COVID has upended our world, and medical conferences have had to adapt to ever-shifting sands depending on the behavior of the variants of the virus that emerge. The 2021 American Society of Hematology (ASH) Annual Meeting & Exposition was no exception, offering a hybrid meeting for in-person attendees as well as virtual participants. The ASCO Post provided full coverage of the main newsworthy presentations. In addition to our regular coverage of this meeting, here are summaries of some stories with important clinical implications.
Oral Azacitidine Maintenance in AML
Maintenance treatment with oral azacitidine following first remission after intensive chemotherapy improved survival in patients with acute myeloid leukemia (AML) compared with placebo, according to an updated analysis of the phase III QUAZAR AML-001 trial.1
At a median follow-up of 51.7 months, the median overall survival with oral azacitidine was 24.7 months vs 14.8 months with placebo, representing a 31% improvement that was statistically significant (P = .0008). The 3-year rates of overall survival were 37.4% with oral azacitidine maintenance vs 27.9% with placebo; at 5 years, overall survival rates were 26.2% and 19.2%, respectively.
Long-term survival of 3 years or longer in both treatment arms was associated with intermediate cytogenetic risk and NPM1 mutation positivity at diagnosis. Measurable residual disease (MRD) response was also associated with long-term survival. MRD response was twice as high with oral azacitidine vs placebo: 37% and 19%, respectively.
“With more than 1 additional year of follow-up, median overall survival remained unchanged in both treatment arms, but the tails of the oral azacitidine and placebo overall survival curves showed greater separation at later timepoints than in the primary analysis,” said presenting author Andrew H. Wei, MBBS, PhD, of the Alfred Hospital, Monash University, Australia. “These updated data indicate that oral azacitidine maintenance therapy provides a sustained, long-term overall survival benefit in older patients with AML in first remission.”
Andrew H. Wei, MBBS, PhD
Standard intensive induction chemotherapy for AML achieves rates of complete remission ranging from 60% to 80% in patients aged 60 and younger, but it is less successful in older patients, with complete remission rates ranging from 40% to 60%. Most patients will relapse despite achieving complete remission, and more effective treatments are needed.
The placebo-controlled, phase III QUAZAR AML-001 trial was designed to evaluate oral azacitidine, a hypomethylating agent with a distinct pharmacokinetic/pharmacodynamic profile from that of injectable azacitidine, as a maintenance option for patients with AML in remission following intensive chemotherapy. “Patients with core-binding factor were excluded, as were candidates for hematopoietic stem cell transplantation,” Dr. Wei said.
Study participants were randomly assigned 1:1 within 4 months of achieving first complete response to intensive chemotherapy to receive oral azacitidine at a daily dose of 300 mg for 14 days of a 28-day cycle (n = 238) or placebo (n = 234). Stratification factors included age (55–64 years vs 65 years or older), prior myelodysplastic syndrome or chronic myelomonocytic leukemia (yes vs no), cytogenetic risk (intermediate vs poor), and consolidation treatment (yes vs no).
In the primary analysis, at a median follow-up of 41.2 months, oral azacitidine significantly prolonged median overall survival vs placebo: 24.7 months vs 14.8 months, respectively (P < .001). In the most recent analysis presented by Dr. Wei, with an additional 1 year of follow-up, 22.7% of patients in the investigative arm were alive vs 15.0% of controls.
Acalabrutinib vs Ibrutinib in CLL: Effects on the Heart
Patients with chronic lymphocytic leukemia (CLL) treated with acalabrutinib experienced a lower incidence of cardiovascular-related toxicities and a lower overall toxicity burden compared with ibrutinib in a post-hoc analysis of the phase III ELEVATE-RR study.2
The analysis was performed to explore further the adverse events and toxicity profiles of both Bruton’s tyrosine kinase (BTK) inhibitors in the multicenter, open-label, randomized ELEVATE-RR study. The primary endpoint was noninferiority between the two BTK inhibitors by independent review committee–assessed progression-free survival; secondary endpoints included the incidence of any-grade atrial fibrillation or flutter, grade 3 or higher infection, Richter transformation, and overall survival.
