Conventional and novel [18F]FDG PET/CT features as predictors of CAR-T cell therapy outcome in large B-cell lymphoma.

Relapse and toxicity limit the effectiveness of chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL), yet biomarkers that predict outcomes and toxicity are lacking. We examined radiomic features extracted from pre-CAR-T 18F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scans (n = 341) of 180 patients (121 male; median age, 66 years). Three conventional (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG]) and 116 novel radiomic features were assessed, along with inflammatory markers, toxicities, and outcomes. At both pre-apheresis and pre-infusion time points, conventional PET features of disease correlated with elevated inflammatory markers. At pre-infusion, MTV was associated with grade ≥ 2 cytokine release syndrome (odds ratio [OR] for 100 mL increase: 1.08 [95% confidence interval (CI), 1.01-1.20], P = 0.031), and SUVmax was associated with failure to achieve complete response (CR) (OR 1.72 [95% CI, 1.24-2.43], P < 0.001). Higher pre-apheresis and pre-infusion MTV values were associated with shorter progression-free survival (PFS) (HR for 10-unit increase: 1.11 [95% CI, 1.05-1.17], P < 0.001; 1.04 [95% CI, 1.02-1.07], P < 0.001) and shorter overall survival (HR for 100-unit increase: 1.14 [95% CI, 1.07-1.21], P < 0.001; 1.04 [95% CI, 1.02-1.06], P < 0.001). A combined MTV and LDH measure stratified patients into high and low PFS risk groups. Multiple pre-infusion novel radiomic features were associated with CR. These quantitative conventional [18F]FDG PET/CT features obtained before CAR-T cell infusion, which were correlated with inflammation markers, may provide prognostic biomarkers for CAR-T therapy efficacy and toxicity. The use of conventional and novel radiomic features may thus help identify high-risk patients for earlier interventions.

Transplantation and Cellular Therapy for Older Adults-The MSK Approach.

PURPOSE OF REVIEW: Hematologic malignances more commonly affect older individuals and often present with advanced, higher risk disease than younger patients. Allogeneic and autologous hematopoietic cell transplantation is well-established treatment modalities with curative potential following either frontline treatments for these diseases or salvage therapy in the relapsed or refractory setting. More recently, novel cellular immunotherapy such as chimeric antigen receptor T-cell therapy has been shown to lead to high response rate and durable remission in many patients with advanced blood cancers. RECENT FINDINGS: Given unique characteristics of older patients, how best to deliver these higher-intensity and time sensitive treatment modalities for them remains challenging. Moreover, their short-term and potential long-term impact on their functional status, cognitive status, and quality of life may be significant considerations for many older patients. All these issues contributed to the lack of access and significant underutilization of these potential curative treatment strategies. In this review, we present up to date evidence to support potential benefits of transplantation and cellular therapy for older adults, their steady improving outcomes, and most importantly, highlight the use of geriatric assessment to help select appropriate older patients and optimize them prior to and following transplantation and cellular therapy. We specifically describe our approach at Memorial Sloan Kettering Cancer Center and encouraging early results from its implementation.

Reduced-Intensity Compared to Nonmyeloablative Conditioning in Patients with Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Reduced-intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). Although prior studies have suggested that higher-intensity regimens in RIC-NMA conditioning are associated with inferior outcomes in patients with NHL, the optimal conditioning regimen remains unknown. We performed a retrospective single-center analysis to determine outcomes of adult patients with B cell and T cell NHL who underwent allo-HCT and received either RIC or NMA conditioning between March 2008 and December 2019. RIC regimens included fludarabine-cyclophosphamide-thiotepa-4 Gy-total body irradiation (Flu-Cy-TT-4Gy-TBI), fludarabine-melphalan (Flu-Mel), fludarabine-cyclophosphamide-4 Gy-total body irradiation (Flu-Cy-4Gy-TBI), and fludarabine-busulfan-4 (Flu-Bu-4). The NMA regimen comprised fludarabine-cyclophosphamide-2 Gy-total body irradiation (Flu-Cy-2Gy-TBI). The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), nonrelapse mortality (NRM), and the incidence of acute and chronic graft-versus-host-disease (GVHD). Of 279 transplants recipients (median age, 58 years), 110 received RIC (55% Flu-Mel, 38% Flu-Cy-TT-4Gy-TBI, 6% Flu-Bu-4, 1% Flu-Cy-4Gy-TBI) and 169 received NMA conditioning with Flu-Cy-2Gy-TBI. With a median of 64 months of follow-up post-allo-HCT, there was no significant difference in OS between the NMA and RIC groups (median, not reached [NR] versus 103 months; P = .1), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky Performance Status [KPS], Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI], and disease histology), the regression analysis showed no significant difference in PFS with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% confidence interval [CI], .92 to 2.09; P = .24). On univariable analysis, there was no significant difference in NRM between the RIC and NMA arms (100-day estimate, 10.0% versus 1.8%; P = .5). After adjustment for age, ethnicity, KPS, HCT-CI, GVHD prophylaxis, and donor source, RIC conditioning was associated with a significantly higher incidence of NRM compared to NMA conditioning (HR, 2.61; 95% CI, 1.04 to 6.52; P = .039). On multivariable analysis, compared with the NMA arm, the RIC arm had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 to 3.86; P = .002) and grade III-IV acute GVHD (HR, 5.62; 95% CI, 2.03 to 15.6; P < .001). The findings of this study suggest that NMA conditioning with Flu-Cy-TBI-2Gy may be considered over more intensive RIC regimens for patients with NHL undergoing allo-HCT.

