Immunochemotherapy plus lenalidomide for high-risk mantle cell lymphoma with measurable residual disease evaluation.

Chemoimmunotherapy followed by consolidative high-dose therapy with autologous stem cell rescue was a standard upfront treatment for fit patients with mantle cell lymphoma (MCL) in first remission; however, treatment paradigms are evolving in the era of novel therapies. Lenalidomide is an immunomodulatory agent with known efficacy in treating MCL. We conducted a single-center, investigator-initiated, phase II study of immunochemotherapy incorporating lenalidomide, without autologous stem cell transplant consolidation, enriching for patients with high-risk MCL (clinicaltrials gov. Identifier: NCT02633137). Patients received four cycles of lenalidomide-R-CHOP, two cycles of R-HiDAC, and six cycles of R-lenalidomide. The primary endpoint was rate of 3-year progression-free survival. We measured measurable residual disease (MRD) using a next-generation sequencing-based assay after each phase of treatment and at 6 months following end-oftreatment. We enrolled 49 patients of which 47 were response evaluable. By intent-to-treat, rates of overall and complete response were equivalent at 88% (43/49), one patient with stable disease, and two patients had disease progression during study; 3-year progression-free survival was 63% (primary endpoint not met) and differed by TP53 status (78% wild-type vs. 38% ALT; P=0.043). MRD status was prognostic and predicted long-term outcomes following R-HiDAC and at 6 months following end-of-treatment. In a high-dose therapy-sparing, intensive approach, we achieved favorable outcomes in TP53- wild-type MCL, including high-risk cases. We confirmed that sequential MRD assessment is a powerful prognostic tool in patients with MCL.

Diffuse large B-cell lymphoma involving osseous sites: utility of response assessment by PET/CT and good longterm outcomes.

Osseous involvement by diffuse large B-cell lymphoma (DLBCL-bone) is a heterogeneous disease. There is limited data regarding response assessment by positron emission tomography with fluorodeoxyglucose, which may demonstrate residual avidity despite a complete response. We analyzed clinical data of patients with newly diagnosed DLBCL and identified all cases with DLBCL-bone. End of treatment scans were reviewed by two independent experts classifying osseous lesions into Deauville (DV) ≤3; DV ≥4, or reactive uptake in the bone marrow (M), site of fracture (F) or surgery (S). We compared outcomes of DLBCL-bone to other extranodal sites (EN) matched on International Prognotic Index features and regimen. Of 1,860 patients with DLBCL (bone 16%; EN 45%; nodal 39%), 41% had localized disease and 59% advanced. Only 9% (n=27) of patients with initial bone involvement had residual fluorodeoxyglucose avidity at the osseous site. In half of these cases, the uptake was attributed to F/S/M, and of the remaining 13, only two were truly refractory (both with persistent disease at other sites). Overall survival and progression-free survival (PFS) were found to be similar for early- stage nodal DLBCL and DLBCL-bone, but inferior in EN-DLBCL. Advanced-stage disease involving the bone had a similar 5-year PFS to nodal disease and EN-DLBCL. After matching for International Prognotic Index and treatment regiments, PFS between bone and other EN sites was similar. Osseous involvement in DLBCL does not portend a worse prognosis. End of treatment DV ≥4 can be expected in 5-10% of cases, but in the absence of other signs of refractory disease, may be followed expectantly.

Rituximab and lenalidomide for the treatment of relapsed or refractory indolent non-Hodgkin lymphoma: real-life experience.

