02.24.22

Pharmacy SIG Literature Update: Highlights of the 2021 American Society of Hematology Annual Meeting Updates

In this month’s Pharmacy SIG Literature Update: Highlights of the 2021 American Society of Hematology Annual Meeting Updates.

Literature summaries are provided as information only. Please refer to the original published articles for complete details on study methodology, results and discussion.

The American Society of Hematology (ASH) 63rd Annual Meeting and Exposition took place on December 11-14th, 2021 in Atlanta, GA. The meeting was offered through a hybrid format allowing both in-person and virtual registration options. For in-person attendees, vaccination against SARS-CoV-2 was required and unlimited testing was offered for the duration of the meeting. Approximately 50% of presenters and session moderators participated virtually. There were more than 900 oral, 3000 poster, six late-breaking, and six plenary abstract presentations. With a focus on hematopoietic cell transplantation (HCT) and cellular therapy, the 23 most relevant abstracts were selected.

A summary of these abstracts will be presented as ASH Update: Part 1 and ASH Update: Part 2 at the postponed 2022 Tandem Meetings Pharmacy Conference being held in Salt Lake City, Utah on April 23rd and 24th. The first part presented by Dr. Griffin will focus on HCT and is divided into updates on conditioning regimens, supportive care, graft-versus-host disease (GVHD), and post-transplant treatments. The second part presented by Dr. Ziggas will focus on chimeric antigen receptor t-cell (CART) therapy and include updates on non-Hodgkin lymphoma (NHL), multiple myeloma (MM), leukemia, and supportive care. Given the meeting postponement, a summary is provided here as part of the February Literature Update.

Part 1

Updates on Conditioning Regimens:

Superior Outcomes with Fludarabine-Busulfan Based Conditioning for Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis - a Comparative Analysis By CIBMTR.

Guru Murthy GS, et al. ASH 2021; session 721; Abstr 912.

  • Rationale: The optimal condition regimen prior to allogenic HCT (alloHCT) in patients with myelofibrosis remains unknown.
  • Study design: Retrospective database study of adults with myelofibrosis who underwent alloHCT between 2008 and 2018. The Center for International Blood and Marrow Transplant Research 2021 ASH Meeting Updates February 2022 (CIBMTR) database was utilized and outcomes were analyzed separately in the myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) cohorts.
  • Results: 379 patients were included in the MAC cohort (busulfan (Bu)/fludarabine (Flu)=247, Bu/cyclophosphamide (Cy)= 132) and 493 patients in the RIC cohort (Bu/Flu=166 and Flu/melphalan (Mel)=327). In the MAC setting, Bu/Cy was associated with a higher risk of acute GVHD (aGVHD) (grade 2-4 hazard ratio (HR) 2.33, p<0.01; grade 3-4 HR 2.31, p<0.01) and inferior GVHD-free/relapse free survival (GRFS) (HR1.94, p<0.01) as compared to Bu/Flu. In the RIC setting, Flu/Mel was associated with inferior overall survival (OS) (HR 1.80, p<0.01), higher risk of non-relapse mortality (NRM) (HR 1.81, p=0.01) and acute GVHD (grade 2-4- HR 1.45, p=0.03; grade 3-4 HR 2.21, p<0.01) as compared to Bu/Flu.
  • Conclusion: In this retrospective analysis Bu/Flu conditioning was favored in myelofibrosis patients undergoing MAC or RIC prior to alloHCT.

Phase I Dose-Escalation Study of Venetoclax Plus BEAM Followed By Autologous Stem Cell Transplant for Chemoresistant or High-Risk Relapsed/Refractory Non-Hodgkin Lymphoma.

Maakaron J, et al. ASH 2021; session 731; Abstr 656.

  • Rationale: Venetoclax is an oral BCL-2 inhibitor that has significant single-agent and combination activity in relapsed and refractory Non-Hodgkin lymphoma (NHL). Preclinical observations showed that venetoclax potentiates the cytotoxicity of chemotherapy, increases synergistic cell kill, and can overcome chemoresistance even in highly aggressive lymphomas. This trial aimed to test the safety of the combination of venetoclax plus carmustine/etoposide/cytarabine/melphalan (BEAM).
  • Study design: Phase 1, single-center, open-label study with an expansion cohort in adult autologous HCT (aHCT) patients with relapsed/refractory or high-risk NHL. Venetoclax was given for 10 days starting on day -10 at three different dosing levels (400, 800, 1200 mg per day). An expansion phase was planned with the maximum tolerated dose.
  • Results: 19 patients were included overall with 13 patients receiving the 1200 mg dose. The median age was 61 years and most patients were male (79%) with stage 4 disease (79%). No tumor lysis or other venetoclax-related toxicities were observed. Engraftment was as expected with one patient dying from sepsis prior to engraftment. A complete response (CR) was attained in 63% % of patients by day +100 and 47% were in a CR at day +365. Six patients went on to receive CAR-T therapy.
  • Conclusion: The addition to venetoclax to BEAM is well-tolerated.

Peri-Transplant Alemtuzumab Levels Predict Risk of Secondary Graft Failure and Inversely Impact CXCL9 Levels after RIC HCT (A Correlative Biology Study to BMT-CTN 1204 RICHI).

Geerlinks AV, et al. ASH 2021; session 721; Abstr 748.