Outcomes and Management of the SARS-CoV2 Omicron Variant in Recipients of Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy.

Hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell therapy (CAR-T) recipients who develop Coronavirus disease 2019 (COVID-19) can have decreased overall survival (OS), likely due to disease-inherent and therapy-related immunodeficiency. The availability of COVID-19-directed therapies and vaccines have improved COVID-19-related outcomes, but immunocompromised individuals remain vulnerable. Specifically, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infections, including Omicron and its sublineages, particularly in HCT recipients, remain to be defined. The aim of this study was to compare the impact of SARS-CoV-2 Omicron infections in HCT/CAR-T recipients with outcomes previously reported for ancestral SARS-CoV-2 infections early in the pandemic (March to June 2020). This was a retrospective analysis of adult HCT/CAR-T recipients diagnosed with COVID-19 at Memorial Sloan Kettering Cancer Center between July 2021 and July 2022. We identified 353 patients (172 autologous HCT recipients [49%], 152 allogeneic HCT recipients [43%], and 29 CAR-T recipients [8%]), with a median time from HCT/CAR-T to SARS-CoV-2 infection of 1010 days (interquartile range, 300 to 2046 days). Forty-one patients (12%) were diagnosed with COVID-19 during the delta wave, and 312 patients (88%) were diagnosed during the Omicron wave. Risk factors associated with increased odds of COVID-19-related hospitalization were the presence of 2 or more comorbidities (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.4 to 10.7; P < .001), CAR-T therapy compared to allogeneic HCT (OR, 7.7; 95% CI, 3.0 to 20.0; P < .001), hypogammaglobulinemia (OR, 2.71; 95% CI, 1.06 to 6.40; P = .027), and age at COVID-19 diagnosis (OR, 1.03; 95% CI, 1.0 to 1.05; P = .04). In contrast, infection during the Omicron variant BA5/BA4-dominant period compared to variant BA1 (OR, .21; 95% CI, .03 to .73; P = .037) and more than 3 years from HCT/CAR-T therapy to COVID-19 diagnosis compared to early infection at <100 days (OR, .31; 95% CI, .12 to .79; P = .011) were associated with a decreased odds for hospitalization. The OS at 12 months from COVID-19 diagnosis was 89% (95% CI, 84% to 94%), with 6 of 26 deaths attributable to COVID-19. Patients with the ancestral strain of SAR-CoV-2 had a lower OS at 12 months, with 73% (95% CI, 62% to 84%) versus 89% (95% CI, 84% to 94%; P < .001) in the Omicron cohort. Specific COVID-19 treatment was administered in 62% of patients, and 84% were vaccinated with mRNA COVID-19 vaccines. Vaccinated patients had significantly better OS than unvaccinated patients (90% [95% CI, 86% to 95%] versus 82% [95% CI, 72% to 94%] at 12 months; P = .003). No significant difference in OS was observed in patients infected with the Omicron and those infected with the Delta variant (P = .4) or treated with specific COVID-19 treatments compared with those not treated (P = .2). We observed higher OS in HCT and CAR-T recipients infected with the Omicron variants compared to those infected with the ancestral strain of SARS-CoV2. The use of COVID-19 antivirals, mAbs, and vaccines might have contributed to the improved outcomes.

Optimizing high dose melphalan.

