Key clinical trends leading into 2021: Highlights from ASH 2020

Instead of traveling to sunny San Diego, California, medical professionals from around the world virtually attended the 62nd Annual Meeting of the American Society of Hematology (ASH) from December 5-8, 2020. This premier hematology conference showcased nearly 3,500 abstracts in all areas of hematologic disorders, and addressed research examining disparities in hematology care, as well as the impact of COVID-19 on the outcomes of patients with hematologic conditions.

While it is not possible to summarize the wealth of new developments in hematology, we present some key trends that emerged at ASH 2020 that will lead the way into 2021 and beyond as it pertains to drug development in hematology. This summary reflects the combined views of clinical experts including Medical Officers Bruce Feinberg, DO and Ajeet Gajra, MD, as well as select external key opinion leaders.

• COVID-19
• Gene therapy
• CAR-T therapy
• Myeloid disorders (AML, CML, MF, MDS)
• Lymphoid and plasma cell (CLL, ALL, non-Hodgkin’s, Hodgkin’s, Multiple Myeloma)

COVID-19 and blood disorders

The ASH Research Collaborative COVID-19 registry for Hematology was developed to look at outcomes of COVID-19 infection in patients with underlying hematologic malignancies, including leukemia, lymphoma, and plasma cell neoplasms (Abstract 215). A key finding is that patients with hematologic malignancies are at an increased risk for adverse COVID-19 outcomes with an overall mortality rate of 28%. The risks are greatest in those who are older, have advanced disease or poor prognosis, or who forego intensive management for their COVID-19 infection. While intuitive, these data are nonetheless important to bear as we continue to care for patients during these challenging times.

There has been much discussion regarding the role of ABO blood group and outcomes with COVID-19. In a U.S.-based study from Detroit MI, ABO blood groups and Rhesus factor did not correlate with disease severity, use of mechanical ventilation, or mortality in hospitalized COVID-19 patients (Abstract 104). Elderly, male patients with COPD were at increased risk of death. Contrary to perceived belief, African Americans were not at an increased risk of mortality, compared to Caucasians with COVID-19 infection.

An ongoing evolution in gene therapy

Gene therapy is making a paradigm shift that will alter our understanding of medicines. With time, the technology behind gene therapy is expected to become more accessible and less expensive, overcoming the technical, logistical and conceptual hurdles currently present. ASH 2020 saw several key abstracts highlighting the progress of gene therapy.

Etranacogene dezaparvovec (AMT-061) is an investigational gene therapy for hemophilia B, comprising a viral vector containing a human factor IX (FIX) gene. In abstract LBA-6, a single dose of AMT-061 significantly increased FIX activity without the need for prophylactic immunosuppression, even in the presence of neutralizing antibodies of the viral vector. In addition, bleeding was well controlled in the majority of patients, even without bleeding prophylaxis.

In another report for the same product (Abstract 672), three patients with FIX levels ≤1% were treated with AMT-061 and experienced rapid increase of FIX activity to a mean of 31% at week six and sustained improvement of FIX activity into mild-to normal range at week 52 without bleeding events, FIX replacement  and inhibitors to FIX. A single intravenous (IV) dose of AMT-061 appears to transform severe hemophilia B into a functionally curative state. Despite their small sample sizes, these studies offer a proof of concept supported by sustained efficacy and acceptable adverse event profile of AMT-061 in hemophilia B.

Similarly, promising results were reported with another investigational gene therapy product,   Autologous CRISPR-CAS9–Modified CD34+ Hematopoietic Stem and Progenitor Cells (CTX001), (Abstract 4) which led to consistent and sustained responses in patients with sickle cell disease and beta thalassemia. This experimental therapy eliminated the need for transfusions in patients with beta thalassemia and reduced vaso-occlusive crises in patients with sickle cell disease. These data focus positive attention on gene-editing therapy, especially for diseases with high unmet needs.

Chimeric Antigen Receptor T (CAR-T) Cell Therapy competition ramps up

The currently approved CAR-T cell therapies in adults are indicated for large B cell lymphoma and mantle cell lymphoma, however there has been progress in the development of CAR-T therapies in other common hematologic malignancies, such as multiple myeloma and indolent lymphomas, as well as production of off-the-shelf CAR-T products. The following abstracts offer a view into the future potential of CAR-T therapy:

ALLO-715 is an off-the-shelf CAR-T cell therapy targeting B-cell maturation antigen (BCMA). (Abstract 129) In this first-in-human clinical trial of allogeneic BCMA CAR-T cell therapy, nearly 90% of patients with heavily pre-treated relapsed/refractory multiple myeloma (RRMM) showed response within five days of enrollment, without needing any bridging therapy. Allogeneic CAR-T cell therapy offers the potential for scalable manufacturing of products for on-demand treatment with shorter wait times, which would address some of the logistical challenges posed by autologous CAR-T cell therapy. BCMA is also the target for ciltacabtagene autoleucel (cilta-cel), a conventional CAR-T therapy in myeloma. Data from CARTITUDE-1 trial indicate a 95% remission rate in patients with relapsed/refractory myeloma treated with cilta-cel (Abstract 177).

