LaCasce, Ann S.

PURPOSE Patients with bulky stage I/II classic Hodgkin lymphoma (cHL) are typically treated with chemotherapy followed by radiation. Late effects associated with radiotherapy include increased risk of second cancer and cardiovascular disease. We tested a positron emission tomography (PET)–adapted approach in patients with bulky, early-stage cHL, omitting radiotherapy in patients with interim PET-negative (PET−) disease and intensifying treatment in patients with PET-positive (PET+) disease. METHODS Eligible patients with bulky disease (mass > 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray) received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by interim fluorodeoxyglucose PET (PET2). Patients with PET2–, defined as 1-3 on the 5-point scale, received four additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Patients with PET2+ received four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone followed by 30.6 Gy involved-field radiation. RESULTS Of 94 evaluable patients, 53% were female with median age 30 years (range, 18-58 years). Eight-five (90%) had stage II disease, including 48 (51%) with stage IIB/IIBE. Seventy-eight (78%) were PET2– and 21 (22%) were PET2+. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia and one developing sepsis. The primary end point of 3-year progression-free survival (PFS) was 93.1% in PET2– and 89.7% in PET2+ patients. Three-year overall survival was 98.6% and 94.4%, respectively. The estimated hazard ratio comparing PFS of patients with PET2+ and patients with PET2− was 1.03 (85% upper bound 2.38) and was significantly less than the null hypothesis of 4.1 (one-sided P = .04). CONCLUSION Our study of PET-adapted therapy in bulky stage I/II cHL met its primary goal and was associated with an excellent 3-year PFS rate of 92.3% in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.

Abstract With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Abstract Background The National Institutes of Health define African Americans or Blacks, American Indians, Alaska Natives, Hispanics or Latinos, Native Hawaiians, and other Pacific Islanders as being underrepresented in medicine. A number of studies have demonstrated that improving diversity of such underrepresented demographics within the medical profession improves patient outcomes, medical education and reduces health disparities in patients from vulnerable racial or socioeconomic groups. Despite this recognition, significant underrepresentation of various racial, ethnic, and sexual identities still exists within nearly all medical specialties. Aims The purpose of this study was to a gain a greater understanding of the current state of diversity, equity, and inclusion (DEI) efforts among U.S. hematology and medical oncology fellowship training programs. We explored the perspectives of adult and pediatric fellowship program directors regarding current recruitment strategies and suggestions for improvement to help mitigate the effects of implicit and explicit bias. Here, we present an interim analysis of the data using descriptive statistics. Methods: We convened a multi-institutional collaboration of fellowship program directors, teaching faculty, and staff members of the American Society of Hematology to develop a survey examining perceptions of DEI efforts among hematology and medical oncology fellowship program directors. The survey was pilot tested in a small group of program directors representing 6 different academic programs (5 adult, 1 pediatric). The final online survey was distributed via email to 224 fellowship program directors at U.S. adult and pediatric hematology and medical oncology fellowship programs. The survey included 29 questions regarding perspectives on bias within the fellowship selection process, current DEI initiatives, and current faculty and fellow demographics. Survey respondents were asked to rate the importance of numerous factors in determining which applicants to invite utilizing a scale of 0-10, with 0 and 10 representing lowest and highest importance, respectively. To measure program director perceptions of certain applicant groups, survey respondents were asked to rate applicant demographics as being advantaged/disadvantaged based on survey options ranging from 0-5, with 0 and 5 representing very disadvantaged and very advantaged, respectively. Results: At interim analysis, 41 of 224 program directors completed the survey for an interim response rate of 21%, including 25 adult program directors and 16 pediatric program directors, with representation from university and community programs. Of the program directors surveyed, 28 (68%) reported having access to a dedicated diversity committee or DEI policies in place to improve recruitment of underrepresented applicants. In determining which applicants to invite, respondents placed highest value on the applicant's program director letter (mean score ± standard deviation: 7.44±1.93), caliber of the applicant's residency program (7.28±2.06) and letters of recommendations (7.15±2.23). Survey respondents viewed white and male applicants as representing the most advantaged demographic group, while LGBTQI, age>40, and U.S. citizen and non-citizen international medical graduates were the most disadvantaged (Table 1). Suggestions regarding improving DEI in the fellowship selection process included implementing bias training, identifying potentially disadvantaged applicants in ERAS, increasing faculty diversity, and pairing underrepresented applicants with interviewers based on applicant preference. Conclusion: While the majority of hematology and medical oncology fellowship program directors report having DEI programs or policies to improve recruitment of underrepresented applicants, perceptions of advantaged/disadvantaged groups may extend beyond demographics traditionally viewed as being underrepresented in medicine. As our survey is ongoing, we plan to reanalyze our data when the survey has been finalized with a higher response rate utilizing multivariable regression to identify themes that may further improve DEI efforts within the fellowship selection process. Figure 1 Figure 1. Disclosures LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Murphy: North American Thrombosis Foundation: Honoraria. Naik: Rigel: Research Funding. Podoltsev: Pfizer: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; PharmaEssentia: Honoraria; Bristol-Myers Squib: Honoraria; CTI BioPharma: Honoraria.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody–drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1–mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