Melphalan, has been a major component of myeloma therapy since the 1950s. In the context of hematopoietic cell transplantation (HCT), high dose melphalan (HDM) is the most common conditioning regimen used due to its potent anti-myeloma effects and manageable toxicities. Common toxicities associated with HDM include myelosuppression, gastrointestinal issues, and mucositis. Established approaches to reduce these toxicities encompass dose modification, nausea prophylaxis with 5HT3 receptor antagonists, cryotherapy, amifostine use, and growth factors. Optimization of melphalan exposure through personalized dosing and its combination with other agents like busulfan, or bendamustine show promise. Propylene glycol-free melphalan (Evomela) represents a novel formulation aiming to enhance drug stability and reduce adverse effects. This review explores strategies to enhance the efficacy and mitigate the toxicity of HDM in multiple myeloma. Future directions involve exploring these strategies in clinical trials to improve the safety and efficacy of HDM, thereby enhancing outcomes for multiple myeloma patients undergoing autologous HCT.

Utility of routine pulmonary function test after autologous hematopoietic cell transplantation in lymphoma.

This study aims to evaluate the predictive value of routine pulmonary function testing (PFT) at the 12-month mark post-autologous hematopoietic cell transplant (AHCT) in identifying clinically significant lung disease in lymphoma survivors. In 247 patients, 173 (70%) received BEAM (carmustine, etoposide, cytarabine, melphalan), and 49 (20%) received TBC (thiotepa, busulfan, cyclophosphamide) conditioning regimens. Abnormal baseline PFT was noted in 149 patients (60%). Thirty-four patients had a significant decline (reduction of >/= 20% in DLCO or FEV1 or FVC) in post-AHCT PFT, with the highest incidence in the CNS lymphoma group (39%). The incidence of clinically significant lung disease post-transplant was low at 2% and there was no association between abnormal pre- and 1-year post-transplant PFTs with the development of clinical lung disease. While this study illustrates the impact of treatment regimens on PFT changes, it did not demonstrate a predictive value of scheduled PFTs in identifying clinically significant post-AHCT lung disease.

The Simplified Comorbidity Index predicts non-relapse mortality in reduced-intensity conditioning allogeneic haematopoietic cell transplantation.

Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo-HCT) is essential for estimating non-relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high-yield' comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34-selected allo-HCT. Here, we evaluated the SCI in a single-centre cohort of 327 patients receiving reduced-intensity conditioning followed by unmanipulated allografts from HLA-matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0-1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3-year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all-cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1-, 2- and 3-year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo-HCT from HLA-matched donors after reduced-intensity conditioning.

CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results.

In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor (CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion. The primary endpoint was the rate of severe (grade ≥3) ICANS. Key secondary endpoints included the rates of all-grade cytokine release syndrome (CRS) and ICANS and overall disease response. Among 31 treated patients, 74% received axicabtagene ciloleucel, 13% received brexucabtagene ciloleucel and 4% received tisagenlecleucel. All-grade ICANS occurred in 19%, and severe ICANS occurred in 9.7% of patients. There were no grade 4 or 5 ICANS events. All-grade CRS occurred in 74%, and severe CRS occurred in 6.4% of patients. The overall disease response rate was 77% with 65% complete response rate. These initial results show that prophylactic anakinra resulted in a low incidence of ICANS in patients with lymphoma receiving anti-CD19 CAR T-cell therapy and support further study of anakinra in immune-related neurotoxicity syndromes.

A phase 2 study of pembrolizumab after autologous stem cell transplantation in patients with T-cell non-Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) is often used as consolidation for several subtypes of peripheral T-cell lymphoma (PTCL) in first remission. However, many patients relapse after ASCT and have a very poor prognosis. There are no approved treatment options for posttransplantation maintenance or consolidation in PTCL. PD-1 blockade has demonstrated some efficacy for patients with PTCL. We, therefore, conducted a phase 2 multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab after ASCT in patients with PTCL in first remission. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles within 21 days from post-ASCT discharge (and within 60 days of stem cell infusion). The primary end point was progression-free survival (PFS) at 18 months after ASCT. Twenty-one patients were treated in this study and 67% (n = 14) completed 8 cycles of treatment. Among all patients who were evaluable, 13 of 21 were alive and achieved PFS at 18 months after ASCT, meeting the study's primary end point. The estimated 18-month PFS was 83.6% (95% confidence interval [CI], 68-100), and overall survival 94.4% (95% CI, 84-100). The toxicity profile was consistent with the known toxicity profile of pembrolizumab, with no grade 5 toxicities. In conclusion, PD-1 blockade after ASCT with pembrolizumab is feasible with a favorable safety profile and promising activity, supporting further confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant.

BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; "Rick" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.

Bridging Radiation Rapidly and Effectively Cytoreduces High-Risk Relapsed/Refractory Aggressive B Cell Lymphomas Prior to Chimeric Antigen Receptor T Cell Therapy.

Greater tumor burden before CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy predicts lower complete response rate and shorter overall survival (OS) in patients with aggressive non-Hodgkin lymphoma (NHL). Recent patterns of failure studies have identified lesion characteristics, including size, standard uptake value (SUV), and extranodal location, as associated with post-CAR-T therapy failure. Here we analyzed the effect of bridging radiation-containing treatment (BRT) on pre-CAR-T therapy lesion- and patient-level characteristics and post-CAR-T therapy outcomes, including patterns of failure. Consecutive NHL patients who received radiation therapy from 30 days before leukapheresis until CAR T cell infusion were reviewed. Metabolic tumor volume (MTV) was contoured with a threshold SUV of 4. The first post-CAR-T therapy failures were categorized as preexisting/new/mixed with respect to pre-CAR-T therapy disease and in-field/marginal/distant with respect to BRT. Forty-one patients with diffuse large B cell lymphoma (DLBCL; n = 33), mantle cell lymphoma (n = 7), or Burkitt lymphoma (n = 1) were identified. BRT significantly improved established high-risk parameters of post-CAR-T therapy progression, including in-field median MTV (45.5 cc to .2 cc; P < .001), maximum SUV (18.1 to 4.4; P < .001), diameter (5.5 cm to 3.2 cm; P < .001), and lactate dehydrogenase (LDH; 312 to 232; P = .025). DLBCL patients with lower LDH levels post-BRT had improved progression-free survival (PFS; P = .001). In DLBCL, first failures were new in 7 of 19 patients, preexisting in 5 of 19, and mixed in 7 of 19; with respect to BRT, 4 of 19 were in-field and 4 of 19 were marginal. Post-CAR-T therapy survival was similar in patients with initially low MTV and those with newly low MTV post-BRT using a statistically determined threshold of 16 cc (PFS, 26 months versus 31 months; OS unreached for both). BRT produced significant cytoreductions in diameter, SUV, MTV, and LDH, all predictors of poor post-CAR-T therapy outcomes. Similar PFS and OS in patients with initially low MTV and those who achieved newly low MTV after BRT suggest that BRT may "convert" poor-risk patients to better risk. In the future, the response to BRT may allow for risk stratification and individualization of bridging strategies.

Open-label pilot study of romiplostim for thrombocytopenia after autologous hematopoietic cell transplantation.

There are no standard treatments to prevent or hasten the recovery from severe conditioning-regimen-induced thrombocytopenia occurring after autologous hematopoietic cell transplantation (auto-HCT). We conducted an open-label, single-arm pilot study of romiplostim, a thrombopoietin receptor agonist, to enhance platelet recovery in patients with multiple myeloma or lymphoma undergoing auto-HCT. All patients were treated weekly with romiplostim starting day +1 after auto-HCT until the platelet count was >50 × 109/L without transfusion. Compared with contemporary retrospective data from romiplostim-naïve patients (N = 853), romiplostim-treated patients (N = 59) had a similar median number of days of grade 4 thrombocytopenia or days requiring transfusions, time to platelet engraftment, and number of platelets transfusions during the auto-HCT. However, romiplostim-treated patients had enhanced platelet recovery to normal values beginning at approximately day +15. In matched cohort multivariable analyses, romiplostim treatment was associated with higher platelet counts by an average of 40 × 109/L (95% confidence interval (CI) (14, 67), P = .003) and 118 × 109/L (95% CI [84, 152], P<.001) at days +21 and +30, respectively, compared with those of no romiplostim. Only 1 adverse event was deemed possibly attributable to romiplostim: a low-risk pulmonary embolism in a patient with multiple myeloma. In conclusion, romiplostim showed promising activity and safety after auto-HCT, but the improvement in platelet counts occurred later than the goal of shortening the duration and depth of the platelet nadir. This trial was registered at www.clinicaltrials.gov (#NCT04478123).

Minimal residual disease in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation.

