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.     

Ofatumumab,Etoposide, and Cytarabine Intensive Mobilization Regimen in Patients with High-risk Relapsed/Refractory Diffuse Large B-Cell Lymphoma Undergoing Autologous Stem Cell Transplantation

BackgroundMore than one-half of high-risk patients with relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) relapse after autologous hematopoietic cell transplantation (auto-HCT). In this phase II study, we investigate the long-term outcomes of high-risk patients with rrDLBCL receiving intensive consolidation therapy (ICT) with OVA (ofatumumab, etoposide, and high-dose cytarabine) prior to auto-HCT.Patients and MethodsThe primary endpoints were the ability of OVA to mobilize peripheral stem cells and the 2-year progression-free survival (PFS) rate following OVA. Secondary endpoints included safety, 2-year overall survival (OS), impact of cell of origin (COO), and the prognostic utility of next-generation sequencing minimal residual disease (MRD) testing. We simultaneously retrospectively assessed the outcomes of DLBCL patients who underwent ICT with a similar regimen at our institution.ResultsTwenty-seven patients received salvage chemotherapy, with a response rate of 25% in patients with germinal center B-cell (GCB)-DLBCL versus 92% in patients with non-GCB-DLBCL (P = .003). Nineteen responding patients underwent ICT with OVA (100% successful stem cell mobilization). The 2-year PFS and OS rate was 47% and 59%, respectively, with no difference based on COO. Similar findings were observed when the study and retrospective cohorts were combined. Neutropenia was the most common toxicity (47%). MRD-negative patients at the completion of salvage had a median OS of not reached versus 3.5 months in MRD-positive patients (P = .02).ConclusionsOVA followed by auto-HCT is effective and safe for high-risk rrDLBCL. Patients with GCB-DLBCL had a lower response to salvage chemotherapy, but no difference in outcomes based on COO was seen after auto-HCT. MRD testing in the relapsed setting was predictive of long-term survival.     

Ibrutinib Monotherapy in Relapsed or Refractory,Transformed Diffuse Large B-cell Lymphoma

BackgroundHistologic transformation to diffuse large B-cell lymphoma (tDLBCL) occurs in a significant proportion of indolent lymphomas. However, few studies of novel agents inform its management, particularly when relapsed after or refractory (R/R) to prior treatment.Patients and MethodsWe prospectively evaluated ibrutinib monotherapy in pathologically documented patients with R/R tDLBCL in a single-arm study. The primary endpoint was overall response rate.ResultsTwenty patients who had received a median of 4 (range, 2-9) prior lines of therapy overall (median, 2.5; range, 1-9 for tDLBCL) were treated. The overall response rate was 35%, including complete responses in 15%. The median progression-free survival and overall survival were 4.1 months (95% confidence interval, 2.4-6.2 months) and 22.4 months (95% confidence interval, 7.5 months to not reached), respectively. Disease control > 2 months was seen in 75% and > 1 year in 15%. Response was associated with either low tumor bulk or low metabolic tumor volume (P = .05) but not with antecedent lymphoma histology (P = 1.0). Treatment-related adverse events were consistent with prior studies of ibrutinib.ConclusionsIbrutinib showed low toxicity and meaningful efficacy in R/R tDLBCL, including short-term disease control in most cases. Results demonstrate the potential utility of ibrutinib in this challenging clinical setting, including as a potential bridge to more definitive treatments.     

造血干细胞支持下大剂量LACE方案对27例难治复发性淋巴瘤疗效观察

目的:评价在造血干细胞支持下,LACE预处理方案对难治性、复发性淋巴瘤临床疗效.方法:自2001年3月至2003年7月对27例难治性、复发性淋巴瘤在造血干细胞支持下,应用LACE预处理方案:罗氮芥(L)200mg/m2,1次口服(移植前第7天),足叶乙甙(E)1g/m2,静脉点滴(移植前第7天),阿糖胞苷(A)2g/m2×d-1,静脉点滴(移植前第6、5天),环磷酰胺(C)1.8/m2×d-1,静脉点滴(移植前第4、3、2天),0天进行自体干细胞输注并进行随访观察.结果:27例患者均可耐受化疗,无移植相关死亡病例,并对移植后的患者进行随访观察,随访中位期14个月(7～35),6例复发,21例缓解.统计分析2年无瘤生存率可达70%,预计5年生存率可达55%.结论:对难治性复发性淋巴瘤,在造血干细胞支持下,LACE方案是较好的一种预处理方案.     