  • Rationale: The Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 1204 study for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies was a single arm study testing safety and efficacy of RIC with alemtuzumab (1mg/kg), fludarabine (150 mg/m2 ) and melphalan (140 mg/m2 ). Survival was favorable compared to historical studies, but patients experienced high rates of mixed chimerism and ultimate secondary graft failure. The authors set out to evaluate cytokine patterns and alemtuzumab levels and their association with durable engraftment.
  • Study design: Correlative sample study looking at alemtuzumab levels at the time of transplant and a comprehensive cytokine analysis for 100 analytes at day -14, -7, -1, +1, +14, +28, +42, +70, and +100.
  • Results:33 patients (25 with hemophagocytic lymphohistiocytosis) were included. All patients received bone marrow grafts and 82% had matched unrelated donors (MUD). 1 patient developed primary graft failure (GF), 67% developed mixed chimerism, and 11 patients developed secondary GF. Patients with secondary GF had lower levels of C-X-C motif chemokine ligand 9 (CXCL9) on day +14 and +28. Patients with day 0 alemtuzumab levels >0.32μg/mL had lower CXCL9 levels compared to patients with levels ≤0.32μg/mL. Patients with day 0 alemtuzumab levels ≤0.32μg/mL had a lower cumulative incidence of mixed chimerism (14.3% vs 90.9%, p=0.03) and a lower incidence of secondary GF (0% vs 54%, p=0.08) compared to patients with levels >0.32μg/mL.
  • Conclusion: There is a correlation between alemtuzumab levels, CXCL9 levels, incidence of mixed chimerism, and incidence of secondary graft failure—suggesting that precision alemtuzumab dosing strategies warrant further research.

Updates on Supportive Care:

Internal and External Validation of the High-2-Low Model: A Predictive Score for Venous Thromboembolism after Allogeneic Transplant.

Li A, et al. ASH 2021; session 721; Abstr 750

  • Rationale: Venous thromboembolism (VTE) remains a serious complication that lacks validated risk assessment models in alloHCT. A previously described HIGH-2-LOW score was developed using clinical predictors at day +30. This study served as the validation for that scoring tool.
  • Study design: A large validation study utilizing two independent cohorts of alloHCT patients treated at Fred Hutchinson (2015-2019) and MD Anderson (2016-2020). The score was comprised of seven clinical predictors (history of catheter related deep vein thrombosis (DVT), inpatient admission at day +30, grade 2-4 GVHD, history of pulmonary embolism (PE)/DVT, lymphoma diagnosis, obesity, and elevated white blood cell count). Two points were added to the score for history of PE/DVT and one point for all other predictors. Patients with a score >1 were classified as high risk.
  • Results: High vs. low/intermediate-risk was associated with an odds ratio (OR) of 2.99 (1.20- 7.49) for VTE and 19.93 (2.38-166.6) for PE/lower extremity-DVT in the Fred Hutchinson validation cohort (n=772). High vs. low/intermediate-risk was associated with OR of 4.58 (2.69- 7.79) for VTE and 12.05 (3.17-45.81) for PE/lower extremity-DVT in the MD Anderson validation cohort (n=1109). The VTE risk stratification separated early and persisted beyond 100 days.
  • Conclusion: The HIGH-2-LOW score can identify high-risk VTE patients after alloHCT

A Phase 3, Randomized, Adaptive Study of Defibrotide Vs Best Supportive Care for the Prevention of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Patients Undergoing Hematopoietic Cell Transplantation: Preliminary Results.

Grupp SA, et al. ASH 2021; session 721; Abstr 749.

  • Rationale: A recent meta-analysis of >1000 pts, including a phase 3 trial in high-risk pediatric patients, reported a significantly lower risk of SOS (sinusoidal obstructive syndrome) with prophylactic defibrotide. This prospective study set out to evaluate the prophylactic use of defibrotide vs best supportive care (BSC).
  • Study design: Phase 3, randomized, multi-center, open label study in patients >1 month scheduled to undergo alloHCT or aHCT (pediatric only) at high risk of SOS. Defibrotide was given at a dose of 25 mg/kg/day for up to 21 days.
  • Results: 190 patients were enrolled in in defibrotide group and 182 in the BSC group with a median age of 13 and 15 years, respectively. The day +30 SOS-free survival was 67 vs 70%, p=0.85. There were also similar rates at day +100 and similar rates of adverse events between the two groups.
  • Conclusion: Prophylactic defibrotide did not provide a benefit in SOS-free survival in high-risk patients.

Updates on Graft-Versus-Host Disease:

A Single-Arm, Open-Label, Pilot Study of the JAK1 Selective Inhibitor Itacitinib for the Prophylaxis of Graft-Versus-Host Disease and Cytokine Release Syndrome in T-Cell Replete Haploidentical Peripheral Blood.

Abboud R, et al. ASH 2021; session 722; Abstr 100.

  • Rationale: Interferon-γ and IL-6 are important mediators in both aGVHD and cytokine release syndrome (CRS), and this study investigated the hypothesis that JAK1 inhibition with itacitinib could prevent these toxicities without impairing engraftment.
  • Study design: Single-arm, open-label, pilot study in adult patients with AML, ALL, or NHL in remission undergoing haploidentical HCT (haploHCT) treated with itacitinib 200 mg/day on day - 3 through +100.
  • Results: A total of 20 patients who underwent HCT between 11/2019 and 3/2021 were included in the study. Median age was 40 years, 13 patients had AML, and median follow-up was 319 days. There were no cases of engraftment failure and median time to neutrophil and platelet engraftment were both 14 days. There were no cases of grade 3-4 aGVHD and three patients experienced grade 2 aGVHD. There were no extensive cases of cGVHD however, 2 patients experience skin GVHD during itacitinib taper. There were no cases of severe CRS however 90% of patients experience grade 1 CRS. All patients had full donor engraftment and >95% chimerism at day +100.
  • Conclusion: Patients treated in this study with itacitinib experienced limited toxicity and relatively low rates of GVHD and severe CRS.

Role of Extracorporeal Photopheresis in Prevention of Graft-Versus-Host Disease in Patients Treated with Allogeneic Hematopoietic Stem Cell Transplantation: A Randomized Controlled Trial.

Ali MM, et al. ASH 2021; session 722; Abstr 102.

