Autologous Stem Cell Transplantation Consolidation Research Articles

Autologous stem cell transplantation in T-cell/histiocyte-rich large B-cell lymphoma: EBMT Lymphoma Working Party study.

Although broadly employed, consolidative autologous hematopoietic stem cell transplantation (autoHCT) for relapsed/refractory (r/r) T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) has never been specifically investigated. Here we have analyzed outcomes of autoHCT for THRLBCL compared to diffuse large cell B-cell lymphoma not otherwise specified (DLBCL). Eligible for this retrospective registry study were adult patients with r/r THRLBCL and DLBCL, respectively, who underwent a first autoHCT in a salvage-sensitive disease status as assessed by PET-CT between 2016 and 2021 and were registered with the European Society for Blood and Marrow Transplantation (EBMT) database. Primary endpoint was progression-free survival (PFS) 2 years after transplantation. Two-hundred-one patients with THRLBCL and 5,543 with DLBCL were included. There were no significant differences in terms of disease status at HCT, pretreatment lines, and interval from diagnosis to transplant between the cohorts, but patients with THRBCL were significantly younger, contained a higher proportion of men, and had a better performance status. Compared to DLBCL, THRLBCL was associated with significantly better 2-year PFS (78% vs. 59%; p<0.001) and overall survival (OS; 81% vs. 74%; p=0.02) because of a significantly lower 2-year relapse incidence (RI; 16% vs. 35%; p<0.001). On multivariate analysis, favorable relapse risk (hazard ratio (HR) 0.46, 95%CI 0.31-0.7) and PFS (HR 0.58, 95%CI 0.41-0.82) of patients with THRLBCL remained significant, while OS benefits (HR 0.78, 95%CI 0.54-1.12) did not. These results were validated in a propensity-score matched analysis. These data prove autoHCT as an effective treatment option for salvage-sensitive r/r THRLBCL.

Sequencing of cellular therapy and bispecific antibodies for the management of diffuse large B-cell lymphoma.

Historically, management of relapsed or refractory (R/R) Diffuse large B-cell (DLBCL) following first-line chemoimmunotherapy has been second-line chemotherapy, followed by high-dose chemotherapy and consolidative autologous hematopoietic stem cell transplantation (auto-HSCT), resulting in durable remissions in approximately 40% of patients. In 2017, chimeric antigen receptor (CAR) T-cell therapy changed the landscape of treatment for patients with R/R DLBCL, with complete response rates ranging from 40-58% and long-term disease-free survival of >40% in the highest risk subgroups, including patients who relapsed after auto-HSCT. Since that time further studies have demonstrated improved overall response rates (ORRs) and survival outcomes in patients with primary refractory or early-relapse (relapse 50% of patients will relapse in the post-CAR T-cell setting. In the past two years, two CD20 x CD3 bispecific antibodies (BsAbs) were FDA approved for the treatment of R/R DLBCL after two or more lines of systemic therapy. These BsAbs have demonstrated ORRs exceeding 50% and durable remissions at > 2yrs of follow-up. Additionally, a notable treatment advantage of BsAbs is their ability to be administered in the community setting, making treatment more accessible for patients. The development and advancement of these novel therapies raise questions regarding the ongoing role of HSCT in the management of relapsed and refractory DLBCL and how to best sequence cellular and Bi-specific therapies to optimize patient outcomes.

Autologous Stem Cell Transplant in Fit Patients With Late Relapsed Diffuse Large B-Cell Lymphoma That Responded to Salvage Chemotherapy

The standard of care (SOC) for fit patients with relapsed diffuse large B-cell lymphoma (DLBCL) ≥12 months after completing frontline therapy is salvage chemotherapy (ST) followed by autologous stem cell transplant (ASCT). However, this strategy may not be optimal for patients with certain clinical characteristics. We retrospectively studied 151 patients with DLBCL that relapsed ≥12 months after R-CHOP or R-CHOP-like frontline therapy who underwent ST and ASCT at Mayo Clinic between July 2000 and December 2017 or the University of Iowa between April 2003 and April 2020. Clinical characteristics, treatment information, and outcome data were abstracted. Progression-free survival (PFS) and overall survival (OS) from the time of ASCT were analyzed using the Kaplan–Meier method. The median time from frontline therapy completion to 1st relapse was 26.9 months. The median line of ST was 1 (range 1–3), and 17 (11%) patients required >1 line of ST. Best response before ASCT was partial response (PR) in 60 (40%) and complete response (CR) in 91 (60%) patients. The median age at ASCT was 64 yr (range 19–78), and 36 (24%) patients were of ≥70 yr. The median follow-up after ASCT was 87.3 months. The median PFS and OS were 54.5 and 88.9 months, respectively. There was no significant difference in PFS and OS based on the age at ASCT (including patients aged ≥70–78 yr), sex, transplant era, time to relapse, LDH, extranodal site involvement, and central nervous system/nerve involvement at relapse. However, patients with advanced-stage relapse had inferior PFS than those with early-stage relapse (median 45.3 versus 124.7 months, P = .045). Patients who required > 1 line of ST, compared to those requiring 1 line, had significantly inferior PFS (median 6.1 versus 61.4 months, P < .0001) and OS (17.8 versus 111.7 months, P = .0004). There was no statistically significant difference in survival in patients who achieved PR versus CR, though numerically inferior in the former, with median PFS of 38.9 versus 59.3 months (P = .23) and median OS of 78.3 versus 111.7 months (P = .62). Patients achieving CR after 1 line of ST had excellent post-ASCT outcomes, with median PFS of 63.7 months. In conclusion, survival after ASCT was unfavorable in patients with late relapsed DLBCL (≥12 months) who required more than 1 line of ST to achieve PR or CR, and such patients should be treated with alternative therapies. Conversely, survival was favorable in patients who required only 1 line of ST, supporting the current clinical practice of ASCT consolidation in these patients. Moreover, outcomes were favorable in patients aged ≥70 to 78 yr at ASCT, similar to younger patients, highlighting the safety and feasibility of this approach in such patients.

1p and 1q: Partners in crime in multiple myeloma.