Brazilian Experience Using High-Dose Sequential Chemotherapy Followed by Autologous Hematopoietic Stem Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma

PurposeWe evaluate the effectiveness and toxicity of high-dose sequential chemotherapy (HDS) as salvage therapy in patients with advanced-stage Hodgkin lymphoma.Patients and MethodsWe performed a retrospective analysis on 77 patients receiving HDS between 1998 and 2006. Patients enrolled were in disease progression or relapsed disease, or did not achieve a complete remission after first-line treatment. HDS consisted of the sequential administration of cyclophosphamide and granulocyte colony-stimulating factor with stem cell harvesting, followed by methotrexate plus vincristine and etoposide.ResultsThe majority of patients had stage III/IV (64%) and B symptoms (71.4%). Disease status improvement after HDS was observed in 24 of 57 patients (42%) previously in disease progression or relapse. HDS-related deaths occurred in 8 of 77 patients (10.4%). Four patients (5.2%) developed acute myeloid leukemia/myelodysplastic syndrome. Overall, disease-free and progression-free survival was 27%, 57%, and 25%, respectively.ConclusionDespite the treatment-related mortality, HDS is feasible, with satisfactory response rates, even in patients with poor prognosis.     

Salvage Chemotherapy Followed by Autologous Stem-Cell Transplantation Using Targeted Busulfan for Refractory Diffuse Large B-Cell Lymphoma With Dialysis-Dependent End-Stage Renal Disease

BackgroundA treatment strategy is needed for hemodialysis-dependent patients with end-stage renal disease who have relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We examined the feasibility of salvage chemotherapy followed by autologous stem-cell transplantation (ASCT) and busulfan as a conditioning regimen.Patients and MethodsWe provided a patient with refractory DLBCL who was receiving hemodialysis with modified salvage chemotherapies that were based on the mechanism of drug pharmacokinetics and an evaluation of the pharmacokinetics of busulfan. After chemotherapy, the patient underwent ASCT.ResultsThe regimen was successfully administered without adverse events.ConclusionChemotherapy followed by ASCT using a conditioning regimen of reduced melphalan and pharmacokinetically targeted busulfan is a promising strategy for treating patients with relapsed or refractory DLBCL who also have end-stage renal disease and are receiving hemodialysis.     

Favorable Consolidative Effect of High-Dose Melphalan and Total-Body Irradiation Followed by Autologous Peripheral Blood Stem Cell Transplantation After Rituximab-Containing Induction Chemotherapy With In Vivo Purging in Relapsed or Refractory Follicular Lymphoma

PurposeIn this study, we sought to evaluate the efficacy and toxicity of high-dose therapy followed by autologous peripheral blood stem cell transplantation (autoPBSCT) after rituximab-containing induction chemotherapy with in vivo purging for relapsed or refractory chemosensitive advanced-stage follicular lymphoma (FL).Patients and MethodsA rituximab-containing regimen was used as induction chemotherapy and as in vivo purging before PBSC collection. Patients achieving partial or complete response received a regimen consisting of high-dose melphalan and total-body irradiation (TBI).ResultsA total of 18 patients with a median age of 45 years were enrolled. The number of previous chemotherapy regimens was 2. The principal nonhematologic toxicities were grade 3 febrile neutropenia and diarrhea. One patient experienced pneumocystis pneumonia, 2 developed interstitial pneumonitis, and 1 experienced agammaglobulinemia, all of whom had complete improvement except for the patient having agammaglobulinemia. Grade 4 toxicities were not observed, and there have been neither treatment-related mortality nor secondary malignancy to date. At a median follow-up of 4.0 years, the 4-year estimated overall and failure-free survival rates were 100% and 88.9%, respectively.ConclusionConsolidation of high-dose melphalan and TBI followed by autoPBSCT with in vivo purging is feasible and effective for relapsed or refractory chemosensitive FL. Longer follow-up is needed to confirm the role and late toxicities.     

Phase 2 Study of Daratumumab in Relapsed/Refractory Mantle-Cell Lymphoma,Diffuse Large B-Cell Lymphoma,and Follicular Lymphoma

