The Combined Annual Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood & Marrow Transplant Research (CIBMTR) were held in Orlando, Florida, from February 19–23, 2020. The scientific program addressed the most timely issues in hematopoietic cell transplantation and cellular therapy. For health-care professionals who may have missed the meeting proceedings, here are selected abstracts highlighting some of the novel transplant and cellular therapies currently under investigation.
Guest Editors
Syed Ali Abutalib, MD
Parameswaran Hari, MD
Autologous Transplantation
ABSTRACT 27: MASTER trial: Impact of autologous hematopoietic cell transplant (auto-HCT) on measurable residual disease (MRD) by next-generation sequencing (clonoSEQ) in the setting of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) quadruplet induction (ClinicalTrials.gov identifier NCT03224507)1
Background: MRD had been established as one of the strongest predictors of progression-free survival in multiple myeloma.2,3 The study is trying to answer a few questions: (1) What proportion of patients administered novel four-drug induction followed by autologous hematopoietic cell transplantation (auto-HCT) will achieve MRD-negative responses, allowing patients to safely discontinue therapy?; and (2) To what extent does auto-HCT benefit MRD responses to four-drug induction therapy?
Methods: Patients received four cycles of Dara-KRd as induction; auto-HCT; and zero, four, or eight cycles of Dara-KRd consolidation, according to MRD status at each phase of therapy. MRD was evaluated at the end of induction, after transplant, and during each four-cycle block of Dara-KRd consolidation. Patients received therapy until achievement of two consecutive MRD reads < 10–5 (confirmed MRD-negative remission; eg, postinduction and posttransplant or posttransplant and during consolidation; primary endpoint). Patients with confirmed MRD-negative remission received no further therapy and were under surveillance for MRD resurgence 6 and 18 months after treatment discontinuation. Patients who did not meet the criteria for confirmed MRD-negative remission received lenalidomide maintenance therapy. Secondary endpoints included achievement of complete remission and of MRD < 10–6.
Results: At the time of abstract presentation, 82 patients had been enrolled, and 77 patients have disease trackable by next-generation sequencing. Of those patients, 54 have completed postinduction and 29, posttransplant assessment. The median age of the cohort is 61 years (range, 36–79 years), 31% have high-risk fluorescent in situ hybridization abnormality [t(4;14) or t(14;16) or del17p] and 20.3% had International Staging System stage III disease.
Patients with MRD < 10–5: 31% postinduction and 76% posttransplant
Patients with MRD < 10–6: 24% postinduction and 48% posttransplant
All patients obtained objective responses, with rates of best responses of at least a very good partial response of 93% after induction and 100% after auto-HCT and rates of stringent complete response of 46% and 79%, respectively.
Two patients died (one due to metapneumovirus pneumonia and one suddenly, unwitnessed, 58 days posttransplant).
Clinical Implications: This study is designed to form the basis for transplant-based MRD goal and an MRD-driven cessation of maintenance therapy. Dara-KRd induction, auto-HCT, and Dara-KRd consolidation guided by MRD seem to be feasible, with an acceptable safety profile as well as rapid and near-universal responses. This approach can form the basis for two disparate clinical efforts: (1) to reduce the burden of continuous therapy in those with confirmed MRD-negative remissions (at two separate timelines); and (2) to induce as many patients to a deep MRD-negative response as soon as possible after diagnosis of myeloma. Of note, the clonoSEQ test is approved by the U.S. Food and Drug Administration, and results are unique to individual patients. Therefore, a sample from an “optimal” marrow specimen must be available to ensure accurate tracking of MRD.3 Study accrual is continuing, with the aim of reaching 126 patients.
“Dara-KRd induction, auto-HCT, and Dara-KRd consolidation guided by MRD seem to be feasible, with an acceptable safety profile as well as rapid and near-universal responses.”— Syed Ali Abutalib, MD, and Parameswaran Hari, MD
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Fractionated Conditioning Regimen for Allogeneic Transplantation
ABSTRACT 6: Myeloablative fractionated busulfan conditioning regimen in older adults (up to 70 years; n = 52): Results of a phase II study across a variety of myeloid neoplastic diseases4
Background: Traditionally, a pretransplant conditioning regimen is given over 4 to 6 days before allogeneic HCT (allo-HCT). Delivering a high-dose chemotherapy preparative regimen over an extended period has not been tested previously in patients with hematologic malignancies and adequate organ function. Investigators hypothesized that the delivery of a myeloablative dose of busulfan over a 3-week period may reduce toxicity and nonrelapse mortality without affecting relapse and tested this in a prospective phase II study.