7571 Background: Cytogenetic abnormalities in multiple myeloma (MM) highly influence the disease course, response to treatment and survival. Trisomies and immunoglobulin H chain translocations are primary CA while del(17p), gain(1q), del(1p) among others are secondary CA. Gain (3 copies) and amplification (&gt;3 copies) 1q have been recognized as adverse prognostic markers and incorporated into the second revision of the International Staging System (R2-ISS). However, the role of del(1p) is less well defined, especially in the era of novel therapies. We aimed to analyze the outcomes of newly diagnosed MM (NDMM) patients with chromosome 1 abnormalities, mainly del 1p, treated with autologous stem cell transplant (ASCT) consolidation at our institution. Methods: We conducted a retrospective study of all NDMM patients who were treated with ASCT from 1/1/2015-2/13/2019 (n=511). High-risk cytogenetics (HRC) were defined by the presence of del(17p), t(4;14), or t(14;16) similar to R-ISS; standard-risk cytogenetics (SRC) were defined as the absence of HRC. Modified HR cytogenetics (mHRC) included gain/amp 1q and/or t(14;20) in addition to HRC, while ultra high-risk (uHRC) included 2 or more mHRC CA. Results: Of 511 pts transplanted, 453 had cytogenetic data at the time of diagnosis. SRC were seen in 353 pts (77.9%), while 100 (22.1%) had HRC, 156 (34.4%) had mHRC, and 43 (9.5%) had uHRC. Thirty-two (7.1%) pts had del(1p) while 105 (23.2%) had gain 1q and 30 (6.6%) had amplification 1q. As expected, compared to SRC pts, pts with HRC, mHRC and uHRC had higher risk of relapse or death. Patients with gain and amp 1q had inferior outcomes in terms of progression-free survival (PFS) (HR 1.35; 95% CI 1.06-1.73, p=0.016), time to next treatment (TTNT) (HR 1.84; 95% CI 1.40-2.42, p&lt;0.001) and overall survival (OS) (HR 1.47; 95% CI 1.06-2.02, p=0.02) compared to those without, consistent with published literature. The median PFS, TTNT and OS from ASCT in pts with gain/amp 1q were 3.17 years (y), 3.95y and 7.13y, respectively, compared to 4.01y, 7.60y and 8.21y in pts without gain/amp 1q. Pts with del(1p) had inferior PFS (median 2.43y versus 3.98y; HR 1.75; 95% CI 1.16-2.64, p=0.008), TTNT (median 2.72y versus 6.17y; HR 1.96; 95% CI 1.22-3.14, p=0.005) and OS (median 4.11y versus 8.38y; HR 2.19; 95% CI 1.34-3.58, p=0.002) from the time of ASCT compared to those without del(1p). Conclusions: In our study of NDMM patients that underwent AHCT, del(1p) at diagnosis was an independent predictor of shorter PFS, TTNT and OS. Despite induction therapy involving novel drugs and ASCT consolidation, patients with del(1p) at diagnosis continue to have inferior outcomes. Larger analyses are needed to validate the prognostic value of del(1p) and investigate its role in predicting outcomes in MM.

Treatment strategies and outcome in relapsed peripheral T-cell lymphoma: results from the Netherlands Cancer Registry

AbstractOptimal treatment in patients with refractory or relapsed peripheral T-cell lymphomas (R/R T-NHLs) is unknown. In this population-based study, outcomes in R/R peripheral T-cell lymphoma not otherwise specified (PTCL NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic lymphoma kinase-positive (ALK+) and ALK-negative (ALK–) anaplastic large cell lymphoma (ALCL) were evaluated. Patients with PTCL NOS, AITL, ALK+ ALCL, and ALK– ALCL (≥18 years) diagnosed in 2014 to 2019 were identified using the Netherlands Cancer Registry. End points were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). The 2-year PFS of 821 patients was 57%. Among 311 patients with a relapse, 243 received second-line treatment: 44% received salvage chemotherapy, 20% received brentuximab vedotin (BV), and 36% received other treatment. In third-line treatment, BV was most commonly used (38%). ORR after second-line treatment was 47%. Two-year PFS and OS after relapse were 25% and 34%, respectively. The risk of second relapse was negatively affected by early relapse (<12 months after diagnosis), whereas BV reduced this risk compared with salvage chemotherapy. Reduced risk of relapse was independent of histological subtype. The best outcomes were observed for patients treated with salvage chemotherapy receiving consolidative autologous and allogeneic stem cell transplantation (SCT) (2-year OS 68%), patients treated with BV achieving a second complete remission (2-year OS 74%) and patients with allogeneic SCT (2-year OS 60%). The risk of second relapse was significantly lower for patients with R/R T-NHL treated with BV compared with patients treated with salvage chemotherapy, and this was irrespective of subtype. Therefore, the use of salvage chemotherapy for patients with R/R T-NHL is challenged.

Immune checkpoint inhibitors in advanced and relapsed/refractory Hodgkin lymphoma: current applications and future prospects.

Classic Hodgkin lymphoma (cHL) treatment paradigms are undergoing a shift with the integration of immune checkpoint inhibitors (ICIs) into both first-line and relapsed/refractory (R/R) regimens. In first-line therapy, the synergy between ICIs and chemotherapy may surpass the previous standards of ABVD and BV-AVD established by landmark trials including RATHL and ECHELON-1. In R/R disease, the combination of ICIs with chemotherapy has begun to challenge the paradigm of chemotherapy as a bridge to consolidative autologous stem cell transplantation. The clinical advances heralded by ICI offer unique challenges to management. ICI treatment and the associated inflammatory response can make the traditional timing and modalities of treatment response assessment difficult to interpret. In contrast to ABVD and BV-AVD, pembrolizumab-AVD results in PET2 positivity rates that are higher and less predictive of treatment response even when ultimate outcomes may be superior. This suggests that the predictive value of PET2 may be less reliable in the ICI era, prompting a reevaluation of response assessment strategies. Looking forward, circulating tumor DNA (ctDNA) may be a promising tool in response-adapted therapy. Its potential to complement or even supersede PET scans in predicting response to ICIs represents a critical advancement. The integration of ctDNA analysis holds the promise of refining response-adapted approaches and enhancing precision in therapeutic decision-making for patients with cHL. This review navigates the evolving landscape of cHL therapy, emphasizing the paradigmatic shift brought about by ICIs. This article explores the impact of combining ICIs with chemotherapy in both relapsed/refractory and first-line settings, scrutinizes the challenges posed to response-adapted therapy by ICIs, and highlights the potential role of ctDNA as an adjunct in refining response-adapted strategies for cHL.