AbstractThis phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

Abstract Introduction Brentuximab vedotin (BV) is an ADC directed against CD30, a receptor expressed by malignant Reed-Sternberg (RS) cells present in the inflammatory/immune cell microenvironment of classical Hodgkin lymphomas (cHL). Through induction of immunogenic cell death, BV may prime an antitumor immune response via microtubule disruption of CD30-expressing RS cells (Gardai 2015). Tumor cells expressing PD-1 ligands use the PD-1 pathway to evade an immune response. Nivolumab (Nivo) blocks the PD-1 receptor, inhibits binding of PD-1 ligands, and restores an effective antitumor immune response. Targeted killing of CD30-expressing RS cells, concurrent with restoration of the immune response, may lead to higher complete response (CR) rates in patients (pts) with relapsed or refractory cHL (R/R HL), as well as improved durability of responses post autologous stem cell transplant (ASCT). Here we present updated results from the phase 1/2 study of BV + Nivo in pts with R/R HL. Methods BV + Nivo was evaluated in cHL that had relapsed or was refractory to frontline (FL) chemotherapy in adult pts (NCT02572167). Pts were excluded if they had received prior salvage therapy, BV or immuno-oncology therapy, or allogeneic SCT or ASCT. Pts were treated in 21-day cycles for up to 4 cycles. In Parts 1 and 2 of the trial, BV (1.8 mg/kg) was given on Cycle 1 Day 1 and Nivo (3 mg/kg) on Cycle 1 Day 8. For Cycles 2-4, BV and Nivo were given on Day 1. After the Cycle 4 response assessment, pts were eligible to undergo ASCT. The investigators assessed response per the Lugano Classification (Cheson 2014). Results 62 pts with R/R HL were enrolled in Parts 1 and 2; 61 pts received BV + Nivo, of whom 58 completed treatment (tx). 4 pts discontinued the study due to pt decision (2), AE (1), and investigator decision (1). Median age was 36 years, 52% were female, and 90% had received FL ABVD. 45% of pts had primary refractory disease and 31% experienced relapse within 1 year of FL therapy. Infusion-related reactions (IRRs) occurred in 41% of pts. Tx emergent AEs occurred in 98% of pts prior to ASCT (33% G3, 5% G4). Excluding IRRs, potential immune-related AEs (IrAEs) occurred in 84% of pts (10% G3, 3% G4) with 5 pts (8%) treated with systemic steroids for G4 pneumonitis, G4 pneumonitis and colitis, G2 pneumonitis, G3 diarrhea and G2 colitis, and G3 AST elevation. Among the 60 efficacy-evaluable pts, the CR rate was 62%, (48% of CR pts had Deauville ≤ 2) with an objective response rate of 85%; 5 pts (8%) had stable disease and 4 pts (7%) progressed on tx. At the time of this analysis, 39 pts had initiated ASCT with a median 5.1x106 CD34+ cells/kg (range; 3-60) collected. Median times to neutrophil and platelet engraftment were 12 and 15 days, respectively. Pts were followed for a median of 3 months from ASCT (N=39, range; 0-12) and 5.7 months from first dose (N=61, range; 1-17). BV and Nivo effects on the immune system were evaluated by peripheral blood immunophenotyping, serum cytokine/chemokine analyses, T-cell receptor sequencing, and intracellular cytokine staining. The first dose of BV resulted in elevation of pro-inflammatory cytokines and chemokines and concurrent reduction in serum TARC levels, with these results maintained post Nivo. We observed a reduction in Tregs and other T cell subsets after the first dose of BV with an elevation of T cell subsets post BV + Nivo. While TCR clonality in the periphery did not change over the course of the trial, T cell clonal expansion was observed post BV + Nivo, concurrent with T cell elevation measured by flow cytometry. Ex vivo peptide stimulation of PBMCs isolated from blood revealed the enhanced ability of T cell subsets to respond to MHC I and MHC II antigens following BV + Nivo compared to baseline: e.g., effector memory