Myelodysplastic Syndrome

Key clinical point: A myeloablative, fractionated busulfan (f-Bu) regimen reduces relapse and boosts survival without increasing nonrelapse mortality (NRM) in older patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Major finding: At 2 years, the f-Bu group had a significantly better progression-free survival than the nonfractionated, lower dose busalfan (Bu) group (45% vs 24%; hazard ratio [HR], 0.6; P = .004), attributed to a significant reduction in progression (34% vs 59%; HR, 0.5; P = .003) without an increase in NRM (21% vs 15%; HR, 1.4; P = .3). Overall survival also improved in the f-Bu group vs the Bu group (51% vs 31%, HR, 0.6; P = .01).

Study details: In an open-label, phase 2 trial, patients with AML or MDS were randomly assigned to either myeloablative f-Bu over 2 weeks (n = 84; median age, 65 years) or a standard Bu regimen over 4 days (n = 78; median age, 66 years).

Disclosures: This study was supported in part by a grant from the National Cancer Institute. Q Bashir, C Hosing, K Rezvani and UR Popat reported relationships with various pharmaceutical companies and/or research organizations. The remaining authors declared no conflicts of interest.

Source: Oran B et al. Cancer. 2021 Jan 20. doi: 10.1002/cncr.33383

Key clinical point: A myeloablative, fractionated busulfan (f-Bu) regimen reduces relapse and boosts survival without increasing nonrelapse mortality (NRM) in older patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Major finding: At 2 years, the f-Bu group had a significantly better progression-free survival than the nonfractionated, lower dose busalfan (Bu) group (45% vs 24%; hazard ratio [HR], 0.6; P = .004), attributed to a significant reduction in progression (34% vs 59%; HR, 0.5; P = .003) without an increase in NRM (21% vs 15%; HR, 1.4; P = .3). Overall survival also improved in the f-Bu group vs the Bu group (51% vs 31%, HR, 0.6; P = .01).

Study details: In an open-label, phase 2 trial, patients with AML or MDS were randomly assigned to either myeloablative f-Bu over 2 weeks (n = 84; median age, 65 years) or a standard Bu regimen over 4 days (n = 78; median age, 66 years).

Disclosures: This study was supported in part by a grant from the National Cancer Institute. Q Bashir, C Hosing, K Rezvani and UR Popat reported relationships with various pharmaceutical companies and/or research organizations. The remaining authors declared no conflicts of interest.

Source: Oran B et al. Cancer. 2021 Jan 20. doi: 10.1002/cncr.33383

Key clinical point: A myeloablative, fractionated busulfan (f-Bu) regimen reduces relapse and boosts survival without increasing nonrelapse mortality (NRM) in older patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Major finding: At 2 years, the f-Bu group had a significantly better progression-free survival than the nonfractionated, lower dose busalfan (Bu) group (45% vs 24%; hazard ratio [HR], 0.6; P = .004), attributed to a significant reduction in progression (34% vs 59%; HR, 0.5; P = .003) without an increase in NRM (21% vs 15%; HR, 1.4; P = .3). Overall survival also improved in the f-Bu group vs the Bu group (51% vs 31%, HR, 0.6; P = .01).

Study details: In an open-label, phase 2 trial, patients with AML or MDS were randomly assigned to either myeloablative f-Bu over 2 weeks (n = 84; median age, 65 years) or a standard Bu regimen over 4 days (n = 78; median age, 66 years).

Disclosures: This study was supported in part by a grant from the National Cancer Institute. Q Bashir, C Hosing, K Rezvani and UR Popat reported relationships with various pharmaceutical companies and/or research organizations. The remaining authors declared no conflicts of interest.

Source: Oran B et al. Cancer. 2021 Jan 20. doi: 10.1002/cncr.33383

Key clinical point: Baseline and serial molecular profiling by next-generation sequencing (NGS) can predict outcomes with hypomethylating agents (HMAs) in myelodysplastic syndromes (MDS). Serial molecular profiling during therapy of patients with mutant TP53 can identify patients who may benefit from allogeneic transplantation.

Major finding: Mutations in TET2 and ASXL1 genes emerged as the most informative variables associated with response to HMA therapy (overall response rate, 62.1%; complete remission rate, 34.5%). The number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02) and mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were independent covariates associated with inferior overall survival (OS). Serial molecular profiling demonstrated that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic transplantation.

Study details: This study evaluated response and OS in 247 patients molecularly profiled by NGS before first-line HMA therapy; a subset of 108 patients were sequenced serially during treatment.

Disclosures: This study was supported in part by the S Foundation Young Investigator Grant, the Early Career Award of the Dresner Foundation, and the Edward P. Evans Foundation Award. DA Sallman, E Padron, and AF List received research funding from Celgene. The remaining authors declared no conflicts of interest.

Source: Hunter AM et al. Blood Adv. 2021 Feb 23. doi: 10.1182/bloodadvances.2020003508.

Key clinical point: Baseline and serial molecular profiling by next-generation sequencing (NGS) can predict outcomes with hypomethylating agents (HMAs) in myelodysplastic syndromes (MDS). Serial molecular profiling during therapy of patients with mutant TP53 can identify patients who may benefit from allogeneic transplantation.

Major finding: Mutations in TET2 and ASXL1 genes emerged as the most informative variables associated with response to HMA therapy (overall response rate, 62.1%; complete remission rate, 34.5%). The number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02) and mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were independent covariates associated with inferior overall survival (OS). Serial molecular profiling demonstrated that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic transplantation.