  • Rationale: Due to limited existing data and lack of randomized controlled trials, this study set out to investigate the role of extracorporeal photopheresis (ECP) in GVHD prophylaxis.
  • Study design: Single center, open-label, RCT in adults with a hematologic malignancy treated with alloHCT between 6/2017 and 2/2020. After engraftment, ECP was given over eight sessions in addition to standard GVHD prophylaxis twice weekly for 2 weeks then once weekly for 4 weeks.
  • Results: Seventy- six patients were included in the ECP group and 81 in the control group. The cohorts were well matched regarding patient characteristics. In the intervention group the median age was 59 years, the most common diagnosis was acute leukemia (57%), donor source was MUD (83%), conditioning was MAC (55%), and GVHD prophylaxis was with cyclosporine (CSA)/methotrexate (MTX) (79%). Fifty-one percent of patients completed all 8 ECP treatments. There was no difference in the 1-year incidence of GVHD between the two groups (59% vs 64%, respectively, p=0.5). There was no difference in the characteristics of the GVHD and no difference in survival endpoints.
  • Conclusion: ECP does not provide a benefit as an adjunct to standard GVHD prophylaxis.

Safety, Tolerability, and Efficacy of Axatilimab, a CSF-1R Humanized Antibody, for Chronic Graft-Versus-Host Disease after 2 or More Lines of Systemic Treatment.

Lee SJ, et al. ASH 2021; Session 722; Abstr 263.

  • Rationale: Activation of colony-stimulating factor 1 receptor (CSF-1R) signaling is a key pathway involved in the expansion and infiltration of donor-derived macrophages in chronic GVHD (cGVHD). This study investigated the use of an IgG4 monoclonal antibody with high affinity binding to CSF-1R—axatilimab,
  • Study design: Phase 1/2, multi-center, open-label, single arm study in patients ≥6 years with cGVHD despite 2 lines of systemic therapy with a data cutoff of 6/2021. The dose expansion phase evaluated axatilimab 1 mg/kg every 2 weeks. There were also patients included that received 3 mg/kg every 4 weeks.
  • Results: A total of 32 patients with a median age of 59 years were included in the analysis (26 at 1 mg/kg and 6 at 3 mg/kg) who had received a median of 4 prior therapies. Treatment related adverse events occurred in 66% of these patients (most common periorbital edema and elevations of aspartate transaminase, creatine phosphokinase, and alanine transaminase) and 13% experienced a grade 3-4 event (hypersensitivity and septic arthritis). Elevation in liver enzymes were believed to be related to CSF-1R blockade on Kupffer cells and not hepatoxicity. The best overall response rate was 70%.
  • Conclusion: This data demonstrates safety and clinical activity of axatilimab in cGVHD. The Phase 3 trial is currently enrolling.

Phase II Clinical Trial of Abatacept for Steroid-Refractory Chronic Graft Versus Host Disease.

Koshy AG, et al. ASH 2021; Session 722; Abstr 264.

  • Rationale: Abatacept, through attenuation of CD28-mediated T cell activation, has been shown to have clinical activity in steroid refractory cGVHD in phase 1 studies.
  • Study design: Phase 2, single-center, open label trial in adult alloHCT patients with steroid refractory GVHD. Abatacept was given at 10 mg/kg for a total of 6 doses (with potential to receive 12 additional doses based on response).
  • Results: A total of 39 patients (17 with moderated and 22 with severe cGVHD) with a median age of 62 years were included. The overall response rate was 49% with no cases of complete response. Progression of disease occurred in 10 patients. There were significant reductions in median daily steroid use (27% reduction at 1 month and 50% at 5 months). The most common adverse events were neutropenia, fatigue, headache, and upper respiratory infection.
  • Conclusion: Abatacept has clinical activity in steroid refractory cGVHD and is well tolerated.

Updates on Maintenance Therapy and Treatment of Relapse:

A Phase II Study of Ruxolitinib Pre-, during- and Post-Hematopoietic Cell transplantation for Patients with Primary or Secondary Myelofibrosis.

Hobbs G, et al. ASH 2021; session 732; Abstr 169.

  • Rationale: Ruxolitinib is a Janus kinase 1/2 inhibitor approved for myelofibrosis and GVHD. Many myelofibrosis patients are on ruxolitinib prior to alloHCT and have this therapy discontinued prior to starting conditioning therapy. The interim analysis of this study set out to investigate the safety of continued ruxolitinib therapy.
  • Study design: Phase 2, multi-center, open-label, single arm study in adults with myelofibrosis treated with alloHCT between 9/2018 and 1/2021. Ruxolitinib was given at a dose of 5 mg twice daily prior to, during RIC with Flu/Mel, and after transplant for 1 year in combination with standard tacrolimus (FK)/MTX prophylaxis.
  • Results: A total of 26 patients were included in the pre-planned interim analysis. The median age was 66 years, 88% has matched related donor (MRD), and 92% has intermediat-2 or high Dynamic International Prognostic Scoring System risk disease at the time of transplant. There were no unexpected ruxolitinib-related toxicities with 4 patients and 3 patients experiencing grade 3-4 anemia and thrombocytopenia respectively. Two patients experienced grade 3-4 infection and one patient experienced grade 3-4 hypertriglyceridemia. Median time to neutrophil engraftment was 15 days and median chimerism was 100% at day +30. One-year GRFS was 65%. There was one case of grade 3 aGVHD and no cases of severe cGVHD.
  • Conclusion: When combined with Flu/Mel RIC and FK/MTX GVHD prophylaxis, continued administration of ruxolitinib to patients with myelofibrosis was not associated with any unexpected toxicity.

Phase II Trial of Eprenetapopt (APR-246) in Combination with Azacitidine As Maintenance Therapy for TP53 Mutated AML or MDS Following Allogeneic Stem Cell Transplantation.

Mishra A, et al. ASH 2021; session 723; Abstr 409.