The combination of rituximab and lenalidomide (R-len) stands as an established treatment for relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, the reproducibility of clinical trial results in routine clinical practice is unknown. To address this gap in knowledge, we reviewed our experience with patients diagnosed with R/R follicular lymphoma (FL) or marginal zone lymphoma (MZL) treated with this combination. Eighty-four patients underwent treatment with R-len, 69 (82%) affected by FL and 15 (18%) by MZL. The median age at the time of treatment initiation was 65 years (range, 39-94), 38 patients (45%) had a pre-treatment FLIPI score of 3-5, 19 (23%) had a bulky disease, 29 (37%) had a lymphoma refractory to the last treatment line, while in 20 (24%) cases the disease was refractory to rituximab. The best overall response rate (ORR) was 82%, and 52% achieved a complete response (CR). The best CR rates for FL and MZL patients were 55% and 40%, respectively. With a median follow-up of 22 months, the median progression-free survival (mPFS) was 22 months (95% CI 19-36) and the 2-year overall survival (OS) was 83% (95% CI 74-93). The median duration of CR (DoCR) was 46 months (95% CI 22-NR). Factors associated with shorter PFS in multivariate analysis were bulky disease and rituximab refractoriness. The most common adverse events (AE) included hematologic toxicity, fatigue and gastrointestinal disorders, such as diarrhea and constipation. Neutropenia and thrombocytopenia were the most common severe toxicities (grade ≥3 in 25% and 4%, respectively). No new safety signals were reported. Real-life results of R-len in patients with R/R iNHL appear consistent with those reported in prospective studies, and further support its use as comparator arm in controlled clinical trials.

Clinical efficacy and safety of chimeric antigen receptor T-cell therapy for mantle cell lymphoma with secondary central nervous system involvement.

Data describing outcomes of chimeric antigen receptor (CAR) T-cell therapy in patients with secondary central nervous system (SCNS) involvement of mantle cell lymphoma (MCL) are limited. We identified 10 patients with MCL and SCNS involvement treated with anti-CD19 CAR T-cell therapy at three US academic centres. Frequent objective responses were observed in the CNS (86%) and systemically (90%), and the 1-year progression-free survival was 47%. Seven patients developed immune-effector-cell-associated-neurotoxicity-syndrome (n = 2 Grade 1, n = 5 Grade 3). Our results suggest that anti-CD19 CAR T-cell therapy in this setting is feasible and additional data regarding neurotoxicity in this population may be warranted.

Clinical characteristics and outcomes of extranodal stage I diffuse large B-cell lymphoma in the rituximab era.

This retrospective study aimed to better define the characteristics and outcomes of extranodal stage I diffuse large B-cell lymphoma (DLBCL) in the rituximab era. Patients diagnosed with stage I DLBCL from 2001 to 2015 treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or R-CHOP-like regimens with or without radiation (RT) were included. We identified 1955 patients with newly diagnosed DLBCL, of whom 341 had stage I and were eligible for this analysis. Extranodal presentation was observed in 224 (66%) patients, whereas 117 (34%) had nodal involvement. The most common extranodal sites were as follows: bone, 21%; stomach, 19%; testis, 9%; intestine, 8%; breast, 8%. Overall, 69% extranodal patients and 68% nodal patients received RT. Median follow-up was 5.5 years (interquartile range, 4.3-8.2). Ten-year overall survival (OS) and disease-free survival were 77% (95% confidence interval [CI], 67%-83%) and 77% (95% CI, 68%-85%). In the multivariable analyses, extranodal involvement was associated with worse OS (hazard ratio [HR], 3.44; 95% CI, 1.05-11.30) and progression-free survival (PFS; HR, 3.25; 95% CI, 1.08-9.72) compared with nodal involvement. Consolidation RT was associated with better OS (HR, 0.26; 95% CI, 0.12-0.49) and PFS (HR, 0.35; 95% CI, 0.18-0.69) in the extranodal population; however, the benefit was no longer observed in patients that were positron emission tomography (PET) negative at the end of immunochemotherapy. Relapses occurred usually late (median, 37 months), and the most common sites were the lymph nodes (31%) and the central nervous system (27%). Extranodal stage I DLBCL had a worse outcome than nodal stage 1 DLBCL. End of immunochemotherapy PET results may help select extranodal patients for consolidation RT.

