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ASH 2020: A virtual scientific retreat amidst viral chaos

Dr Prashant Mehta MD DM, Dr Kartik A Purohit MD DNB

Department of Medical Oncology, Hematology and BMT
Asian Institute of Medical Sciences
Faridabad

Email: prashantcipher7@gmail.com

This year 62nd American Society of Haematology (ASH) annual meeting was organised in virtual world, however, with real world experience. The coronavirus pandemic, its treatment and vaccines have always dominated medical journals this year. However, ASH annual meet gave us reassurance that there has been adequate research in haematology/oncology too during this global catastrophe. It was a great experience of having interactions on a virtual platform, and we feel that such kind of virtual meetings should continue to get organised even beyond the pandemic alongside real meetings.

Let us delve into what ASH 2020 had to offer!

Functional cure in Chronic lymphocytic leukaemia (CLL)

Chronic lymphocytic leukaemia (CLL) has witnessed radical changes in therapeutic landscape right from simple alkylator agents to highly efficacious targeted therapies. Focus is now on fixed duration of targeted therapy that can achieve long term treatment free remission, analogous to the management of chronic myeloid leukaemia (CML). Updated results from multicentric phase II CAPTIVATE study1 (abstract no: 123) showed that a fixed duration therapy, of a combination of ibrutinib and venetoclax in frontline is feasible. Among 164 patients, baseline high-risk features were del(17p) in 16%, del(11q) in 17%; del(17p) or TP53 mutation in 20%; complex karyotype in 19%; and unmutated IGHV in 60%. After 12 cycles of venetoclax + ibrutinib, 58% of patients achieved confirmed undetectable minimal residual disease (MRD) (µMRD, <10-4 by 8-color flow cytometry) in pre-randomisation phase of study. These patients with µMRD (n=86) were randomised in double blind fashion to ibrutinib and placebo. In the confirmed µMRD group, 1-year disease free survival (DFS) rate was not significantly different for patients randomized to placebo (95.3%; 95% CI 82.7-98.8) versus ibrutinib (100%; P=0.1475). Patients who did not achieve µMRD after 12 cycles were randomised to either continuing the combination or Ibrutinib alone. The increases in MRD negativity with time, was more with the combination on follow up.

Five-year analysis of MURANO trial2 by Kater et al., (abstract no: 125) showed that in relapsed/refractory setting, fixed duration therapy; venetoclax + rituximab (Ven-R) was superior to bendamustine- rituximab (BR). Median progression-free survival (PFS) was 53.6 months for Ven-R and 17.0 months for BR (HR-0.19, CI 0.15-. 26, p< .0001). Five-year OS estimate was 82.1% for Ven-R vs 62.2% for BR (HR= 0.40, CI-0.26-.62, p<.0001).

Another study UNITY-CLL3 (abstract no: 543) by Gribben et al., was presented, comparing umbralisib + ublituximab (U2) to obinutuzumab + chlorambucil in both treatment naive and relapsed refractory CLL patients. The primary end point of the study, PFS was significantly prolonged with U2 as compared to obinutuzumab + chlorambucil (median 31.9 months vs 17.9 months; HR 0.546, 95% CI 0.413-0.720, P<0.0001).

Newer and exciting strategies for acute myeloid leukemia (AML) continue to evolve and succeed!

Recently, several new drugs for AML were approved in frontline as well as relapsed setting and more new drugs are knocking at the door. In acute promyelocytic leukemia (APL) and acute lymphoblastic leukemia (ALL) maintenance therapy is considered as a cornerstone. However, for AML it is not a standard of care. The multi-centre, double-blind placebo-controlled phase III QUAZAR AML-0014 trial (abstract no: 103) by Wei et al., compared oral azacytidine (CC-486) to placebo as a maintenance therapy in 472 AML patients of age > 55 years who achieved CR/CRi with induction and consolidation therapy and were ineligible for hematopoietic stem cell transplantation (HSCT). Patients with intermediate and high-risk cytogenetics were enrolled. A total of 45% patients (CC-486 :110, placebo: 102) received only one cycle of consolidation. One-year relapse rate was 53% (95% CI: 46-59) in CC-486 arm vs 71% (95% CI: 65-77) in the placebo arm. Median overall survival (OS) was extended by 9.9 months ( 24.7 vs 14.8 , HR 0.69, p<0.009) and median relapse free survival (RFS) extended by 5.3 months (10.2 vs 4.8, p< 0.0001) with CC-486. The subset analysis showed apparently more benefit in OS for >65 years of age, and those in complete remission (CR) rather than Complete Remission with Incomplete Count Recovery (CRi), although it is difficult to draw any concrete conclusions from the subsets. In those with early first relapse (5-15 % blasts), an escalated dose of CC-486 was able to regain a response one out of four times, although not leading to a statistically significant OS advantage.