  • Rationale: Mutations in tumor suppressor gene TP53 are found in up to 20% of patients with acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS) and outcomes after alloHCT remain poor. Eprenetapopt is a p53 stabilizer with pre-clinical data demonstrating synergistic myeloid cell toxicity in combination with azacitidine (AZA). This study sought to evaluate the tolerability and efficacy of this combination.
  • Study design: Phase 2, multi-center, open label study in adults alloHCT patients with a known TP53 mutation with a data cutoff of 6/2021. Treatment consisted of up to 12 cycles of eprenetapopt 3.7g on days 1-4 with AZA 36 mg/m2 on days 1-5 every 28 days.
  • Results: A total of 33 patients (19 MDS, 14 AML) were included with a median age of 65 years and 76% having received RIC. Nine percent had >1 TP53 mutation and 82% had complex cytogenetics. With a median duration of follow-up of 413 days, median relapse free survival was 368 days. Grade ≥3 treatment-related adverse events occurring in ≥10% of patients were platelet count decreased (36%), white blood cell count decreased (33%), anemia (27%), neutrophil count decreased (24%), thrombocytopenia and hypertension (12% each).
  • Conclusion: Post-HCT maintenance therapy with eprenetapopt in combination with AZA was tolerated and associated with promising efficacy in patients with myeloid malignancies and TP53 mutations.

Ixazomib Plus Lenalidomide/Dexamethasone Versus Lenalidomide /Dexamethasone Maintenance after Autologous Stem Cell Transplant in Patients with Newly Diagnosed Multiple Myeloma: Results of the Spanish GEM2014MAIN Trial.

Rosinol L, et al. ASH 2021; session 653; Abstr 466.

  • Rationale: Lenalidomide is a cornerstone of maintenance therapy post-HCT in multiple myeloma (MM). The addition of bortezomib to thalidomide has been shown to be superior to thalidomide alone but associated with high rates of peripheral neuropathy. The authors of this study hypothesized that the combination of ixazomib and lenalidomide/dexamethasone would be superior to lenalidomide/dexamethasone alone.
  • Study design: Phase 3, multi-center, open label study in adults with at least stable disease after an autologous stem cell transplant (aHCT). Lenalidomide 15 mg on day 1-21, dexamethasone 20 mg on days 1-4 and 9-12, plus/minus ixazomib 4 mg on days 1, 8, 15 were given every 28 days. If minimal residual disease (MRD) negative at 2 years, treatment was discontinued. If MRD positive, treatment with lenalidomide and dexamethasone continued for 3 more years.
  • Results: After a median follow-up of 56 months, there was no difference in progression-free survival (PFS) (62% vs 63%) in the ixazomib group. There was no difference when stratified based on disease risk or disease status. Grade 3-4 thrombocytopenia (16% vs 7%, p=0.01) and grade 3-4 GI toxicity (15% vs 2%, p<0.001) were greater in the ixazomib group. Patients with MRD negative disease had improved outcomes compared to patients with MRD positive disease.
  • Conclusion: The addition of ixazomib to lenalidomide/dexamethasone maintenance therapy after aHCT for MM did not improve PFS and was associated with increased toxicity.

Impact of Autologous Hematopoietic Cell Transplant Followed By Dendritic Cell/Myeloma Fusion Vaccine with Lenalidomide Maintenance in Increasing Multiple Myeloma Immunity (BMT CTN 1401).

Chung DJ, et al. ASH 2021; session 653; Abstr 899.

  • Rationale: In a prior phase 2 study, personalized cancer vaccination with autologous dendritic cells fused with primary MM tumor cells induced the expansion of circulating MM-reactive lymphocytes and was associated with conversion to complete response post-aHCT in the absence of maintenance therapy.
  • Study design: Phase 2, multicenter, randomized, open-label study in adult patients with MM undergoing aHCT. Patients received standard lenalidomide maintenance alone, lenalidomide with granulocyte macrophage colony-stimulating factor (GM-CSF), or lenalidomide with GM-CSF and three doses of the fusion vaccine.
  • Results: Thirty-six of the 68 (53%) evaluable patients on the vaccine arm and 34 of the 68 (50%) of the non-vaccine arms achieved CR/stringent CR at 1-year post-transplant (p=0.3). The rates of post-transplant grade 3-4 toxicities were 77%, 63% for the vaccine, and non-vaccine arms, respectively (p=0.07). There were no grade 5 toxicities in any of the cohorts. The overall grade 2- 3 infection rate was 23% (24% on the vaccine arm, 14% on the lenalidomide/GM-CSF arm, and 31% on the lenalidomide alone arm). Patients in the vaccine arm demonstrated a significant expansion of MM-reactive CD8 cells, representing 2.9%, 3.5%, and 16% of the lymphocyte population prior to post-transplant maintenance, following 1 cycle of lenalidomide and following 3 vaccinations at 1-year post-transplant, respectively.
  • Conclusion: Dendritic Cell/Myeloma fusion vaccination was associated with measurable antiMM immune reactivity but no difference in 1-year CR rates.

Treatment of MDS, AML and CMML Relapse after Allogeneic Blood Stem Cell Transplantation with Azacitidine, Lenalidomide and Donor Lymphocyte Infusions - Final Results of the Prospective AzalenaTrial (NCT02472691).

Schroeder T, et al. ASH 2021; Session 723; Abstr 411.

  • Rationale: Lenalidomide has been shown to have immunomodulatory and anti-leukemic properties. This study investigates if lenalidomide provides synergistic benefit when combined with AZA and donor lymphocyte infusion (DLI).
  • Study design: Phase 2, multi-center, open label, single arm study in adults with relapsed MDS, AML, and chronic myelomonocytic leukemia (CMML) after first alloHCT. Lenalidomide given on days 1-21 was combined with 75 mg/m2 of AZA on days 1-7 for up to 8 cycles and up to 3 escalating T-cell doses of DLI. After a planned safety analysis, the dose of lenalidomide was increased from 2.5 mg to 5 mg daily.
  • Results: A total of 50 patients with molecular (58%) or hematological relapse (42%) of MDS (48%), AML (46%), or CMML (6%) were included. Overall response rate was 56% (CR=50%, PR=6%). Median time to CR was 112 days and 20 patients remained in CR after a median followup of 15 months. Treatment-related grade 3-4 adverse events included neutropenia (92%), thrombocytopenia (80%), and anemia (36%). 46% of patients developed aGVHD (10% grade 3-4) and 52% developed cGVHD (10% severe). Three patients developed a secondary carcinoma.
  • Conclusion: Lenalidomide up to 5 mg per day can be safely added to the combination of AZA and DLI in relapsed myeloid malignancies after alloHCT.