Long-term remission after upfront autologous hematopoietic stem cell transplant for CD5+ diffuse large-B cell lymphoma

CD5+ diffuse large B-cell lymphoma (DLBCL) is a rare subtype characterized by an inferior outcome. While dose-dense therapy shows promising activity, the optimal management remains to be determined. To evaluate the benefit of consolidative autologous hematopoietic stem cell transplantation (ASCT), we retrospectively reviewed the medical records of 47 consecutive patients with newly diagnosed de novo CD5+ DLBCL. Of 19 patients ≤ 70 of age with age-adjusted International Prognostic Index 2–3, eight underwent upfront ASCT, and nine did not, despite preserved organ function and response after induction therapy. The remaining two, ineligible for ASCT due to early progression or comorbidities, had a dismal clinical course. Among younger 17 high-risk patients eligible for ASCT, ASCT was associated with better overall (p = 0.0327) and progression-free survival (p = 0.0184). Younger patients without ASCT demonstrated similar outcomes to older patients with similar risk profiles. ASCT could be considered for high-risk CD5+ DLBCL with a response after induction therapy.

Clinical and pathological characteristics and prognosis analysis of gray zone lymphoma

To explore the clinical and pathological characteristics as well as therapies and prognosis of gray zone lymphoma (GZL). The clinical data of 10 GZL patients admitted to the First Affiliated Hospital of Soochow University from December 2016 to December 2022 were retrospectively collected. The clinical and pathological characteristics, therapies and prognosis were analyzed. The cut-off time for follow-up visits was December 31, 2022, and the median time for follow-up visits [M(Q1, Q3)] was 40.0 (28.3, 59.8) months. Treatment efficacy was divided into complete remission (CR), partial remission (PR), stable disease (SD) and progressive disease (PD). There were 6 males and 4 females, with a median age [M(Q1, Q3)] of 33.5 (27.3-39.5) years. Among them, 8 patients had mediastinal (thymus) involvement and 7 patients were accompanied with extranodal involvement. According to Ann Arbor staging, 1 case was in the limited stage and 9 cases were in the progressive stage. The immunophenotypes of 4 patients were strong expression of CD20, expression of CD30, and no expression of CD15. The immunophenotypes of 6 patients were unequal expression of CD20 and strong expression of CD30 and CD15. One patient received classical hodgkin lymphoma(cHL)-like immunochemotherapy and only achieved PR, and then received enhanced diffuse large b-cell lymphoma (DLBCL)-like immunochemotherapy to achieve CR. Five patients received enhanced DLBCL-like immunochemotherapy for induction therapy and achieved CR. All 4 patients who did not achieve CR achieved CR after receiving second-line or third-line salvage therapy. All patients were given autologous stem cell transplantation (ASCT) for consolidation therapy. One patient relapsed and died during the follow-up visit in the 33rd month, and the remaining patients currently maintained a state of sustained remission. It is found that GZL mostly occurs in young patients, mediastinal involvement is common, and diagnosis relies on pathological morphology and immunophenotype. GZL may be more sensitive to DLBCL-like intensive immune regimens. Sequential ASCT for consolidation can reduce the risk of relapse.

Re-examining the role of hematopoietic stem cell transplantation in relapsed large B-cell lymphoma in the era of chimeric antigen receptor (CAR) T-cell therapy.

Historically, salvage chemoimmunotherapy with consolidative autologous hematopoietic stem cell transplantation (ASCT) was the only potentially curative therapeutic option for patients with relapsed/refractory large B-cell lymphoma (LBCL). Treatment options were few and outcomes poor for patients whose lymphoma failed to respond to salvage chemotherapy/ASCT and for patients not eligible for ASCT. The approval of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory LBCL revolutionized the treatment landscape with unprecedented response rates and durability of responses. As a result, earlier intervention with CAR T-cell therapy has been explored, and the enthusiasm for CAR T-cell therapy has overshadowed ASCT. In this article, we will review the data available for ASCT and CAR T-cell therapy in relapsed LBCL and will examine the role for ASCT in relapsed/refractory LBCL in the era of CAR T-cell therapy.

The Unfortunate Event - Extramedullary Myeloma Of The Urinary Tract

Extramedullary disease is an uncommon manifestation of multiple myeloma (MM). It can present de-novo or develop as a result of disease progression or relapse. We present a rare case of extramedullary myeloma (EMM) of the urinary tract in a 65-year-old gentleman. The incidence of EMM is ~13% of the MM population with a higher predilection for males in the fifth decade. The common sites for EMM were lymph nodes, skin, and soft tissue, however, involvement of the urinary tract is exceedingly rare. Despite the combination of chemotherapy, radiotherapy, the novel agents of immunomodulators, proteosome inhibitors, and consolidative autologous hematopoietic stem cell transplantation, the relapse rate is relatively high. In conclusion, the prognosis of patients with EMM is poor and currently, the optimal treatment strategy for this subset of patients is still debatable.

Second-Line Chimeric Antigen Receptor T-Cell Therapy in Diffuse Large B-Cell Lymphoma : A Cost-Effectiveness Analysis.

First-line treatment of diffuse large B-cell lymphoma (DLBCL) achieves durable remission in approximately 60% of patients. In relapsed or refractory disease, only about 20% achieve durable remission with salvage chemoimmunotherapy and consolidative autologous stem cell transplantation (ASCT). The ZUMA-7 (axicabtagene ciloleucel [axi-cel]) and TRANSFORM (lisocabtagene maraleucel [liso-cel]) trials demonstrated superior event-free survival (and, in ZUMA-7, overall survival) in primary-refractory or early-relapsed (high-risk) DLBCL with chimeric antigen receptor T-cell therapy (CAR-T) compared with salvage chemoimmunotherapy and consolidative ASCT; however, list prices for CAR-T exceed $400 000 per infusion. To determine the cost-effectiveness of second-line CAR-T versus salvage chemoimmunotherapy and consolidative ASCT. State-transition microsimulation model. ZUMA-7, TRANSFORM, other trials, and observational data. "High-risk" patients with DLBCL. Lifetime. Health care sector. Axi-cel or liso-cel versus ASCT. Incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (iNMB) in 2022 U.S. dollars per quality-adjusted life-year (QALY) for a willingness-to-pay (WTP) threshold of $200 000 per QALY. The increase in median overall survival was 4 months for axi-cel and 1 month for liso-cel. For axi-cel, the ICER was $684 225 per QALY and the iNMB was -$107 642. For liso-cel, the ICER was $1 171 909 per QALY and the iNMB was -$102 477. To be cost-effective with a WTP of $200 000, the cost of CAR-T would have to be reduced to $321 123 for axi-cel and $313 730 for liso-cel. Implementation in high-risk patients would increase U.S. health care spending by approximately $6.8 billion over a 5-year period. Differences in preinfusion bridging therapies precluded cross-trial comparisons. Neither second-line axi-cel nor liso-cel was cost-effective at a WTP of $200 000 per QALY. Clinical outcomes improved incrementally, but costs of CAR-T must be lowered substantially to enable cost-effectiveness. No research-specific funding.