BackgroundDaratumumab is a CD38 monoclonal antibody approved for treating relapsed/refractory and newly diagnosed multiple myeloma. Preclinical daratumumab studies demonstrated cytotoxic activity and reduced tumor growth in B-cell non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle-cell lymphoma (MCL).Patients and MethodsThis was a phase 2, open-label, multicenter, 2-stage trial. Patients with relapsed/refractory DLBCL, FL, or MCL with ≥ 50% CD38 expression were eligible for stage 1. Daratumumab (16 mg/kg; 28-day cycles) was administered intravenously weekly for 2 cycles, every 2 weeks for 4 cycles, and every 4 weeks thereafter. Overall response rate was the primary end point. Pharmacokinetic and safety were also evaluated. Stage 2 was planned to further assess daratumumab in larger populations of NHL subtypes if futility criteria were not met. The study was registered with ClinicalTrials.gov (NCT02413489).ResultsThe trial screened 138 patients resulting in accrual of 15 patients with DLBCL, 16 with FL, and 5 with MCL. Median CD38 expression across treated patients was 70%. Overall response rate was 6.7%, 12.5%, and not evaluable in DLBCL, FL, and MCL cohorts, respectively. The most common grade 3/4 treatment-emergent adverse event was thrombocytopenia (11.1%), and 4 (11.1%) patients discontinued treatment because of treatment-emergent adverse events. Infusion-related reactions occurred in 72.2% of patients (3 patients with grade 3; no grade 4).ConclusionIn NHL, the safety and pharmacokinetics of daratumumab were consistent with myeloma studies. Screen-fail rates were high, prespecified futility thresholds were met in 2 cohorts, and the study was terminated. Studies in other hematologic malignancies and amyloidosis are ongoing.     

Phase II Study of Vincristine Sulfate Liposome Injection (Marqibo) and Rituximab for Patients With Relapsed and Refractory Diffuse Large B-Cell Lymphoma or Mantle Cell Lymphoma in Need of Palliative Therapy

BackgroundVSLI (Marqibo) is active in advanced non-Hodgkin lymphoma (NHL) and untreated aggressive NHL. Because of its favorable hematologic toxicity profile, VSLI might be useful in patients unable to tolerate myelosuppressive therapies.Patients and MethodsTwenty-two patients with heavily pretreated, advanced CD20⁺ DLBCL or MCL were treated with VSLI 2.0 mg/m², without a dose cap, every 2 weeks plus 4 weekly doses of rituximab 375 mg/m². ORR, complete response (CR), or partial response (PR), was the primary end point. Secondary end points included response duration, time to progression (TTP), and OS. Safety variables included adverse events and neurologic assessments.ResultsThe ORR was 13 of 22 (59%); 6 patients achieved a CR (27%), and 7 patients achieved a PR (32%). Median response duration, TTP, and OS were 147 days, 121 days, and 322 days, respectively. The median number of VSLI doses was 5, the median individual VSLI dose was 3.5 mg, and the maximum cumulative VSLI dose was 43 mg. Grade 3 peripheral neuropathy, febrile neutropenia, and constipation were reported in 4, 2, and 1 patients, respectively.ConclusionVSLI plus rituximab resulted in durable responses in patients with heavily pretreated advanced stage DLBCL and MCL. The toxicity profile was predictable and manageable with limited hematologic toxicity. Despite near-universal previous VCR exposure (96%) and doses of VSLI unachievable with standard VCR treatment, peripheral neuropathy and constipation were modest. This study supports further evaluation of VSLI as a component of DLBCL management.     

The Novel Therapeutic Landscape for Relapsed/Refractory Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is an aggressive malignancy that has been traditionally treated with anthracycline-based chemotherapy, but approximately one-third of patients relapse after first-line therapy or have primary refractoriness. In this focused review, we discuss the 7 novel Food & Drug Administration (FDA)-approved medications for relapsed/refractory (R/R) DLBCL. We describe 5 CD19-targeted therapies, 3 of which are chimeric antigen receptor (CAR)-T cell therapies. We also highlight novel non–cell-based targeted therapies and discuss optimal sequencing considerations based on the goal of treatment, with an emphasis on CAR-T cell therapy as curative intent. We consider the limited tolerability of certain novel agents, prospects for elderly patients, and financial aspects of these approaches. We discuss advantages and limitations of these targeted therapies based on seminal clinical trials. Finally, we summarize ongoing trials involving promising agents making their way into the pharmacologic pipeline. These therapies include allogeneic CAR-T treatments and multi-antigen targeting therapies such as the CD19/CD22 CAR-T and the CD3/CD20 bispecific antibodies mosunetuzumab and odronextamab. We summarize our approach based on the best available evidence as we enter 2022.     

Salvage High-dose Melphalan With Autologous Stem cell Transplantation as Bridge to Consolidation Therapy for Chemoresistant Aggressive B-cell Lymphoma