Part 2

CAR-T Updates in Non-Hodgkin Lymphoma:

Primary Analysis of ZUMA‑7: A Phase 3 Randomized Trial of Axicabtagene Ciloleucel Versus Standard‑of‑Care Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma.

Locke F, et al. ASH 2021; Plenary Scientific Session; Abstract 2.

  • Rationale: Patients with aggressive B-cell NHL who experience early relapse, defined as less than or equal to 12 months, experience poor outcomes following traditional second-line treatment options. Axicabtagene ciloleucel (Axi-Cel), an autologous CAR T-cell therapy, is approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after ≥ 2 lines of therapy based on the results of the ZUMA-1 trial. ZUMA-7 was designed to evaluate Axi-Cel versus standard of care (SOC) as second-line therapy for patients with R/R LBCL.
  • Study design: ZUMA-7 is a randomized, global, multicenter, Phase III study comparing Axi-Cel to SOC in patients with LBCL that was primary refractory to or relapsed within 12 months of firstline therapy and were intended to proceed to autologous HCT (aHCT). Patients in the Axi-Cel arm received cyclophosphamide 500 mg/m2 IV and fludarabine 30 mg/m2 IV daily on Days -5 to - 3. Axi-Cel was infused at a target dose of 2 x 106 CAR T-cells/kg. Patients in the SOC arm received investigator-selected platinum-based chemotherapy with one of the following, R-GDP, R-DHAP, R-ICE, or R-ESHAP. Bridging therapy with chemotherapy was not permitted.
  • Results: 180 patients received Axi-Cel and 179 patients received SOC. Baseline characteristics were balanced, with 1/3 of patients being greater than 65 years of age, 2/3 having primaryrefractory disease, and 1/2 having double expressor lymphoma. The primary endpoint of event free survival (EFS) was superior for Axi-Cel compared to SOC (HR 0.398 (95% CI, 0.308-0.514); P<0.0001). At a median follow-up of 24.7 months, the median EFS was 8.3 months in the Axi-Cel group and 2 months in the SOC group, and the two-year EFS was 40.5% and 16.3%, respectively. The objective response rate (ORR) was higher in the Axi-Cel arm with 83% responding as compared to 50% in the SOC arm. In an interim analysis, the median overall survival (OS) was not reached for the Axi-Cel group and was 35.1 months for the SOC group. Adverse events, including high grade, serious events, were similar between arms. For patients who received AxiCel, Grade 3 or higher cytokine release syndrome (CRS) occurred in 6% and Grade 3 or higher neurotoxicity occurred in 21%. Median time to onset for CRS and neurotoxicity were 3 days and 7 days, respectively. Median duration for CRS and neurotoxicity were 7 days and 9 days, respectively.
  • Conclusion: Axi-Cel demonstrated significant improvements in EFS and response compared with SOC treatment. Toxicities were as expected and manageable.

Lisocabtagene Maraleucel, a CD19-Directed CAR T-Cell Therapy, Versus Standard of Care with Salvage Chemotherapy Followed By Autologous Stem Cell Transplantation As Second-Line Treatment in Patients with Relapsed or Refractory Large B-Cell Lymphoma: Results from the Randomized Phase 3 Transform Study.

Kamdar M, et al. ASH 2021; Session 704; Abstract 91.

  • Rationale: Patients with aggressive B-cell NHL who experience early relapse, defined as less than or equal to 12 months, have worse outcomes following traditional second-line treatment options. Lisocabtagene maraleucel (Liso-Cel) is an autologous anti-CD19 CAR T-cell therapy with defined composition of CD8+ and CD4+ T-cell components administered at equal target doses and is approved for treatment of adult patients with R/R LBCL after ≥ 2 lines of therapy. TRANSFORM was designed to evaluate the safety and efficacy of Liso-Cel versus SOC as second-line therapy for patients with R/R LBCL.
  • Study design: TRANSFORM is a randomized, multicenter, Phase III study comparing Liso-Cel to SOC in patients with LBCL that was primary refractory to or relapsed within 12 months of first-line therapy and were intended to proceed to aHCT. Patients in the Liso-Cel arm received cyclophosphamide 300 mg/m2 IV and fludarabine 30 mg/m2 IV daily for three days prior to Liso-Cel infusion. Liso-Cel was infused at a target dose of 100 x 106 CAR T-cells/kg. Patients in the SOC arm received investigator-selected platinum-based chemotherapy with one of the following, R-GDP, R-DHAP, or R-ICE. Optional bridging therapy was permitted.
  • Results: 92 patients received Liso-Cel and 92 patients received SOC. Baseline characteristics were balanced, with the majority of patients having DLBCL NOS and having primary-refractory disease. The primary endpoint of EFS was met with Liso-Cel demonstrating superiority over SOC (HR 0.349 [95% CI, 0.229-0.53]; P<0.0001). The median study follow-up at the time of analysis was 6.2 months and the median EFS was 10.1 months for the Liso-Cel arm and 2.3 months for the SOC arm. Rates of EFS at 6- and 12-months were nearly doubled for the Liso-Cel arm (63.3 vs. 33.4 and 44.5 vs. 23.7, respectively). A complete response rate of 66% was achieved in the Liso-Cel arm compared with 39% in the SOC arm (P=0.0001). Median progression free survival in Liso-Cel arm was longer at 14.8 months than SOC arm at 5.7 months. Overall survival for Liso-Cel was not reached at time of data cut-off. The most common treatment emergent adverse events (TEAEs) in both arms were neutropenia (82% Liso-Cel vs. 54% SOC), anemia (63% Liso-Cel vs. 64% SOC), and thrombocytopenia (58% Liso-Cel vs. 68% SOC). CRS occurred in 49% of patients in the Liso-Cel arm with 1% grade 3/4. Median time to onset was 5 days and median duration was 4 days. Neurotoxicity was reported in 12% of patients in the Liso-Cel arm with 4% grade 3/4. Median time to onset was 11 days and median duration was 6 days.
  • Conclusion: Liso-Cel demonstrated significant improvements in EFS, CR, and PFS compared with SOC treatment. Toxicities were as expected and manageable.