Methods: Patients (median age of 62; range, 39–69 years) received a fixed dose of busulfan at 80 mg/m2 as an outpatient on days –20 and –13, followed by fludarabine at 40 mg/m2 on days –6 to –2, followed by busulfan dosed to achieve a target AUC of 20,000 mol/min for the whole course based on pharmacokinetic studies. Graft-vs-host disease prophylaxis was posttransplant cyclophosphamide at 50 mg/kg on days 3 and 4 and tacrolimus. Mycophenolate mofetil was added to later, unrelated donor recipients. The primary endpoint was day 100 nonrelapse mortality. Low-, intermediate-, high-, and very-high disease risk index was present in 3 patients (6%), 34 patients (65%), 14 patients (27%), and 1 patient (2%), respectively. The HCT comorbidity index was more than 3 in 23 patients and between 1 and 2 in 23 patients. A majority of patients (n = 32, 62%) had an unrelated donor.
Results: With a median follow-up of 14 months (range, 3–23 months), nonrelapse mortality at day 100 was 1.9%, and at 1 year, it was 8% (95% confidence interval [CI] = 0%–15%). The rates of overall survival, progression-free survival, and relapse at 1 year were 83% (95% CI = 73%–95%), 78% (95% CI = 67%–91%), and 14% (95% CI = 4%–24%), respectively. There were no graft failures. Day 100 grade 2 to 4 and grade 3 or 4 acute graft-vs-host disease rates were 37% (95% CI = 23%–50%) and 6% (95% CI = 0%–12%), respectively; 1-year chronic graft-vs-host disease and extensive chronic graft-vs-host disease rates were 9% (95% CI = 0%–17%) and 7% (95% CI = 0%–14%), respectively. Overall survival at 1 year differed significantly among patients with a low/intermediate disease risk index (94%; 87%–100%) and those with a high/very-high disease risk index (53%; 31%–91%; P = .001).
Clinical Implications: Busulfan regimens have been associated with higher regimen-related toxicity in patients receiving posttransplant cyclophosphamide as graft-vs-host disease prophylaxis. In addition, myeloablative busulfan-based regimens are often not feasible in older adults. This strategy of extended administration of a myeloablative fractionated busulfan-based regimen (with posttransplant cyclophosphamide graft-vs-host disease prophylaxis) is feasible even in older adults; it has a low incidence of severe acute graft-vs-host disease, chronic graft-vs-host disease, and nonrelapse mortality. In practice, this offers a way of reducing regimen-related toxicity and still achieving myeloablative busulfan exposure. One of the immediate implications is that older adults with MRD-positive disease prior to transplant could potentially benefit from such a strategy.
HLA-Haploidentical Transplantation
ABSTRACT 74: Cytokine-release syndrome after haploidentical HCT [and posttransplant cyclophosphamide]: An international multicenter collaboration5
Background: T-cell–replete HLA-haploidentical HCT (haplo-HCT) is often complicated by cytokine-release syndrome. The impact of severe cytokine-release syndrome has not been well defined in a multicenter setting.
Methods: The study goal was to determine the effect of cytokine-release syndrome (Lee criteria6) on outcomes, which were assessed using no cytokine-release syndrome as the comparison group. Study investigators compared overall survival and cumulative incident functions across three cytokine-release syndrome grade groups.
Results: The incidence of cytokine-release syndrome was high (89%), and 17% of patients had severe (grade 3–5) cytokine-release syndrome. The incidence of severe cytokine-release syndrome was higher in patients receiving peripheral blood grafts (19.5% vs 4.9%, P = .0026).
Relapse: Lower in patients with both mild cytokine-release syndrome (hazard ratio [HR] = 0.429, P = .0002) and severe cytokine-release syndrome (HR = 0.324, P = .0004).
Transplant-related mortality: Not significantly different with in patients with mild cytokine-release syndrome but much higher in patients with severe cytokine-release syndrome (HR = 5.332, P = .0002).
Neutrophil and platelet engraftment: Not significantly different in patients with mild cytokine-release syndrome but worse in patients with severe cytokine-release syndrome (HR = 0.476, P = .0008 and HR = 0.590, P = .0296).
Chronic graft-vs-host disease (all grades): Significantly reduced in patients with severe cytokine-release syndrome (HR = 0.256, P = .0273).
Multivariable models adjusting for potential confounders confirmed these effects. These effects did not differ by CD34-positive cell source.
