Metheny, Leland

ABSTRACT Transformed follicular lymphoma (tFL) is typically associated with chemotherapy resistance and a poor prognosis. There are limited data regarding outcomes after CD19‐directed chimeric antigen receptor T‐cell (CAR T) therapy in relapsed/refractory (R/R) tFL. A total of 923 adult patients with R/R tFL who received commercial CD19 CAR T therapy between 2017 and 2023 were identified in the Center for International Blood and Marrow Transplant Research registry. Median age was 64 years (range: 30–86) and median prior lines of therapy was 4 (range: 1–18). Most patients (78%) received axicabtagene ciloleucel, with 67% of patients having resistant disease at the time of CAR T infusion. At a median follow‐up of 25 months (range: 1–72) from CAR T infusion, the 2‐year overall survival (OS) was 57% (95% CI: 53–60) and progression‐free survival (PFS) was 43% (95% CI: 40–47). The 2‐year cumulative incidences of relapse or progression (rel/prog) and non‐relapse mortality (NRM) were 47% (95% CI: 44–51) and 9% (95% CI: 7–11), respectively. The overall response rate to CAR T was 76%, with a complete response rate of 63%. Grade ≥ 3 cytokine release syndrome (CRS) was observed in 7.1% and grade ≥ 3 immune effector cell–associated neurologic syndrome (ICANS) in 21.6% of patients. Multivariable analysis suggested that resistant disease status at the time of CAR T, use of bridging therapy, and high comorbidity index ≥ 3 were associated with inferior PFS and OS. Older age ≥ 60 significantly increased the risk of NRM. Our study suggests that CD19 CAR T is effective and safe for tFL.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase–CML. The primary goal of TKI therapy in patients with chronic phase–CML is to prevent disease progression to accelerated phase–CML or blast phase–CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase–CML.

Abstract The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.

Background The relative benefits of haploidentical HCT using PTCy compared to traditional matched-sibling donor, traditional unrelated donor and umbilical cord blood (UCB) allogeneic HCT for adult acute lymphoblastic leukemia (ALL) is still being defined. Methods We performed a retrospective analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database comparing post-HCT outcomes of haploidentical donors with PTCy to HLA-identical sibling donors, 8/8 HLA-MUDs, 7/8 HLA-MUDs, and UCB. Outcomes were overall survival (OS) leukemia-free survival (LFS), relapse, non-relapse mortality (NRM), grade 2-4 and grade 3-4 acute graft-versus-host disease (aGVHD), and chronic GVHD (cGVHD). Eligible patients were adults with ALL in complete remission (CR1, CR2, or CR3) undergoing first allogeneic HCT from 2013 to 2017. Key exclusion included not receiving PTCy for haploidentical HCT and ex vivo T-cell depleted or CD34-selected grafts. Cox proportional hazards multivariable regression analysis was used to compare the treatment groups. Results 4201 patients were studied: 393 haploidentical donor (92 centers), 1627 HLA-identical sibling donor (206 centers), 1646 8/8 HLA-MUD (181 centers), 230 7/8 HLA-MUD (90 centers), and 305 UCB (79 centers). Groups were well matched, however, notable differences between included race, time from diagnosis to HCT (CR1 only), conditioning regimen intensity, donor age, graft source for non-cord (peripheral blood or bone marrow), GVHD prophylaxis modality, and the use of in vivo T-cell depletion. Compared to other groups, haploidentical HCT had the lowest percentage of non-Hispanic white patients (43% vs. 49-74%), was more likely to use reduced-intensity conditioning (42% vs 17-25%), and was more likely to use bone marrow (41% vs. 14-29%). In multivariate analysis comparing haploidentical to matched-sibling donor HCT, no differences were observed in OS, LFS, NRM, relapse, or aGVHD. Compared to haploidentical HCT, the risk of cGVHD was significantly higher with matched-sibling donor HCT (D/R sex match F/M, HR 2.59, P<0.001, D/R sex match, other, HR 1.37, P=0.003). Comparing haploidentical to 8/8 HLA-MUD HCT, no differences were seen in OS, LFS, relapse, or Grade 2-4 aGVHD but 8/8 HLA-MUD HCT was associated with increased incidences of NRM (HR 1.42, P=0.02), grade 3-4 aGVHD (HR 1.59, P=0.005), and cGVHD (HR D/R sex match F/M, HR 2.91, P<0.001, D/R sex match, other, HR 1.38, P=0.001). Comparing haploidentical to 7/8 HLA-MUD HCT, no differences were seen in LFS or relapse but 7/8 HLA-MUD HCT was associated with worse OS (HR 1.38, P=0.01) and increased incidences of NRM (HR 2.13, P=<0.001), grade 2-4 aGVHD (HR 1.33, P=0.04) , grade 3-4 aGVHD (HR 1.86, P=0.003), and cGVHD (HR 1.72, P=<0.001). Comparing haploidentical to UCB HCT, no differences were seen in late OS (>18 months), late LFS, relapse, or cGVHD. Compared to haploidentical HCT, UCB HCT was associated with worse early OS (≤18 months, HR 1.93, P<0.001), worse early LFS (HR 1.40, P=0.007) and increased incidences of NRM (HR 2.08, P<0.001), grade 2-4 aGVHD (HR 1.83, P<0.001), and grade 3-4 aGVHD (HR 1.97, P<0.001). Similar outcomes were observed in sensitivity analyses restricting cohorts to (1) MA conditioning with peripheral blood stem cells and (2) calcineurin inhibitor-based GVHD prophylaxis for matched-sibling, unrelated donor, and UCB HCT. Conclusions For OS and LFS, haploidentical HCT using PTCy for adult ALL was superior to traditional HCT using 7/8 HLA-MUDs and UCB but equivalent to traditional HCT using matched-sibling donors and 8/8 HLA-MUDs. Results were consistent across all subgroups. Haploidentical HCT had a lower incidence of aGVHD compared to 8/8 HLA-MUD, 7/8 HLA-MUD, and UCB HCT and a lower incidence of cGVHD compared to matched-sibling donor, 8/8 HLA-MUD, and 7/8 HLA-MUD HCT. Based on these data, haploidentical HCT with PTCy results in similar survival with less GVHD compared to traditional matched-sibling and 8/8 HLA-matched donor HCT and is the superior alternative donor option for adult patients with ALL needing allogeneic HCT in CR. Figure Disclosures Wieduwilt: Leadiant: Research Funding; Shire: Research Funding; Merck: Research Funding; Macrogeneics: Research Funding; Amgen: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. de Lima:Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board; Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board. Kebriaei:Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Ziopharm: Other: Research Support; Amgen: Other: Research Support; Jazz: Consultancy. Hourigan:Merck: Other: Research Support (CRADA); Sellas: Other: Research Support (CRADA). Weisdorf:FATE Therapeutics: Consultancy; Incyte: Research Funding.