Prephase rituximab/prednisone therapy and aging-related, proinflammatory cytokine milieu in older, vulnerable patients with newly diagnosed diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) predominantly affects older adults with suboptimal therapeutic outcomes due to increased treatment-related mortality and toxicities in vulnerable patients, clinically defined by geriatric impairments such as functional limitation, multimorbidity, or cognitive deficits. In this prospective pilot study, we evaluated a rituximab/prednisone prephase treatment strategy in 33 older, vulnerable patients with newly diagnosed DLBCL, defined by either age ≥70 years or age 60-70 years with Karnofsky performance scale (KPS) <80. A single dose of rituximab 375 mg/m2 between 3-10 days and oral prednisone for at least 5 days prior to the first dose of chemoimmunotherapy was administered. All patients completed prephase treatment and all but one commenced anthracycline-based chemoimmunotherapy. Only one early cycle death occurred. Toxicity events, defined by either unplanned hospitalization, unplanned dose reduction/delay, or chemotherapy discontinuation, occurred in 22 patients (67%). Sixteen patients (48%) experienced grade 3 or higher non-hematologic toxicities and/or grade 4 or higher hematologic toxicities. With a median follow-up of 4.4 years, both 5-year progression-free survival and overall survival were at 81% (95% confidence interval: 69-96). Importantly, we found that phenotypic impairments in basic and instrumental activities of daily living, physical function, mobility, KPS, and Cancer and Aging Research Group chemotherapy toxicity risk score were significantly associated with senescence-associated, proinflammatory cytokine milieu which was readily reversed with prephase treatment, potentially explaining its clinical effectiveness. Prephase therapy with rituximab/prednisone should be considered for all older, vulnerable DLBCL patients prior to curative intent, anthracycline-based chemoimmunotherapy. This trial was registered as clinicaltrials gov. Identifier: NCT89028394.

Hodgkin lymphoma survivor perspectives on their engagement in treatment decision-making and discussion of late effects.

BACKGROUND: Hodgkin lymphoma has a bimodal age distribution with the first peak occurring within young adulthood and the second, among older adults. Although current therapy provides excellent disease control, survivors are at risk of developing treatment-related late effects (LEs). We sought to understand how survivors in active survivorship care perceived their role in treatment decision-making and when they acquired an understanding of LEs. METHODS: Semi-structured interviews were conducted until saturation was reached. Themes were identified through direct content analysis and consensus coding by a multidisciplinary team of coders, including hematology/oncology providers, patient navigators, and survivor stakeholders. RESULTS: Seventeen interviews were conducted. Role in initial treatment decision-making fluctuated between passive and active engagement with providers identified as being crucial to this process. Half of interviewees (53%) expressed unmet information needs. Survivors reported having learned about LEs at multiple time points, spanning from before treatment commenced through when a LE was diagnosed. The majority (71%) expressed a desire to have learned about LEs before initial treatment ended. The impact of cancer and fertility discussions were also disclosed. DISCUSSION: Participants highlighted the importance of discussions on LEs early in the care continuum. These preliminary data will be incorporated in a planned treatment decision-making tool that incorporates information on potential LEs. IMPLICATIONS FOR CANCER SURVIVORS: Patient-centered communication approaches should be embraced to assist in treatment decision-making, while considering long-term health consequences. Survivors must be educated on their risk of LEs and encouraged to disclose their perspectives and preferences with their providers to optimize outcomes.

Active surveillance for nodular lymphocyte-predominant Hodgkin lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of lymphoma that, like other Hodgkin lymphomas, has historically been treated aggressively. However, in most cases, NLPHL has an indolent course, which raises the question of to what extent these patients require aggressive upfront treatment. We describe the management and outcomes of consecutive NLPHL patients diagnosed at Memorial Sloan Kettering Cancer Center (MSK), with a focus on evaluating active surveillance. All patients aged 16 years or older diagnosed and followed at MSK between 1974 and 2016 were included. Treatment outcomes were compared between management with active surveillance and other strategies. We identified 163 consecutive patients who were treated with radiotherapy alone (46%), active surveillance (23%), chemotherapy (16%), combined modality (12%), or rituximab monotherapy (4%). Median follow-up was 69 months. Five-year progression-free survival (PFS), second PFS (PFS2), and overall survival (OS) estimates were 85% (95% confidence interval [CI], 78-90), 97% (95% CI, 92-99), and 99% (95% CI, 95-100), respectively. Only 1 of 7 deaths was lymphoma related. Patients managed with active surveillance had slightly shorter PFS than those receiving any active treatment, with 5-year PFS of 77% (95% CI, 56-89) vs 87% (95% CI, 79-92; P = .017). This difference did not translate into better PFS2 or OS. Only 10 patients managed with active surveillance (27%) eventually required treatment, after a median of 61 months, and none died. NLPHL has an excellent prognosis. Within the limitations of a retrospective analysis, active surveillance is a viable initial management strategy for selected NLPHL patients.