Improved biomarkers are required to guide the optimal use of autologous stem cell transplantation (ASCT) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples, post-ASCT peripheral blood mononuclear cell (PBMC), and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in of 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, P < .001) and inferior overall survival (52% vs 68%, P = .05). The sensitivity and specificity of ASC MRD positivity for progression and death were 36% and 93%, respectively. Positive ASC MRD remained a significant predictor of PFS in multivariable analysis (hazard ratio [HR], 3.7; P < .001). Post-ASCT surveillance MRD testing of plasma, but not PBMC samples, reliably identified patients with an impending relapse. A positive plasma MRD result was associated with inferior PFS (HR, 3.0; P = .016) in a multivariable analysis. The median lead time from MRD detection to relapse was 62 days (range, 0-518 days). In conclusion, the detection of MRD in ASC samples is associated with a very high risk of relapse, justifying alternative treatment strategies or trials of novel consolidation options in these patients. Furthermore, post-ASCT MRD monitoring may facilitate the evaluation of the early initiation of treatment at molecular relapse. This trial has been registered at www.clinicaltrials.gov as #NCT02362997.

Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma.

Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57-69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6-11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10-4.72]), lack of response to CAR-T (2.33 [1.02-5.29]), age >65 years (HR 2.65 [1.49-4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61-5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise.

Prognostic value of minimal residual disease among patients with classical Hodgkin lymphoma undergoing autologous stem cell transplantation.

Improved biomarkers are needed to guide patient selection for autologous stem cell transplantation (ASCT) and post-ASCT maintenance therapies in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the prognostic value of minimal residual disease (MRD) using immunoglobulin-based high-throughput sequencing (Ig-HTS), we analyzed pre- and post-ASCT peripheral blood and pre-ASCT apheresis stem cell (ASC) samples in 36 cHL patients. A tumor clonotype was detected in only 12 patients (33%). Among these patients, MRD within plasma samples was closely associated with impending relapse. All patients (n = 3) with detectable MRD in any post-ASCT plasma sample relapsed (100% specificity), and MRD was not detected in any patients in remission. MRD testing from cellular specimens (peripheral blood mononuclear cell or ASC samples) was not associated with relapse. In this small cohort, plasma-based MRD testing appeared to be a promising biomarker in cHL, but given low clonotype detection rates with Ig-HTS, alternative MRD approaches should be investigated.

Vitamin D Insufficiency and Clinical Outcomes with Chimeric Antigen Receptor T-Cell Therapy in Large B-cell Lymphoma.

Vitamin D insufficiency is a potentially modifiable risk factor for poor outcomes in newly diagnosed large B-cell lymphoma (LBCL). However, the role of circulating vitamin D concentrations in relapsed/refractory LBCL treated with CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) is currently unknown. This was a single-center, observational study that evaluated the association of pre-CAR-T 25-hydroxyvitamin D (25-OHD) status with 100-day complete response, progression-free survival, overall survival, and CAR-T-related toxicity in 111 adult relapsed/refractory LBCL patients. Vitamin D insufficiency was defined as ≤30 ng/mL in accordance with the Endocrine Society guidelines. The median pre-CAR-T 25-hydroxyvitamin D concentration was 24 ng/mL (interquarile range = 18-34). Vitamin D-insufficient patients (≤30 ng/mL; n = 73 [66%]) were significantly younger than their vitamin D-replete (>30 ng/mL; n = 38 [34%]) counterparts (P= .039). The vitamin D-insufficient cohort was enriched for de novo LBCL as the histological subtype (P= .026) and had a higher proportion of tisagenlecleucel as the CAR-T product (P= .049). There were no other significant differences in the baseline characteristics between the two groups. In vitamin D-insufficient compared to -replete patients, 100-day complete response was 55% versus 76% (P= .029), and 2-year overall survival was 41% versus 71% (P= .061), respectively. In multivariate analysis, vitamin D insufficiency remained significantly associated with 100-day complete response (odds ratio 2.58 [1.05-6.83]; P= .045) and overall survival (hazard ratio 2.24 [1.08-4.66], P= .030). In recipients of tisagenlecleucel, vitamin D insufficiency was associated with significantly lower cell viability of the infused CAR-T product (P= .015). Finally, pretreatment vitamin D insufficiency did not predict for subsequent CAR-T-related toxicity. This is the first report to demonstrate that vitamin D insufficiency is associated with inferior clinical outcomes in CAR-T recipients. Further study into the mechanistic insights of this finding, and the potential role of vitamin D supplementation to optimize CAR-T are warranted.