Tisagenlecleucel vs Standard of Care As Second-Line Therapy of Primary Refractory or Relapsed Aggressive B-Cell Non-Hodgkin Lymphoma: Analysis of the Phase III Belinda Study.

Bishop M, et al. ASH 2021; Late-Breaking Abstracts Session; Abstract 6.

  • Rationale: Patients with aggressive B-cell NHL who experience early relapse, defined as less than or equal to 12 months, have worse outcomes following traditional second-line treatment options. Tisagenlecleucel (Tisa-Cel) is an autologous anti-CD19 CAR T-cell therapy approved for the treatment of R/R DLBCL after ≥ 2 lines of therapy. BELINDA was designed to evaluate the safety and efficacy of Tisa-Cel versus SOC as second-line therapy for patients with R/R LBCL.
  • Study design: BELINDA is a global, randomized, multicenter, Phase III study comparing Tisa-Cel to SOC in patients with LBCL that was primary refractory to or relapsed within 12 months of first-line therapy and were intended to proceed to aHCT. Patients in the Tisa-Cel arm received cyclophosphamide 250 mg/m2 IV and fludarabine 25 mg/m2 IV daily for three days or bendamustine 90 mg/m2 IV daily for two days prior to Tisa-Cel infusion. Tisa-Cel was infused at a target dose of 0.6-6 x 108 CAR T-cells/kg. Patients in the SOC arm received one of four pre-determined investigator-selected platinum-based chemotherapy regimens. Optional bridging therapy was permitted.
  • Results: 162 patients received Tisa-Cel and 160 patients received SOC. Baseline characteristics were balanced, with the majority of patients having DLBCL NOS and having primary-refractory disease. There was a slight imbalance between arms with a higher percentage of patients with high-grade B-cell lymphoma in the Tisa-Cel arm (19.8% vs. 11.9%). No difference in EFS was found between treatment arms (HR 1.07 (95% CI, 0.82-1.4); P 0.69). The median EFS for both arms was 3 months. Differences in EFS were observed based on disease burden status at infusion with the worst outcomes seen in patients with progressive disease. The ORR at week 6 was 38% vs. 54% in the Tisa-Cel arm compared to the SOC arm and at week 12 was 46% vs. 43% in the Tisa-Cel arm compared to the SOC arm. The most common adverse events were cytopenias. CRS occurred in 59% of patients in the Tisa-Cel arm with 5% grade 3/4. Neurotoxicity was reported in 10% of patients in the Tisa-Cel arm with 2% grade 3/4.
  • Conclusion: Tisa-Cel did not significantly improve EFS when compared with SOC treatment. Toxicities were as expected and manageable.

Primary Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel as First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma

Neelapu S, et al. ASH 2021; Session 704; Abstract 739.

  • Background: Patients with high-risk LBCL have poor outcomes. Patients with primary treatment failure to chemo-immunotherapy have worse OS and an increased risk for death. Axi-Cel is an autologous anti-CD19 CAR T-cell therapy approved for the treatment of adults with R/R LBCL after ≥ 2 lines of therapy based on ZUMA-1. ZUMA-12 evaluated the use of Axi-Cel in the firstline setting for high risk LBCL.
  • Study Design: The ZUMA-12 trial is a multicenter, open-label, single-arm, Phase II study of AxiCel as a first-line therapy for patients with high-risk LBCL. Patients received lymphodepleting chemotherapy with cyclophosphamide 500 mg/m2 IV and fludarabine 30 mg/m2 IV daily on days -5 to -3. Axi-Cel was infused at a target dose 2 x 106 CAR T-cells/kg.
  • Results: 40 patients received Axi-Cel. Median age was 61 years; 68% were males; 40% had double-hit or triple-hit lymphoma, and 78% had an IPI score ≥ 3. The ORR was 89% with 78% of patients achieving a complete response (CR) and 11% a partial response (PR). The median time to response was one month. Median duration of response, EFS, and PFS were not reached. The 12-month OS rate was 91%. CRS was reported in 100% of patients with 8% grade 3/4. Median time to CRS onset was 4 days and median duration was 6 days. Neurotoxicity was reported in 73% of patients with 23% grade 3/4. Median time to onset was 9 days and median duration was 7 days. CAR T-cell expansion was greater in ZUMA-12 than in ZUMA-1 and levels of CCR7+CD45RA+ T-cells were increased in ZUMA-12 compared to ZUMA-1.
  • Conclusion: Axi-Cel demonstrated rapid and durable responses when used in the frontline setting in high risk LBCL. Toxicities were as expected and manageable. Axi-Cel product in the first-line setting was associated with a higher frequency of younger phenotype CAR T-cells suggesting better T-cell fitness.

Tisagenlecleucel Demonstrates Safety, Efficacy and CNS Trafficking in Primary CNS Lymphoma

Frigault M, et al. ASH 2021; Session 704; Abstract 258.