Introduction: Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT) while full engraftment remains a challenge in some recipients. Therapeutic approaches, such as recombinant hematopoietic growth factors, salvage only a minority of patients leaving affected patients at risk for recurrent infections and multiple blood products transfusions. PLX-R18 cells have been shown to mitigate bone marrow failure in rodent and non-human primate models. Further, these human placenta-derived mesenchymal-like adherent stromal cells secrete many cytokines after intramuscular (IM) injection that have been shown to stimulate growth and migration of bone marrow cells in vitro, e.g. MCP-1, IL-6, and IL-8. The initial results of the first cohort of this phase I trial were previously reported (ASH 2018 abstract 3379). Methods: Enrollment for this multi-center, open label, dose-escalation, phase I trial (ClinicalTrials.gov: NCT03002519) began in October 2017. Eligibility criteria included patients age ≥18 years who underwent either autologous (auto) or allogeneic (allo) HCT but suffered from incomplete hematopoietic recovery at least 3 months post-transplant, defined as failure to maintain either hemoglobin (Hb) >8g/dL and/or neutrophil count (ANC) >1,000/μL and/or platelet (PLT) count >50,000/μL. Other eligibility criteria included no evidence of underlying malignancy at time of enrollment, no active infection and no evidence of grade 3-4 acute or severe chronic GvHD. Subjects were enrolled into 3 dose-escalating cohorts: low-dose at 1M cells/kg (n=3), intermediate-dose at 2M cells/kg (n=6), and high-dose at 4M cells/kg (n=10). The specified dose of PLX-R18 cells was injected IM in multiple locations and given twice, 1 week apart. Cohorts were recruited sequentially, and progression to the next cohort was based on the safety assessment of its predecessor. Adverse event grading used the NCI CTCAE criteria. As of July 2020, all patients in cohorts 1 and 2 (3 & 6 patients, respectively) and 10 patients in cohort 3 were treated. Data were analyzed using the lmerTest package (ver. 3.1.0) in R (ver. 3.6.1) to produce baseline-adjusted least square means. As study is in progress and data collection ongoing, not all subjects have data on all parameters for all time points. Results: Data on 19 subjects (29-75 yrs) with either allo (n=17) or auto (n=2) HCT are reported herein. Not all patients reached the 9 month time point. Four patients died while on study and 2 withdrew consent within the 1 year follow up period. All deaths and other severe adverse events (SAEs) occurred due to progression of primary disease and were assessed as not related by investigators and sponsor. Most frequent related AEs were injection-site reactions. The table summarizes number of patients who improved from below the critical level, as defined above, at day 0 to above the critical level for a sustained period. Only those patients that were below the critical blood levels at day 0 are shown. To date, the majority of such patients improved to above the critical level after treatment. For example, 9 patients had ANC <1000/μL at day 0. Of the 4 patients for which data currently exists, all improved to ≥1000/μL at 9 months. The plots show changes in Hb, ANC and PLT up to 9 months following treatment. The dashed lines represent respective critical levels. Overall, there was improvement in the 3 parameters, with the greatest improvement observed in patients receiving the predicted optimal dose of 4M cells/kg. In this cohort, Hb levels increased from 9.29±0.5 to 13.19±1.2 (p=0.0019), ANC increased from 1.09±0.6 to 5.13±1.7 (p=0.018) and PLT increased from 45.7±10 to 175.9±28 (p=0.000012). Conclusions: Treatment with PLX-R18 is safe, well-tolerated and clearly effective in some patients. The most frequent AEs were reversible injection site reactions, all without sequelae. An overall improvement was observed in most patients, and among the high-dose cohort clinically impressive improvements in Hb, ANC and PLT were observed. The trial continues to follow up on patients. Upon completion, a large phase II trial, using the optimal dose, is considered for the same indication. Other attractive clinical areas for PLX-R18 therapy include acute radiation syndrome, bone marrow failure, aplastic anemia, myelofibrosis and with HCT as a "pan" cytokine to enhance rapid count recovery in all cells lines. Figure Disclosures Lazarus: Pluristem ltd: Consultancy. McGuirk:Astellas: Research Funding; Bellicum Pharmaceutical: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Allo Vir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding. Rowley:AbbVie: Current equity holder in publicly-traded company; FATE Therapeutics: Consultancy. Ofir:Pluristem: Current Employment. Shani:Pluristem ltd: Current Employment. Rowe:Pluristem ltd: Consultancy.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