Phase II Trial of Duvelisib Maintenance after Autologous Stem Cell Transplant in T-Cell and B-Cell Non-Hodgkin Lymphomas: Results of Safety Lead in

Introduction Duvelisib is a potent phosphoinositide-3-kinase delta (PI3K-δ) and gamma (PI3K-γ) inhibitor which has demonstrated efficacy in T-cell lymphomas (TCL) and low-grade B-cell Non-Hodgkin Lymphomas (B-NHL). It exerts its effect through inhibition of malignant cell proliferation and differentiation, as well as disruption of the tumor microenvironment. We aimed to evaluate the safety and efficacy of one year of duvelisib maintenance after consolidative autologous stem cell transplant (autoSCT) in patients with TCL and B-NHL. Methods Patients with TCL or B-NHL who received standard consolidative autoSCT began duvelisib maintenance after count recovery (approximately 30 days after transplant) and continued for 11 cycles (one year after transplant). Duvelisib started at 25 mg orally twice daily for two 28-day cycles (schedule 1), followed by 25 mg twice daily for 14 days on/ 14 days off (schedule 2) if the patient was in complete remission (CR) at day +100 or if intolerable toxicities developed. Patients in partial remission (PR) at day +100 continued schedule 1, and those with stable (SD) or progressive disease (PD) were taken off study. Results Twelve patients have been enrolled, starting in July 2020. Histologic subtypes were transformed follicular lymphoma (FL, n= 5), peripheral T-cell lymphoma (PTCL, n= 1), anaplastic large cell lymphoma (ALCL, n= 3), and angioimmunoblastic T-cell lymphoma (AITL, n= 3). Seven patients were male, median age was 62 (range, 25-71), and 10 patients had stage III/IV disease at diagnosis. Pre-transplant, 11 patients were in CR and 1 patient was in PR. Median follow-up was 23.7 months and median duration of duvelisib treatment was 8.7 months. Following enrollment of 7 patients, 2 patients developed grade 3 toxicities (elevated liver enzymes and diarrhea, respectively), prompting them to come off study. Patients were enrolled at schedule 2 thereafter, with subsequent improvement in tolerability. Most common adverse events (AEs) were hematologic, gastrointestinal, and hepatic (Table. 1). Grade 2-3 AEs probably related to treatment were seen in 6 patients: neutropenia (n= 2), lymphopenia (n= 1), diarrhea (n= 2), and elevated liver enzymes (AST/ALT) (n= 1). There were no grade 4-5 AEs and no deaths related to treatment. Permanent discontinuation of duvelisib due to grade 3 AEs occurred in 3 patients: elevated liver enzymes (AST/ALT), diarrhea, and lower extremity muscle weakness, respectively. The latter was deemed unlikely related to treatment and symptoms resolved upon follow-up. Of the 12 patients enrolled, 4 have relapsed (TCL, n= 2 and B-NHL, n= 2) and proceeded to additional treatment. All patients remain alive to date. Conclusions Duvelisib maintenance for up to one year after consolidative autoSCT in patients with TCL or B-NHL is safe and well tolerated at a dose schedule of 25 mg twice daily for 14 days on/ 14 days off, of 28-day cycles. Enrollment of patients undergoing consolidative autoSCT for TCL is ongoing to evaluate the efficacy of duvelisib maintenance.

Risk and Response Adapted Approach for Treatment of Myeloma: Pushing Autologous Transplant Down the Hierarchy

Background &amp; Significance: In current recommendations, consolidative autologous stem cell transplant (ASCT) is essential in management of NDMM. The IFM 2009 Trial showed that RVd followed by ASCT with 1-year lenalidomide maintenance was associated with a better PFS vs. RVd with 1-year lenalidomide maintenance alone (Attal M et al, NEJM 2017). A longer follow up (8 years) of IFM trial concluded that a delayed transplant (in 2 nd line) had no impact on the PFS2 (Perrot A et al, Blood 2020). We evaluated the merit of frontline ASCT (CR1) vs. post salvage ASCT (CR2) in light of indefinite maintenance therapy post novel triplet/quadruplet induction. Material &amp; Methods: We conducted this retrospective analysis, of symptomatic myeloma patients who underwent ASCT at Rajiv Gandhi Cancer Centre, Delhi between April 2017 and October 2022. Patients were segregated into 2 cohorts; a) ASCT CR1- who received 4 to 6 cycles of RVd (+/- Anti CD38 antibody) induction followed by transplant and indefinite maintenance and b) ASCT CR2- patients who relapsed after 4-6 cycles of RVd induction+maintenance then salvaged with 2 to 6 cycles of novel agent-based therapy (Carfilzomib/ Pomalidomide/ Daratumumab) followed by ASCT and indefinite maintenance. Patient characteristics were balanced for age, gender, ISS, RISS and high risk cytogenetics (Del p53, t(4;14), t (14;16), 1qGain, 1pDel, 13qDel). Response was assessed as per IMWG criteria. PFS was defined as the time from induction/salvage to progression on next line of therapy or death. Results: Of 161 patients included, we compared outcomes of ASCT CR 1 (N=122) to ASCT CR-2 (N=39). All patients received maintenance (PI/IMID or in combination) post ASCT. Significant patients in ASCT-CR2 received novel salvage therapy (Carfilzomib/ Pomalidomide/ Daratumumab) (CR1-14 % vs CR2-100%, p value- &amp;lt;0.01). 86% patients in ASCT CR1 received RVd. Both groups were substantially exposed to Lenalidomide. Median time from diagnosis to transplant was 5.9 months (range 4-12) in ASCT- CR1 group and 29.5 months (range 18-64) in ASCT CR2 group (p value- 0.004). After a median follow up of 44 months for ASCT CR1 vs. ASCT CR2, the ORR (97% vs. 95.4%, p=0.88) and CR (85% vs. 78%, p=0.67), respectively. 42.6% patients in ASCT CR1 and 38.4% patients in ASCT CR2 relapsed (p value- 0.4%). The median PFS for both groups (ASCT CR1 and ASCT CR2) were similar 45 months and 43 months, respectively, (p value- 1.09). The 1-, 3- and 5-year PFS showed a similar trend across cohorts (CR-1: 95%, 59.1%, 39.7% and CR-2: 84%, 57.1%, 41.3%). Patients with high-risk cytogenetics in ASCT CR 1 (N=50) had a better median PFS (25 months) compared to ASCT CR2 (N=16, median PFS=17.9 months, p=0.059), fig:1 though statistically insignificant. Table:1 No difference in PFS for standard risk noted (p=0.38). On regression analysis, factors predictive of progression were: ISS stage III (univariate only), high-risk cytogenetics, IMID based maintenance therapy. We noted better PFS in patients receiving &amp;gt;24 months of maintenance. Depth of response prior to transplant, Melphalan dosage and remission (CR1 vs CR2) did not predict progression. Conclusion: In the light of above findings, does transplant decision need re-sequencing? Our findings are not in agreement with the hypothesis that exposure to novel agents in relapsed/refractory settings leads to resistant clone selection under stress. The pattern of relapse in standard risk myeloma remains same across lines of therapy. Excellent response rates are observed with novel agents at relapse therefore delaying transplant appears reasonable in standard risk. High-risk myeloma represents a unique subset where patients experience early/aggressive relapse indicating that current therapy offers little modification of kinetics or natural history of disease. Changing treatment paradigm based on disease risk and response appears pragmatic. Myeloma is the disease of elderly with plethora at hand, its time to individualize.

