Autologous Stem Cell Transplantation Consolidation Research Articles

Favourable Outcome of Relapsed PCNSL Among Transplant Eligble Patients.

The prognosis of relapsed primary central nervous system lymphoma remains a concern. This study aimed to compare the effects of various patient- and disease-related factors on the prognosis of relapsed primary central nervous system lymphoma (PCNSL). We retrospectively collected real-world data from eight Finnish hospitals on 198 patients diagnosed with PCNSL between 2003 and 2020. Characteristics of the patients were available. At total of 63 patients with relapses were included after excluding seven isolated ocular relapses. The median progression-free survival after relapse was 3 months. The median overall survival after the first relapse (OS2) was 4 months. Patients aged 70 or younger with good performance status who received autologous stem cell transplantation (ASCT) consolidation as second-line treatment had significantly better OS2 of 39 months (p = 0.002). OS2 for patients without ASCT consolidation remained at 3 months. Age over 70 years, poor performance status, and a first-line progression-free survival of less than 6 months negatively impacted the prognosis. This study confirms previous findings of poor outcomes in patients with relapsed PCNSL. Some subgroups, particularly those receiving ASCT consolidation, can achieve long-term remission with current treatment options. New treatment strategies are needed for patients ineligible for ASCT or those who do not respond to salvage induction therapies.

Your chemo is no good here: management of high-risk MCL.

Historically considered a lymphoma with limited treatment options and poor outcomes, the treatment landscape in mantle cell lymphoma (MCL) has evolved remarkably in the last decade. Chemoimmunotherapy (CIT) remains the primary frontline treatment for most patients with MCL, typically with an intensive approach in younger and fit patients. The role of consolidative autologous stem cell transplantation remains controversial, with recent data further questioning its benefit. Novel agents have shown promising results in recent frontline clinical trials and challenge the current paradigm in MCL, particularly in high-risk patients who generally have poor outcomes with CIT. Risk stratification is key to incorporating novel agents in the frontline treatment of MCL, identifying patients who do not benefit from or could be spared CIT, guiding treatment intensity and duration, and improving overall outcomes, including safety and quality of life. The MCL International Prognostic Index and Ki-67 play an important role in identifying patients with high-risk MCL. TP53 aberrations, particularly mutations, currently identify patients with the highest risk, limited benefit from CIT, and greatest need for novel therapies. Other genetic aberrations and biological clusters are being identified but currently have limited clinical utility.

Treatment Patterns and Attitudes Among US-Based Physicians in Using BTK Inhibitors to Treat Relapsed/Refractory CLL and MCL

