Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study.

ABSTRACT: In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed or refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and substantially lower progression-free survival and overall survival, compared with the L-MIND registration clinical trial for TL.

Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma.

New therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant and chimeric antigen receptor therapy. The CD30-targeted, antibody-drug conjugate brentuximab vedotin (BV) and the immunomodulator lenalidomide (Len) have demonstrated promising activity as single agents in this population. We report the results of a phase 1/dose expansion trial evaluating the combination of BV/Len in rel/ref DLBCL. Thirty-seven patients received BV every 21 days, with Len administered continuously for a maximum of 16 cycles. The maximum tolerated dose of the combination was 1.2 mg/kg BV with 20 mg/d Len. BV/Len was well tolerated with a toxicity profile consistent with their use as single agents. Most patients required granulocyte colony-stimulating factor support because of neutropenia. The overall response rate was 57% (95% CI, 39.6-72.5), complete response rate, 35% (95% CI, 20.7-52.6); median duration of response, 13.1 months; median progression-free survival, 10.2 months (95% CI, 5.5-13.7); and median overall survival, 14.3 months (95% CI, 10.2-35.6). Response rates were highest in patients with CD30+ DLBCL (73%), but they did not differ according to cell of origin (P = .96). NK cell expansion and phenotypic changes in CD8+ T-cell subsets in nonresponders were identified by mass cytometry. BV/Len represents a potential treatment option for patients with rel/ref DLBCL. This combination is being further explored in a phase 3 study (registered on https://clinicaltrials.org as NCT04404283). This trial was registered on https://clinicaltrials.gov as NCT02086604.

Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety findings in the phase II L-MIND study.

Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma based on the results of the phase II L-MIND study (NCT02399085). We report the final 5-year analysis of this study. Eighty patients ≥18 years who had received one to three prior systemic therapies, and had Eastern Cooperative Oncology Group performance status 0-2 received up to 12 cycles of co-administered tafasitamab and lenalidomide, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. The primary endpoint was the best objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, and safety. Exploratory analyses evaluated efficacy endpoints by prior lines of therapy. At data cutoff on November 14, 2022, the objective response rate was 57.5%, with a complete response rate of 41.3% (n=33), which was consistent with prior analyses. With a median follow-up of 44.0 months, the median duration of response was not reached. The median progression-free survival was 11.6 months (95% confidence interval [95% CI]: 5.7-45.7) with a median follow-up of 45.6 months. The median overall survival was 33.5 months (95% CI: 18.3-not reached) with a median follow-up of 65.6 months. Patients who had received one prior line of therapy (n=40) showed a higher objective response rate (67.5%; 52.5% complete responses) compared to patients who had received two or more prior lines of therapy (n=40; 47.5%; 30% complete responses), but the median duration of response was not reached in either subgroup. Other exploratory analyses revealed consistent long-term efficacy results across subgroups. Adverse events were consistent with those described in previous reports, were manageable, and their frequency decreased during tafasitamab monotherapy, with no new safety concerns. This final 5-year analysis of L-MIND demonstrates that the immunotherapy combination of tafasitamab and lenalidomide is well tolerated and has long-term clinical benefit with durable responses.

Prognostic relevance of circulating lymphoma cells at diagnosis in newly diagnosed follicular lymphoma patients.

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma. Circulating lymphoma (CL) cells can be seen at diagnosis in some FL patients, however, previous studies evaluating this have shown mixed results. Therefore, we sought to evaluate the impact of CL at diagnosis on outcomes in patients with newly diagnosed FL using data from a single center. Patients were divided into CL+ and CL- based on immunophenotyping via peripheral blood (PB) flow cytometry. CL was defined as detectable clonally restricted B-cells that matched the actual or expected B-cell immunophenotype of FL. The primary endpoint was progression-free survival (PFS) after first-line treatment and secondary endpoints included overall response rate (ORR), overall survival (OS), diagnosis to treatment interval (DTI), progression of disease within 2 years of diagnosis (POD24), and cumulative incidence of transformation between the two groups. Among the 541 patients with FL, 204 had PB flow cytometry performed at diagnosis, and after excluding patients not meeting the eligibility criteria, 147 cases remained with 24 (16%) CL+ at diagnosis. Patients in the CL+ group were younger (53 vs. 58 years, p = 0.02), had more extranodal involvement (83% vs. 44%, p < 0.01), follicular lymphoma international prognostic index 3-5 (55% vs. 31%, p = 0.01), and a higher proportion received first-line immunochemotherapy (75% vs. 43%, p = 0.01) compared to the CL-group. The median PFS was not significantly different between CL+ (6.27 years, 95% CI = 3.61-NR) and CL- (6.61 years, 95% CI = 5.10-9.82) cohorts regardless of the first-line treatment or level of absolute PB CL cells. There was no significant difference in ORR, median OS, DTI, POD24, and cumulative incidence of transformation between the two groups. In our study, we found that the presence of CL cells at diagnosis in FL in the contemporary era did not impact outcomes and survival.