Experience with Gray Zone Lymphoma (GZL) at Mayo Clinic: A Review of Clinical Characteristics and Treatment Outcomes

Introduction: Gray zone lymphoma (GZL) is a rare lymphoid neoplasm exhibiting features intermediate between diffuse large B-cell lymphoma and Hodgkin lymphoma. Due to its rarity and relatively recent recognition by the World Health Organization in 2008, the natural history, clinical behavior, and best treatment strategies are still evolving. We present a retrospective review of GZL patients diagnosed and managed at the Mayo Clinic. This study aims to explore the clinical characteristics, treatment modalities, and outcomes of this poorly understood disease. Methods: After reviewing the electronic medical records of patients presented to the Mayo Clinic Cancer Center between March 2012 and July 2022 at the Mayo Clinic, we identified the patients who were diagnosed with GZL. Clinicopathological characteristics, disease features, treatment modalities, and outcomes were analyzed. The Kaplan-Meier method was utilized to assess survival outcomes. Results: Six patients (n=6) with GZL, all Caucasian and predominantly male 4/6 (67%), were identified. The median age at diagnosis was 37 years (range 24-57). Disease characteristics included high rates of mediastinal involvement 5/6 (83%) and bulky disease 4/6 (67%), with various stages of Ann Arbor classification represented. First-line treatment regimen varied between R-CHOP, ABVD, and DA R-EPOCH. The R-CHOP regimen was received in 3/6 patients (50%); the first patient achieved Complete Remission (CR), then managed with R-ICE, followed by consolidative autologous stem cell transplantation (auto-SCT) when relapsed. The second patient had Partial Response (PR) to R-CHOP and required consolidative radiotherapy to achieve CR, and the third R-CHOP patient achieved CR however, after multiple disease progressions that were managed with multiple regimens including R-ICE, R-CODOX-M/IVAC regimen, Nivolomab/Ipilumuab, consolidative radiotherapy, and Brentuximab vedotin. The ABVD regimen was received by 2/6 patients (33%). The first patient had CR, and the second patient had disease progression, which required treatment with R-ICE, followed by consolidative radiotherapy and auto-SCT. One patient (17%) received the DA R-EPOCH regimen and achieved CR, consolidated with auto-SCT. The median follow-up for our cohort is nine years (range, 5-13). All six GZL patients are alive and in CR (since 2019 or before) at the time of the study analysis, with an excellent flat overall survival curve. For this reason and due to the small patient sample, we could not calculate the progression-free survival data. Conclusions: Our Mayo Clinic review provides unique insights into managing Gray Zone Lymphoma (GZL), a rare disease. We reported 100% survival and remission in six GZL patients using diverse treatment strategies, contrasting with varied outcomes from other institutions. This underscores the potential of individualized treatments for GZL and the need for further, broader studies to validate our findings and refine optimal treatment approaches for this rare disease entity.

Second-Line Chimeric Antigen Receptor T Cell Therapy (CAR-T) As Standard of Care for Relapsed-Refractory Large B-Cell Lymphoma (LBCL)

