Favorable Outcome After Adjuvant Involved-Field Radiotherapy After Autologous Hematopoietic Stem-Cell Transplantation in Patients With High-Risk Relapsed/Refractory Lymphoma: A Single-Center Experience

BackgroundPatients with refractory or relapsed lymphoma diagnosed with bulky disease at relapse or with residual disease after salvage treatment are considered to have a dismal outcome, even after autologous hematopoietic stem-cell transplantation, as a result of disease recurrence. To minimize the risk of relapse after receipt of a transplant, involved-field radiotherapy (IFRT) to sites of either bulky or localized residual disease has been utilized; however, the ideal timing for irradiation remains controversial. The aim of this study was to assess the safety and efficacy of IFRT in the early period after transplantation.Patients and MethodsWe retrospectively evaluated the outcome of 24 autografted patients with relapsed/refractory lymphoma who presented with bulky disease at relapse or who had a persistent localized residual mass after salvage treatment and consolidated with IFRT within 4 months after autografting.ResultsNo significant toxicity was noticed during the early postradiotherapy period, while graft function was not impaired. After a median follow-up of 3 years for survivors, 21 patients were alive, 19 of whom were event free, while 2 patients died of disease recurrence and 1 died of treatment-related myelodysplastic syndrome. The 3-year overall, lymphoma relapse-free, and event-free survival rates were 86%, 86%, and 82%, respectively.ConclusionTaking into consideration the poor-risk features of the study cohort, IFRT provided early after autologous hematopoietic stem-cell transplantation showed a safe and well-tolerated toxicity profile and demonstrated long-term effective tumor control, as reflected in the promising survival rates.     

Prognostic Factors for the Long-Term Survival after Hematopoietic Stem Cell Transplantation in Patients with Hodgkin Lymphoma

Objectives: This study investigated the possible prognostic factors for the long-term survival (Cure Rate) of Hodgkin Lymphoma patients who underwent HSCT. Methods: This retrospective cohort study analyzed 116 Patients diagnosed with Hodgkin Lymphoma who received autologous hematopoietic stem cell transplantation (Auto-HSCT) between the years 2007 and 2014 and followed up until 2017. The information regarding patients’ survival had been collected using phone calls, and their pre-transplant information was available in the archived documents. Prognostic effects were investigated using long-term survival models. Results: Patients with obesity had five times higher odds of long-term survival (cure) than the others (P=0.06). Also, the recurrence experience after HSCT negatively impacted the curing potential by 78% (P=0.05). Also, with 32 years as the change point, patients younger than 32 had 76% fewer odds of surviving long-term (P=0.03), and Poor transfused stem cell dose of CD34+ (<0.16 × 106 cells/ml) reduced the odds of long-term survival by 92% (P=0.01). Conclusion: According to the statistical models used in this study, obesity can increase the curing potential of Hodgkin lymphoma after transplantation. Meanwhile, aging, poor transfused CD34+ cells, and recurrence after HSCT were associated with lower survival following HSCT.     

应用多重标记法探讨经典型Hodgkin 淋巴瘤H/RS 细胞的细胞属性

 目的 探讨经典型Hodgkin淋巴瘤H／RS细胞的细胞属性。方法 应用免疫组化多重标记法和原位杂交技术检测CD3、CD20、CD15、CD30、CD10、MP0、bcl一6、κ cmRNA和λmRNA在62例经典型Hodgkin淋巴瘤H／RS细胞的表达。结果 62例的H／RS细胞CD30全部阳性，41例表达CD15，只有5例表达CD20，均不表达CD3、bcl-6、CD10、κcmRNA、λmRNA。结论 经典型Hodgkin淋巴瘤的H／RS细胞为生发中心后期分化的B细胞起源；H／RS细胞对B系标记有较大的变异。它不表达免疫球蛋白轻链κ和λ，可能是这些肿瘤细胞无免疫球蛋白的合成。     

Impact of Cell of Origin on Outcomes After Autologous Hematopoietic Cell Transplant in Diffuse Large B-Cell Lymphoma

Germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) at diagnosis is associated with superior long-term outcomes compared to non-GCB-DLBCL in patients treated with conventional chemo-immunotherapy. Whether cell of origin (COO) by Hans algorithm retains its prognostic significance in patients with (R/R) relapsed/refractory DLBCL undergoing autologous hematopoietic cell transplant (auto-HCT) is not well established. Three hundred and fifty-seven patients underwent auto-HCT between 2005 and 2018. The COO status was determined in 284 patients and these were included in the analysis. One hundred ninety-four patients had GCB-DLBCL while 90 had non-GCB-DLBCL. Median follow up was 1.7 (0-13) years. The GCB-DLBCL was associated with inferior 5-year overall survival at 44% (95%CI, 36-52) versus 64% (95%CI, 54-77) (P = .004) and a higher relapse incidence at 67% (95%CI, 58-74) versus 49% (95%CI, 35-60) (P = .01) in the non-GCB-DLBCL. The difference between GCB and non-GCB-DLBCL remained statistically significant in multivariate analysis. Additionally, response at the time of transplant was an independent prognostic factor. GCB-DLBCL was enriched in double-hit and triple hit phenotype based on available fluorescence in situ hybridization data. These results suggest an enrichment of high-risk genetic rearrangements in R/R GCB-DLBCL resulting in limited efficacy of auto-HCT.     

Brentuximab Vedotin and Bendamustine Produce Long-Term Clinical Benefit in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma: A Multicenter Real-Life Experience

BackgroundPatients with relapsed or refractory classical Hodgkin lymphoma (R/R cHL) have limited opportunities for curative therapy. High-dose therapy followed by autologous stem cell transplantation (HDT-ASCT) produces cure rates of 50% to 60%. Patients relapsing after, or ineligible for HDT-ASCT have limited therapeutic options and long-term remission is uncommon. Furthermore, few patients are candidate to allogeneic stem cell transplantation (AlSCT), a potentially curative approach. The combination of brentuximab vedotin and bendamustine (BVB) is a promising treatment for patients with R/R cHL, regardless of SCT eligibility.Patients and methodsWe conducted a real-life study of BVB in 41 patients with R/R cHL after failure of ≥ 1 therapy including ASCT, AlSCT, or BV.ResultsAmong 40 patients evaluable for efficacy, the overall response rate and complete response (CR) rate were 75% and 50%, respectively. No significant differences were observed between patients with primary refractory and relapsed disease, previously treated with ≤ 2 and ≥ 3 lines of therapy, or BV-exposed and BV-naïve. After a median follow-up of 38 months, the median progression free survival (PFS) for the entire population is 26 months; PFS is not reached, 10.5 months, and 4 months for patients achieving CR, partial response and no response, respectively (P < .0001). BVB was well tolerated and no grade 4 toxicity or new safety signals were observed. The most common treatment-emergent adverse events were infections.ConclusionOur experience supports the efficacy and tolerability of the BVB combination in R/R cHL as a bridge to SCT, or as a definitive therapy for SCT-ineligible patients. Larger comparative studies testing BVB against standards of care are warranted in both settings.     

Late Relapses After High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients With Diffuse Large B-cell Lymphoma in the Rituximab Era

BackgroundThe standard of care for diffuse large B-cell lymphoma (DLBCL) relapsing after front-line therapy is high-dose chemotherapy and autologous stem cell transplantation (ASCT). Evidence has suggested that early relapses (ie, within 1 year) after this approach portends exceptionally poor outcomes. However, data examining relapses > 1 year after ASCT for patients with refractory or relapsed DLBCL are limited, in particular, in the rituximab era. We sought to examine the effect of early (≤ 1 year) and late (> 1 year) relapse after ASCT in a single-institution cohort of patients with relapsed and refractory DLBCL treated with chemoimmunotherapy.Materials and MethodsA retrospective analysis was performed on the data from 85 consecutive patients who had undergone ASCT for biopsy-confirmed relapsed or refractory DLBCL from 2001 to 2010 at the University of Rochester Medical Center. All patients had received rituximab as a part of treatment. Of the 85 patients, 35 developed relapse after ASCT. These 35 patients were divided into 2 groups according to the timing of the relapse (≤ 1 year and > 1 year after ASCT).ResultsThe median follow-up period was 6.4 years. For all patients, the overall survival (OS) from post-ASCT relapse was 5.2 years. For the 27 patients developing relapse at ≤ 1 year after ASCT, the median OS was 0.6 year and progression-free survival was 0.4 year. For the 8 patients developing relapse at > 1 year after ASCT, the median OS was 5.9 years and progression-free survival was 2.9 years.ConclusionPatients with relapsed or refractory DLBCL experiencing relapse > 1 year after ASCT had good outcomes. Despite the relative rarity in incidence, a significant risk of relapse of DLBCL after ASCT remains, suggesting the need for continued monitoring because of the possibility of later progression.     