John F. Seymour, AM, MBBS, PhD
“Event-based analyses demonstrated a higher BTK inhibitor–related toxicity burden with ibrutinib in this head-to-head trial,” said lead author John F. Seymour, AM, MBBS, PhD, of the Peter MacCallum Centre and the Royal Melbourne Hospital, Melbourne. “Exposure-adjusted assessments of atrial fibrillation or flutter, hypertension, and bleeding events demonstrated a lower toxicity burden with acalabrutinib compared with ibrutinib. Cumulative incidences of hypertension and atrial fibrillation or flutter were also lower with acalabrutinib in patients without a history of these events.”
Patients enrolled in ELEVATE-RR had previously been treated for CLL with one or more prior lines of therapy, presence of deletion 17p and/or 11q, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower. Stratification factors were deletion 17p status, ECOG performance status, and number of prior therapies.
At a median follow-up of 41 months, adverse cardiotoxicity events were assessed in 268 patients receiving acalabrutinib and 265 patients receiving ibrutinib. Of these events, any-grade atrial fibrillation or flutter, hypertension, and bleeding were statistically higher with ibrutinib. Exposure-adjusted incidence and exposure-adjusted time with these events were about 1.5 to 4.1 times higher with ibrutinib.
Other BTK inhibitor–related adverse events significantly more commonly observed with ibrutinib included any-grade diarrhea (46% vs 35%), arthralgia (23% vs 16%), back pain (13% vs 8%), muscle spasms (13% vs 6%), and dyspnea (12% vs 4%). Exposure-adjusted incidence and exposure-adjusted time with events were about 1.4 to 13.1 times higher with ibrutinib.
The only adverse events more frequently observed with acalabrutinib included any-grade headache and cough, which occurred at rates of 35% and 29%, respectively, with acalabrutinib vs 20% and 21% with ibrutinib. Acalabrutinib-associated headache was linked to a 1.6 times higher exposure-adjusted incidence and exposure-adjusted time with events, and cough was associated with a 1.2 times higher exposure-adjusted incidence and exposure-adjusted time with events.
Investigators observed a longer median time to onset of any-grade atrial fibrillation or flutter with acalabrutinib vs ibrutinib, at 28.8 months and 16.0 months, respectively. The median time to onset of any-grade hypertension was similar for both therapies. Concomitant medication use for atrial fibrillation, flutter, or hypertension for all patients was less common with acalabrutinib.
The cumulative incidence of any-grade atrial fibrillation or flutter and hypertension was consistently lower with acalabrutinib up to 36 months, regardless of the number of prior therapies, age, and no history of such cardiac events. For patients with no history of atrial fibrillation, flutter, or hypertension, a lower cumulative incidence of both conditions was observed in patients treated with acalabrutinib compared with ibrutinib.
A similar time to onset of any-grade bleeding events was seen with acalabrutinib and ibrutinib. The incidence was lower for the acalabrutinib arm regardless of age and in patients with one to three prior lines of therapy. Few patients in either treatment arm required dose modification due to bleeding events. Also, fewer patients given acalabrutinib used concomitant medication for bleeding events compared with the ibrutinib-treated group. The cumulative incidence of any-grade bleeding over 36 months was lower with acalabrutinib.
Next-Generation PI3K Inhibitor in Relapsed Follicular Lymphoma
The next-generation PI3K inhibitor parsaclisib conferred rapid, durable responses in patients with relapsed or refractory follicular lymphoma in the phase II CITADEL-203 study.3 Four PI3K inhibitors are approved for patients with relapsed or refractory follicular lymphoma. Parsaclisib is a next-generation PI3K inhibitor that is highly selective for the δ vs α/β/γ isoforms—a feature that minimizes the risk of hepatotoxicity, said Ryan C. Lynch, MD, of the University of Washington and Seattle Cancer Care Alliance, who presented the findings of the multicenter, open-label trial.