Background: The clinical management of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) continues to evolve. FDA-approved BTK inhibitors (BTKis), including the covalent BTKis acalabrutinib and zanubrutinib and the noncovalent BTKi pirtobrutinib, are recommended by guidelines and experts as options for first- and/or later-line treatment. However, with rapid advances in therapy, healthcare professionals (HCPs) may be challenged to remain current with optimal use of these agents. Here, we report treatment patterns and attitudes of US-based physicians in using BTKis to treat relapsed/refractory (R/R) CLL and MCL. Methods: Physicians practicing in the US and actively treating patients with CLL and/or MCL were invited to participate in a survey on the management of patients with R/R CLL or MCL followed by a workshop in which participants could discuss cases from the survey with an expert/high-volume treater of CLL and MCL. Invitees were identified through a database of HCPs with an interest in CME on hematologic malignancies. Respondents to the invitation were vetted for eligibility based on NPI numbers and enrolled in the study on a first-come-first-served basis and offered an honorarium for their participation. Data from survey responses and anecdotes from workshop discussions were analyzed to determine treatment trends in the management of R/R CLL and MCL, with a focus on BTKi therapy. Results: Among the 59 US-based physicians participating in this study from October 2023 to April 2024, 66% reported practicing at a community center and 44% in an academic setting. Most (75%) reported treating ≥11 patients with CLL and/or MCL per month. Data from the survey showed that for a patient with CLL with mutated TP53/unmutated IGHV/del11q and relapse after first-line venetoclax plus obinutuzumab, most participants recommended zanubrutinib (55%) or acalabrutinib ± obinutuzumab (34%). In a patient with CLL with the above higher-risk features and an acquired BTK C481 mutation after relapse with both venetoclax-based therapy and a covalent BTKi, most participants (80%) recommended pirtobrutinib. Continuing with this patient, most participants recommended lisocabtagene maraleucel in the fourth-line setting after relapse with pirtobrutinib (70%). In the workshops, the most frequently asked questions surrounding R/R CLL centered on when to use an anti-CD20 antibody with acalabrutinib, factors impacting choice of acalabrutinib or zanubrutinib, resistance testing, utility of MRD testing, and best practices in transitioning to pirtobrutinib. For R/R MCL, preferred treatment for relapsed disease after induction R-CHOP/R-AraC and consolidation autologous stem cell transplant was evenly split between acalabrutinib (46%) and zanubrutinib (39%). For a patient who experienced problematic diarrhea and bleeding/bruising with a covalent BTKi and wished to discontinue therapy, the most common recommendations were distributed between continuation of the covalent BTKi (25%), switch to pirtobrutinib (33%), and observation (34%). For adverse event management, most participants (70%) recommended dose reduction for a case patient who started a covalent BTK inhibitor and experienced progressive joint aches with associated decline in quality of life consistent with guideline and expert recommendations. However, there was disagreement among participants in how to treat MCL in a case of a covalent BTKi hold for atrial fibrillation that was subsequently resolved, with participants split among strategies that included resuming the BTKi with counseling (29%), resuming the BTKi at a reduced dose (14%), transitioning to another BTKi (30%), or observation (16%). In the workshops, frequently asked questions focused on optimal use of BTKis in patients with thrombocytopenia and hypertension risk with available BTKis. Conclusions: These data suggest that many US-based physicians who manage patients with R/R CLL and MCL provide therapy in line with expert and guideline recommendations. However, areas of disagreement and uncertainty exist, including scenarios of therapy transitions in the presence of comorbidities or adverse events, indicating ongoing educational needs.

The evolving role of checkpoint inhibitors in the treatment of Hodgkin lymphoma.

Since their initial approval as single agent therapy for multiply relapsed/refractory Hodgkin lymphoma (HL), the PD-1 inhibitors nivolumab and pembrolizumab have been incorporated into second-line salvage regimens, and they are being investigated in upfront therapy of newly diagnosed patients. As second-line therapy in combination with brentuximab vedotin or multi-agent chemotherapy, nivolumab and pembrolizumab provide high complete remission rates and durable progression-free survival after consolidative autologous stem cell transplant. Incorporation of these agents into frontline chemotherapy regimens is feasible, and early results from a Phase III trial of nivolumab-AVD compare favorably with the existing standard for advanced stage HL, brentuximab vedotin plus AVD. As nivolumab and pembrolizumab move into earlier lines of HL therapy, open research questions include the efficacy of checkpoint inhibitor regimens in patients who relapse after frontline exposure to nivolumab or pembrolizumab; the selection of patients with relapsed HL who can achieve durable remissions without autologous stem cell transplant; and the efficacy of the PD-1 inhibitors in the frontline therapy of patients with early stage Hodgkin lymphoma.

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

Historically, the management of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) following first-line chemoimmunotherapy has been second-line chemotherapy, followed by high-dose chemotherapy and consolidative autologous hematopoietic stem cell transplantation (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 autologous HSCT. Since that time further studies have demonstrated improved overall response rates and survival outcomes in patients with primary refractory or early-relapsed (relapse within 1 year) DLBCL treated with CAR T-cell therapy compared with autologous HSCT, advancing CAR T-cell therapy into the second-line setting. However, >50% of patients will relapse in the post-CAR T-cell setting. In the past 2 years, two CD20 x CD3 bispecific antibodies were approved by the Food and Drug Administration for the treatment of R/R DLBCL after two or more lines of systemic therapy. These bispecific antibodies have demonstrated overall response rates exceeding 50% and durable remissions at >2 years of follow-up. Additionally, a notable treatment advantage of bispecific antibodies 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 R/R DLBCL and the best sequence of cellular and bispecific therapies to optimize patients' outcomes.