Romidepsin and lenalidomide-based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase I studies with expansion cohorts.

Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. Forty-nine patients were treated in study A (27 TCL, 17 BCL, 5 Hodgkin lymphoma (HL)) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8 mg/m2 on days 1 and 8, lenalidomide 10 mg oral on days 1-14 and carfilzomib 36 mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.

Genome-wide identification of estrogen receptor binding sites reveals novel estrogen-responsive pathways in adult male germ cells.

Spermatogenesis occurs in the seminiferous epithelium that shows the presence of estrogen receptors alpha (ERα) and beta (ERß), both of which regulate gene transcription by binding to the DNA. Estrogen responsive phases of spermatogenesis are well documented; however, the genes regulated remain inexplicit. To study the regulation of genes by estrogen in male germ cells, we performed chromatin immunoprecipitation (ChIP) sequencing for ERα and ERß under normal physiological conditions. A total of 27 221 DNA binding regions were enriched with ERα and 20 926 binding sites with ERß. Majority of the peaks were present in the intronic regions and located 20 kb upstream or downstream from the transcription start site (TSS). Pathway analysis of the genes enriched by ChIP-Seq showed involvement in several biological pathways. Genes involved in pathways whose role in spermatogenesis is unexplored were validated; these included prolactin, GnRH, and oxytocin signaling. All the selected genes showed the presence of estrogen response elements (EREs) in their binding region and were also found to be significantly enriched by ChIP-qPCR. Functional validation using seminiferous tubule culture after treatment with estrogen receptor subtype-specific agonist and antagonist confirmed the regulation of these genes by estrogen through its receptors. The genes involved in these pathways were also found to be regulated by the respective receptor subtypes at the testicular level in our in vivo estrogen receptor agonist rat models. Our study provides a genome-wide map of ERα and ERß binding sites and identifies the genes regulated by them in the male germ cells under normal physiological conditions.

Predictors of Loss to Follow-Up Among Pediatric and Adult Hematopoietic Cell Transplantation Survivors: A Report from the Center for International Blood and Marrow Transplant Research.

Follow-up is integral for hematopoietic cell transplantation (HCT) care to ensure surveillance and intervention for complications. We characterized the incidence of and predictors for being lost to follow-up. Two-year survivors of first allogeneic HCT (10,367 adults and 3865 children) or autologous HCT (7291 adults and 467 children) for malignant/nonmalignant disorders between 2002 and 2013 reported to the Center for International Blood and Marrow Transplant Research were selected. The cumulative incidence of being lost to follow-up (defined as having missed 2 consecutive follow-up reporting periods) was calculated. Marginal Cox models (adjusted for center effect) were fit to evaluate predictors. The 10-year cumulative incidence of being lost to follow-up was 13% (95% confidence interval [CI], 12% to 14%) in adult allogeneic HCT survivors, 15% (95% CI, 14% to 16%) in adult autologous HCT survivors, 25% (95% CI, 24% to 27%) in pediatric allogeneic HCT survivors, and 24% (95% CI, 20% to 29%) in pediatric autologous HCT survivors. Factors associated with being lost to follow-up include younger age, nonmalignant disease, public/no insurance (reference: private), residence farther from the tranplantation center, and being unmarried in adult allogeneic HCT survivors; older age and testicular/germ cell tumor (reference: non-Hodgkin lymphoma) in adult autologous HCT survivors; older age, public/no insurance (reference: private), and nonmalignant disease in pediatric allogeneic HCT survivors; and older age in pediatric autologous HCT survivors. Follow-up focusing on minimizing attrition in high-risk groups is needed to ensure surveillance for late effects.

Autophagy in aging and longevity.