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Clinical Treatment Guidelines for Tafasitamab Plus Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 24% of new cases of B-cell non-Hodgkin lymphoma in the US each year. Up to 50% of patients relapse or are refractory (R/R) to the standard first-line treatment option, R-CHOP. The anti-CD19 monoclonal antibody tafasitamab, in combination with lenalidomide (LEN), is an NCCN preferred regimen for transplant-ineligible patients with R/R DLBCL and received accelerated approval in the US (July 2020) and conditional marketing authorization in Europe (August 2021) and other countries, based on data from the L-MIND study. The recommended dose of tafasitamab is 12 mg/kg by intravenous infusion, administered in combination with LEN 25 mg for 12 cycles, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. Tafasitamab + LEN is associated with durable responses in patients with R/R DLBCL. The majority of clinically significant treatment-associated adverse events are attributable to LEN and can be managed with dose modification and supportive therapy. We provide guidelines for the management of patients with R/R DLBCL treated with tafasitamab and LEN in routine clinical practice, including elderly patients and those with renal and hepatic impairment, and advice regarding patient education as part of a comprehensive patient engagement plan. Our recommendations include LEN administration at a reduced dose if required in patients unable to tolerate the recommended dose. No dose modification is required for tafasitamab in special patient populations.

Outcomes of patients with limited-stage plasmablastic lymphoma: A multi-institutional retrospective study.

Plasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1-196), the 3-year progression-free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3-year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper-CVAD or auto-SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.

NCCN Guidelines® Insights: Hodgkin Lymphoma, Version 2.2022.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma.

Single-agent ibrutinib is active in patients with previously treated mantle cell lymphoma (MCL); however, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type Bruton's tyrosine kinase (BTK). Therefore, we conducted a phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. From August 2014 to June 2016, a total of 27 patients (21 men, 6 women) were enrolled. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3 to 4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase 2 multicenter clinical trial to further characterize efficacy is now ongoing. The current trial was registered at www.clinicaltrials.gov as #NCT02159755.

Prognostic significance of translocations in the presence of mutated IGHV and of cytogenetic complexity at diagnosis of chronic lymphocytic leukemia.

Mutations of the IGH variable region in patients with chronic lymphocytic leukemia (CLL) are associated with a favorable prognosis. Cytogenetic complexity (>3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within one year of diagnosis of CLL and correlated these features with outcome and other clinical features including IGHV. Of 329 untreated patients, 53 (16.1%) had a complex karyotype (16.1%), and 85 (25.8%) had a translocation. Median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (p3.5, log-transformed WBC, unmutated IGHV, complex karyotype, translocation, and FISH for trisomy 8, del(11q) and del(17p). In multivariable analysis, there was significant effect modification of IGHV status on the relationship between translocation and TFT (p=0.002). In IGHV mutated patients, those with a translocation had over 3.5 times higher risk of starting treatment than those without a translocation (p.

Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma.

Not available.

Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma.

Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months' follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months' follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085.

Transducin ß-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkin's lymphoma and is characterized by a remarkable heterogeneity with diverse variants that can be identified histologically and molecularly. Large-scale gene expression profiling studies have identified the germinal center B-cell (GCB-) and activated B-cell (ABC-) subtypes. Standard chemo-immunotherapy remains standard front line therapy, curing approximately two thirds of patients. Patients with refractory disease or those who relapse after salvage treatment have an overall poor prognosis highlighting the need for novel therapeutic strategies. Transducin ß-like protein 1 (TBL1) is an exchange adaptor protein encoded by the TBL1X gene and known to function as a master regulator of the Wnt signalling pathway by binding to ß-CATENIN and promoting its downstream transcriptional program. Here, we show that, unlike normal B-cells, DLBCL cells express abundant levels of TBL1 and its overexpression correlates with poor clinical outcome regardless of DLBCL molecular subtype. Genetic deletion of TBL1 and pharmacological approach using tegavivint, a first-in-class small molecule targeting TBL1 (Iterion Therapeutics), promotes DLBCL cell death in vitro and in vivo. Through an integrated genomic, biochemical, and pharmacologic analyses, we characterized a novel, ß-CATENIN independent, post-transcriptional oncogenic function of TBL1 in DLBCL where TBL1 modulates the stability of key oncogenic proteins such as PLK1, MYC, and the autophagy regulatory protein BECLIN-1 through its interaction with a SKP1-CUL1-F-box (SCF) protein supercomplex. Collectively, our data provide the rationale for targeting TBL1 as a novel therapeutic strategy in DLBCL.