Limited Utility of Surveillance Imaging for Detecting Disease Relapse in Patients With Non-Hodgkin Lymphoma in First Complete Remission

IntroductionSurveillance imaging with computed tomography (CT) or positron emission tomography with CT (PET/CT) is commonly used in practice in patients with non-Hodgkin lymphoma (NHL) who are in remission after front-line therapies. We aimed to determine the utility of routine imaging for detecting first relapse in patients with NHL in complete remission (CR) after first-line therapies.Patients and MethodsWe retrospectively analyzed patients with NHL who achieved CR after first-line therapies and then subsequently had disease relapse. We evaluated whether the relapse was detected solely by surveillance CT or PET/CT or by patient-reported symptoms or physical examination findings, or both. Subgroup analysis was performed on baseline histologic type (indolent vs. aggressive NHL). Data were also collected to determine the cost of surveillance PET/CT and the number of additional diagnostic imaging procedures, invasive procedures, and iatrogenic complications directly resulting from an abnormality detected on a surveillance scan.ResultsOne hundred sixty-three patients with first relapse of NHL between January 1, 2000 and December 31, 2010 were included. The majority of the relapses were detected by patient-reported symptoms or physical examination, or both, as opposed to surveillance imaging (77.9% [n = 127] vs. 22.1% [n = 36]; P < .0001). There was no overall survival difference between the 2 groups (P = .66). Patient-reported symptoms led to the detection of the majority of relapses in aggressive (85.7% [n = 72] vs. 14.3% [n = 12]; P < .0001) as well as indolent NHL (69.6% [n = 55] vs. 30.4% [n = 24]; P = .0007). Surveillance PET/CT contributed to more than 75% of follow-up health care costs in the first 2 years of monitoring for relapse. The surveillance imaging group had 1 reported case of iatrogenic pneumothorax.ConclusionOur retrospective analysis suggests that there is a limited role for surveillance imaging by CT or PET/CT in detecting first relapse in NHL. There was no difference in survival outcomes between the 2 groups in our study.     

Improving Survival of Patients With Hodgkin Lymphoma Over 4 Decades: Experience of the British National Lymphoma Investigation (BNLI) With 6834 Patients

BackgroundThe management of Hodgkin lymphoma (HL) has changed markedly over the last 50 years. This is due to the expanding understanding about the biology of the disease, the development of increasingly efficacious multimodal treatment, and the recognition of how to reduce late effects. The British National Lymphoma Investigation (BNLI) was formed in the 1970s to coordinate UK research in the diagnosis and treatment of lymphoma. We describe the improvement in trial patient survival over 4 decades.Patients and MethodsThis analysis is of data on 6834 patients with a de novo diagnosis of HL registered onto studies with BNLI oversight from January 1, 1970, to December 31, 2009. Patients were subdivided in 4 groups according to their decade of registration; 1970s, 1980s, 1990s, and 2000s. Because of the lengthy data collection period, there is a difference in duration of follow-up between decade groups, with median follow-up in the 1970s group of 28.2 years, 18.0 years in the 1980s group, 9.4 years in the 1990s group, and 5.4 years in the 2000s group. Comparison between data in all 4 groups is not possible beyond 13.4 years (maximum duration of follow-up in the 2000s group), and so a cutoff has been applied at 14 years. Data on overall survival, cause of death, primary treatment modality, and incidence of secondary malignancy were collected.ResultsClear and statistically significant improvements in survival curves between the decades were present, with 10-year overall survival increasing from 62.4% in the 1970s to 89.6% in the 2000s. There was a suggestion that second malignancy and cardiac-related deaths have been reducing over time, but longer follow-up is needed for the later decades to confirm this trend.ConclusionResults support existing registry data demonstrating that survival for HL has improved over the 4 decades analyzed. This data set is robust and validated, and it adds valuable understanding to the reasons behind the survival curves, which are a balance between efficacious therapies and decreased death related to cardiac conditions and second malignancies.     