Ryan C. Lynch, MD
CITADEL-203 evaluated 126 patients with relapsed or refractory follicular lymphoma and at least two prior therapies after treatment with either weekly or daily doses of parsaclisib. The weekly dosing group received parsaclisib at 20 mg/d for 8 weeks, followed by 20 mg weekly. The daily dosing group received parsaclisib at 20 mg/d for 8 weeks followed by 2.5 mg continuously. Dr. Lynch presented data for the daily dosing cohort (n = 103) and for the whole population (n = 126).
Objective response rate by independent review was 77.7% in the daily dosing group and 75.4% in all treated patients; complete responses were achieved by 19% and 18%, respectively. Median duration of response was 14.7 months in both groups, and median progression-free survival was 15.8 months and 14.0 months, respectively. Almost three-quarters of patients had their first documented response at the first disease assessment (ie, at 8 weeks), and for 95% of evaluable patients, target lesions regressed, he reported.
“Parsaclisib was generally well tolerated and had a manageable safety profile,” Dr. Lynch said, though he reported two treatment-related deaths: one from Stevens-Johnson syndrome and another from pneumonia. Diarrhea and colitis were generally manageable with dose modifications, though almost half the patients had doses interrupted for this side effect, and 8% and 5%, respectively, discontinued treatment because of them. Clinically significant transaminase elevations were uncommon, he said.
Novel CAR T-Cell Therapy Explored in DLBCL
YTB323, a novel, autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, had a favorable safety profile and efficacy across multiple dose levels in adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in a phase I trial.4
“YTB323 is manufactured through an innovative process called T-Charge™,” said Ian W. Flinn, MD, PhD, of the Sarah Cannon Research Institute, Nashville. “[This process] preserves the naive/stem memory T cells in the final product.”
“YTB323 merits continued exploration as a therapy for adults with relapsed or refractory DLBCL.”— Ian W. Flinn, MD, PhD
Tweet this quote
T-Charge minimizes the ex vivo culture time and reduces the manufacturing process time to less than 2 days. The process starts from cryopreserved leukapheresis; T cells are then transduced with a lentiviral vector encoding for the same CAR used for tisagenlecleucel. Data from the trial showed that this platform preserved naive and stem cell memory T cells in the final product, which is expected to result in longer CAR T-cell persistence and, in turn, higher response rates and longer durability of response.
At a median follow-up of 14 months, patients treated at dose level 1 (DL1; n = 4) experienced an overall response rate of 75%; all responses were complete responses. One patient had progressive disease. At month 3, one patient had a complete response, and three patients had progressive disease.
The median follow-up with dose level 2 (DL2; n = 15) was 6.2 months. The objective response rate was 80%, and the complete response rate was 73%. Two patients had progressive disease. All patients in the DL2 group who achieved a complete response responded by month 3. At that time, two patients had progressive disease.
Eligibility requirements were adults with measurable disease at enrollment and an ECOG performance status of 0 or 1 and at least two prior lines of therapy, including autologous hematopoietic stem cell transplantation.
Lymphodepleting chemotherapy was given as intravenous (IV) fludarabine (30 mg/m2 daily for 3 days) plus cyclophosphamide (500 mg/m2 IV daily for 3 days) or bendamustine (90 mg/m2 IV daily for 2 days). YTB323 was administered as a single IV dose; DL1 consisted of 2.5 × 106 CAR-positive cells, and DL2 consisted of 12.5 × 106 CAR-positive cells. The first efficacy assessment was performed after 28 days.
The primary endpoint of the trial was to identify the incidence of dose-limiting toxicities and safety to determine a recommended dose going forward. Secondary endpoints included cellular kinetics, objective response rate, duration of response, and overall survival.
The median patient age at DL1 was 69 years (range = 60–74); at DL2, the median patient age was 66 years (range = 41–78). All patients at both dose levels experienced an adverse event of any grade. Grade 3 or higher adverse events occurred in 100% and 75% of patients treated at DL1 and DL2, respectively. Two patients treated at DL1 died while on the study, and three died at DL2. Investigators determined that none of these deaths was related to treatment.