Aging Phenotypes and Restoring Functional Deficits in Older Adults With Hematologic Malignancy.

BACKGROUND: Gauging fitness remains a challenge among older adults with hematologic malignancies, and interventions to restore function are lacking. We pilot a structured exercise intervention and novel biologic correlates of aging using epigenetic clocks and markers of immunosenescence to evaluate changes in function and clinical outcomes. METHODS: Older adults (n=30) with hematologic malignancy actively receiving treatment were screened and enrolled in a 6-month exercise intervention, the Otago Exercise Programme (OEP). The impact of the OEP on geriatric assessment metrics and health-related quality of life were captured. Clinical outcomes of overall survival and hospital utilization (inpatient length of stay and emergency department use) in relationship to geriatric deficits were analyzed. RESULTS: Older adults (median age, 75.5 years [range, 62-83 years]) actively receiving treatment were enrolled in the OEP. Instrumental activities of daily living and physical health scores (PHS) increased significantly with the OEP intervention (median PHS: visit 1, 55 [range, 0-100]; visit 2, 70 [range, 30-100]; P<.01). Patient-reported Karnofsky performance status increased significantly, and the improvement was sustained (median [range]: visit 1, 80 [40-100]; visit 3, 90 [50-100]; P=.05). Quality of life (Patient-Reported Outcome Measurement Information System [PROMIS]) improved significantly by the end of the 6-month period (median [range]: visit 1, 32.4 [19.9-47.7]; visit 3, 36.2 [19.9-47.7]; P=.01]. Enhanced measures of gait speed and balance, using the Short Physical Performance Battery scores, were associated with a 20% decrease in risk of death (hazard ratio, 0.80; 95% CI, 0.65-0.97; P=.03) and a shorter hospital length of stay (decrease of 1.29 days; 95% CI, -2.46 to -0.13; P=.03). Peripheral blood immunosenescent markers were analyzed in relationship to clinical frailty and reports of mPhenoAge epigenetic analysis are preliminarily reported. Chronologic age had no relationship to overall survival, length of stay, or emergency department utilization. CONCLUSIONS: The OEP was effective in improving quality of life, and geriatric tools predicted survival and hospital utilization among older adults with hematologic malignancies.

Multi-center analysis of practice patterns and outcomes of younger and older patients with mantle cell lymphoma in the rituximab era.

Clinical outcomes and predictors of survival in patients with newly diagnosed mantle cell lymphoma (MCL) treated in the rituximab era (2000-2015) at 12 US academic centers were assessed to identify determinants of survival across age groups. Objectives were to characterize and compare practice patterns, outcomes and prognostic factors for survival in younger patients (age < 65) and older patients (age ≥ 65 years). Among 1162 patients included, 697 were younger and 465 were older. In younger patients, 2-year progression free survival (PFS) and overall survival (OS) rates were 79% and 92% respectively; blastoid histology, ECOG ≥ 2, and lack of maintenance rituximab (MR) remained statistically relevant to poor OS on univariate analysis (UVA) and multivariate analysis (MVA). In older patients, 2-year PFS and OS rates were 67% and 86% respectively; lack of maintenance rituximab remained significantly associated with inferior PFS and OS on UVA and MVA (p < 0.001). Two-year PFS rates were 79%, and 67% and 2-year OS rates were 92% and 86% for ages < 65 and ≥ 65 respectively (p < 0.001). First-line high-dose cytarabine exposure and/or MR lessened the negative impact of age on survival. Taken collectively, survival outcomes for older patients remain inferior to those of younger patients in the rituximab era. However, maintenance rituximab and potentially high-dose cytarabine-based induction can mitigate the negative impact of age on survival.

Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study.