Introduction: The randomized registrational ZUMA-7 (Locke, NEJM 2022) and TRANSFORM (Kamdar, Lancet 2022) trials in second line (2L) LBCL showed superiority of CAR T when compared to standard of care (SOC) chemotherapy-based regimens with a goal of consolidative autologous stem cell transplant. These results led to the FDA approval of axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) in 2L for LBCL with refractory disease or relapse within 1 year of completing induction chemotherapy. Significant differences exist between the registrational trial patient population and the real-world commercial CAR-T recipients in 3L+ setting (Nastoupil, JCO 2020, Jacobson, JCO 2020). Herein, we describe the outcomes of patients with LBCL treated with 2L commercial CAR T therapy. Methods: Five US academic institutions contributed data to this retrospective study. CAR T associated toxicities were graded by ASTCT consensus grading criteria (Lee, TCT 2019) and investigator assessed responses were reported per Lugano 2014 criteria. Patients who received CAR T therapy in 2L after the histologic diagnosis of LBCL were included, with leukapheresis between SOC approval on 4/1/2022, and 4/25/23. Patients were included if they received intermediary therapies before CAR T-cell infusion. These intermediary therapies included disease-holding therapy, defined as therapy given between relapse and the time of leukapheresis, given with the intent to “hold” patients' disease under control until CAR T-cell therapy was arranged (Bucklein, Hemasphere 2023). Patients who received therapy after relapse with the intent of restaging to decide on subsequent CAR T-cell therapy were excluded. Patients who received bridging therapy, defined as therapy given between leukapheresis and the start of lymphodepleting (LD) chemotherapy were also included. Kaplan-Meier analysis was used to calculate median progression-free survival (PFS) and overall-survival (OS). Results: 112 patients were leukapheresed with intention to receive commercial CAR T as 2L (103 axi-cel, 9 liso-cel). All but two patients received CAR T infusion (one manufacturing failure and one delayed due to infection). The median follow-up of the cohort was 6.2 months (95%CI 4.32 - 7.61). Median age of the cohort was 66.5 yrs (range 23-83) with male predominance (66%). The median international prognostic index (IPI) score was 3 (range 0-5) and 72% of the patients had stage III/IV disease. Fifty-nine percent of the patients had primary refractory disease. The median time between documentation of progression after 1L therapy and patient evaluation for 2L CAR T was 22 days (IQR 15-32). The median time from patient evaluation to CAR T infusion was 47.5 days (IQR 36.25 - 67). Forty-two patients (37.5%) received disease-holding therapy and 77 (69%) received bridging therapy. Twenty-nine patients (26%), received both disease-holding therapy and bridging therapy. Receipt of these therapies was associated with longer CAR T evaluation-to-infusion times, with a median time of 61 days for patients who received both disease-holding therapy and bridging therapy, as opposed to 38 days for patients who didn't receive either therapy. This is presumably related to washout requirements and the time needed to allow for count recovery prior to either leukapheresis or LD therapy. Among 110 CAR T infused patients, cytokine release syndrome(CRS) occurred in 88% (n=97) of the patients with grade 3 or 4 in 6.3% (n=7). Immune effector cell associated neurologic syndrome (ICANS) occurred in 59% (n= 65) with grade 3 or 4 in 30% (n= 33). No deaths from CRS or ICANS were observed. Overall response rate (ORR) was 82.7% and complete remission rate was 61.8%. Median PFS and OS were not reached. Point estimates of PFS and OS at six months were 64.1% (95% CI: 52.8 - 73.4), and 84.4% (95% CI: 73.8 - 90.9), respectively ( Figure 1). Conclusions: This multicenter retrospective study provides insights into practice and outcomes of SOC CAR T therapy for 2L relapsed-refractory LBCL. In clinical practice, patients commonly receive “disease-holding therapy” to control disease while organizing CAR T-cell consultation and leukapheresis. Despite the relatively short follow-up duration, the best response and toxicity profiles were comparable to those observed in the pivotal clinical trials. Updated follow-up and subgroup analysis will be presented at the meeting. SD and JYS contributed equally.

Autologous Stem Cell Transplantation Remains a Curative Option As Second Line Treatment for Patients with Relapsed/Refractory Large B Cell Lymphoma: Spanish Multicenter Geth-TC/Geltamo Study

Introduction: High dose therapy and Autologous Stem Cell Transplantation (ASCT) has remained the treatment of choice for transplant-eligible patients with relapsed/refractory (R/R) large B cell lymphoma (LBCL) and chemosensitive disease. Recently, CART therapy has been approved in second line for patients with primary refractory disease or early relapse (&amp;lt;1 year of first-line therapy) and the current role of ASCT has been questioned. However, several studies have shown that despite early failure of first line, patients with chemosensitive disease after salvage therapy can be cured with ASCT consolidation. Our objective was to analyze the efficacy of ASCT in patients with R/R LBCL after a long-term follow up and try to define the optimal role of ASCT. Patients and methods: We performed a retrospective multicenter study based on GETH-TC database of ASCT. We included patients from centers of GETH-TC/GELTAMO with R/R LBCL who underwent ASCT from January 2010 to December 2021. All the patients received rituximab and anthracycline-based frontline therapy. Diffuse LBCL NOS, high-grade B-cell lymphoma double/triple hit and NOS, primary mediastinal, transformed follicular lymphoma (tFL) and other less frequent LBCL subtypes were included. Plasmablastic and primary central nervous system lymphoma were excluded. Patients who underwent ASCT in first CR were also excluded except patients with tFL who had received previous anthracycline-based frontline therapy for the indolent lymphoma. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in the overall series and according to different prognostic factors, including disease status at ASCT. Disease status was defined as complete remission (CR), partial response (PR) and refractory disease (stable disease or progression) assessed by PET/CT. Results: Seven-hundred and ninety-one patients fulfilled the inclusion criteria. Patients characteristics are summarized in Table 1. After a median follow-up of 74 months (95%CI 68-81), 65% of the patients were alive and 84% of them free of disease. Six-year-PFS and OS were 51% (95%CI 47-54) and 63% (95%CI 60-67), respectively. Non-relapse mortality at 1 year was 9% (95%CI 7-11). The main causes of death were progression in 161 (58%), ASCT-related toxicity in 18 (6%) and other causes in 98 (35%). PFS was significantly influenced by age at ASCT, treatment lines prior to ASCT and disease status at ASCT (p&amp;lt;0.01). OS was influenced by age at diagnosis, R-IPI at diagnosis, age at ASCT, treatment lines prior to ASCT and disease status at ASCT (p&amp;lt;0.01). In the multivariate analysis, age &amp;gt;60 years at ASCT [HR 1.31 (95%IC: 1.06-1.62), p=0.011], ASCT as ≥3 th line [HR 1.81 (95%IC: 1.42-2.31), p&amp;lt;0.001] and PR versus CR at ASCT [HR 1.46 (95%IC: 1.18-1.81), p&amp;lt;0.001] were the only independent variables influencing PFS, Figure 1. Age &amp;gt;60 years at ASCT [HR 1.62 (95%IC: 1.24-2.12), p&amp;lt;0.001], ASCT as ≥3 th line [HR 1.77 (95%IC: 1.32-2.37), p&amp;lt;0.001] and PR versus CR at ASCT [HR 1.58 (95%IC: 1.22-2.05), p&amp;lt;0.001] were the only independent variables for OS. From 307 (39%) patients who relapsed after ASCT, 59 received CART therapy (median PFS 8.9 months) and 69 allo-SCT (median PFS 10.8 months). Refractory disease or early relapse did not significantly influenced survival. Analyzing this population separately (n=477), disease status at ASCT (PR versus CR) and ASCT as ≥3 th line were the only independent variables for both PFS [HR 1.46 (95%IC: 1.11-1.92), p=0.007; HR 1.79 (95%IC: 1.32-2.43), p&amp;lt;0.001, respectively] and OS [HR 1.92 (95%IC: 1.38-2.67), p&amp;lt;0.001; HR 1.91 (95%IC: 1.35-2.69), p&amp;lt;0.001, respectively]. Conclusions: To our knowledge, this is the largest series analyzing the efficacy of ASCT in patients with R/R LBCL after rituximab-containing frontline therapy. Our results indicate that ASCT is a curative option for patients with chemosensitive disease (especially in CR after salvage), regardless of the timing of relapse after frontline treatment. These data support that ASCT could be considered in patients with primary refractory or early relapse, provided the disease is sensitive to salvage therapy.