Study details: This study evaluated response and OS in 247 patients molecularly profiled by NGS before first-line HMA therapy; a subset of 108 patients were sequenced serially during treatment.

Disclosures: This study was supported in part by the S Foundation Young Investigator Grant, the Early Career Award of the Dresner Foundation, and the Edward P. Evans Foundation Award. DA Sallman, E Padron, and AF List received research funding from Celgene. The remaining authors declared no conflicts of interest.

Source: Hunter AM et al. Blood Adv. 2021 Feb 23. doi: 10.1182/bloodadvances.2020003508.

Key clinical point: Baseline and serial molecular profiling by next-generation sequencing (NGS) can predict outcomes with hypomethylating agents (HMAs) in myelodysplastic syndromes (MDS). Serial molecular profiling during therapy of patients with mutant TP53 can identify patients who may benefit from allogeneic transplantation.

Major finding: Mutations in TET2 and ASXL1 genes emerged as the most informative variables associated with response to HMA therapy (overall response rate, 62.1%; complete remission rate, 34.5%). The number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02) and mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were independent covariates associated with inferior overall survival (OS). Serial molecular profiling demonstrated that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic transplantation.

Study details: This study evaluated response and OS in 247 patients molecularly profiled by NGS before first-line HMA therapy; a subset of 108 patients were sequenced serially during treatment.

Disclosures: This study was supported in part by the S Foundation Young Investigator Grant, the Early Career Award of the Dresner Foundation, and the Edward P. Evans Foundation Award. DA Sallman, E Padron, and AF List received research funding from Celgene. The remaining authors declared no conflicts of interest.

Source: Hunter AM et al. Blood Adv. 2021 Feb 23. doi: 10.1182/bloodadvances.2020003508.

Key clinical point: Dysregulated erythroferrone (ERFE) expression in CD71⁺ erythroid progenitors is associated with myelodysplastic syndromes (MDS) outcome and predicts patient survival independently of International Prognostic Scoring System (IPSS) stratification.

Major finding: The expression of ERFE was significantly higher in CD71⁺ cells of MDS patients vs. healthy donors group (median normalized mean fold change, 2.42 vs. 0.78). Elevated expression of ERFE in erythroid progenitors was associated with superior survival (hazard ratio, 0.35; P = .0017) independently of IPSS stratification. For growth/differentiation factor 15, the result was similar, but not statistically significant (P = .0543).

Study details: The data come from a study of 111 patients with MDS (median age, 73 years; 66.7% males).

Disclosures: This study was supported by funds of the Deutsche Forschungsgemeinschaft. The authors declared no conflicts of interest.

Source: Riabov V et al. Br J Haematol. 2021 Jan 24. doi: 10.1111/bjh.17314.

Key clinical point: Dysregulated erythroferrone (ERFE) expression in CD71⁺ erythroid progenitors is associated with myelodysplastic syndromes (MDS) outcome and predicts patient survival independently of International Prognostic Scoring System (IPSS) stratification.

Major finding: The expression of ERFE was significantly higher in CD71⁺ cells of MDS patients vs. healthy donors group (median normalized mean fold change, 2.42 vs. 0.78). Elevated expression of ERFE in erythroid progenitors was associated with superior survival (hazard ratio, 0.35; P = .0017) independently of IPSS stratification. For growth/differentiation factor 15, the result was similar, but not statistically significant (P = .0543).

Study details: The data come from a study of 111 patients with MDS (median age, 73 years; 66.7% males).

Disclosures: This study was supported by funds of the Deutsche Forschungsgemeinschaft. The authors declared no conflicts of interest.

Source: Riabov V et al. Br J Haematol. 2021 Jan 24. doi: 10.1111/bjh.17314.

Key clinical point: Dysregulated erythroferrone (ERFE) expression in CD71⁺ erythroid progenitors is associated with myelodysplastic syndromes (MDS) outcome and predicts patient survival independently of International Prognostic Scoring System (IPSS) stratification.

Major finding: The expression of ERFE was significantly higher in CD71⁺ cells of MDS patients vs. healthy donors group (median normalized mean fold change, 2.42 vs. 0.78). Elevated expression of ERFE in erythroid progenitors was associated with superior survival (hazard ratio, 0.35; P = .0017) independently of IPSS stratification. For growth/differentiation factor 15, the result was similar, but not statistically significant (P = .0543).

Study details: The data come from a study of 111 patients with MDS (median age, 73 years; 66.7% males).

Disclosures: This study was supported by funds of the Deutsche Forschungsgemeinschaft. The authors declared no conflicts of interest.

Source: Riabov V et al. Br J Haematol. 2021 Jan 24. doi: 10.1111/bjh.17314.

Key clinical point: A novel risk scoring system termed 'mutation combined with revised international prognostic scoring system (MIPSS-R)' was more effective in predicting prognosis and guiding treatment in patients with myelodysplastic syndromes (MDS) than the revised international prognostic scoring system (IPSS-R).

Major finding: Kaplan-Meier survival curves demonstrated superiority of MIPSS-R over IPSS-R in separating patients from different groups in the training cohort (P = 1.71e-08 vs P = 1.363e-04) and in the validation cohort (P = 1.788e-04 vs P = 2.757e-03). Area under the receiver operating characteristic of MIPSS-R was 0.79 in the training cohort and 0.62 in the validation cohort.