BACKGROUND: Patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for autologous stem-cell transplantation have poor outcomes and few treatment options. Tafasitamab (MOR208) is an Fc-enhanced, humanised, anti-CD19 monoclonal antibody that has shown preclinical and single-agent activity in patients with relapsed or refractory B-cell malignancies. Preclinical data suggested that tafasitamab might act synergistically with lenalidomide. We aimed to assess the antitumour activity and safety of tafasitamab plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for autologous stem-cell transplantation. METHODS: In this multicentre, open-label, single-arm, phase 2 study (L-MIND), patients older than 18 years with histologically confirmed diffuse large B-cell lymphoma, who relapsed or had refractory disease after previous treatment with one to three systemic regimens (with at least one anti-CD20 therapy), were not candidates for high-dose chemotherapy and subsequent autologous stem-cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0-2, and had measurable disease at baseline were recruited from 35 academic and community hospitals in ten countries. Patients received coadministered intravenous tafasitamab (12 mg/kg) and oral lenalidomide (25 mg/day) for up to 12 cycles (28 days each), followed by tafasitamab monotherapy (in patients with stable disease or better) until disease progression. The primary endpoint was the proportion of patients with an objective response (centrally assessed), defined as a complete or partial response according to the 2007 International Working Group response criteria for malignant lymphoma. Antitumour activity analyses are based on all patients who received at least one dose of both tafasitamab and lenalidomide; safety analyses are based on all patients who received at least one dose of either study medication. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, NCT02399085. FINDINGS: Between Jan 18, 2016, and Nov 15, 2017, 156 patients were screened: 81 were enrolled and received at least one dose of either study medication, and 80 received at least one dose of both tafasitamab and lenalidomide. Median follow-up was 13·2 months (IQR 7·3-20·4) as of data cutoff on Nov 30, 2018. 48 (60%; 95% CI 48-71) of 80 patients who received tafasitamab plus lenalidomide had an objective response: 34 (43%; 32-54) had a complete response and 14 (18%; 10-28) had a partial response. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (39 [48%] of 81 patients), thrombocytopenia (14 [17%]), and febrile neutropenia (ten [12%]). Serious adverse events occurred in 41 (51%) of 81 patients. The most frequently reported serious adverse events (in two or more patients) were pneumonia (five [6%]), febrile neutropenia (five [6%]), pulmonary embolism (three [4%]), bronchitis (two [2%]), atrial fibrillation (two [2%]), and congestive cardiac failure (two [2%]). INTERPRETATION: Tafasitamab in combination with lenalidomide was well tolerated and resulted in a high proportion of patients with relapsed or refractory diffuse large B-cell lymphoma ineligible for autologous stem-cell transplantation having a complete response, and might represent a new therapeutic option in this setting. FUNDING: MorphoSys.

Gemcitabine and bendamustine is a safe and effective salvage regimen for patients with recurrent/refractory Hodgkin lymphoma: Results of a phase 1/2 study.

BACKGROUND: Both gemcitabine and bendamustine have been evaluated in patients with recurrent/refractory Hodgkin lymphoma but to the authors' knowledge not as a doublet. The authors completed a phase 1/2 trial to identify the optimal dose and frequency of administration and to assess the efficacy of this combination in patients with recurrent/refractory Hodgkin lymphoma. METHODS: Patients were treated up to a maximum dose of gemcitabine (1000 mg/m2 on day 1) and bendamustine (120 mg/m2 on days 1 and 2), which was determined to be the recommended phase 2 dose, administered every 21 days for up to 6 cycles. Patients could discontinue study therapy after 2 cycles to proceed with autologous or allogeneic stem cell transplantation. RESULTS: No dose-limiting toxicities were identified, but 4 patients experienced grade 3 to 5 pulmonary adverse events (toxicity was graded according to Common Terminology Criteria for Adverse Events [version 4]). A total of 26 patients were enrolled having completed a median of 4 prior lines of therapy (range, 1-7 lines), including 13 patients at the recommended phase 2 dose, in whom the overall response rate was 69% and the complete response rate was 46%. The median progression-free survival for the phase 2 patients was 11 months (95% CI, 3 months to not reached), and the median overall survival for this group had not been reached at the time of last follow-up (95% CI, 4 months to not reached). CONCLUSIONS: This doublet was found to be tolerable and effective, but patients must be monitored closely for pulmonary toxicity. The authors currently are evaluating this doublet in combination with nivolumab.

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure.

BACKGROUND: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy. CONCLUSIONS: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.

Poor outcomes for double-hit lymphoma patients treated with curative-intent second-line immunochemotherapy following failure of intensive front-line immunochemotherapy.

While patients with double-hit lymphoma (DHL) are now frequently treated with intensive front-line immunochemotherapy, outcomes for those who fail these regimens and subsequently receive curative-intent second-line immunochemotherapy are unknown. We identified 55 such patients who achieved an overall/complete response rate of 29%/11%, median progression-free/overall survival (PFS/OS) of 2/5·1 months and one-year PFS/OS of 10/19% following the start of second-line therapy. These outcomes may serve as a standard against which future second-line treatment strategies for relapsed/refractory DHL can be measured and justify investigation of non-cytotoxic therapies in the second-line setting for these patients.