS for the whole group was 4.7 months. For patients who received 3rd line the OS was significantly longer than those who didn’t (13.4 vs. 3.4 months, p=0.001). Among the whole set of patients, performance status, lactate dehydrogenase, tertiary age-adjusted International Prognostic Index, 3rd line treatment, response to 3rd line and transplantation had significant impact on OS.Conclusion: Third line treatment may be feasible in selected HL and aggressive NHL patients who failed 2nd line.

Analysis of clinical efficacy and prognostic factors of double autologous hematopoietic stem cell transplantation in treatment of aggressive non-Hodgkin lymphoma

Objective To investigate the clinical efficacy and prognostic factors of double autologous hematopoietic stem cell transplantation (DAHSCT) in treatment of aggressive non-Hodgkin lymphoma (NHL). Methods From March 2001 to December 2014, a total of 48 patients with aggressive NHL who underwent scheduled DAHSCT in Tangdu Hospital, the Fourth Military Medical University were selected as the study subjects. Among them, 29 patients were male and 19 cases were female; and 22 patients were with B-cell non-Hodgkin lymphoma (B-NHL), 26 cases were with T-cell non-Hodgkin lymphoma (T-NHL). All 48 patients underwent the second autologous hematopoietic stem cell transplantation (auto-HSCT) within 2 to 6 months after receiving the first auto-HSCT. Retrospective analysis was used to collect clinical data from all patients, including age, occurrence of B symptoms, clinical staging of Ann Arbor/Cotswolds staging system, level of serum lactate dehydrogenase (LDH), international prognostic index (IPI) score, occurrence of extra-nodal lesions, and remission status of disease before the first and second auto-HSCT, etc.. Kaplan-Meier method was used to analyze the survival of 48 NHL patients. Univariate Cox regression analysis was used to analyze the factors that may influence the overall survival (OS) period of NHL patients after DAHSCT. According to the available research results and clinical experience, the further multivariate Cox regression analysis was carried out for the factors that were statistically significant in the univariate analysis, as well as some factors that were not statistically significant in the univariate analysis, but with clinical significance. Results ① All 48 aggressive NHL patients were collected enough peripheral blood stem cells, and got hematopoietic reconstitution after receiving auto-HSCT. In this study, the median number of CD34+ cells transfused was 3.40×106/kg [(2.70-8.70)×106/kg] in the first auto-HSCT and 3.68×106/kg [(2.95-8.00)×106/kg] in the second auto-HSCT, respectively. And the median time of platelet reconstruction was 12.0 d (9.0-17.0 d) in the first auto-HSCT and 14.0 d (9.0-18.0 d) in the second auto-HSCT, respectively. The median time of neutrophil reconstruction after transplantation was 12.0 d (9.0-16.0 d) in the first auto-HSCT and 13.0 d (9.0-16.0 d) in the second auto-HSCT, respectively. ② For all 48 patients, the overall response rate of DAHSCT was 93.8% (45/48) after receiving DAHSCT. The median follow-up time was 78.0 months (42.0-105.0 months). In this study, the rates of disease-free survival, recurrence and mortality were 64.6% (31/48), 16.7% (8/48) and 22.9% (11/48), respectively. ③ In this study, 5-year OS rate was 76.6% and 5-year progression-free survival (PFS) rate was 65.8%. ④ Results of univariate Cox regression analysis showed that achievement of complete remission (CR) before the second auto-HSCT was a protective influencing factor of OS period for aggressive NHL patients (HR=0.174, 95%CI: 0.051-0.598, P=0.005). And multivariate Cox regression analysis of factors that may influence the OS period of NHL patients showed that achievement of CR before the second auto-HSCT was an independent protective influencing factor of OS period for aggressive NHL patients (HR=5.046, 95%CI: 1.031-24.683, P=0.046). Conclusions DAHSCT treatment for aggressive NHL has good efficacy, especially for the patients with CR before the second auto-HSCT. However, whether DAHSCT deserves further clinical application in treatment of aggressive NHL patients still needs further study to confirm. Key words: Lymphoma, non-Hodgkin; Hematopoietic stem cell transplantation; Transplantation, autologous; Autologous hematopoietic stem cell transplantation

Polypharmacy and potentially inappropriate medication use in older patients with aggressive non-Hodgkin lymphoma (NHL) leads to inferior survival and increased treatment-related toxicities.