Patients who develop therapy-related myelodysplastic syndromes (t-MDSs) or acute myeloid leukemia (t-AML) following prior chemotherapy or an autologous hematopoietic cell transplant (HCT), have a poor prognosis. An earlier analysis of allogeneic HCT (n=868, 1990-2004) showed 5-year overall survival (OS) and disease free survival (DFS) were 22% and 21% (reference). Furthermore, older age, graft source other than a HLA-matched sibling or HLA well matched unrelated donor (URD), t-AML not in remission or advanced t-MDS, and poor risk cytogenetics were associated with worse outcomes. Modern supportive care and conditioning regimens including reduced intensity (RIC) regimens may have improved outcomes. Therefore we analyzed 1531 HCT for t-AML (n = 772) or t-MDS (n = 759) performed from 2000 to 2014. The median age at transplant was 52 (18-77) for t-AML and 59 (18-74) for t-MDS. Eleven percent of patient with t-AML and 24% of patient with t-MDS had a prior autologous transplant. A myeloablative regimen was used for conditioning in 61% of patients with t-AML and 49% of patients with t-MDS (Table 1). For t-AML, the 5-year non-relapse mortality (NRM) and relapse rates (RR) were 33% (95% confidence interval [CI], 30-36) and 43% (40-47), respectively. For t-MDS, the 5 year TRM and RR were 32% (29-36) and 46% (43-50), respectively. Five year DFS and OS were 24% (21-27) and 25% (22-28), respectively, for patients with t-AML. Five year DFS and OS were 21% (18-24) and 27% (23-31), respectively, for patients with t-MDS. In multivariate analysis, t-AML OS and DFS was worse for: previous autologous transplant, relapsed disease at HCT, intermediate or adverse cytogenetics, partially matched and cord blood grafts, and RIC. For t-MDS: age greater than 60, previous autologous transplant, very high IPSS score, and use of HLA-partially matched unrelated grafts. A significant minority of patients with t-AML and t-MDS can achieve long-term remission with allogeneic HCT, yet risks of both NRM and relapse are still excessive. Relapse is the major cause of treatment failure. Disclosures Metheny: Takeda: Speakers Bureau; Incyte: Speakers Bureau. Weisdorf:Incyte: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy. Kebriaei:Jazz: Consultancy; Amgen: Research Funding; Pfizer: Honoraria; Kite: Honoraria.