Chimeric antigen receptor T-cell infusion for large B-cell lymphoma in complete remission: a center for international blood and marrow transplant research analysis.

CD19 CAR T-cell (CAR-T) therapy is commonly administered to patients with relapsed or refractory large B-cell lymphomas (LBCL), but salvage or bridging therapy can sometimes lead to a complete response (CR) prior to infusion. Limited studies have assessed the outcomes of patients infused in CR. A total of 134 patients with LBCL in CR prior to CAR-T infusion were identified from the CIBMTR registry, with median prior lines of therapy of 3 (range 2-9). At two years post-infusion, the probability of progression-free survival was 43.5% (95% CI 34.4-52.8) and the probability of overall survival was 63.8% (95% CI 54.4-72.6). The cumulative incidence rates of non-relapse mortality and relapse/progression at two years were 9.2% (95% CI 4.5-15.4) and 47.3% (95% CI 38.2-56.6), respectively. The rate of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were 2.2% and 8.2%, respectively. In summary, CAR-T in heavily pretreated patients with LBCL who are in CR following two or more lines of prior therapy demonstrate that a subset of patients may remain free of progression at two years. Additionally, the toxicity profile was impressive with very low rates of grade 3 CRS and ICANS.

Infectious and Noninfectious Corneal Ulcers in Ocular Graft-Versus-Host Disease: Epidemiology, Clinical Characteristics, and Outcomes.

PURPOSE: To evaluate the incidence, clinical characteristics, microbiological profile, and therapeutic outcomes of corneal ulcers in individuals with chronic ocular graft-vs-host disease (coGVHD). DESIGN: Retrospective clinical cohort study. METHODS: Review of individuals diagnosed with coGVHD following hematopoietic stem cell transplantation (HSCT) who were seen at the Bascom Palmer Eye Institute between May 2010 and November 2021. Baseline demographics, clinical characteristics, microbiological profile, risk factors for corneal ulceration, and treatment outcomes were collected. Etiology was deemed infectious in individuals with a positive culture or appropriate clinical scenario (presence of stromal infiltrate or hypopyon); otherwise, ulcers were presumed to be noninfectious. Treatment success was defined as reepithelialization with infiltrate resolution, and treatment failure as progression to corneal perforation or keratoplasty. Kaplan-Meier survival analysis estimated the incidence of ulceration. Cox regression analyses examined demographic and risk factors. Infectious and noninfectious ulcer groups were compared using 2-way independent t tests, 1-way analysis of variances, and χ2 tests, as appropriate. RESULTS: 173 individuals were included (53.7±14.4 years old; 59.0% male). Thirty-three individuals developed an ulcer 74.5±54.3 months after HSCT, with estimated 5- and 10-year incidences of 14% and 30%, respectively. Twenty-two (66.6%) ulcers were deemed infectious (15 microbiologically confirmed, 7 clinically) and 11 (33.3%) were deemed noninfectious. Risk factors for corneal ulceration included Black race (hazards ratio [HR] 2.89, 95% CI 1.30-6.42, P < .01), previous ocular surgery (HR 9.16, 95% CI 3.86-21.72, P < .01), eyelid margin abnormalities (HR 3.44, 95% CI 1.69-6.99, P < .01), and topical steroid use (HR 2.74, 95% CI 1.33-5.62, P < .01). Conversely, contact lens use reduced the risk of corneal ulceration (HR 0.29, 95% CI 0.13-0.66, P < .01). Infectious ulcers had a significantly higher frequency of treatment failure than noninfectious ulcers (57.1% vs 20.0%, P = .04). CONCLUSION: Corneal ulceration is a potential complication of coGVHD, with several clinical features identified as risk factors. Infectious ulcers had worse outcomes than noninfectious ulcers.

Conjunctival inflammation and dry eye symptoms at day 100 post-transplantation do not predict risk for chronic graft-versus-host disease.