10039 Background: Survival outcomes for older patients with aggressive NHL are disproportionally inferior to those of younger patients. While differences in tumor biology may play a role, older patients are often frail with comorbidities, polypharmacy, and use potentially inappropriate medications (PIM) such as anticholinergics and benzodiazepines. Methods: Using Cox proportional hazard and logistic regression models, we analyzed all aggressive NHL patients age ≥60 treated at our two affiliated hospitals from 2009-2014 to examine the association of polypharmacy and PIM use with progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Results: In this updated and final analysis, we included 171 patients with complete records from these two hospitals. They share similar demographic, clinical, and laboratory characteristics except for higher International Prognostic Index (IPI) in patients from one hospital. The median age was 70 years (range 65-77). At the time of diagnosis, 46% of patients used more than 4 medications (polypharmacy) and 47% used at least one PIM. Only 43% of patients received first-line chemotherapy of adequate relative dose intensity (>85% dosage), and 65% experienced ≥grade 3 toxicities. Polypharmacy and PIM use were associated with shortened PFS and OS by log-rank test. Most importantly, PIM use remained an independent predictor of PFS, OS, and ≥ grade 3 toxicities in multivariable analyses (Table). Conclusions: This is the first report of significantly adverse survival impacts of polypharmacy and PIM use in older patients with aggressive NHL, presumably from drug-drug interactions that increase toxicities and impair the delivery of adequate chemotherapy dosage. Our findings support the use of evidence-based geriatric principles to guide meticulous medication management to improve outcome disparity for these patients. [Table: see text]

Haploidentical Stem Cell Transplantation after Myeloabaltive Conditioning Is a Valid and Safe Option for Young Patients with Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma: A Study Compared with HLA-Matched Transplant

Purpose: The role of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) therapy for refractory or relapsed (R/R) aggressive non-Hodgkin lymphoma (NHL) patients was still unknown. In this study, we aimed to explore the clinical outcome of R/R aggressive NHL patients received haplo-HSCT treatment.Patients and Methods: 23 R/R aggressive NHL patients who had undergone haplo-HSCT in our center between February 2006 and October 2015 were retrospectively analyzed, and 25 R/R aggressive NHL patients who received HLA-matched HSCT at the same period were also involved in this study. All patients received myeloablative conditioning (MAC) regimen, and antithymocyte globulin, cyclosporine A, mycophenolate mofetil and short course of methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. 12 patients had experienced autologous HSCT prior to allo-HSCT.Results: The median age of the total 48 patients was 33 (16-58) years old, and there were 33 males and 15 females in the total cohorts. The diagonosis were as following: 16 (33%) diffuse large B cell lymphoma and 22 (46%) peripheral T cell lymphoma. There were no difference in sex, age at transplantation, histologic diagnosis, aaIPI score, previous ASCT and conditioning regime between HLA-matched HSCT and Haplo-hsct groups. 44 patients had achieved engrafment, and the median times to neutrophil and platelet recovery were 12 and 15 days, respectively. Incidences of grade 3-4 acute GVHD were 18.3% in haplo-HSCT group and 16.7% in HLA-matched HSCT groups(p=0.87), while 2 years cumulative incidences of chronic GVHD in these two groups were 43.5% and 36.7% (P=0.68). For 16 patients who had chemoresistant disease at transplantation in haplo-HSCT group, four patients achieved complete remission, and ten patients achieved partial remission, while the other two patients experienced disease progression at 21 days and 37 days, respectively. With a median follow-up of 25 months, 12 patients experienced disease recurrence or progression in haplo-HSCT. And four patients died of transplantation related mortality: infection (n=2); acute GVHD (n=1) and multi-organ failure (n=1). There were no differences in overall survival (OS) rate at 2 years (52.8% vs 57.0%, P=0.85) and 2 years progress free survival (PFS) rate (52.7% vs 56.9%, p=0.73) between the haplo-SCT and HLA-matched SCT groups. Multivariate analyses suggested that old age (>45 years)(p=0.02), primarychemorefractory (p=0.04)and occurrence of grade3-4 aGVHD (p=0.01) may contribute to poor prognosis.Conclusion: Haploidentical hematopoietic stem cell transplantation withmyeloablative conditioning regimenachieved satisfactory outcome with acceptable side-effects. This approachcan be a feasible and acceptabletherapy for young patients withR/R NHLwho have no access to a HLA-matched donor. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Contribution of polypharmacy and potentially inappropriate medication use to inferior survival in older patients with aggressive lymphoma.