Our understanding of the process of autophagy and its role in health and diseases has grown remarkably in the last two decades. Early work established autophagy as a general bulk recycling process which involves the sequestration and transport of intracellular material to the lysosome for degradation. Currently, autophagy is viewed as a nexus of metabolic and proteostatic signalling that can determine key physiological decisions from cell fate to organismal lifespan. Here, we review the latest literature on the role of autophagy and lysosomes in stress response and longevity. We highlight the connections between autophagy and metabolic processes, the network associated with its regulation, and the links between autophagic dysfunction, neurodegenerative diseases, and aging.

First-line treatment in older patients with Hodgkin lymphoma: a Surveillance, Epidemiology, and End Results (SEER)-Medicare population-based study.

While Hodgkin lymphoma (HL) is highly curable in younger patients, older patients have higher relapse and death rates, which may reflect age-related factors, distinct disease biology and/or treatment decisions. We described the association between patient, disease and geographic factors and first-line treatment in older patients (≥65 years) with incident HL using Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 1999 to 2014 (n = 2825). First-line treatment initiated at ≤4 months after diagnosis was categorised as: full chemotherapy regimen (n = 699, 24·7%); partial chemotherapy regimen (n = 1016, 36·0%); single chemotherapy agent or radiotherapy (n = 382, 13·5%); and no treatment (n = 728, 25·8%). Among the fully treated, ABVD [doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine]/AVD was most common (n = 635, 90·8%). Adjusted multinomial logistic regression identified factors associated with treatment. Older age, Medicaid dual eligibility, not married, frailty, cardiac comorbidity, prior cancer, earlier diagnosis date, histology, advanced disease Stage, B symptoms and South region were independently associated with increased odds of not receiving full chemotherapy regimens. In conclusion, we found variability in first-line HL treatment for older patients. Treatment differences by Medicaid and region may indicate disparities. Even after adjusting for frailty and cardiac comorbidity, age was associated with treatment, suggesting factors such as end-of-life care or shared decision-making may influence treatment in older patients.

A phase 1 study of ibrutinib in combination with R-ICE in patients with relapsed or primary refractory DLBCL.

In the postrituximab era, approximately half of the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response to standard salvage therapy, and are thus ineligible to proceed to autologous stem cell transplantation with curative intent. The Bruton tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, particularly of non-germinal center (non-GC) cell of origin. We conducted a single-center phase 1 study evaluating dose-escalated ibrutinib, in a 3-by-3 design, in combination with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in physiologically transplant-eligible rel/ref DLBCL patients. Twenty-one patients have been treated and are evaluable for toxicity with no dose-limiting toxicities observed through expansion with ibrutinib at 840 mg daily at dose level 3. Of the 20 patients evaluable for response, per modern International Conference on Malignant Lymphoma criteria, 11 patients achieved complete remission (CR) and 7 patients achieved partial remission for an overall response rate of 90%. All evaluable patients with non-GC DLBCL achieved a metabolic CR. Ibrutinib in combination with R-ICE demonstrates tolerability and efficacy in rel/ref DLBCL, particularly of non-GC phenotype. This treatment program warrants further investigation in later-phase studies. This trial was registered at www.clinicaltrials.gov as #NCT02219737.

Management of Mantle Cell Lymphoma in the Era of Novel Oral Agents.

Objectives: To discuss (1) recent and emerging data for pharmacological management of untreated and relapsed/refractory (R/R) mantle cell lymphoma (MCL) with agents approved in the United States, (2) important considerations for toxicity monitoring and management, and (3) preliminary data and ongoing studies for agents in MCL-specific clinical trials. Data Sources: PubMed/MEDLINE, EMBASE, Google Scholar, product labeling, National Comprehensive Cancer Network, American Cancer Society, and ClinicalTrials.gov were searched for studies published between January 1, 2017, and January 31, 2020, and key historical trials. Study Selection and Data Extraction: Relevant studies conducted in humans and selected supporting preclinical data were reviewed. Data Synthesis: MCL is a rare but usually aggressive non-Hodgkin lymphoma that most commonly affects the older population. Traditionally, the treatment of MCL has been determined based on transplant eligibility. Newer data suggest that more tolerable frontline therapy may produce outcomes similar to intensive historical induction regimens, possibly precluding fewer patients from autologous stem cell transplant and producing better long-term outcomes in transplant-ineligible patients. In the R/R setting, novel regimens are improving outcomes and changing the landscape of treatment. Relevance to Patient Care and Clinical Practice: This review summarizes and discusses recent and emerging data for management of newly diagnosed and R/R MCL; key supportive care considerations for agents are also discussed. Conclusions: Recent study results are changing management of MCL. Although these data have complicated the picture of regimen selection, increasingly effective and tolerable therapy and additional anticipated data point to a brighter future for patients with MCL.