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

AbstractAlthough broadly used, consolidative autologous hematopoietic stem cell transplantation (auto-HCT) 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 auto-HCT for THRLBCL compared with 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 auto-HCT in a salvage-sensitive disease status as assessed by positron emission tomography–computed tomography between 2016 and 2021 and were registered with the European Society for Blood and Marrow Transplantation database. The primary end point was progression-free survival (PFS) 2 years after transplantation. A total of 201 patients with THRLBCL and 5543 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 THRLBCL were significantly younger, contained a higher proportion of men, and had a better performance status. Compared with DLBCL, THRLBCL was associated with significantly better 2-year PFS (78% vs 59%; P < .001) and overall survival (OS, 81% vs 74%; P = .02) because of a significantly lower 2-year relapse incidence (16% vs 35%; P < .001). On multivariate analysis, favorable relapse risk (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.31-0.7) and PFS (HR, 0.58; 95% CI, 0.41-0.82) of patients with THRLBCL remained significant, whereas 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 auto-HCT as an effective treatment option for salvage-sensitive R/R THRLBCL.

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.

Mantle Cell Lymphoma: Evolving Frontline Treatment Strategies

Mantle cell lymphoma (MCL) is a mature B-cell non-Hodgkin lymphoma (NHL) that accounts for 3-10% of new NHL cases in Canada. The clinical course of MCL is heterogeneous, ranging from indolent behavior that does not require therapy for years, to highly aggressive disease with limited prognosis. As such, the 2022 International Consensus Classification (ICC) and World Health Organization (WHO) classifications subdivide MCL into two categories: 1) indolent MCL, which is characterized by blood involvement, splenomegaly without nodal involvement, or low-burden nodal involvement (mutated immunoglobulin heavy chain [IGHV], SOX11 negative, low Ki67 proliferative index); and 2) aggressive MCL, which is characterized by pleomorphic and blastoid morphologic appearance, TP53 aberrancy, high Ki67, and unmutated IGHV. While traditionally, patients with MCL had a median overall survival (OS) of only 3 to 5 years, there has been significant improvement over the last two decades, owing to chemoimmunotherapy with rituximab, cytarabine-based induction regimens, addition of consolidative autologous stem cell transplant (ASCT), rituximab maintenance, and the advent of novel targeted therapies (including Bruton kinase inhibitors [BTKi], venetoclax, and lenalidomide) in the relapsed setting. Despite these advances, MCL remains incurable even with aggressive therapy, and most patients will invariably relapse. As such, prospective studies integrating novel therapies with either a chemotherapy backbone or evaluating chemotherapy-free regimens are ongoing, aiming to improve outcomes and reduce toxicities. This review summarizes the current understanding of disease prognostication, treatment options, and novel therapeutic strategies that will reshape the treatment paradigm of MCL in the near future.

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.

Graft-versus-host disease-like gastroenteritis after autologous stem cell transplantation with busulfan/thiotepa conditioning for primary central nervous system lymphoma

Graft-versus-host disease (GVHD) is less common in autologous stem cell transplantation (ASCT) recipients than in allogeneic SCT recipients. However, some cases of severe GVHD, especially involving the gastrointestinal (GI) tract, have been documented. We present a patient with primary central nervous system lymphoma (PCNSL) exhibiting severe GI-GVHD after ASCT with busulfan/thiotepa conditioning. A 59-year-old woman with PCNSL in complete remission was admitted for consolidative ASCT. She developed severe diarrhea following busulfan/thiotepa conditioning, which was considered to be neutropenic enterocolitis induced by the conditioning regimen. However, her diarrhea worsened after neutrophil engraftment, and endoscopic findings and GI tract biopsies were suggestive of autologous GVHD. The diarrhea improved markedly with systemic steroid therapy, but she developed cytomegalovirus (CMV) gastroenterocolitis due to severe immunosuppression during systemic steroid therapy for GVHD. After CMV antigenemia negativity was achieved with ganciclovir, pathological examination showed persistent gastrointestinal mucosal edema and erythema with regenerative changes, which indicated a need for continuous GVHD treatment. Treatment with systemic steroids and budesonide for more than 2 months led to remission. It is important to suspect autologous GI-GVHD and consider prompt and aggressive immunosuppressive therapy in patients that manifest persistent diarrhea after engraftment following ASCT with busulfan/thiotepa conditioning.

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.