129 Background: Survival outcomes for older patients with aggressive non-Hodgkin’s lymphoma (NHL) are disproportionally inferior to those of younger patients. While differences in tumor biology may play a role, older patients are often frail with comorbidities, polypharmacy, and use potentially inappropriate medications (PIM). Methods: Using Cox proportional hazard and logistic regression models, we retrospectively analyzed all aggressive NHL patients age 60 and older diagnosed and treated at our institution from 2009-2014 to examine the effect of polypharmacy and PIM use on progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Results: We included 141 patients with evaluable data after excluding patients with incomplete record. The median age was 71 years. At the time of diagnosis, 44% of patients used more than 4 medications and 47% used at least one PIM. During first-line treatment, only 43% of patients received chemotherapy of adequate relative dose intensity (>85% scheduled dose), and 63% experienced grade 3 or greater toxicities. Age, International Prognostic Index, and PIM use correlated with each other. Number of medications (p = 0.005) and PIM use (p < 0.001) were associated with shortened PFS by log-rank test, and PIM use remained a strong independent predictor of PFS in multivariable analysis (HR 1.84, p = 0.005). Number of medications (p = 0.003) and PIM use (p = 0.009) were also associated with shortened OS by log-rank test, although only albumin level predicted OS in multivariable analysis. Most importantly, PIM use was strongly associated with grade 3 or greater toxicities in multivariable analysis (OR 7.4, p = 0.001). Conclusions: We report here for the first time adverse impacts of polypharmacy and PIM use in older patients with aggressive lymphoma. We suggest that drug-drug interactions may significantly impair the delivery of adequate chemotherapy dosage and increase toxicities thus resulting in inferior survival outcome. Our findings support the use of evidence-based geriatric and palliative care principles to guide meticulous medication management to eliminate outcome disparity in older lymphoma patients.

Outcome of haploidentical hematopoietic stem cell transplantation for non-Hodgkin lymphoma

目的探讨单倍型造血干细胞移植（Haplo-HSCT）治疗复发难治侵袭性非霍奇金淋巴瘤（NHL）患者的疗效和安全性。方法回顾性分析2004年1月至2015年3月采用亲缘Haplo-HSCT治疗的26例复发难治侵袭性NHL患者临床资料。结果26例患者中弥漫大B细胞淋巴瘤（DLBCL）4例，滤泡性淋巴瘤1例，B淋巴母细胞淋巴瘤／白血病5例，T淋巴母细胞淋巴瘤／白血病9例，间变性大细胞淋巴瘤（ALK阴性）1例，外周T细胞淋巴瘤（非特指型）5例，NK/T细胞淋巴瘤1例。Ann Arbor分期：Ⅲ期6例，Ⅳ期20例。26例患者移植前状态：第1次完全缓解（CR1) 7例，第2次完全缓解（CR2）4例，部分缓解（PR）7例，疾病稳定（SD）1例，疾病进展（PD）7例。其中复发难治性病例19例。移植后26例患者均获粒系造血重建，粒细胞中位植入时间为12(11~17) d。25例患者获巨核系造血重建，血小板中位植入时间为14(11~31) d。所有患者在+30 d经植入鉴定证实为完全供者嵌合体。中位随访时间14(4~136）个月，26例患者中20例（76.92%）存活，15例（57.69%）无病存活，7例（26.92%）复发（其中2例死亡，5例存活）。预处理相关不良反应经对症处理后症状均消失。Haplo-HSCT后2年累积复发率为42.20%；2年总生存（OS）率为71.60%；2年无病生存（DFS）率为48.90%。移植前CR患者移植后2年OS与DFS率均明显高于移植前未达CR的患者（OS：100.0％对52.4%，P=0.023；DFS：88.9％对27.0%，P=0.013）。结论对于不适合行自体造血干细胞移植且无完全相合供者的复发难治侵袭性NHL患者，尝试进行Haplo-HSCT有效、安全。