PURPOSE: Chronic graft-versus-host disease (cGVHD) is a significant cause of morbidity and mortality among patients after allogeneic hematopoietic stem cell transplant (HCT). The objective of our study was to determine if early assessment of matrix metalloproteinase-9 (MMP-9) and dry eye (DE) symptoms (via the DE Questionnaire-5 [DEQ-5]) had prognostic utility for the development of cGVHD and/or severe DE symptoms after HCT. MATERIALS AND METHODS: This was a retrospective study of 25 individuals who underwent HCT and had MMP-9 (InflammaDry) and DEQ-5 performed on day 100 post-HCT (D + 100). Patients also completed the DEQ-5 at 6, 9, and 12 months post-HCT. The development of cGVHD was determined by chart review. RESULTS: Overall, 28% of patients developed cGVHD over a median follow-up of 229 days. At D + 100, 32% of patients had a positive MMP-9 in at least one eye and 20% had a DEQ-5 ≥6. However, neither the presence of a positive MMP-9 nor a DEQ-5 score ≥6 at D + 100 predicted the development of cGVHD (MMP-9: hazard ratio [HR]: 1.53, 95% confidence interval [CI]: 0.34-6.85, P = 0.58; DEQ-5 ≥6: HR: 1.00, 95% CI: 0.12-8.32, P = 1.00). In addition, neither of these measures predicted the development of severe DE symptoms (DEQ-5 ≥12) over time (MMP-9: HR: 1.77, 95% CI: 0.24-12.89, P = 0.58; DEQ-5 >6: HR: 0.03, 95% CI: 0.00-889.93, P = 0.49). CONCLUSION: Within our small cohort, DEQ-5 and MMP-9 assessment at D + 100 did not predict the development of cGVHD or severe DE symptoms.

Cryopreservation and storage patterns of hematopoietic progenitor stem cells for multiple myeloma.

Autologous hematopoietic stem cell transplantation (HCT) has been a standard of care treatment for eligible patients with newly diagnosed multiple myeloma (MM). Guidelines generally recommend hematopoietic progenitor cell (HPC) harvest for two potential HCT. There is a paucity of data reporting use of such collections in the era of novel approved therapies. In this single-center retrospective study, our goal was to determine the HPC utilization rate and costs associated with leukocytapheresis, collection, storage, and disposal to guide future HPC collection planning. We included 613 patients with MM who underwent HPC collection over a nine-year period. The patients were separated into four groups based on HPC utilization: 1) patients who never proceeded to HCT, or Harvest and Hold (14.8 %), 2) patients who proceeded to one HCT with banked HPC remaining (76.8 %), 3) patients who proceeded to one HCT without HPC remaining (5.1 %), and 4) patients who proceeded to two HCTs (3.3 %). After collection, 73.9 % of patients underwent HCT within 30 days. Of patients with banked HPC, defined as not undergoing HCT within 30 days of leukocytapheresis, the overall utilization rate was 14.9 %. At 2- and 5-years post HPC collection, utilization rate was 10.4 % and 11.5 %, respectively. In conclusion, our results suggest very low utilization of stored HPC, raising into question the current HPC collection targets. Given advances in MM therapy, as well as significant costs associated with harvest and storage, collection for unplanned future use warrants reconsideration. As a result of our analysis, our institution has reduced our HPC collection targets.

Axatilimab for Chronic Graft-Versus-Host Disease After Failure of at Least Two Prior Systemic Therapies: Results of a Phase I/II Study.

PURPOSE: Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity after allogeneic hematopoietic cell transplantation. Colony-stimulating factor 1 receptor (CSF-1R)-dependent macrophages promote cGVHD fibrosis, and their elimination in preclinical studies ameliorated cGVHD. Axatilimab is a humanized monoclonal antibody that inhibits CSF-1R signaling and restrains macrophage development. PATIENTS AND METHODS: This phase I (phI)/phase II (phII) open-label study (ClinicalTrials.gov identifier: NCT03604692) evaluated safety, tolerability, and efficacy of axatilimab in patients age ≥ 6 years with active cGVHD after ≥ 2 prior systemic therapy lines. Primary objectives in phI were to identify the optimal biologic and recommended phII dose and in phII to evaluate the overall (complete and partial) response rate (ORR) at the start of treatment cycle 7. RESULTS: Forty enrolled patients (17 phI; 23 phII) received at least one axatilimab dose. In phI, a dose of 3 mg/kg given once every 4 weeks met the optimal biologic dose definition. Two dose-limiting toxicities occurred at the 3 mg/kg dose given once every 2 weeks. At least one treatment-related adverse event (TRAE) was observed in 30 patients with grade ≥ 3 TRAEs in eight patients, the majority known on-target effects of CSF-1R inhibition. No cytomegalovirus reactivations occurred. With the 50% ORR at cycle 7 day 1, the phII cohort met the primary efficacy end point. Furthermore, the ORR in the first six cycles, an end point supporting regulatory approvals, was 82%. Responses were seen in all affected organs regardless of prior therapy. Fifty-eight percent of patients reported significant improvement in cGVHD-related symptoms using the Lee Symptom Scale. On-target activity of axatilimab was suggested by the decrease in skin CSF-1R-expressing macrophages. CONCLUSION: Targeting profibrotic macrophages with axatilimab is a therapeutically promising novel strategy with a favorable safety profile for refractory cGVHD.