Cytokine-release syndrome of any grade was present in 25% and 31% of patients at DL1 and DL2, respectively. Neurologic adverse events of any grade occurred in 25% of patients treated at both dose levels. Half of the patients treated at DL1 experienced infections of any grade; at DL2, the rate was 19%. All patients at both dose levels experienced grade 3 or higher cytopenia.
“YTB323 is effective with comparable in vivo expansion to tisagenlecleucel in [patients with] DLBCL at a 25-fold lower dose,” Dr. Flinn said. “YTB323 merits -continued exploration as a therapy for adults with relapsed or refractory DLBCL.”
Pelabresib Under Study in Myelofibrosis
The global, open-label phase II MANIFEST trial is evaluating pelabresib monotherapy in patients with advanced myelofibrosis who are intolerant of, refractory to, or ineligible for ruxolitinib—a population typically with a poor prognosis. Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule inhibitor of bromodomain and extraterminal domain proteins that can modify the expression of genes involved in nuclear factor kappa B signaling in patients with myelofibrosis.
Marina Kremyanskaya, MD, PhD
Updated findings of MANIFEST were reported by Marina Kremyanskaya, MD, PhD, of the Tisch Cancer Institute at Mount Sinai, New York. Her analysis was based on 86 patients, including 35 who were transfusion-dependent and 50 who were transfusion-independent.5
The primary endpoint was red blood cell transfusion independence (defined as no transfusion for ≥ 12 weeks) in the transfusion-dependent cohort and ≥ 35% spleen volume reduction (SVR35) at week 24 in the nontransfusion-dependent cohort. A key secondary endpoint was the number of patients with at least 50% total symptom score reduction (TSS50) at week 24.
“We observed clinical activity based on preliminary results of spleen volume reduction, symptom reduction, and hemoglobin benefits,” Dr. Kremyanskaya said. “Exploratory analysis showed bone marrow fibrosis improvement in a subset of patients, and we saw that plasma cytokines involved in the pathogenesis of myelofibrosis were reduced during treatment with pelabresib.”
In evaluable patients, the conversion rate from transfusion dependence to independence was 16%, and the median duration of transfusion independence was 41 weeks. In the nontransfusion-dependent cohort, 38% of patients had a hemoglobin response. SVR35 was attained by 11% of nontransfusion-dependent patients, and SVR25 achieved by 31%. Median spleen volume change was –24%.
The great majority of patients reported fewer symptoms on treatment; TSS50 was attained by 38%, with a median change of –40%. Approximately 24% of patients had an improvement in bone marrow fibrosis. Changes in the levels of myelofibrosis-associated and inflammation-related cytokines were observed, with downregulation occurring within 14 days and remaining stable through 24 weeks. Most treatment-emergent adverse events were low grade; 19% of patients discontinued treatment due to toxicity.
MANIFEST-2, a phase III trial of pelabresib plus ruxolitinib vs placebo plus ruxolitinib in patients naive to JAK inhibitors, is open for enrollment.
Update of CARTITUDE-1 in Myeloma
Longer-term results were reported for the phase Ib/II CARTITUDE-1 trial of the CAR T-cell therapy ciltacabtagene autoleucel in relapsed or refractory multiple myeloma.6 The study’s 97 patients continued to show a very high overall response rate of 98%, with deepening of responses over time. After 21.7 months of median follow-up, 83% of the study’s 97 patients treated with ciltacabtagene autoleucel achieved a stringent complete response—an increase from 80% previously reported after 18 months of median follow-up. In 95% of patients, very good partial responses or better were observed, according to Thomas G. Martin, MD, of the University of California San Francisco School of Medicine.
Thomas G. Martin, MD
Median progression-free survival and median overall survival have not been reached, suggesting long-term durability of responses and survival, Dr. Martin said. At 2 years, 61% of patients were progression-free and 74% were alive. Of the 61 patients evaluable for MRD, 92% achieved MRD negativity at the 10-5 threshold. Among patients with sustained MRD negativity for more than 12 months, 100% remained progression-free at 2 years.