BackgroundPatients suffering from refractory aggressive B-cell lymphoma not responding to salvage chemotherapy have a dismal prognosis. CAR T-cells or allogeneic stem cell transplantation (SCT) are potentially curative approaches. However, obtaining a remission, and lowering tumor burden before consolidation seems crucial for long-term efficacy of both treatment modalities.Materials and MethodsIn this retrospective analysis, we reviewed patients with chemoresistant aggressive B-cell lymphoma, defined as being refractory or progressive to at least second line salvage chemotherapy including the regimen immediately preceding autologous stem cell transplantation (ASCT), treated at 2 tertiary centers, who were eligible for intensive treatment using single agent high-dose (HD) melphalan to obtain a remission before consolidating therapy.ResultsWe identified 36 patients that received single agent HD melphalan and ASCT as remission induction followed by CAR T-cells or allogeneic stem cell transplantation (SCT). Thirteen of the evaluable patients (39.4%) achieved a partial remission and 9 patients (27.73%) a complete remission, resulting in an overall response rate (ORR) of 66.7%. High remission rates were seen across all subgroups including patients with primary refractory lymphoma (ORR 58.3%), uncontrolled disease and high tumor burden as indicated by increased LDH levels (ORR 66.7% for patients with elevated LDH above 2 times upper limit of norm). 22 patients proceeded to allogeneic SCT and 5 to CAR T-cell therapy. Treatment related mortality of ASCT was 5.5% (2 patients, both due to infections). Two-year overall survival of all patients was 15.8%, primarily due to a high non–relapse mortality (45.5%) of allogeneic SCT patients treated with myeloablative conditioning chemotherapy.ConclusionSingle agent HD melphalan produces high remission rates in patients with chemoresistant, uncontrolled aggressive B-cell lymphoma and provides a window of opportunity for consolidation therapy.MicroabstractPatient with refractory/relapsed aggressive B-cell lymphoma after salvage therapy are an unmet medical need because of their very poor prognosis. In our retrospective analysis of 36 patients we showed that single agent high-dose melphalan can achieve high response rates (ORR 66.7%) even in uncontrolled disease enabling consolidation therapy e.g. with allogeneic stem cell transplantation or CAR T-cell therapy.     

Potential Benefit of Involved-Field Radiotherapy for Patients With Relapsed-Refractory Hodgkin's Lymphoma With Incomplete Response Before Autologous Stem Cell Transplantation

IntroductionWe investigated for a possible role for peritransplantation involved-field radiotherapy (IFRT) by comparing patients who received IFRT before after autologous stem cell transplantation (ASCT) and patients who received salvage chemotherapy (CT) alone.Patients and MethodsWe retrospectively evaluated 73 consecutive patients with Hodgkin lymphoma treated with ASCT between 2003 and 2014. Twenty-one patients (28.8%) received peritransplantation radiotherapy. A Cox regression analysis (multivariate analysis; MVA) was performed to evaluate the prognostic role of any risk factor. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of ASCT. Response to CT and ASCT were evaluated with positron emission tomography (PET) scan.ResultsMedian follow-up was 41 months (range, 1-136 months). Overall, no significant difference appeared between patients who received IFRT and patients treated with CT alone; however, patients who were treated with IFRT had worse prognostic factors. In the MVA, advanced stage at relapse and persistent disease before ASCT (evident on PET scan [PET+]) were related to worse PFS and OS. In patients with limited stage disease at relapse and PET+, peritransplantation radiotherapy showed higher 3-year OS rates (91.7% vs. 62.3%) and PFS rates (67.5% vs. 50%) compared with patients treated with CT alone, although this difference was not significant (P = .14 and P = .22, respectively).ConclusionIFRT used before or after ASCT might partially compensate for worse prognostic factors among the overall population; subgroup analysis showed a trend for survival benefit at 3 years in patients with limited stage disease at relapse and PET+ before ASCT.     

Outcome of Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma Referred for Autologous Bone Marrow Transplantation

Fifty-one patients with relapsed or refractory intermediate- or high-grade non-Hodgkin's lymphoma were referred for autologous bone marrow transplantation (ABMT). The primary criterion for eligibility was sensitivity to conventional-dose salvage chemotherapy. Of 47 patients who received salvage chemotherapy, 30 demonstrated chemotherapy-sensitive disease. Six eligible patients did not undergo ABMT for various reasons. A total of 24 patients underwent ABMT, with etoposide, melphalan ± total body irradiation as the intensive therapy regimen. There was one early treatment-related death and three non-responders. Of the remaining patients, 9 relapsed, while 11 remain in continuous complete remission (CR) at a median follow-up of 21 months after transplant (range 5-37 months). Two patients with chemosensitive disease and bone marrow involvement underwent allogeneic BMT with marrow from HLA-identical siblings. Both are in continuous CR at 6 and 12 months follow-up. Of the 25 patients who did not undergo ABMT, all have died (median survival 5 months).

The results indicate that approximately one-half of relapsed or refractory aggressive histology lymphoma patients referred for ABMT eventually undergo transplantation, if chemotherapy-sensitive relapse is the major criterion for eligibility. Approximately 25% of the referred patients may become long-term disease-free survivors with this approach. Reports of marrow transplant series should include all patients referred for ABMT as the denominator for calculating disease-free survival in order to reduce the bias of patient selection.