Phase II Study of Lenalidomide Maintenance after Salvage Therapy for Relapsed or Refractory Peripheral T-Cell Lymphomas

Introduction Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas. Their prognoses are still poor especially after they relapse or become refractory to the first-line treatment. Although salvage chemotherapy followed by autologous stem cell transplantation (ASCT) could be used for those relapsed or refractory patients, a substantial number of patients relapse even after ASCT. Furthermore, ASCT is not always possible because elderly or frail patients are not eligible for high-dose chemotherapy followed by ASCT. Thus, there are limited treatment option for patients who failed after ASCT or ineligible for ASCT because there is no established salvage treatment strategy and the impact of novel therapies in previous trials is unknown. Lenalidomide is widely used for the treatment of B-cell lymphomas as well as multiple myeloma, however, there are a few data about its efficacy in patients with PTCLs. Considering the mode of action is related with the immune modulatory effect on tumor microenvironment, lenalidomide might have a role in the management of relapsed or refractory PTCLs. Thus, we hypothesized that the use of lenalidomide as a maintenance therapy for patients who achieve response after salvage therapy might produce survival benefit comparable to that of ASCT after salvage therapy. Methods This is a prospective, open-labeled, single-arm, multi-center phase II study for relapsed or refractory PTCLs. The inclusion criteria are as follows: 1) Patients should have relapsed or refractory disease after at least one-line of prior chemotherapy; 2) Patients should not be eligible for ASCT; 3) Patients should have any subtypes of PTCLs including PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase (ALK)-positive or -negative anaplastic large-cell lymphoma (ALCL), extranodal NK/T-cell lymphoma (ENKTL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), hepatosplenic T-cell lymphoma (HSTL), and mycosis fungoides (MF). When patients eligible for the study achieve complete response (CR) or partial response (PR) after four cycles of any kinds of salvage chemotherapy, they can receive lenalidomide as a maintenance therapy. One cycle is 28 days consisting of lenalidomide 25 mg (day 1 - day 21). The treatment can be repeated until progression or the occurrence of intolerable toxicities (up to 2 years). The primary end point is 1-year progression-free survival, and the target rate is 35%. Results A total of 58 patients were enrolled between February 2019 and May 2023. The median age was 62 years (range: 20 - 83 years) and male was dominant (male: 35, female: 23). Patients who failed after ASCT or could not undergo ASCT due to their health status participated in the study. Patients with AITL (n = 23) and PTCL-NOS (15) accounted for 66% of patients whereas other subtypes included ENKTL (n = 4), ALK-negative ALCL (n = 3), MEITL (n = 3), HSTL (n = 2) and MF (n = 7). Prior to the maintenance therapy with lenalidomide, their disease status was CR (n = 22, 38%) and PR (n = 36, 62%). At the median follow-up of 20.7 months (95% CI: 17.7 - 23.7 months), seven patients completed the planned treatment of 2 years, and three patients withdrew their informed consents. Disease progression was documented in 21 patients during the maintenance and the other 20 patients discontinued the treatment due to their adverse events. At the time of analysis, seven patients were maintaining their treatments. Out of 36 patients with PR before maintenance, five patients achieved CR and 13 patients showed PR. However, 18 patients showed disease progression during maintenance. On the other hand, only three patients showed disease progression among 22 patients with CR prior to lenalidomide maintenance. Thus, 1-year PFS after enrollment was 49% and the median OS was (34.1 months, 95% CI: 7.9 - 18.6 months, Figure 1). The most common hematologic toxicities were neutropenia and thrombocytopenia; thus, dose-reduction should be done in patients with grade 4 hematologic toxicity. The most frequent non-hematologic toxicities included skin rash (40%), nausea (35%), and diarrhea (20%) however, they were manageable. Conclusions The lenalidomide maintenance might be a feasible and effective treatment approach for patients with relapsed or refractory PTCLs who are ineligible for ASCT or intensive consolidation chemotherapy.

Upfront Autologous Stem Cell Transplant at First Complete Remission in Patients with Advanced-Stage Extra-Nodal NK/T Cell Lymphoma: A Multicenter Retrospective Study

Objective: Treatment outcome of patients with advanced-stage extranodal NK/T cell lymphoma (NKTCL) remains unsatisfactory. The role of consolidation therapy with autologous stem cell transplantation (ASCT) at first complete remission (CR1) in these patients is controversial. This study aimed to investigate the effect of upfront ASCT on the prognosis of patients with advanced-stage NKTCL achieving CR1 to frontline therapy. Methods:This is a multicenter retrospective study. Data were collected from patients diagnosed with NKTCL between 2006 and 2021 in the China Lymphoma Collaborative Group (CLCG) database. The inclusion criteria were as follows: pathologically confirmed diagnosis of NKTCL, age≤65 years at diagnosis, stage III or IV disease, and achievement of CR1 at the completion of frontline induction therapy. Clinical characteristics, treatment including the use of ASCT, and follow-up information were reviewed. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 99 patients from 14 medical centers in China were included in this study. The median age was 38 years (range: 6-64 years). Sixteen patients (16%) had an ECOG-PS≥2 at diagnosis, and 26 patients (26%) presented with primary extra-nasal disease. The baseline Prognostic Index for NK-cell lymphoma (PINK) was≥2 in 63 patients (64%). Regarding first-line treatment, 85 patients (86%) received non-anthracycline-based chemotherapy, and the remaining patients received anthracyline-based chemotherapy. At the time of CR1, 32 patients (32%) received upfront ASCT consolidation and 67 patients did not. Baseline clinical characteristics were comparable between the ASCT group and non-ASCT group. With a median follow-up time of 33 months, median PFS was not reached in the ASCT group versus 46 months in the non-ASCT group (3-year PFS: 76.6% versus 54.9%, P=0.012). OS was not significantly different between the ASCT group and the non-ASCT group (3-year OS: 85.2% versus 69.4%, P=0.098). In multivariate analyses, upfront ASCT was independently associated with better PFS (HR=0.40, 95%CI 0.17-0.94, P=0.037) after adjusting for baseline PINK score and types of first-line chemotherapy (anthracyline-based versus non-anthracyline-based). Only non-anthracyline-based first-line chemotherapy (HR=0.32, 95%CI 0.11-0.88, P=0.028) was associated with better OS in multivariate analysis. Conclusions: In this multicenter real-world study, upfront ASCT improves PFS of patients with advanced stage NKTCL achieving CR1 to front-line chemotherapy, but the effect of upfront ASCT on OS in the era of non-anthracycline-based chemotherapy remains uncertain. The specific subgroups of patients most likely to gain a survival benefit from upfront ASCT need to be further investigated.