Identification of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the peripheral blood of Hodgkin and non-Hodgkin lymphoma patients.

Human granulocytic myeloid-derived suppressor cells (G-MDSCs) have been described as low-density immunosuppressive CD66b+CD33dimHLA-DR-granulocytes that co-purify with mononuclear cells after density gradient centrifugation of blood from cancer patients. The role of G-MDSCs in Hodgkin (HL) and non-Hodgkin lymphoma (NHL) remains unclear.The percentage and immunophenotype of CD66b+CD33dimHLA-DR-cells were analyzed in PBMCs from HL and B-cell NHL patients (n = 124) and healthy donors (n = 48). The immunosuppressive functions of these cells were tested in vitro. Correlations between CD66b+CD33dimHLA-DR-cells and patient clinicopathological features and outcome, were evaluated.CD66b+CD33dimHLA-DR-cells were increased in PBMCs from HL and B-cell NHL patients as compared to healthy donors: 2.18 (0.02–70.92) vs 0.42 (0.04–2.97), p < 0.0001. Their percentage remained significantly higher even considering HL (n = 31), indolent (n = 31) and aggressive (n = 62) B-cell NHL patients separately: 1.54 (0.28–26.34), 2.15 (0.02–20.08), and 2.96 (0.25–70.92), respectively, p < 0.0001. CD66b+CD33dimHLA-DR-cells in patient PBMCs were mostly composed of mature CD11b+CD16+ low-density neutrophils in an activated status, as revealed by their higher CD11b and CD66b expression as compared to conventionally isolated (normal-density) autologous or healthy donor neutrophils. The in vitro depletion of CD66b+ cells from patient PBMCs restored the proliferation of autologous T cells. Higher frequencies of CD66b+CD33dimHLA-DR− G-MDSCs correlated significantly with unfavorable prognostic index scores and a shorter freedom from disease progression.PBMCs from HL and B-cell NHL patients contain a population of CD66b+CD33dimHLA-DR− G-MDSCs, mostly composed of activated low-density neutrophils with immunosuppressive properties. These findings disclose a previously unknown G-MDSC-mediated mechanism of immune-escape in lymphomas, therefore anticipating possible targets for therapeutic interventions.

A multicenter phase II study of sepantronium bromide (YM155) plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma

This phase II study evaluated YM155, a novel small-molecule survivin suppressant, in combination with rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who failed or were not candidates for autologous stem cell transplant (ASCT). During 14-day cycles, 41 patients received YM155 (5mg/m2/d) by continuous intravenous (IV) infusion for 168 hours (day 1–7), and rituximab (375mg/m2) IV on days 1 and 8 during cycles 1–4 and repeated for 4 cycles every 10 cycles. Forty patients (97.6%) had prior rituximab and 15 patients (36.6%) prior ASCT. Most frequent grade 3–4 adverse events were neutropenia (19.5%) and thrombocytopenia (12.2%). In the per-protocol set (n = 34), objective response rate was 50% and median progression-free survival 17.9 months. Median overall survival was not reached at study termination (median follow-up, 23 months). YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients.