Durable Survival Outcomes in Primary and Secondary Central Nervous System Lymphoma After High-dose Chemotherapy and Autologous Stem Cell Transplantation Using a Thiotepa,Busulfan, and Cyclophosphamide Conditioning Regimen

BackgroundHigh-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement and has shown promising results.Patients and MethodsA retrospective analysis was performed of 48 consecutive patients who had undergone HDC/ASCT with TBC (thiotepa, busulfan, cyclophosphamide) conditioning for PCNSL (27 patients), secondary CNS lymphoma (SCNSL) (8 patients), or relapsed disease with CNS involvement (13 patients) from July 2006 to December 2017. Of the 27 patients with PCNSL, 21 had undergone ASCT at first complete remission (CR1).ResultsThe 2-year progression-free survival (PFS) rate was 80.5% (95% confidence interval [CI], 69.9-92.9) and the 2-year overall survival (OS) rate was 80.1% (95% CI, 69.2%-92.7%) among all patients. The 2-year PFS and OS rate for patients with PCNSL in CR1 was 95.2% (95% CI, 86.6%-100%) and 95.2% (95% CI, 86.6%-100%), respectively. On univariate analysis of the patients with PCNSL, ASCT in CR1 was the only variable statistically significant for outcome (P = .007 for PFS; P = .008 for OS). Among patients with SCNSL or CNS relapse, the 2-year PFS and OS rate were comparable at 75.9% (95% CI, 59.5%-96.8%) and 75.3% (95% CI, 58.6%-98.6%), respectively. The most common side effects were febrile neutropenia (89.6%; of which 66.7% had an infectious etiology identified), nausea/vomiting (85.4%), diarrhea (93.8%), mucositis (89.6%), and electrolyte abnormalities (89.6%). Four patients (8.3%) died of treatment-related overwhelming infection; of these patients, 3 had SCNSL.ConclusionHDC and ASCT using TBC conditioning for both PCNSL and secondary CNS NHL appears to have encouraging long-term efficacy with manageable side effects.     

Allogeneic Hematopoietic Cell Transplantation Outcomes in Patients Carrying Isocitrate Dehydrogenase Mutations

BackgroundMutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown.Patients and MethodsWe report on the clinical outcome of a cohort of AML patients, who were tested for IDH mutations and underwent alloHCT at City of Hope (2015-2017). Of a total of 317 screened patients, 99 (31%) underwent alloHCT, of whom 23 carried and 76 did not carry IDH mutations (control).ResultsNo statistical significance was detected in patient’s overall survival (P = .84). With a median follow-up of 7.8 months, 1-year relapse rate of 29% and 13% was seen in the IDH-mutated and control group, respectively (P = .033). IDH1/2 mutation status remained significantly associated with relapse (hazard ratio, 2.8; P = .046) after inclusion of pre-HCT disease status in a multivariable model.ConclusionOur results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT. Further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDH mutations.     

Autologous Hematopoietic Cell Transplantation in Patients With Multiple Myeloma: Effect of Age

BackgroundIn the novel and pre–novel agent era, high-dose therapy, followed by autologous hematopoietic cell transplantation (AHCT), has been shown to prolong survival in patients with multiple myeloma (MM) in randomized trials. However, these trials only included patients aged ≤ 65 years. Given that the median age at diagnosis is 66 years, it is important to know the outcomes of AHCT in older patients. Similarly, definite outcomes of AHCT in very young patients (aged < 50 years) are also lacking because they represent a very small proportion of patients in clinical trials.Materials and MethodsWe analyzed a consecutive cohort of patients with MM receiving AHCT from 2000 to 2015 in 2 different age groups, older (> 70 years) and younger (≤ 50 years), and compared the outcomes. The primary objectives were to assess overall survival, progression-free survival (PFS), and nonrelapse mortality in these 2 groups.ResultsOf the 191 patients, 86 were young (age ≤ 50 years) and 105 were old (age > 70 years). The younger patients had better performance status and a lower comorbidity index, and most of the older patients had received a melphalan dose of 140 to 180 mg/m². The median follow-up period for the young group was 33 months (range, 2-164 months) compared with 22.5 months (range, 3-133 months) in the old group (P = .02). The PFS rate at 1 year was 60% (95% confidence interval [CI], 46%-72%) for the young group and 58% (95% CI, 45%-69%) for the old group. The overall survival rate at 1 year was 92% (95% CI, 84%-96%) for the young group and 85% (95% CI, 76%-91%) for the old group. On multivariate analysis, age did not have any effect on survival (P = .82); however, the patients with high-risk cytogenetics (hazard ratio [HR], 2.2; 95% CI, 1.06-4.6; P = .04) had worse overall mortality. High-risk cytogenetics (HR, 1.2; 95% CI, 1.1-3.5; P = .004) and no disease response or progressive disease at transplantation (HR, 5.0; 95% CI, 1.8-13.5; P = .02) were significantly associated with worse PFS.ConclusionAge should not be a limiting factor in considering the modality of AHCT. However, younger patients might also benefit from additional novel treatment approaches in the setting of clinical trials, given their similar outcomes with the older patients in our study.     