  • Background: Tisagenlecleucel (Tisa-Cel), an autologous anti-CD19 CAR T-cell therapy approved for the treatment of R/R DLBCL after ≥ 2 lines of therapy, has previously been reported as a safe and effective treatment for secondary CNS lymphoma. Treatment of primary CNS lymphoma is prohibited by FDA-labeling for all current commercially available CAR T-cell products. Concerns with use in this patient population include an increased risk for neurologic events and a lack of CNS trafficking for the product.
  • Study Design: Adult patients with primary CNS lymphoma who previously failed systemic methotrexate-based therapy were eligible for enrollment. Patients received lymphodepletion followed by Tisa-Cel.
  • Results: 12 patients received Tisa-Cel. The ORR was 7/12 (58%), with CR 5/12 (42%) and PR 2/12 (17%). The median time to response was 3.4 months. Median PFS was 5.9 months (range, 1.6- 15.9) and median OS was 15.7 months (range, 2.6-not reached). Grade 1 CRS was reported in 58% of patients. Median time to CRS onset was 4 days and median duration was 2 days. Neurotoxicity was reported in 50% of patients with 10% grade 3. Median time to onset was 5 days and median duration was 3 days. CAR transgene levels were detected in the CSF at Day +7.
  • Conclusion: Tisa-Cel was observed to be safe and effective in this small sample size, with only one case of severe neurotoxicity noted, which ultimately resolved. Median OS and PFS exceeded those observed in previously reported outcomes with LBCL. Data suggest a possible expansion of access to Tisa-Cel for this population.

CAR-T Updates in Multiple Myeloma:

Efficacy and Safety of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy, in Lenalidomide-Refractory Patients with Progressive Multiple Myeloma after 1 to 3 Prior Lines of Therapy: Updated Results from CARTITUDE-2

Cohen Y, et al. ASH 2021; Session 704; Abstract 3866.

  • Rationale: Ciltacabtagene autoleucel (Cilta-Cel) is a CAR T-cell therapy with two BCMA-targeting, single-domain antibodies. The phase 1b/2 CARTITUDE-1 trial demonstrated that a single infusion of Cilta-Cel produced deep, durable responses in heavily pre-treated patients with R/R MM. Treatment options are limited for patients with progressive multiple myeloma who are refractory to lenalidomide and/or proteasome inhibitors. CARTITUDE-2 was designed to evaluate Cilta-Cel in earlier-line settings.
  • Study design: CARTITUDE-2 is a multicohort, Phase II study and Cohort A assessed patients with MM, who were lenalidomide-refractory and had received 1 to 3 prior lines of therapy. Patients received lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2 IV and fludarabine 30 mg/m2 IV daily on days -5 to -3. The Cilta-Cel infusion target dose was 0.75 x 106 CAR Tcells/kg on Day 1. Optional bridging therapy was permitted.
  • Results: 20 patients in this cohort received Cilta-Cel. The median age was 60 years; 65% of patients were male. Patients had a median of 2 prior therapies; 85% received a previous aHCT autologous and no patients received an allogeneic stem cell transplant, 40% were triple-class refractory, 5% were penta-refractory, and 95% of patients were refractory to their last line of therapy. All patients were exposed to a proteasome inhibitor, immunomodulatory drug, and steroid. Overall response rate was 95%, with 85% achieving ≥ CR and 90% achieving ≥ VGPR. Median time to first response was 1 month (range, 0.7-3.3) and the median duration of response was not reached. The 12-month PFS was 84% (95% CI, 59.1-94.7). The most common adverse events were neutropenia (95%), thrombocytopenia (80%), and anemia (75%). CRS occurred in 95% of patients with 10% grade 3/4. Median time to onset was 7 days and median duration was 4 days. Neurotoxicity was reported in 20% of patients with none grade 3/4. Median time to onset was 8 days and median duration was 3 days. Four deaths occurred; 2 due to progressive disease, 1 due to sepsis, and 1 due to COVID-19.
  • Conclusion: Cilta-Cel continued to demonstrate early and deep responses in this patient population. Toxicities were as expected and manageable.

CAR-T Updates in Leukemia:

Outcomes after Reinfusion of CD19-Specific Chimeric Antigen Receptor Modified T-Cells in Children and Young Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Myers R, et al. ASH 2021; Session 704; Abstract 474.

  • Background: CD19 CAR T-cell treatment for acute lymphoblastic leukemia demonstrated remarkable responses, but relapse remains a challenge. Up to 78% of relapses are caused by loss of CAR T-cell surveillance. This study was designed to determine the effectiveness of 4-1BB CAR T-cell reinfusions in prolonging persistence to reduce risk for relapse, treat relapsed disease, and produce response in non-responders.
  • Study Design: This was a retrospective, single-center, cohort study of patients less than 30 years of age, treated with a CD19 CAR T-cell product (CTL019/tisagenlecleucel [Tisa-Cel] or huCART19) who received reinfusion with the same CAR product due to poor persistence within 6 months, new MRD-positivity/relapse, or non-response to initial infusion.
  • Results: Among 262 patients who previously received CAR therapy, 81 patients received reinfusion (68 patients received CTL019/Tisa-Cel and 13 patients received HuCART19). Indications for reinfusion included peripheral B-cell recovery (n=38), hematogones (n=25), CD19+ MRD/relapse (n=10), and non-response to initial infusion (n=7). Of the patients who received reinfusion for relapse prevention 52% achieved a CR at Day 28. At a median follow-up of 38 months, 17 patients remained in remission following reinfusion, 3 patients remained in remission following alternative therapy, and 13 patients relapsed. Incidence of relapse (IR) and OS were not statistically significantly different between patients who responded versus those who did not (IR, p=0.26; OS, p=0.25). Of the patients who received reinfusion for relapse, 50% achieved a CR at Day 28. One patient remained in remission following re-infusion, 1 patient remained in remission following HCT, and 8 patients relapsed. All 7 patients with non-response to initial infusion died of progressive disease at a median of 105 days after reinfusion. CRS occurred in 19 patients with Grade 3/4 events only occurring in patients with active disease at time of reinfusion. Neurotoxicity was infrequently observed with only one Grade 3 event reported.
  • Conclusion: Reinfusion with CTL019/Tisa-Cel or huCART19 may reduce relapse risk in a subset of patients with short CAR persistence and induce remissions in patients with CD19+ MRD/relapsed disease. Reinfusion was deemed safe based on limited events of CRS and neurotoxicity. Reinfusion did not demonstrate efficacy for patients with non-response to initial CAR infusion.