Study details: MIPSS-R was developed by integrating IPSS-R and the mutation scores. MIPSS-R was further compared with IPSS-R in a training cohort of 63 MDS patients and a validation cohort of 141 MDS patients. 

Disclosures: The study was supported in part by The National Natural Science Foundation of China, Jiangsu Provincial Special Program of Medical Science, Jiangsu Province “333” project, The Fundamental Research Funds for the Central Universities, Milstein Medical Asian American Partnership Foundation Research Project Award in Hematology, and Key Medical of Jiangsu Province. The authors declared no conflicts of interest.

Source: Gu S et al. BMC Cancer. 2021 Feb 6. doi: 10.1186/s12885-021-07864-y.

Key clinical point: A novel risk scoring system termed 'mutation combined with revised international prognostic scoring system (MIPSS-R)' was more effective in predicting prognosis and guiding treatment in patients with myelodysplastic syndromes (MDS) than the revised international prognostic scoring system (IPSS-R).

Major finding: Kaplan-Meier survival curves demonstrated superiority of MIPSS-R over IPSS-R in separating patients from different groups in the training cohort (P = 1.71e-08 vs P = 1.363e-04) and in the validation cohort (P = 1.788e-04 vs P = 2.757e-03). Area under the receiver operating characteristic of MIPSS-R was 0.79 in the training cohort and 0.62 in the validation cohort.

Study details: MIPSS-R was developed by integrating IPSS-R and the mutation scores. MIPSS-R was further compared with IPSS-R in a training cohort of 63 MDS patients and a validation cohort of 141 MDS patients. 

Disclosures: The study was supported in part by The National Natural Science Foundation of China, Jiangsu Provincial Special Program of Medical Science, Jiangsu Province “333” project, The Fundamental Research Funds for the Central Universities, Milstein Medical Asian American Partnership Foundation Research Project Award in Hematology, and Key Medical of Jiangsu Province. The authors declared no conflicts of interest.

Source: Gu S et al. BMC Cancer. 2021 Feb 6. doi: 10.1186/s12885-021-07864-y.

Key clinical point: A novel risk scoring system termed 'mutation combined with revised international prognostic scoring system (MIPSS-R)' was more effective in predicting prognosis and guiding treatment in patients with myelodysplastic syndromes (MDS) than the revised international prognostic scoring system (IPSS-R).

Major finding: Kaplan-Meier survival curves demonstrated superiority of MIPSS-R over IPSS-R in separating patients from different groups in the training cohort (P = 1.71e-08 vs P = 1.363e-04) and in the validation cohort (P = 1.788e-04 vs P = 2.757e-03). Area under the receiver operating characteristic of MIPSS-R was 0.79 in the training cohort and 0.62 in the validation cohort.

Study details: MIPSS-R was developed by integrating IPSS-R and the mutation scores. MIPSS-R was further compared with IPSS-R in a training cohort of 63 MDS patients and a validation cohort of 141 MDS patients. 

Disclosures: The study was supported in part by The National Natural Science Foundation of China, Jiangsu Provincial Special Program of Medical Science, Jiangsu Province “333” project, The Fundamental Research Funds for the Central Universities, Milstein Medical Asian American Partnership Foundation Research Project Award in Hematology, and Key Medical of Jiangsu Province. The authors declared no conflicts of interest.

Source: Gu S et al. BMC Cancer. 2021 Feb 6. doi: 10.1186/s12885-021-07864-y.

Key clinical point: In patients with myelodysplastic syndrome (MDS) with less than 5% marrow myeloblasts and no leukemic myeloblasts in blood before allogeneic hematopoietic cell transplant (alloHCT), ultra-deep DNA sequencing for mutations in 10 gene regions previously shown to be high risk in acute myeloid leukemia could help identify which patients are likely to relapse after alloHCT.

Major finding: Twenty (42%) patients had mutations detectable before conditioning treatment. The presence of mutations within a previously identified set of 10 gene regions before alloHCT was associated with increased rates of relapse (3-year relapse, 75% vs. 17%; P = .003) and decreased relapse-free survival (RFS; 3-year RFS, 13% vs. 49%; P = .003) in patients with MDS who received reduced intensity conditioning (RIC) vs. myeloablative conditioning (MAC).

Study details: The researchers performed targeted error-corrected DNA sequencing on preconditioning blood samples from patients with MDS (n=48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase 3 trial before random assignment to MAC (n=25) or RIC (n=23) for alloHCT.

Disclosures: This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health and by grants to the Blood and Marrow Transplant Clinical Trials Network from the NHLBI and the National Cancer Institute. The authors declared no conflicts of interest.

Source: Dillon LW et al. JCO Precis Oncol. 2021 Jan 25. doi: 10.1200/PO.20.00355.

Key clinical point: In patients with myelodysplastic syndrome (MDS) with less than 5% marrow myeloblasts and no leukemic myeloblasts in blood before allogeneic hematopoietic cell transplant (alloHCT), ultra-deep DNA sequencing for mutations in 10 gene regions previously shown to be high risk in acute myeloid leukemia could help identify which patients are likely to relapse after alloHCT.

Major finding: Twenty (42%) patients had mutations detectable before conditioning treatment. The presence of mutations within a previously identified set of 10 gene regions before alloHCT was associated with increased rates of relapse (3-year relapse, 75% vs. 17%; P = .003) and decreased relapse-free survival (RFS; 3-year RFS, 13% vs. 49%; P = .003) in patients with MDS who received reduced intensity conditioning (RIC) vs. myeloablative conditioning (MAC).