Clinical significance of interleukin-4 and interleukin-18 levels in aggressive non-Hodgkin's lymphoma patients.

Strong evidence indicates that tumor growth can be actively controlled by the immune system, and interleukins (ILs) are known to play an influential role in immune response regulation. Moreover, inflammatory cytokines are significantly involved in lymphoma pathogenesis. We aimed to investigate serum levels of IL-4 and IL-18 in aggressive non-Hodgkin's lymphoma (A-NHL) patients and their relationship with prognostic parameters and therapy outcome. These serum factors were measured by enzyme-linked immunosorbent assay in 46 patients with pathologically verified A-NHL before and after chemotherapy, and in 20 healthy controls. No significant difference in serum IL-4 (P = 0.11) and IL-18 (P = 0.261) levels was observed between the A-NHL and controls groups. None of the prognostic parameters analyzed significantly correlated with serum IL-4 concentration, while only lactate dehydrogenase (LDH) measurements were associated with IL-18 values. Serum IL-18 was elevated in the patients with high LDH levels compared to those exhibiting normal values (P = 0.045). In addition, no correlation was found between the concentrations of serum IL-4 and IL-18 in A-NHL patients (r = 0.188, P = 0.187). While IL-18 values did not change, serum IL-4 levels decreased following chemotherapy, independently from treatment response (P = 0.002). Our study is the first to report the response of serum IL-4 levels to chemotherapy. In conclusion, although IL-4 serum concentration has no diagnostic role, it is sensitivite to standard chemotherapy in A-NHL. However, serum IL-18 measurements have no diagnostic or prognostic role in this disease.

Persistent Disparities Among Patients With T-Cell Non-Hodgkin Lymphomas and B-Cell Diffuse Large Cell Lymphomas Over 40 Years: A SEER Database Review.

As of 2013, more than 550,000 people are living with non-Hodgkin lymphoma (NHL). We undertook a large Surveillance Epidemiology and End Results (SEER) based analysis to describe outcome disparities in different subgroups of aggressive T-cell and B-cell NHL patients, with a focus on various ethnicities. The final analysis included 7662 patients with T-cell and 84,910 with B-cell NHL. Survival analysis revealed that male sex and increasing age were independent predictors of worse overall survival (OS; P < .001). For aggressive T-cell NHL, there was no significant improvement in median OS between 1973 and 2011 (P = .081), and ethnic minorities (Asians, Hispanics, and African Americans) had significantly worse OS than whites (P < .001). There were similar trends for age, sex, and race for diffuse large B-cell NHL, but a significant improvement in median OS was seen over time (P < .001). These results are the first to elicit outcomes in a broad classification of ethnic minorities and underscore the urgency for development of novel therapeutics, especially in T-cell NHL. In addition, in-depth studies of disease biology and health care utilization are required for better triage of health care resources, especially for ethnic minorities.

Are the high serum interleukin-6 and vascular endothelial growth factor levels useful prognostic markers in aggressive non-hodgkin lymphoma patients?

Objective:Pro-inflammatory and pro-angiogenic cytokines play an important role in the pathogenesis of lymphoma, and recent studies have shown that cytokines can be used as prognostic markers. Non-Hodgkin lymphoma (NHL) patients with high levels of serum interleukin-6 (s-IL6) and serum vascular endothelial growth factor (s-VEGF) have poor prognosis and shorter survival time. We aimed to determine pre-treatment levels of s-IL6 and s-VEGF and their relation with known prognostic markers, especially International Prognostic Index (IPI) scores, and to examine their effects on overall survival in newly diagnosed, untreated aggressive NHL patients. Materials and Methods:The study included 51 newly diagnosed NHL patients and 17 healthy controls. Blood samples were obtained to study s-IL6 and s-VEGF cytokine levels. Results:Patients with aggressive NHL diagnosis had higher s-VEGF and s-IL6 levels than the healthy population. If the s-IL6 levels of patients were above the cut-off levels, the overall survival time was shorter. There was no relation between s-VEGF and overall survival time. Conclusion:s-IL6 is an independent prognostic factor that may be included in IPI risk classification. In addition to the s-IL6 level, age, erythrocyte sedimentation rate, beta-2 microglobulin, WHO performance status, and IPI score are independent prognostic factors that are effective, especially for overall survival, in the clinical follow-up of NHL patients.