After approval as a single agent in relapsed setting; gilteritinib was evaluated upfront in combination with a classical anthracycline + cytarabine backbone and early data is not showing added toxicities. A total of 80 patients were enrolled in this phase 1 study. Serious treatment-related adverse events (AEs) and discontinuation of gilteritinib occurred in 12.7% and 5.1% of patients, respectively. One death occurred across all treatment groups. Median OS for FLT3mut+ patients has not been reached till this analysis. Data from phase I/II study5 by Aldoss et al., (abstract no: 331) on bispecific T-cell engager (BiTE) flotetuzumab (CD123/CD3) brings some hope for patients with AML with primary induction failure (PIF) or early relapse (ER). The overall complete response rate (CRR, <5% bone marrow blasts) was 42.1%, and 68.8% later underwent allogenic stem cell transplant. Cytokine release syndrome (CRS) was the most frequently reported treatment related adverse event (TRAE), mostly mild-to-moderate (grade ≤ 2).

Will MAbs change the game for acute lymphoblastic leukemia (ALL)?

After encouraging results of blinatumomab in relapsed refractory setting, it was hypothesized that upfront use of blinatumomab will decrease need of intensive therapy and will be able to achieve deep and durable remissions in Philadelphia (Ph) negative ALL. In a phase 2 study6 by Short et al., (abstract no: 464) from MD Anderson centre; patients were administered hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to four cycles, followed by four cycles of blinatumomab at standard doses. Among evaluable 28 patients, CR was 100% and MRD negativity by six-color flow cytometry was achieved in 97% overall. There were no early deaths, and the 60-day mortality rate was 0%. With a median follow-up of 22 months (range, 1-40 months), the 2-year continuous remission and OS rates were 79% and 86%, respectively. However, 31 % of patients had a blinatumomab related neurological AE, and four patients developed grade 2-3 cytokine release syndrome (CRS), which we should remain mindful of despite very encouraging results in terms of efficacy.

Stamp of STAMP inhibitor

An open label multi-centre phase 3 study ASCEMBL7 compared head-to-head asciminib and bosutinib in chronic myelogenous leukemia in chronic phase (CML-CP) patients previously treated with ≥2 Tyrosine Kinase Inhibitors (TKIs). Asciminib is a first in class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor. In this study, by Hochhaus et al., (LBA-4); patients with known bosutinib-resistant T315I or V299L mutations were excluded. The primary endpoint was major molecular response (MMR) rate at a pre-specified time point of 24 weeks. MMR rate at 24 weeks was 25.5% with asciminib and 13.2% with bosutinib which met the primary objective. Grade ≥3 adverse events (AEs) occurred in 50.6% and 60.5% of patients receiving asciminib and bosutinib respectively. However, a worrisome finding was of two deaths in asciminib arm as a result of arterial occlusive event.

Embarking on IMbark

Primary myelofibrosis (PMF) is the most symptomatic myeloproliferative neoplasm (MPN). IMbark (abstract no: 53) was a two-dose, randomized, single-blinded, phase 2 study8 of imetelstat in R/R intermediate-2/high-risk PMF patients. Imetelstat, is a first in class telomerase inhibitor. Study patients were administered imetelstat 9.4 mg/kg or 4.7 mg/kg IV every 3 weeks. In an intent- to- treat analysis (ITT), Mascarenhas et al., showed that at a median follow-up of 41.7 months, median OS was 28.1 months in the 9.4 mg/kg arm (95% CI 22.8-31.6) and 19.9 months in the 4.7 mg/kg arm (95% CI 17.1-33.9).

Continue to be PROUD!

Interferon is believed to have disease modifying potential in polycythemia vera (PV). Data from PROUD-PV and its extension CONTINUATION-PV9 was presented. In this study (abstract no: 481), Gisslinger et al., compared long-term treatment with ropeginterferon Alfa-2b (70 patients) with standard cytoreductive therapy (57 patients) with regard to thromboembolic events as well as disease evolution over five years. Hematocrit <45% was maintained without the need for phlebotomy in 81.8% patients in the ropeg arm, as compared to 63.2% in the control group (p=0.01). 4.2% patients experienced a major thromboembolic event in the ropeg arm, as compared to 6.6% of patients in the control arm. JAK2 median allele burden declined from 37.3% at baseline to 7.3% over five years in the ropeg arm, as compared to control arm where the median allele burden increased from 38.1% to 42.6% (p<0.0001). Only one case of progression to myelofibrosis was reported in ropeg arm and no leukemic transformation occurred as opposed to two cases of progression to myelofibrosis and two cases of transformation to acute leukemia in control arm. Treatment related adverse events occurred in 25.6% and 24.2% of patients in the ropeg and control arms, respectively.