Study details: The researchers performed targeted error-corrected DNA sequencing on preconditioning blood samples from patients with MDS (n=48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase 3 trial before random assignment to MAC (n=25) or RIC (n=23) for alloHCT.

Disclosures: This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health and by grants to the Blood and Marrow Transplant Clinical Trials Network from the NHLBI and the National Cancer Institute. The authors declared no conflicts of interest.

Source: Dillon LW et al. JCO Precis Oncol. 2021 Jan 25. doi: 10.1200/PO.20.00355.

Key clinical point: In patients with myelodysplastic syndrome (MDS) with less than 5% marrow myeloblasts and no leukemic myeloblasts in blood before allogeneic hematopoietic cell transplant (alloHCT), ultra-deep DNA sequencing for mutations in 10 gene regions previously shown to be high risk in acute myeloid leukemia could help identify which patients are likely to relapse after alloHCT.

Major finding: Twenty (42%) patients had mutations detectable before conditioning treatment. The presence of mutations within a previously identified set of 10 gene regions before alloHCT was associated with increased rates of relapse (3-year relapse, 75% vs. 17%; P = .003) and decreased relapse-free survival (RFS; 3-year RFS, 13% vs. 49%; P = .003) in patients with MDS who received reduced intensity conditioning (RIC) vs. myeloablative conditioning (MAC).

Study details: The researchers performed targeted error-corrected DNA sequencing on preconditioning blood samples from patients with MDS (n=48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase 3 trial before random assignment to MAC (n=25) or RIC (n=23) for alloHCT.

Disclosures: This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health and by grants to the Blood and Marrow Transplant Clinical Trials Network from the NHLBI and the National Cancer Institute. The authors declared no conflicts of interest.

Source: Dillon LW et al. JCO Precis Oncol. 2021 Jan 25. doi: 10.1200/PO.20.00355.

Key clinical point: Eprenetapopt in combination with azacitidine yielded high rates of clinical response and complete remission (CR) and was well tolerated in patients with TP53-mutant myelodysplastic syndromes (MDS).

Major finding: Overall response rate in patients with MDS was 73% (95% confidence, [CI], 56%-85%) with 50% (95% CI, 34%-66%) of patients achieving CR. The median time to first response and CR was 1.9 and 3.1 months, respectively. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapies.

Study details: Findings come from a phase 1b/2 open-label, dose-escalation/expansion study that assessed safety, recommended dose, and efficacy of eprenetapopt and azacitidine combination in 55 patients with TP53-mutant MDS (n=40) or acute myeloid leukemia with 20%-30% marrow blasts.

Disclosures: The study was supported by the MDS Foundation Young Investigator Grant, the Early Career Award of the Dresner Foundation (DAS), and the Edward P. Evans MDS Clinical Research Consortium. The study was supported in part by the Flow Cytometry and Molecular Genomics Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute. Some of the authors reported relationships with various pharmaceutical companies while some others declared no conflicts of interest.

Source: Sallman DA et al. J Clin Oncol. 2021 Jan 15. doi: 10.1200/JCO.20.02341.

Key clinical point: Eprenetapopt in combination with azacitidine yielded high rates of clinical response and complete remission (CR) and was well tolerated in patients with TP53-mutant myelodysplastic syndromes (MDS).

Major finding: Overall response rate in patients with MDS was 73% (95% confidence, [CI], 56%-85%) with 50% (95% CI, 34%-66%) of patients achieving CR. The median time to first response and CR was 1.9 and 3.1 months, respectively. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapies.

Study details: Findings come from a phase 1b/2 open-label, dose-escalation/expansion study that assessed safety, recommended dose, and efficacy of eprenetapopt and azacitidine combination in 55 patients with TP53-mutant MDS (n=40) or acute myeloid leukemia with 20%-30% marrow blasts.

Disclosures: The study was supported by the MDS Foundation Young Investigator Grant, the Early Career Award of the Dresner Foundation (DAS), and the Edward P. Evans MDS Clinical Research Consortium. The study was supported in part by the Flow Cytometry and Molecular Genomics Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute. Some of the authors reported relationships with various pharmaceutical companies while some others declared no conflicts of interest.

Source: Sallman DA et al. J Clin Oncol. 2021 Jan 15. doi: 10.1200/JCO.20.02341.

Key clinical point: Eprenetapopt in combination with azacitidine yielded high rates of clinical response and complete remission (CR) and was well tolerated in patients with TP53-mutant myelodysplastic syndromes (MDS).

Major finding: Overall response rate in patients with MDS was 73% (95% confidence, [CI], 56%-85%) with 50% (95% CI, 34%-66%) of patients achieving CR. The median time to first response and CR was 1.9 and 3.1 months, respectively. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapies.

Study details: Findings come from a phase 1b/2 open-label, dose-escalation/expansion study that assessed safety, recommended dose, and efficacy of eprenetapopt and azacitidine combination in 55 patients with TP53-mutant MDS (n=40) or acute myeloid leukemia with 20%-30% marrow blasts.

Disclosures: The study was supported by the MDS Foundation Young Investigator Grant, the Early Career Award of the Dresner Foundation (DAS), and the Edward P. Evans MDS Clinical Research Consortium. The study was supported in part by the Flow Cytometry and Molecular Genomics Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute. Some of the authors reported relationships with various pharmaceutical companies while some others declared no conflicts of interest.