Predictors of Hospice Utilization Among Patients with Lymphoma

Background: Although there is an increasing focus on the provision of quality end of life (EOL) care for cancer patients, little is known about the factors that influence hospice use for patients with lymphoma. Utilization of palliative services is also felt to be lower in hematologic oncology. We aimed to characterize the prevalence and predictors of hospice enrollment in a large population of patients with B-cell non-Hodgkin lymphoma (NHL).Methods: We conducted a retrospective analysis using the Surveillance Epidemiology and End Results (SEER)-Medicare database. Patients ≥ 65 years of age who were diagnosed with any B-cell NHL, lived for at least 30 days, and died between January 1, 2000 and December 31, 2010 were eligible. We divided the cohort into three groups: those with indolent NHL (chronic lymphocytic leukemia and follicular, marginal zone, and lymphoplasmacytic lymphoma), aggressiveNHL (diffuse large B-cell, Burkitt, primary mediastinal B-cell, and primary effusion lymphoma), and mantle cell lymphoma (MCL). MCL was considered a unique group because, while it is largely incurable like indolent NHL, it often has a more aggressive clinical course. We first characterized the prevalence and covariates of hospice use in the cohort. Next, we fit a multivariable logistic regression model to characterize factors associated with hospice use, including NHL type (indolent, aggressive, MCL) and patient sociodemographic characteristics with p < 0.05 in univariable analyses.Results: A total of 18, 815 patients were eligible, of which 9,666 had indolent NHL, 8,241 had aggressive NHL, and 908 had MCL. Of the total cohort, 7,820 (42%) enrolled in hospice, with 6,450 (34% of the total cohort) enrolled ≥ 3 days before death. There were significant differences in hospice use by NHL type, with 39% of indolent NHL patients, 44% of aggressive NHL patients, and 48% of MCL patients enrolling in hospice respectively (p < 0.001). Multivariable associations of patient characteristics with hospice use are shown below. [Display omitted] The median time from diagnosis to death was significantly longer for patients who enrolled in hospice (37.5 months) compared with those who did not enroll (31.8 months, p < 0.001); effects were similar in analyses stratified by lymphoma type.Conclusions: In this large cohort of patients with B-cell NHL, the rate of hospice use ≥ 3 days before death (34%) was substantially lower than the 2007 national average of 43% for all cancer decedents (National Hospice and Palliative Care Organization Facts and Figures, 2012). This finding is provocative: it suggests either the need for improvements in enrollment and/or that our current hospice model is not meeting the specific needs of lymphoma patients in the United States. We also found disparities in hospice use similar to those previously observed in solid malignancies, with non-white patients and those of lower socioeconomic status less likely to enroll. Moreover, patients who enrolled were more likely to have lived longer after their diagnosis, perhaps due to increased experience with and thus desire to avoid the burden of additional treatments. Finally, the fact that patients with MCL had the highest rate of enrollment may reflect its increased symptom burden, and often aggressive course in the context of being incurable. These may be clearer indicators of the EOL phase and the need for hospice. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic hematopoietic stem cell transplantation for aggressive lymphomas

SUMMARY The heterogeneity of lymphomas results in a wide therapeutic options including both autologous and allogeneic hematopoietic stem cell transplantation (allo-HSCT). We reviewed the role of allo-HSCT in a high-risk group of aggressive non-Hodgkin lymphoma patients such as those with relapsed or refractory disease, especially after autologous HSCT. Moreover, we have analyzed the different modalities of conditioning with myeloablative, reduced-intensity or non-myeloablative regimens, considering their pro and contra, in order to highlight the best approach with allo-HSCT for different scenarios.