CD8+ T cells from some pts displayed increased intracellular IL-2, and TNFa after stimulation with MHCI and MHCII peptide pools compared to baseline, potentially indicating elevated activation status of the immune system following combination tx. Conclusion R/R HL remains an unmet clinical need despite recent medical advances. These data suggest the combination BV + Nivo is a well tolerated and an active salvage therapy with a high rate of CR (62%) that has no adverse impact on stem cell collection. The safety and activity of this novel combination support further exploration in an ongoing pivotal phase 3 trial in pts with R/R HL who have either already received or are considered ineligible for ASCT (NCT03138499). Disclosures Herrera: Seattle Genetics: Research Funding; Merck: Consultancy; Genentech: Consultancy; BMS: Consultancy; Pharmacyclics: Consultancy. Moskowitz: Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; Incyte: Research Funding; ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding. Bartlett: Novartis: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Vose: Merck: Research Funding; Kite: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Allos Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Research Funding; Onyx: Research Funding; Seattle Genetics: Research Funding; US Biotest: Research Funding; Bristol-Myers Squibb: Research Funding. Ramchandren: Seattle Genetics: Consultancy; MERCK: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Feldman: AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Kite Pharma: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy. LaCasce: BMS: Consultancy; Forty Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding. Ansell: Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding. Moskowitz: Celgene: Consultancy; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Genentech BioOncology: Consultancy; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding. Fenton: Seattle Genetics: Employment, Equity Ownership. Ogden: Seattle Genetics: Employment, Equity Ownership. Taft: Seattle Genetics: Employment, Research Funding. Zhang: Seattle Genetics: Employment, Research Funding. Kato: Bristol-Myers Squibb: Employment, Equity Ownership; Seattle Genetic: Research Funding. Campbell: Seattle Genetics: Employment, Equity Ownership; CTI BioPharma: Employment, Equity Ownership. Advani: Agensys: Research Funding; Pharmacyclics: Research Funding; Regeneron: Research Funding; FortySeven: Research Funding; Nanostring: Consultancy; Celgene: Research Funding; Pharmacyclics: Consultancy; Merck: Research Funding; Juno Therapeutics: Consultancy; Kura: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Seattle Genetics: Research Funding; Gilead: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Spectrum: Consultancy; Bayer Healthcare Pharmaceuticals: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Cell Medica: Research Funding; Sutro: Consultancy.

Abstract Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.

Abstract Approximately one‐third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high‐risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4–7, enrolled in the ECHELON‐1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first‐line therapy after a median follow‐up of 37.1 months. Among patients treated with A + AVD ( n = 664) or ABVD ( n = 670), 64% had Stage IV disease and 26% had an IPS of 4–7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537–0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4–7 (HR, 0.588; 95% CI, 0.386–0.894; p = 0.012). The most common adverse events (AEs) in A + AVD‐treated versus ABVD‐treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4–7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high‐risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON‐1 shows a favorable benefit‐risk balance in high‐risk patients.