Source: Sallman DA et al. J Clin Oncol. 2021 Jan 15. doi: 10.1200/JCO.20.02341.

A novel T-cell engineered product, Orca-T (Orca Bio), was associated with lower incidence of both acute and chronic graft-versus-host disease (GVHD) and more than double the rate of GVHD-free and relapse-free survival, compared with the current standard of care for patients undergoing hematopoietic stem cell transplants (HSCT), investigators said.

In both a multicenter phase 1 trial (NCT04013685) and single-center phase 1/2 trial (NCT01660607) with a total of 50 patients, those who received Orca-T with single-agent GVHD prophylaxis had a 1-year GVHD-free and relapse-free survival rate of 75%, compared with 31% for patients who received standard of care with two-agent prophylaxis, reported Everett H. Meyer, MD, PhD, from the Stanford (Calif.) University.

“Orca-T has good evidence for reduced acute graft-versus-host disease, reduced chromic graft-versus-host disease, and a low nonrelapse mortality,” he said at the Transplant & Cellular Therapies Meetings.

The product can be quickly manufactured and delivered to treatment centers across the continental United States, with “vein-to-vein” time of less than 72 hours, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Orca-T consists of highly purified, donor-derived T-regulatory (Treg) cells that are sorted and delivered on day 0 with hematopoietic stem cells, without immunosuppressants, followed 2 days later with infusion of a matching dose of conventional T cells.

“The Treg cells are allowed to expand to create the right microenvironment for the [conventional T cells],” he explained.

In preclinical studies, donor-derived, high-purity Tregs delivered prior to adoptive transfer of conventional T cells prevented GVHD while maintaining graft-versus-tumor immunity, he said.
 

Two T-cell infusions

He reported updated results from current studies on a total of 50 adults, with a cohort of 144 patients treated concurrently with standard of care as controls.

The Orca-T–treated patients had a median age of 47 and 52% were male. Indications for transplant included acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia, B-cell lymphoma, myelodysplastic syndrome/myelofibrosis, and other unspecified indications.

In both the Orca-T and control cohorts, patients underwent myeloablative conditioning from 10 to 2 days prior to stem cell infusion.

As noted patients in the experimental arm received infusion of hematopoietic stem/progenitor cells and Tregs, followed 2 days later by conventional T-cell infusion, and, on the day after that, tacrolimus at a target dose of 4.6 ng/mL. The conventional T cells were reserved from donor apheresis and were otherwise unmanipulated prior to infusion into the recipient, Dr. Meyer noted.

Patients in the standard-of-care arm received tacrolimus on the day before standard infusion of the apheresis product, followed by methotrexate prophylaxis on days 1, 3, 6 and 11.

Time to neutrophil engraftment, platelet engraftment, and from day 0 to hospital discharge were all significantly shorter in the Orca-T group, at 12 versus 14 days (P < .0001), 11 vs. 17 days (P < .0001), and 15 vs. 17 days (P = .01) respectively.

At 100 days of follow-up, the rate of grade 2 or greater acute GVHD was 30% among standard-of-care patients versus 10% among Orca-T–treated patients. At 1-year follow-up, respective rates of chronic GVHD were 46% vs. 3%.
 

Safety

“In general, the protocol is extremely well tolerated by our patients. We’ve seen no exceptional infectious disease complications, and we’ve seen no other major complications,” Dr. Meyer said.

Cytomegalovirus prophylaxis was used variably, depending on the center and on the attending physician. Epstein-Barr virus reactivation occurred in eight patients, with one requiring therapy, but there was no biopsy or radiographic evidence of posttransplant lymphoproliferative disorder.

In all, 18% of patients had serious adverse events during the reporting period, all of which resolved. There were no treatment-related deaths in the Orca-T arm, compared with 11% of controls.
 

Engraftment differences explored

In the question-and-answer session following the presentation, Christopher J. Gamper, MD, PhD, from the Johns Hopkins Hospital in Baltimore, told Dr. Meyer that “your outcomes from Orca-T look excellent,” and asked about the cost differential, compared with similar, unmanipulated transplants performed with standard GVHD prophylaxis.

“Is this recovered by lower costs for treatment of GVHD?” he asked.

“I have not done an economic cost analysis of course, and I think others may be looking into this,” Dr. Meyer replied. “Graft engineering can be expensive, although it’s an engineering proposition and one could imagine that the costs will go down substantially over time.”

Session moderator Alan Hanash, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, commented on the differences in engraftment between the experimental controls arms, and asked Dr. Meyer: “Do you think this is due to the difference in prophylaxis? Absence of methotrexate? Do you think that it could be a direct impact of regulatory T cells on hematopoietic engraftment?”

“Certainly not having methotrexate is beneficial for engraftment, and may account for the differences we see, Dr. Meyer said. “However, it is possible that Tregs could be playing a facilitative role. There certainly is good preclinical literature that Tregs, particularly in the bone marrow space, can facilitate bone marrow engraftment.”

The Orca-T trials are sponsored by Orca Bio and Stanford, with support from the National Institutes of Health. Dr. Meyer receives research support from Orca and is a scientific adviser to GigaGen, Triursus, Incyte, and Indee Labs. Dr. Hanash and Dr. Gamper had no relevant disclosures.