In a subgroup analysis of the trial, Andrzej Jakubowiak, MD, PhD, of the University of Chicago, reported that all subgroups maintained durable responses after a median follow-up of 18 months.7 Objective response rates were consistently high (95%–100%), comparable to those observed in the overall patient population. Moreover, in all subgroups, between 80% and 100% of patients with MRD assessment achieved MRD negativity at the 10–5 threshold.
Andrzej Jakubowiak, MD, PhD
Of note, the subgroup of patients aged 65 or older (including eight patients ≥ 75) had a response rate of 97.1% and an MRD negativity rate of 91.3%. For the largest subgroup, the 85 patients with triple-class–refractory disease, the response rate was 97.6%, and the MRD negativity rate was 92.6%.
“In most subgroups, the median duration of response was consistent with the overall population. However, it was lower in patients whose baseline disease was stage III, had a high-risk cytogenetic profile, and had plasmacytomas at baseline,” Dr. Jakubowiak said.
Median duration of response in the overall population was 21.8 months, with an 18-month progression-free survival rate of 66% and an overall survival rate of 81%. Both progression-free and overall survival were consistent across all subgroups and similar to those of the overall population. Of note, for patients with high-risk cytogenetics, the overall survival rate at 18 months was 73.7%; however, the progression-free survival rate was lower, 48.4%. For the standard-risk cytogenetic group, these rates were 64.1% and 73.6%, respectively.
The study’s heavily pretreated population received a single infusion of ciltacabtagene autoleucel at 0.75 × 106 CAR-positive viable T cells/kg 5 to 7 days after lymphodepletion. No new safety signals emerged with longer follow-up, and safety within the subgroups was consistent with the overall population.
“Taken together, these results show that most subgroups of patients have durable responses after a few years, with stable responses in high-risk patients,” Dr. Jakubowiak commented.
FT596: Off-the-Shelf CAR Therapy Harnesses Natural Killer Cells
FT596 is an induced pluripotent stem cell–derived, off-the-shelf, CD19-directed CAR natural killer cell therapy capable of targeting multiple antigens in combination with monoclonal antibody therapies. The use of natural killer cells has been associated with a significantly lower risk of side effects with CAR therapy, and their manufacturing from induced pluripotent stem cells can result in a readily available off-the-shelf product, explained Paolo Strati, MD, of The University of Texas MD Anderson Cancer Center, Houston, senior investigator of a phase I trial evaluating FT596.
Paolo Strati, MD
Veronika Bachanova, MD, PhD
At the ASH meeting, the results of treatment with FT596 in 25 patients with relapsed or refractory B-cell lymphoma were reported by the study’s first author, Veronika Bachanova, MD, PhD, of the University of Minnesota.8 FT596 demonstrated dose-dependent responses in a variety of subsets:
- The overall response rate was 72%, and the complete response rate was 44%.
- The response rate was 60% in patients with aggressive lymphomas and 100% in patients with indolent lymphomas.
- Of 18 patients receiving at least 90 million cells, 13 (72%) responded after one cycle; 11 received a second cycle, and most responses were retained or deepened.
At doses of at least 90 million cells, with FT596 given with rituximab, the complete response rate was 56%; complete responders included three patients with prior autologous CAR T-cell therapy.
No dose-limiting toxicities, cases of immune effector cell–associated neurotoxicity syndrome, or graft-vs-host disease were observed at doses up to 300 million cells. Future directions include further dose escalation on the single-dose schedule and incorporation of a multidose schedule.
“In this phase I study, escalating doses were shown to be safe, with no cases of severe cytokine-release syndrome or neurotoxicity. Significant activity was observed in patients with heavily pretreated B-cell lymphoma, particularly when combined with an anti-CD20 antibody. The study shows the possibility of outpatient rather than inpatient infusion,” Dr. Strati said.
The investigators are now looking at further dose escalation, multidose schedules, and alternative lymphodepleting regimens (or their omission).