CAR-T Updates in Supportive Care:

A Phase II Study of Prophylactic Anakinra to Prevent CRS and Neurotoxicity in Patients Receiving CD19 CAR T-Cell Therapy for Relapsed or Refractory Lymphoma

Park J, et al. ASH 2021; Session 704; Abstract 96.

  • Background: CAR T-cell therapies approved for R/R LBCL are associated with varying rates of acute toxicities, such as CRS and neurotoxicity, depending on product administered. Axi-Cel is reported to have the highest incidence for CRS and neurotoxicity of all commercially approved products, with rates as high as 93% for CRS and 65% for neurotoxicity. Current CRS and neurotoxicity treatment guidelines do not provide recommendations for prevention. Based on recent animal data demonstrating the role of Interleukin-1 (IL-1) in the pathogenesis of neurotoxicity/CRS, this study was designed to assess anakinra, an IL-1 receptor antagonist, in patients receiving CD19 CAR T-cell products for prevention of CRS and neurotoxicity.
  • Study Design: This was a Phase II, single-arm study of adult patients with relapsed/refractory LBCL or Mantle Cell Lymphoma (MCL) receiving commercially available CD19 CAR-T products. Patients received anakinra 100 mg subcutaneously (SC) every 12 hours on Days 2 through 10 or after two consecutive fevers ≥38.5◦C. The dose of anakinra was permitted to be increased up to 100 mg SC every 6 hours and the duration of treatment extended beyond 10 days if CRS/neurotoxicity progressed after initiation. Patients were eligible to receive tocilizumab and/or steroids for persistent or worsening CRS and neurotoxicity.
  • Results: 31 patients were enrolled in the study (LBCL=27, MCL=4). The median age was 62 years; 58% of patients were male. Most patients had received ≥ 3 lines of prior therapy (52%). Cellular products administered included Axi-Cel (n=23, 74%), Tisa-Cel (n=4, 13%), and brexucabtagene (n=4, 13%). Twenty-five patients (81%) started anakinra on Day 2 and 6 (19%) patients started anakinra before Day 2. The median duration of anakinra was 11 (range, 6-27) with 2 patients requiring >11 days of treatment. CRS occurred in 74% of patients with 6% grade 3/4. Median duration was 5.5 days. Neurotoxicity was reported in 19% of patients with 10% grade 3/4. Tocilizumab and corticosteroids were used in 9 patients (29%) and 6 patients (19%), respectively. ORR at 1-month was 78%, with 68% CR and 10% PR. At 3-months, CR was 58% and PR was 3%.
  • Conclusion: Early prophylactic use of anakinra appeared to be safe and effective, with low rates of severe CRS and all grade neurotoxicity. Prophylactic anakinra was associated with reduced use of tocilizumab and corticosteroids and disease response was comparable to previously reported studies.

Safety and Efficacy of Two Anakinra Dose Regimens for Refractory CRS or ICANS after CAR T-Cell Therapy

Gazeau N, et al. ASH 2021; Session 704; Abstract 2816.

  • Background: CAR T-cell therapies remain associated with significant toxicities, such as CRS and neurotoxicity. Anakinra, an IL-1 receptor antagonist, has emerged as a promising agent to treat refractory CRS and neurotoxicity after tocilizumab and steroid failure. Optimal anakinra dosing strategies have yet to be determined.
  • Study Design: This was a retrospective analysis of 26 patients, with B-cell or plasma-cell malignancies at 9 institutions, treated with anakinra for CRS or neurotoxicity after CAR T-cell therapy. Anakinra was administered at low-dose 100 mg/day to 200 mg/day or at high-dose 8 mg/kg/day SC or IV.
  • Results: 13 patients received low-dose anakinra and 13 patients received high-dose anakinra. The majority of patients were treated with anakinra for steroid-refractory neurotoxicity (n=23). Two patients were treated for tocilizumab-refractory CRS and one patient was treated for both. All but one patient received corticosteroids concurrently with anakinra. The median age for the high-dose and low-dose groups was 69 years and 52 years, respectively. The majority of patients in both groups received CAR T-cell products for LBCL (92%). Median peak CRS and neurotoxicity grade was 2 (range, 1-4) and 4 (range, 0-5), respectively. Median CRS and neurotoxicity duration was 5 days (range, 1-18) and 12 days (range, 1-38), respectively. Median time from CAR T-cell infusion to anakinra initiation for the high-dose and low-dose groups was 8 days (range, 5-22) and 9 days (range, 6-41), respectively. Median time to response after anakinra for the high-dose and low-dose groups was 3 days (range, 1-4) and 3 days (range, 1-6), respectively. Improvement in CRS/ neurotoxicity was observed in 73% of patients who received anakinra, with higher response rates in the high-dose group compared to low-dose group (100% versus 46%, respectively; p=0.005). Non-relapse mortality rate at day 30 was lower in the highdose group compared to low-dose group (0% versus 38%; p=0.001%). Reported adverse events possibly related to anakinra included elevated liver enzymes, HHV6 encephalitis, and subcutaneous hematoma. Disease response to CAR T-cell therapy at Day 30 was 57%.
  • Conclusion: Early administration of high-dose anakinra led to rapid improvement of refractory CRS/ neurotoxicity. Low-dose anakinra was associated with a high non-relapse, infection-related mortality. High-dose anakinra administration appears to have limited impact on CAR T-cell efficacy.

Shawn Griffin, PharmD, BCOP

University of California, Irvine; Irvine, California

Jamie Elsner Ziggas, PharmD, BCOP

The Johns Hopkins Hospital; Baltimore, Maryland

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