A novel T-cell engineered product, Orca-T (Orca Bio), was associated with lower incidence of both acute and chronic graft-versus-host disease (GVHD) and more than double the rate of GVHD-free and relapse-free survival, compared with the current standard of care for patients undergoing hematopoietic stem cell transplants (HSCT), investigators said.

In both a multicenter phase 1 trial (NCT04013685) and single-center phase 1/2 trial (NCT01660607) with a total of 50 patients, those who received Orca-T with single-agent GVHD prophylaxis had a 1-year GVHD-free and relapse-free survival rate of 75%, compared with 31% for patients who received standard of care with two-agent prophylaxis, reported Everett H. Meyer, MD, PhD, from the Stanford (Calif.) University.

“Orca-T has good evidence for reduced acute graft-versus-host disease, reduced chromic graft-versus-host disease, and a low nonrelapse mortality,” he said at the Transplant & Cellular Therapies Meetings.

The product can be quickly manufactured and delivered to treatment centers across the continental United States, with “vein-to-vein” time of less than 72 hours, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Orca-T consists of highly purified, donor-derived T-regulatory (Treg) cells that are sorted and delivered on day 0 with hematopoietic stem cells, without immunosuppressants, followed 2 days later with infusion of a matching dose of conventional T cells.

“The Treg cells are allowed to expand to create the right microenvironment for the [conventional T cells],” he explained.

In preclinical studies, donor-derived, high-purity Tregs delivered prior to adoptive transfer of conventional T cells prevented GVHD while maintaining graft-versus-tumor immunity, he said.
 

Two T-cell infusions

He reported updated results from current studies on a total of 50 adults, with a cohort of 144 patients treated concurrently with standard of care as controls.

The Orca-T–treated patients had a median age of 47 and 52% were male. Indications for transplant included acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia, B-cell lymphoma, myelodysplastic syndrome/myelofibrosis, and other unspecified indications.

In both the Orca-T and control cohorts, patients underwent myeloablative conditioning from 10 to 2 days prior to stem cell infusion.

As noted patients in the experimental arm received infusion of hematopoietic stem/progenitor cells and Tregs, followed 2 days later by conventional T-cell infusion, and, on the day after that, tacrolimus at a target dose of 4.6 ng/mL. The conventional T cells were reserved from donor apheresis and were otherwise unmanipulated prior to infusion into the recipient, Dr. Meyer noted.

Patients in the standard-of-care arm received tacrolimus on the day before standard infusion of the apheresis product, followed by methotrexate prophylaxis on days 1, 3, 6 and 11.

Time to neutrophil engraftment, platelet engraftment, and from day 0 to hospital discharge were all significantly shorter in the Orca-T group, at 12 versus 14 days (P < .0001), 11 vs. 17 days (P < .0001), and 15 vs. 17 days (P = .01) respectively.

At 100 days of follow-up, the rate of grade 2 or greater acute GVHD was 30% among standard-of-care patients versus 10% among Orca-T–treated patients. At 1-year follow-up, respective rates of chronic GVHD were 46% vs. 3%.
 

Safety

“In general, the protocol is extremely well tolerated by our patients. We’ve seen no exceptional infectious disease complications, and we’ve seen no other major complications,” Dr. Meyer said.

Cytomegalovirus prophylaxis was used variably, depending on the center and on the attending physician. Epstein-Barr virus reactivation occurred in eight patients, with one requiring therapy, but there was no biopsy or radiographic evidence of posttransplant lymphoproliferative disorder.

In all, 18% of patients had serious adverse events during the reporting period, all of which resolved. There were no treatment-related deaths in the Orca-T arm, compared with 11% of controls.
 

Engraftment differences explored

In the question-and-answer session following the presentation, Christopher J. Gamper, MD, PhD, from the Johns Hopkins Hospital in Baltimore, told Dr. Meyer that “your outcomes from Orca-T look excellent,” and asked about the cost differential, compared with similar, unmanipulated transplants performed with standard GVHD prophylaxis.

“Is this recovered by lower costs for treatment of GVHD?” he asked.

“I have not done an economic cost analysis of course, and I think others may be looking into this,” Dr. Meyer replied. “Graft engineering can be expensive, although it’s an engineering proposition and one could imagine that the costs will go down substantially over time.”

Session moderator Alan Hanash, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, commented on the differences in engraftment between the experimental controls arms, and asked Dr. Meyer: “Do you think this is due to the difference in prophylaxis? Absence of methotrexate? Do you think that it could be a direct impact of regulatory T cells on hematopoietic engraftment?”

“Certainly not having methotrexate is beneficial for engraftment, and may account for the differences we see, Dr. Meyer said. “However, it is possible that Tregs could be playing a facilitative role. There certainly is good preclinical literature that Tregs, particularly in the bone marrow space, can facilitate bone marrow engraftment.”

The Orca-T trials are sponsored by Orca Bio and Stanford, with support from the National Institutes of Health. Dr. Meyer receives research support from Orca and is a scientific adviser to GigaGen, Triursus, Incyte, and Indee Labs. Dr. Hanash and Dr. Gamper had no relevant disclosures.

A novel T-cell engineered product, Orca-T (Orca Bio), was associated with lower incidence of both acute and chronic graft-versus-host disease (GVHD) and more than double the rate of GVHD-free and relapse-free survival, compared with the current standard of care for patients undergoing hematopoietic stem cell transplants (HSCT), investigators said.