Video capsule endoscopy for upper gastrointestinal hemorrhage in the emergency department: A systematic review and meta-analysis.

OBJECTIVE: The assessment of the severity of upper gastrointestinal hemorrhage in emergency department (ED) patients is difficult to assess with commonly available diagnostic tools. Small studies have shown that video capsule endoscopy (VCE) is a promising risk-stratification method and may be better than current clinical decision rules such as the Rockall score and the Glasgow Blatchford score. This review aims to assess the accuracy of VCE to detect active upper gastrointestinal hemorrhage compared to a reference standard. METHODS: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology was used to perform a review of studies that have measured the diagnostic accuracy of VCE. Studies were included if they measured ED use of VCE for upper GI hemorrhage as compared to a reference standard of an esophagogastroduodenoscopy (EGD). A meta-analysis was performed on select patients using a fixed effects and random-effects model to determine the primary outcome of diagnostic test accuracy. RESULTS: 40 studies were screened for eligibility and five studies representing 193 patients met the inclusion and exclusion criteria. All patients received both a VCE and an EGD. The sensitivity and specificity of VCE were 0.724 and 0.748, respectively. The diagnostic odds ratio was 6.29 (95% CI: 3.23-12.25) and the summary receiver operating characteristic curve was 0.782. CONCLUSIONS: VCE demonstrated high accuracy for detecting upper GI hemorrhage in this meta-analysis of existing studies. In light of the potential advantages of VCE in the ED, further research is warranted to further establish its role.

Prognostic significance of baseline metabolic tumor volume in relapsed and refractory Hodgkin lymphoma.

Identification of prognostic factors for patients with relapsed/refractory Hodgkin lymphoma (HL) is essential for optimizing therapy with risk-adapted approaches. In our phase 2 study of positron emission tomography (PET)-adapted salvage therapy with brentuximab vedotin (BV) and augmented ifosfamide, carboplatin, and etoposide (augICE), we assessed clinical factors, quantitative PET assessments, and cytokine and chemokine values. Transplant-eligible patients with relapsed/refractory HL received 2 (cohort 1) or 3 (cohort 2) cycles of weekly BV; PET-negative patients (Deauville score ≤2) proceeded to autologous stem cell transplantation (ASCT) whereas PET-positive patients received augICE before ASCT. Serum cytokine and chemokine levels were measured at baseline and after BV. Metabolic tumor volume (MTV) and total lesion glycolysis were measured at baseline, after BV, and after augICE. Sixty-five patients enrolled (45, cohort 1; 20, cohort 2); 49 (75%) achieved complete response and 64 proceeded to ASCT. Three-year overall survival and event-free survival (EFS) were 95% and 82%, respectively. Factors predictive for EFS by multivariable analysis were baseline MTV (bMTV) (P < .001) and refractory disease (P = .003). Low bMTV (<109.5 cm3) and relapsed disease identified a favorable group (3-year EFS, 100%). For patients who received a transplant, bMTV and pre-ASCT PET were independently prognostic; 3-year EFS for pre-ASCT PET-positive patients with low bMTV was 86%. In this phase 2 study of PET-adapted therapy with BV and augICE for relapsed/refractory HL, bMTV and refractory disease were independent prognostic factors for EFS. Furthermore, bMTV improved the predictive power of pre-ASCT PET. Future studies should optimize efficacy and tolerability of salvage therapy by stratifying patients according to risk factors such as bMTV.