Prognostic value of presalvage metabolic tumor volume in patients with relapsed/refractory diffuse large B-cell lymphoma.

Identification of new prognostic factors in relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) is essential for developing risk-adapted approaches. We retrospectively analyzed prognostication based on metabolic tumor volume (MTV) in rel/ref DLBCL (n = 108) before platinum-based salvage chemotherapy. Using 41% SUVmax threshold, patients achieving complete response (CR) exhibited significantly lower baseline values of MTV, compared to those achieving partial response (PR) or with progression of disease (medians MTV 16.26 versus 72.51 versus 98.11 ml, respectively). As a continuous variable, log2(MTV) was predictive of failure to achieve CR (1-unit increase odds ratio [OR] = 1.58, p < 0.001). Log2(MTV) significantly predicted progression-free survival (PFS) and overall survival (OS), and one-unit increase in log2(MTV) was associated with shorter PFS (hazard ratio [HR] = 1.12, p = 0.035) and OS (HR = 1.17, p = 0.007). However, heterogeneity in the selection of post-salvage chemotherapy approaches may have affected survival. These data demonstrate the ability of presalvage MTV to discriminate responders from non-responders to platinum-based chemotherapy and predict survival.

An adapted European LeukemiaNet genetic risk stratification for acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplant. A CIBMTR analysis.

Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes in acute myeloid leukemia (AML) but data assessing the prognostic value of combined genetic models in the HCT setting are limited. We developed an adapted European LeukemiaNet (aELN) risk classification based on available genetic data reported to the Center for International Blood and Marrow Transplant Research, to predict post-transplant outcomes in 2289 adult AML patients transplanted in first remission, between 2013 and 2017. Patients were stratified according to aELN into three groups: favorable (Fav, N = 181), intermediate (IM, N = 1185), and adverse (Adv, N = 923). Univariate analysis demonstrated significant differences in 2-year overall survival (OS) (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p < 0.001); disease-free survival (DFS) (Fav: 57.8%, IM: 55.5% and Adv: 45.3; p < 0.001) and relapse (Fav: 28%, IM: 27.5% and Adv: 37.5%; p < 0.001). Multivariate analysis (MVA) revealed no differences in outcomes between the Fav and IM groups, thus they were combined. On MVA, patients in the Adv risk group had the highest risk of relapse (HR 1.47 p ≤ 0.001) and inferior DFS (HR 1.35 p < 0.001) and OS (HR 1.39 p < 0.001), even using myeloablative conditioning or in those without the pre-HCT measurable-residual disease. Novel approaches to mitigate relapse in this high-risk group are urgently needed.

Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant.

IMPORTANCE: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. OBJECTIVE: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. INTERVENTIONS: Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. RESULTS: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P < .001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P = .03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P = .01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P = .10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. CONCLUSIONS AND RELEVANCE: In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.

Incidence and risk factors associated with a syndrome of persistent cytopenias after CAR-T cell therapy (PCTT).

Anti-CD19 Chimeric Antigen Receptor T cells (CAR-T) have shown dramatic efficacy in treating refractory aggressive B cell Lymphomas leading to FDA approval of axicabtagene ciloleucel and tisagenlecleucel. While long-term remission rate for both is higher than 33%, this treatment is associated with life-threatening complications including cytokine-release syndrome, encephalopathy, and lethal cerebral edema. Here we describe a case series of bone marrow failure syndromes with or without co-existing clonal myelodysplastic syndrome. Bone marrow failure was defined as absolute neutrophil count (ANC) <500 neutrophils/µL day 42 after infusion of CAR-T cells or filgrastim support to reach that number. We use "persistent cytopenias after T-cell therapy (PCTT)" to describe this syndrome which has an incidence of 38% with axicabtagene ciloleucel. Platelets <75,000/µL at the time of initiation of lymphodepleting chemotherapy and occurrence of maximum severity of cytokine-release syndrome (CRS) on day 0 or 1 after infusion of CAR-T cells are independent predictors of PCTT.

Lymphoma Causing Gastrosplenic Fistula Revealed by FDG PET/CT.

A 73-year-old man presented with fatigue and weight loss. He had CT-proven splenic mass with fistulous connection to the greater curvature of the stomach, which suggested abscess. FDG PET/CT confirmed gastrosplenic fistula in addition to active lymph nodes in the gastrohepatic ligament and epigastric region. Pathological examination after the biopsy of the spleen was consistent with diffuse large B-cell lymphoma. Chemotherapy was administered with close clinical follow-up and resulted in the resolution of fistula without requirement for surgery.