More agents in line for high risk MDS

In a phase II study10 (P-2001), Zeidner et al., compared combination of NEDD (neural precursor cell expressed, developmentally downregulated) inhibitor pevonedistat + azacytidine to azacytidine alone in high risk MDS/CMML patients (abstract no: 2191). This study showed median event-free survival of 21.0 versus 16.6 months (HR=0.665; P = .076), and overall response rate (ORR) of 71% vs 60% with combination arm as compared with azacytidine alone.

B-Cell maturation antigen (BCMA); a dependable target to treat multiple myeloma

Several abstracts on anti-BCMA CAR-T cell construct, antibody drug conjugate (ADC) and BiTes were presented. CARTITUDE-1 study11 by Madduri et al., showed Ciltacabtagene autoleucel producing ORR (primary endpoint) of 94.8% (95% CI 88.4–98.3), stringent CR of 55.7% (95% CI 45.2–65.8), VGPR of 32.0% (95% CI 22.9–42.2), and PR of 7.2% (95% CI 3.0–14.3) in heavily pre-treated relapsed refractory multiple myeloma (abstract no: 177). Preliminary data from DREAMM-6 Arm B study12 by Popat et al., demonstrated that belantamab mafodotin in combination with bortezomib and dexamethasone could induce high ORR of 78% and VGPR of 50%, with a clinical benefit rate of 83% in relapsed refractory multiple myeloma patients (abstract no: 1419). However, all the patients in study developed keratopathy with near 70% of patients developing blurring of vision; which is a matter of concern. Teclistamab is a BCMA-CD3 BiTe. Garfall et al.,13 evaluated it in a phase 1 study (abstract no: 180). The primary objective of this study was to identify a recommended phase 2 dose. ORR was 63.8% across most active dose levels. Dose of 1500 µg/kg subcutaneously has been selected as phase 2 study dose.

Pearls from non-malignant haematology

In patients with relapsed refractory ITP, BTK inhibitor rilzabrutinib, in a phase I/II study by Kuter et al.,14 showed excellent response, including in those with prior splenectomy with an acceptable side effect profile (abstract no: 22). The primary endpoint was ≥2 consecutive platelet counts of ≥50×109/L and a rise of ≥20×109/L from baseline without rescue medication. Overall, 44% of patients achieved the primary endpoint, and those who responded; maintained platelet counts ≥50×109/L for a median of 71% (range, 33%-100%) of weekly counts. Of all patients, 67% of them were able to achieve clinically meaningful benefit of platelet counts ≥30×109/L.

Ruxolitinib has already been approved in steroid refractory acute Graft-Vs-Host Disease (GVHD). Data from REACH3 study was presented (abstract no: 77). Ruxolitinib performed better as compared to best available treatment in steroid refractory chronic GVHD. In this study15 by Zeiser et al., patients were randomized (1:1) to ruxolitinib 10 mg twice daily or investigator-selected best available treatment (BAT) and were treated for 6 cycles (cycle length=28 days). The primary endpoint was ORR at cycle seven day one (C7D1). ORR was defined as per NIH consensus criteria. The study met its primary endpoint at interim analysis. At C7D1, ORR was significantly higher in the ruxolitinib arm vs BAT (50% vs 26%; OR= 2.99; P < 0.0001. The CR rate was higher with ruxolitinib (7% vs 3%). Rates of AEs up to C7D1 were comparable in the both the arms; (ruxolitinib, 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%]).

Overall, the data from ASH 2020, seems quite exciting, and makes us hopeful of more cures and longer survival for patients in future. There needs to be a concerted effort by clinicians, pharmaceutical industry and governments to make such novel therapies accessible to the last person in the queue and narrow the divide between the privileged, and those less so. Say amen to that.