In both a multicenter phase 1 trial (NCT04013685) and single-center phase 1/2 trial (NCT01660607) with a total of 50 patients, those who received Orca-T with single-agent GVHD prophylaxis had a 1-year GVHD-free and relapse-free survival rate of 75%, compared with 31% for patients who received standard of care with two-agent prophylaxis, reported Everett H. Meyer, MD, PhD, from the Stanford (Calif.) University.

“Orca-T has good evidence for reduced acute graft-versus-host disease, reduced chromic graft-versus-host disease, and a low nonrelapse mortality,” he said at the Transplant & Cellular Therapies Meetings.

The product can be quickly manufactured and delivered to treatment centers across the continental United States, with “vein-to-vein” time of less than 72 hours, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Orca-T consists of highly purified, donor-derived T-regulatory (Treg) cells that are sorted and delivered on day 0 with hematopoietic stem cells, without immunosuppressants, followed 2 days later with infusion of a matching dose of conventional T cells.

“The Treg cells are allowed to expand to create the right microenvironment for the [conventional T cells],” he explained.

In preclinical studies, donor-derived, high-purity Tregs delivered prior to adoptive transfer of conventional T cells prevented GVHD while maintaining graft-versus-tumor immunity, he said.
 

Two T-cell infusions

He reported updated results from current studies on a total of 50 adults, with a cohort of 144 patients treated concurrently with standard of care as controls.

The Orca-T–treated patients had a median age of 47 and 52% were male. Indications for transplant included acute myeloid and acute lymphoblastic leukemia, chronic myeloid leukemia, B-cell lymphoma, myelodysplastic syndrome/myelofibrosis, and other unspecified indications.

In both the Orca-T and control cohorts, patients underwent myeloablative conditioning from 10 to 2 days prior to stem cell infusion.

As noted patients in the experimental arm received infusion of hematopoietic stem/progenitor cells and Tregs, followed 2 days later by conventional T-cell infusion, and, on the day after that, tacrolimus at a target dose of 4.6 ng/mL. The conventional T cells were reserved from donor apheresis and were otherwise unmanipulated prior to infusion into the recipient, Dr. Meyer noted.

Patients in the standard-of-care arm received tacrolimus on the day before standard infusion of the apheresis product, followed by methotrexate prophylaxis on days 1, 3, 6 and 11.

Time to neutrophil engraftment, platelet engraftment, and from day 0 to hospital discharge were all significantly shorter in the Orca-T group, at 12 versus 14 days (P < .0001), 11 vs. 17 days (P < .0001), and 15 vs. 17 days (P = .01) respectively.

At 100 days of follow-up, the rate of grade 2 or greater acute GVHD was 30% among standard-of-care patients versus 10% among Orca-T–treated patients. At 1-year follow-up, respective rates of chronic GVHD were 46% vs. 3%.
 

Safety

“In general, the protocol is extremely well tolerated by our patients. We’ve seen no exceptional infectious disease complications, and we’ve seen no other major complications,” Dr. Meyer said.

Cytomegalovirus prophylaxis was used variably, depending on the center and on the attending physician. Epstein-Barr virus reactivation occurred in eight patients, with one requiring therapy, but there was no biopsy or radiographic evidence of posttransplant lymphoproliferative disorder.

In all, 18% of patients had serious adverse events during the reporting period, all of which resolved. There were no treatment-related deaths in the Orca-T arm, compared with 11% of controls.
 

Engraftment differences explored

In the question-and-answer session following the presentation, Christopher J. Gamper, MD, PhD, from the Johns Hopkins Hospital in Baltimore, told Dr. Meyer that “your outcomes from Orca-T look excellent,” and asked about the cost differential, compared with similar, unmanipulated transplants performed with standard GVHD prophylaxis.

“Is this recovered by lower costs for treatment of GVHD?” he asked.

“I have not done an economic cost analysis of course, and I think others may be looking into this,” Dr. Meyer replied. “Graft engineering can be expensive, although it’s an engineering proposition and one could imagine that the costs will go down substantially over time.”

Session moderator Alan Hanash, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, commented on the differences in engraftment between the experimental controls arms, and asked Dr. Meyer: “Do you think this is due to the difference in prophylaxis? Absence of methotrexate? Do you think that it could be a direct impact of regulatory T cells on hematopoietic engraftment?”

“Certainly not having methotrexate is beneficial for engraftment, and may account for the differences we see, Dr. Meyer said. “However, it is possible that Tregs could be playing a facilitative role. There certainly is good preclinical literature that Tregs, particularly in the bone marrow space, can facilitate bone marrow engraftment.”

The Orca-T trials are sponsored by Orca Bio and Stanford, with support from the National Institutes of Health. Dr. Meyer receives research support from Orca and is a scientific adviser to GigaGen, Triursus, Incyte, and Indee Labs. Dr. Hanash and Dr. Gamper had no relevant disclosures.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

Key clinical point: Information of the flow cytometry immunophenotyping (FCI) data during therapy combined with the hematological response can help physicians identify patients with myelodysplastic syndrome (MDS) with a higher probability of maintaining a good quality of response to 5-azacitidine (AZA) therapy for a longer period of time.

Major finding: After a median of 6 cycles of AZA, an FCI improvement was found in 41% of patients, and this finding correlated with a better clinical response (P less than .001). FCI improvement correlated with hematological improvement (HI), and the probability of maintaining a clinical response at 12 cycles of AZA was twice as large (67%) for those who achieved an HI and an FCI improvement after 6 cycles of AZA compared with patients who only achieved an HI (33%).