Autologous Stem Cell Transplant in Fit Patients with Late Relapsed Diffuse Large B-Cell Lymphoma That Responded to Salvage Chemotherapy

Background: The new standard of care for fit patients with refractory or early relapse of diffuse large B-cell lymphoma (DLBCL) is chimeric antigen receptor T-cell (CAR-T) therapy. However, for patients with a relapse ≥12 months after completing frontline therapy, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) remains the standard of care. There is a need to characterize such patients and their survival in view of the recent shift in treatment paradigm. Methods: Patients with DLBCL that relapsed ≥12 months after R-CHOP or R-CHOP-like frontline therapy who underwent salvage therapy and ASCT at Mayo Clinic or University of Iowa between 07/2000 and 4/2020 were identified from institutional lymphoma and transplant databases. Clinical characteristics, treatment information, and outcome data were abstracted. Progression-free survival (PFS) and overall survival (OS) from the time of ASCT were analyzed using Kaplan-Meier method and Cox proportional hazards models. Statistical analyses were performed in JMP v15. Results: A total of 158 patients with late relapsed DLBCL who underwent salvage chemotherapy and ASCT were identified. Baseline characteristics at relapse/ASCT are shown in Table 1. Median time from frontline therapy completion to 1st relapse was 26.4 months (range 12.0-152.4). Median age at relapse was 63 years (range 19-77), and 96 (61%) patients were male. A minority (3; 3%) had ECOG PS ≥2. 43 (52%) patients had an elevated serum LDH level, 70 (65%) had advanced stage disease, and 12 (11%) had &amp;gt;1 extranodal involvement. Median line of salvage therapy was 1 (range 1-3), and 17 (11%) patients required &amp;gt;1 line of salvage therapy. Best response before ASCT was complete response (CR) in 97 (61%) and partial response (PR) in 61 (39%). Median age at ASCT was 64 years (range 19-78). Median follow-up after ASCT was 91.5 months (95% CI 74.0-103.3). Median PFS and OS were 54.5 (95% CI 31.9-77.8) and 99.8 (95% CI 60.3-144.5) months, respectively. The 2-year PFS and OS rates were 64% (95% CI 56-71) and 81% (95% CI 74-87), respectively. No statistically significant difference in PFS was seen based on age at ASCT, sex, serum LDH, stage, or extranodal site involvement of &amp;gt;1 at relapse (Table 2). However, patients who required &amp;gt; 1 line of salvage therapy, compared to those requiring 1 line of salvage therapy, had significantly inferior PFS (median 6.1 vs 61.8 months, P &amp;lt;0.0001) and OS (17.8 vs 111.7 months, P &amp;lt;0.0004). There was no statistically significant difference in survival in patients who achieved CR vs PR prior to ASCT, with a median PFS of 61.8 vs 37.8 months( P=0.21) and a median OS of 111.7 vs 78.3 months ( P=0.62). Patients who achieved CR after 1 line of salvage therapy had the most favorable PFS and OS, with a median PFS of 65.6 vs 45.4 vs 6.1 vs 7.6 months ( P=0.0004) and a median OS of 133.0 vs 88.9 vs 24.2 vs 17.6 months ( P=0.004) in patients achieving CR after 1 line of salvage therapy vs PR after 1 line of salvage therapy vs CR after &amp;gt;1 line of salvage therapy vs PR after &amp;gt;1 line of salvage therapy, respectively (Table 2). In multivariate Cox regression models adjusted for age at ASCT and sex, patients requiring &amp;gt; 1 line of salvage therapy, compared to those who required 1 line of salvage therapy, had significantly inferior PFS with a hazard ratio (HR) of 3.25 (95% CI 1.82-5.78, P &amp;lt;0.0001) and OS with a HR of 3.50 (95% CI 1.86-6.60, P=0.0001). However, there remained no significant difference in survival based on response status (CR vs PR) with a HR for PFS 0.78 (95% CI 0.52-1.17, P=0.23) and OS 0.93 (95% CI 0.58-1.47, P=0.74). Conclusions: Survival after ASCT was excellent in patients with late relapsed DLBCL achieving CR after 1 line of salvage chemotherapy. Favorable survival outcomes were seen in patients who achieved PR after 1 line of salvage therapy. These data support the current clinical practice of ASCT consolidation in these patients. However, post-ASCT survival was poor in patients who required more than 1 line of salvage chemotherapy, despite achieving a satisfactory response to subsequent lines of salvage therapy. Alternative treatment strategies such as CAR-T therapy should be considered in such patients.

Past, present and future therapeutic approaches in nodal peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCL) encompass over 30 different entities and although they share post-thymic T- or NK-cell derivation, the disease biology and genomic landscape are very diverse across subtypes. In Western populations, nodal PTCL are the most frequently encountered entities in clinical practice and although important achievements have been made in deciphering the underlying biology and in therapeutic advances, there are still large gaps in disease understanding and clinical scenarios in which controversy over best practice continues. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)- based chemotherapy continues to be the 'standard' treatment, with the addition of brentuximab vedotin (BV) in the combination CHP (cyclosphosphamide, doxorubicin, prednisone)-BV representing a new treatment paradigm in CD30+ PTCL although its benefit is less certain in the non-anaplastic large cell lymphoma subtypes. Given the high risk of relapse, consolidative autologous stem cell transplant is considered in nodal PTCL, outside of ALK-positive anaplastic large cell lymphoma; however, in the absence of a randomized controlled trials, practices vary. Beyond CHP-BV, most study activity has focused on adding a novel agent to CHOP (i.e., CHOP + drug X). However, with high complete remission rates observed with some novel therapy combinations, these regimens are being tested in the front-line setting, with a particular rationale in follicular helper T-cell lymphomas which have a clear sensitivity to epigenetic modifying therapies. This is well exemplified in the relapsed/refractory setting in which rational combination therapies are being developed for specific subtypes or guided by underlying biology. Taken together, we have finally moved into an era of a more personalized approach to the management of nodal PTCL.