DISCLOSURE: Dr Wei has received research funding from Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen; and honoraria from Novartis, Astellas, Pfizer, MacroGenics, AbbVie, Genentech, Servier, Celgene, Amgen, AstraZeneca, and Janssen. Dr. Seymour reported relationships with AstraZeneca, Mei Pharma, MorphoSys, Sunesis, Takeda, AbbVie, F. Hoffmann–La Roche, and Celgene. Dr. Lynch has served as a consultant to MorphoSys. Dr. Flinn reported relationships with Incyte, Loxo, Portola, Seattle Genetics, Servier, Roche, Agios, Unum, Calithera Biosciences, Forma, Infinity, Merck, Novartis, Curis, Pfizer, Hutchison MediPharma, Yingli, Vincerx Pharma, Celgene, Rhizen, Teva, Trillium, Acerta Pharma, Century Therapeutics, Johnson & Johnson, Seagen, ArQule, Constellation, Forty Seven, IGM Biosciences, Verastem, Karyopharm, Triphase, Pharmacyclics, Nurix, MorphoSys, Kite, Juno, Janssen, Iksuda, Great Point Partners, Gilead Sciences, BeiGene, and AstraZeneca. Dr. Kremyanskaya has served as a consultant to Protagonist Therapeutics. Dr. Martin has served as a consultant to GlaxoSmithKline. Dr. Jakubowiak has served on advisory committees or boards of directors for Amgen, GlaxoSmithKline, Janssen, Karyopharm, AbbVie, BMS, Gracell, Sanofi, and Celgene. Dr. Strati has served as a consultant or advisor to Roche, Genentech, Hutchinson MediPharma, TG Therapeutics, and ADC Therapeutics, and has received research funding from AstraZeneca, Acerta, and ALX Oncology. Dr. Bachanova has served on the board of directors or advisory committees for Fate Therapeutics, Gamida Cell, and Karyopharm.
REFERENCES
1. Wei AH, Döhner H, Sayar H, et al: Long-term overall survival with oral azacitadine in patients with acute myeloid leukemia in first remission after intensive chemotherapy: Updated results from the phase 3 QUAZAR AML-001 trial. 2021 ASH Annual Meeting & Exposition. Abstract 871. Presented December 13, 2021.
2. Seymour JF, Byrd JC, Hillmen P, et al: Characterization of Bruton tyrosine kinase inhibitor–related adverse events in a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. 2021 ASH Annual Meeting & Exposition. Abstract 3721. Presented December 13, 2021.
3. Lynch RC, Avigdor A, McKinney MS, et al: Efficacy and safety of parsaclisib in patients with relapsed or refractory follicular lymphoma: Primary analysis from a phase 2 study (CITADEL-203). 2021 ASH Annual Meeting & Exposition. Abstract 813. Presented December 13, 2021.
4. Flinn IW, Jaeger U, Shah NN, et al: A first-in-human study of YTB323, a novel, autologous CD19-directed CAR-T cell therapy manufactured using the novel T-ChargeTM platform, for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma. 2021 ASH Annual Meeting & Exposition. Abstract 740. Presented December 13, 2021.
5. Kremyanskaya M, Mascarenhas J, Palandri F, et al: Pelabresib (CPI-0610) monotherapy in patients with myelofibrosis: Update of clinical and translational data from the ongoing MANIFEST trial. 2021 ASH Annual Meeting & Exposition. Abstract 141. Presented December 11, 2021.
6. Martin T, Usmani SZ, Berdeja JG, et al: Updated results from CARTITUDE-1: Phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in patients with relapsed/refractory multiple myeloma. 2021 ASH Annual Meeting & Exposition. Abstract 549. Presented December 12, 2021.
7. Jakubowiak A, Usmani SZ, Berdeja JG, et al: Efficacy and safety of ciltacabtagene autoleucel in patients with relapsed/refractory multiple myeloma: CARTITUDE-1 subgroup analysis. 2021 ASH Annual Meeting & Exposition. Abstract 3938. Presented December 13, 2021.
8. Bachanova V, Ghobadi A, Patel K, et al: Safety and efficacy of FT596, a first-in-class, multi-antigen targeted, off-the-shelf, iPSC-derived CD19 CAR NK cell therapy in relapsed/refractory B-cell lymphoma. 2021 ASH Annual Meeting & Exposition. Abstract 823. Presented December 13, 2021.