Study details: The data come from a study of 81 patients diagnosed with MDS in 5 European centers.

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Source: Subirá D et al. Ann Hematol. 2021 Jan 9. doi: 10.1007/s00277-021-04411-4.

Key clinical point: Information of the flow cytometry immunophenotyping (FCI) data during therapy combined with the hematological response can help physicians identify patients with myelodysplastic syndrome (MDS) with a higher probability of maintaining a good quality of response to 5-azacitidine (AZA) therapy for a longer period of time.

Major finding: After a median of 6 cycles of AZA, an FCI improvement was found in 41% of patients, and this finding correlated with a better clinical response (P less than .001). FCI improvement correlated with hematological improvement (HI), and the probability of maintaining a clinical response at 12 cycles of AZA was twice as large (67%) for those who achieved an HI and an FCI improvement after 6 cycles of AZA compared with patients who only achieved an HI (33%).

Study details: The data come from a study of 81 patients diagnosed with MDS in 5 European centers.

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Source: Subirá D et al. Ann Hematol. 2021 Jan 9. doi: 10.1007/s00277-021-04411-4.

Key clinical point: Information of the flow cytometry immunophenotyping (FCI) data during therapy combined with the hematological response can help physicians identify patients with myelodysplastic syndrome (MDS) with a higher probability of maintaining a good quality of response to 5-azacitidine (AZA) therapy for a longer period of time.

Major finding: After a median of 6 cycles of AZA, an FCI improvement was found in 41% of patients, and this finding correlated with a better clinical response (P less than .001). FCI improvement correlated with hematological improvement (HI), and the probability of maintaining a clinical response at 12 cycles of AZA was twice as large (67%) for those who achieved an HI and an FCI improvement after 6 cycles of AZA compared with patients who only achieved an HI (33%).

Study details: The data come from a study of 81 patients diagnosed with MDS in 5 European centers.

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Source: Subirá D et al. Ann Hematol. 2021 Jan 9. doi: 10.1007/s00277-021-04411-4.

Key clinical point: Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) and azacitidine appears tolerable when given over 5 days and has encouraging response rates in patients with myelodysplastic syndromes (MDS).

Major finding: Two complete responses and 6 marrow responses were seen for an overall response rate (ORR) of 36% in evaluable patients. The ORR for patients receiving plerixafor (any dose), G-CSF, and azacitidine was 53%. Blast mobilization during treatment correlated with response, with patients that mobilized greater than 2-fold having an ORR of 60% vs. 17% for those that did not (P = .035).

Study details: The data come from an open-label, phase 1 study of 28 MDS patients treated with plerixafor, G-CSF, and azacitidine with a standard 3 + 3 design with 3 dose escalation cohorts of plerixafor 320 mg/kg/day, 440 mg/kg/day, and 560 mg/kg/day.

Disclosures: The study was supported by the American Society of Hematology Clinical Research Training Institute. Four of the authors reported receiving honoraria from Sanofi and 1 received honoraria from Bristol Myers Squibb.

Source: Huselton E et al. Leuk Lymphoma. 2021 Jan 19. doi: 10.1080/10428194.2021.

Key clinical point: Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) and azacitidine appears tolerable when given over 5 days and has encouraging response rates in patients with myelodysplastic syndromes (MDS).

Major finding: Two complete responses and 6 marrow responses were seen for an overall response rate (ORR) of 36% in evaluable patients. The ORR for patients receiving plerixafor (any dose), G-CSF, and azacitidine was 53%. Blast mobilization during treatment correlated with response, with patients that mobilized greater than 2-fold having an ORR of 60% vs. 17% for those that did not (P = .035).

Study details: The data come from an open-label, phase 1 study of 28 MDS patients treated with plerixafor, G-CSF, and azacitidine with a standard 3 + 3 design with 3 dose escalation cohorts of plerixafor 320 mg/kg/day, 440 mg/kg/day, and 560 mg/kg/day.

Disclosures: The study was supported by the American Society of Hematology Clinical Research Training Institute. Four of the authors reported receiving honoraria from Sanofi and 1 received honoraria from Bristol Myers Squibb.

Source: Huselton E et al. Leuk Lymphoma. 2021 Jan 19. doi: 10.1080/10428194.2021.

Key clinical point: Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) and azacitidine appears tolerable when given over 5 days and has encouraging response rates in patients with myelodysplastic syndromes (MDS).

Major finding: Two complete responses and 6 marrow responses were seen for an overall response rate (ORR) of 36% in evaluable patients. The ORR for patients receiving plerixafor (any dose), G-CSF, and azacitidine was 53%. Blast mobilization during treatment correlated with response, with patients that mobilized greater than 2-fold having an ORR of 60% vs. 17% for those that did not (P = .035).

Study details: The data come from an open-label, phase 1 study of 28 MDS patients treated with plerixafor, G-CSF, and azacitidine with a standard 3 + 3 design with 3 dose escalation cohorts of plerixafor 320 mg/kg/day, 440 mg/kg/day, and 560 mg/kg/day.

Disclosures: The study was supported by the American Society of Hematology Clinical Research Training Institute. Four of the authors reported receiving honoraria from Sanofi and 1 received honoraria from Bristol Myers Squibb.

Source: Huselton E et al. Leuk Lymphoma. 2021 Jan 19. doi: 10.1080/10428194.2021.