The Impact of Prior Salvage Treatment With Immune Checkpoint Inhibitors on Hodgkin Lymphoma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Single-Center Experience

IntroductionThe objective of the study was to assess the impact of the previous use of immune-checkpoint inhibitors (ICIs) on the clinical course of Hodgkin Lymphoma (HL) patients undergoing autologous hematopoietic stem cell transplantation (ASCT).MethodsA single-center, retrospective chart review of adult HL patients who received ASCT from January 1, 2014, to December 31, 2019, was conducted. Primary endpoints included the length of stay (LOS) and the composite outcome of late-onset noninfectious fever (LONIF) or late-onset hypotension (LOH) requiring intravenous fluid (IVF) resuscitation. Secondary endpoints included number of days until neutrophil engraftment, documented infections, and corticosteroid use.ResultsA total of 52 HL patients were included. Nine (17%) received ICI before ASCT, and 43 (83%) patients underwent standard salvage chemotherapy. The composite outcome of LONIF or LOH requiring IVF resuscitation was significantly higher in patients previously treated with ICIs compared with those who received standard non-ICI salvage chemotherapy (78% vs. 33%; P = .022). The differences between the median LOS and time to neutrophil engraftment were not statistically significant (P = .94 and P = .083, respectively). All LONIF patients received systemic corticosteroids with symptom resolution.ConclusionThe composite outcome of LONIF or LOH requiring IVF resuscitation was significantly higher in patients who received prior ICI salvage therapy. LOS and time to neutrophil engraftment were not affected by prior ICI therapy. Early institution of steroids may prevent the evolution of additional sequelae associated with engraftment or engraftment-like syndrome that can complicate ASCT.     

Characteristics of Hodgkin Lymphoma in a Defined Group of Iranian Pediatric Patients

This study was conducted to describe the characteristics of Hodgkin lymphoma in Iranian children. In a referral center for pediatric oncology (Mofid Hospital) in Tehran, patient data over a 10-year period were retrieved and recorded accordingly. Among 82 cases, 73.2% were male, 26.8% were female, and 70.7% were 5-9 years old. About 40% of patients were in stage III and 42.7% had systemic signs. Cervical nodes were commonly involved (91.5%). The most frequent histological subtype was mixed cellularity. The main hematological features were anemia (47.6%), lymphopenia (20.7%), and eosinophilia (8.7%). Survival rate was 72%, and 8.4% of patients were deceased. A 3% recurrence rate was observed in our patients. A significant relationship was found between the stage of disease and systemic signs (P<0.0005, χ2). Despite diagnosis of odgkin lymphoma in many children in Iran being made in higher stages, the mortality rate is relatively low.     

The Triple Positivity for EBV,PD-1, and PD-L1 Identifies a Very High Risk Classical Hodgkin Lymphoma

BackgroundThe programmed death receptor (PD-1) and ligand (PD-L1) pathway act by suppressing the antitumor response in chronic Hodgkin lymphoma (cHL). In this study, we aimed to investigate the effect of PD-1, PD-L1, and Epstein-Barr virus (EBV) positivity on prognosis at the initial diagnosis of cHL.Material and MethodsThirty-six patients with cHL were retrospectively analyzed. PD-L1 staining was performed for RS cells and tumor microenvironment in the biopsy materials of cases. The presence of EBV was investigated by EBER (EBV-encoded RNA) method in tumor cell. P < .05 was accepted as significant.ResultsThe presence of advanced-stage disease, B symptoms, intermediate or high-risk international prognostic index (IPS), and extranodal involvement were found to be related to both PD-L1 positivity and EBV positivity in RS cells. PD-L1 positivity in RS cells was also associated with EBV positivity. There were 6 (16.7%) triple-positive (EBV⁺, RS-PD-L1⁺, mic-PD-1⁺) patients. All of these patients had advanced-stage disease, B symptoms at the time of diagnosis, and intermediate-high IPS score, and 4 of 6 patients had extranodal involvement. This group also had significantly shortened overall survival compared with others (38.4 months vs. 67.9 months P = .024).ConclusionOur data suggest that there is correlation between PD-L1 positivity and EBV positivity in tumor RS cells that are also associated with extranodal involvement, intermediate and high IPS score, presence of B symptoms, and advanced-stage disease. In addition, we identified a group of triple-positive (EBV⁺, RS-PD-L1⁺, mic-PD-1⁺) cHL patients who have a very high-risk disease.