Clinical Implications: This international, multicenter analysis is consistent with published single-center experiences, which show that cytokine-release syndrome is a common complication after haplo-HCT and that severe (grade ≥ 3) cytokine-release syndrome is associated with increased treatment related mortality and worse overall survival. Of note, these data are the first to show that mild (grade 1–2) cytokine-release syndrome is associated with a lower rate of relapse without affecting treatment-related mortality, thereby improving overall survival. The study is consistent with our biologic understanding of haploidentical transplant cytokine-release syndrome driven by alloreactive T cells from the graft, which may have a role in disease control.
CAR T-Cell Therapy
ABSTRACT 1: A phase II multicenter study (ZUMA-2) evaluating the efficacy of KTE-X19 in subjects with relapsed or refractory mantle cell lymphoma (MCL; NCT02601313)7
Background: Outcomes in patients with MCL whose disease progresses after Bruton’s tyrosine kinase inhibitor therapy remains suboptimal. Compared with allo-HCT, chimeric antigen receptor (CAR) T-cell therapy appears to offer a better alternative strategy as a potentially curative therapy without an inherent risk of graft-vs-host disease. KTE-X19 consists of an anti-CD19 single-chain variable fragment with a CD3 zeta T-cell activation domain and a CD28 signaling domain.
Methods: The study evaluated the efficacy and safety of KTE-X19 in patients with relapsed or refractory MCL.
Results: About 60 patients received KTE-X19l they had received a median of four prior therapies (must have included an anthracycline or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy, ibrutinib, or acalabrutinib). The investigators presented the results of patients with at least 1 year of follow-up. Eight patients received bridging therapy; all had disease present after bridging therapy.
“KTE-X19 represents one of the most active cellular therapies in MCL, and we look forward to further data moving this strategy hopefully to earlier lines of therapy.”— Syed Ali Abutalib, MD, and Parameswaran Hari, MD
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The investigator-assessed overall response rate was 86% (95% CI = 67%–96%), with a complete remission rate of 57% (95% CI = 37%–76%). As of May 30, 2018, 75% of responders remained in response, and 64% of treated patients had ongoing responses. The 12-month rates of duration of response, progression-free survival, and overall survival were 83% (95% CI = 60%–93%), 71% (95% CI = 50%–84%), and 86% (95% C =, 66%–94%), respectively; the medians were not reached.
The most common grade ≥ 3 adverse events were cytopenias. Grade 3 to 4 cytokine-release syndrome (Lee criteria6) and grade 3 to 4 neurologic events occurred in 18% and 46% of patients, respectively. Cytokine-release syndrome and neurologic events were generally reversible. There was one grade 5 event of organizing pneumonia.
Clinical Implications: KTE-X19 demonstrated significant and durable clinical benefit, with a manageable safety profile, in patients with relapsed or refractory MCL. With an overall response rate of 86% and a progression-free survival rate of 71%, KTE-X19 represents one of the most active cellular therapies in MCL, and we look forward to further data moving this strategy hopefully to earlier lines of therapy.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca and Partner Therapeutics. Dr. Hari has received honoraria from Amgen, Celgene, Juno Therapeutics, Novartis, and Sanofi; has served as a consultant or advisor to Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Kite Pharma, Pharmacyclics, Sanofi, and Takeda; and has received institutional research funding from Celgene, Millennium, Onyx, and Spectrum Pharmaceuticals.
REFERENCES
1. Bal S, Godby K, Chhabra S, et al: Impact of autologous hematopoietic stem cell transplant on measurable residual disease by next generation sequencing in the setting of daratumumab, carfilzomib, lenalidomide, and dexamethasone quadruplet induction. 2020 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. Abstract 27. Presented February 19, 2020.
2. Landgren O, Rustad EH: Meeting report: Advances in minimal residual disease testing in multiple myeloma 2018. Adv Cell Gene Ther 2:e26, 2019.
3. Abutalib SA, Landgren O: Selected abstracts on new therapies for newly diagnosed multiple myeloma. The ASCO Post 11:35-36, 2020.
4. Popat UR, Mehta RS, Bassett R, et al: Myeloablative fractionated busulfan conditioning regimen in older patients: Results of a phase II study. 2020 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. Abstract 6. Presented February 21, 2020.
5. Abboud R, Wan F, Mariotti J, et al: Cytokine release syndrome after haploidentical hematopoietic cell transplantation: An international multi-center collaboration. 2020 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. Abstract 74. Presented February 22, 2020.
6. Lee DW, Gardner R, Porter DL, et al: Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188-195, 2014.
7. Wang M, Munoz J, Goy A, et al: KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients with relapsed/refractory mantle cell lymphoma. 2020 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. Abstract 1. Presented February 21, 2020.