References
  • 1. Wierda WG. Ibrutinib (Ibr) Plus Venetoclax (Ven) for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): 1-Year Disease-Free Survival (DFS) Results from the MRD Cohort of the Phase 2 CAPTIVATE Study [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 123. Available from: https://ash.confex.com/ash/2020/webprogram/Paper134446.html
  • 2. Kater A. Five-Year Analysis of Murano Study Demonstrates Enduring Undetectable Minimal Residual Disease (uMRD) in a Subset of Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Patients (Pts) Following Fixed-Duration Venetoclax-Rituximab (VenR) Therapy (Tx) [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 125. Available from: https://ash.confex.com/ash/2020/webprogram/Paper136109.html
  • 3. Gribben J. Umbralisib Plus Ublituximab (U2) Is Superior to Obinutuzumab Plus Chlorambucil (O+Chl) in Patients with Treatment Naïve (TN) and Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): Results from the Phase 3 Unity-CLL Study [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 543. Available from: https://ash.confex.com/ash/2020/webprogram/Paper134783.html
  • 4. Wei A. CC-486 Improves Overall Survival (OS) and Relapse-Free Survival (RFS) for Patients with Acute Myeloid Leukemia (AML) in First Remission after Intensive Chemotherapy (IC), Regardless of Amount of Consolidation Received: Results from the Phase III QUAZAR AML-001 Maintenance Trial [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA) ASH; 2020. Abstract nr 103. Available from: https://ash.confex.com/ash/2020/webprogram/Paper138498.html
  • 5.Aldoss I. Flotetuzumab As Salvage Therapy for Primary Induction Failure and Early Relapse Acute Myeloid Leukemia [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 331. Available from: https://ash.confex.com/ash/2020/webprogram/Paper134576.html
  • 6.Short N. Hyper-CVAD and Sequential Blinatumomab in Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia: Results from a Phase II Study. [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 464. Available from: https://ash.confex.com/ash/2020/webprogram/Paper138565.html
  • 7. Hochhaus A. Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs) [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 632. Available from: https://ash.confex.com/ash/2020/webprogram/Paper143816.html
  • 8. Mascarenhas J. Favorable Overall Survival with Imetelstat Treatment Correlates with Other Clinical Benefits in Intermediate 2 or High Risk Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitor[abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 53. Available from: https://ash.confex.com/ash/2020/webprogram/Paper141013.html
  • 9. Gisslinger H. Long-Term Use of Ropeginterferon Alpha-2b in Polycythemia Vera: 5-Year Results from a Randomized Controlled Study and Its Extension [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA) ASH; 2020. Abstract no 481. Available from: https://ash.confex.com/ash/2020/webprogram/Paper136973.html
  • 10.Zeidner J. Randomized Phase 2 Trial of Pevonedistat Plus Azacitidine Versus Azacitidine in Higher-Risk Myelodysplastic Syndromes/Chronic Myelomonocytic Leukemia or Low-Blast Acute Myeloid Leukemia: Exploratory Analysis of Patient-Reported Outcomes [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr. 2191. Available from: https://ash.confex.com/ash/2020/webprogram/Paper136935.html
  • 11.Madduri D. CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen–Directed Chimeric Antigen Receptor T Cell Therapy, in Relapsed/Refractory Multiple Myeloma [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 177. Available from: https://ash.confex.com/ash/2020/webprogram/Paper136307.html
  • 12. Popat R. DREAMM-6: Safety, Tolerability and Clinical Activity of Belantamab Mafodotin (Belamaf) in Combination with Bortezomib/Dexamethasone (BorDex) in Relapsed/Refractory Multiple Myeloma (RRMM). [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA) ASH; 2020. Abstract nr 1419. Available from: https://ash.confex.com/ash/2020/webprogram/Paper139332.html
  • 13. Garfall A. Updated Phase 1 Results of Teclistamab, a B-Cell Maturation Antigen (BCMA) x CD3 Bispecific Antibody, in Relapsed and/or Refractory Multiple Myeloma (RRMM) [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 653. Available from: https://ash.confex.com/ash/2020/webprogram/Paper138831.html
  • 14. Kuter D. Oral Rilzabrutinib, a Bruton Tyrosine Kinase Inhibitor, Showed Clinically Active and Durable Platelet Responses and Was Well-Tolerated in Patients with Heavily Pretreated Immune Thrombocytopenia [abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA) ASH; 2020. Abstract nr 22. Available from: https://ash.confex.com/ash/2020/webprogram/Paper134932.html
  • 15. Zeiser R. Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients with Steroid-Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study[abstract] In: Proceedings of the 62nd American Society of Haematology Annual Meeting and Exposition; 2020 Dec 5-8; Washington, DC. Philadelphia (PA): ASH; 2020. Abstract nr 77. Available from: https://ash.confex.com/ash/2020/webprogram/Paper137694.html

Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
Editor-in-Chief - Dr. Padmaj Kulkarni