Lisocabtagene Maraleucel (liso-cel), a CD-19 directed CAR-T therapy is being evaluated in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (Abstract 546) in the ongoing phase I TRANSCEND CLL 004 study. Updated results reveal an overall response rate (ORR) of 82% with durable response including high-risk and ibrutinib-treated patients. The phase II monotherapy expansion of this study is currently enrolling patients. Along the same lines, previously approved for large B cell lymphoma, both axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) demonstrate excellent response rate including complete response in indolent lymphomas (Abstracts 700 and 1149).

Updates in myeloid neoplasms (AML, CML, MDS and MPD)

Developments in the treatment of acute myeloid leukemia (AML): Despite recent progress in AML in older patients, outcomes remain poor. A phase 2 study (Abstract 25) of venetoclax added to Cladribine + Low Dose AraC (LDAC) alternating with 5-azacytidine demonstrated  high rates of MRD negative CRs and excellent tolerability in older adults with newly diagnosed AML: the 1-year overall survival (OS) was 70%, and 1-year recurrence-free survival (RFS) was 66%. Importantly, the regimen was well tolerated among the older patient population with an eight-week mortality of only 4%. The venetoclax plus azacitidine combination reported a significant improvement in median OS n treatment-naïve patients with FLT3-mutant AML (Abstract 1904) who were unfit to receive intensive chemotherapy, highlighting the efficacy of bcl-2 inhibition in combination with hypomethylating agents across the spectrum of AML.

Next steps in myelofibrosis treatment: Ruxolitinib, a JAK inhibitor, has been a major advance in managing spleen size and symptoms in myelofibrosis but does not appear to alter the natural history of the disease. Therefore, JAK inhibitors are being combined with other agents and newer drugs are being investigated in hopes of improving current treatment outcomes. ASH 2020 saw early promising results with the addition of navitoclax to ruxolitinib (Abstract 52) in patients with relapsed/refractory myelofibrosis, as well as a favorable overall survival with imetelstat, a telomerase inhibitor in the 2nd line setting (Abstract 53). In the front line setting, the addition of CPI-0610, a bromodomain protein inhibitor, to ruxolitinib appears safe and effective (Abstract 55) whereas momelotinib, a JAK inhibitor, demonstrated robust overall survival and sustained efficacy outcomes in the first line and previously JAK inhibitor treated patients (Abstract 54).

A potential treatment alternative for chronic myeloid leukemia (CML): While tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML, a minority of patients may not respond to currently available agents. The efficacy and safety results from the ASCEMBL trial (Abstract LBA-4), an open label phase 3 study of asciminib, a first-in-class STAMP inhibitor, vs bosutinib in patients with chronic phase CML previously treated with two or more TKIs demonstrated that asciminib significantly improved the rate of major molecular response at 24 weeks compared with bosutinib, meeting the study’s primary objective.

Combination therapies for myelodysplastic syndromes (MDS): It is crucial to build on the success of hypomethylating agents in MDS, especially to improve outcomes in higher risk patients. At ASH 2020 Pevonedistat, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, in combination with azacytidine achieved impressive CR rate of 52%, ORR of 79%, and OS of 24.2 months in patients with higher risk MDS (Abstract 653). The venetoclax and azacytidine combination continues to impress in MDS achieving an ORR of 41% and median OS of 12 months in relapsed disease (Abstract 3109) and an ORR of 79% with median OS of 27.5 months when used frontline (Abstract 656).

Updates in lymphoid and plasma cell disorders (NHL, Hodgkin’s, multiple myeloma)

New horizons in chronic lymphoid leukemia (CLL): BTK inhibitors remained centerstage in management of CLL at ASH 2020. Updated results of the CAPTIVATE (Abstract 123) study in previously untreated patients with CLL treated with MRD negative disease with fixed duration ibrutinib + venetoclax achieved similar 1-year disease-free survival as those who remained on ibrutinib maintenance. LOXO-305, a highly selective, non-covalent Bruton's tyrosine kinase (BTK) inhibitor, demonstrated significant improvement in ORR and consistent safety and efficacy profile in patients with CLL, regardless of previous therapies, reasons for discontinuations of those therapies, or presence of resistance mutations (Abstract 542).

Real World Evidence demonstrates that first-line treatment of high-risk CLL with ibrutinib resulted in improved outcomes compared with chemoimmunotherapy (CIT) and provided sustained clinical benefit regardless of risk status, which is concordant with use in the first-line setting (Abstract 372). The study also highlights the prognostic and predictive value of cytogenetic and molecular testing when a first-line treatment regimen in CLL. However, another report found that prognostic biomarker testing rates remain poor, especially for tumor protein 53 (TP53) and immunoglobulin heavy-chain variable (IGHV) mutational status (Abstract 547).

A need for drugs with longer response duration in patients with RRMM remains. BCMA has emerged as the most favored target for new modalities such as CAR-T, bispecific T-cell engagers and antibody-drug conjugates in RRMM. Early results from multiple bispecific antibody candidates were presented, including: The first-in-human data with AMG 701, a bispecific T cell engager (BiTE®) immuno-oncology therapy targeting BCMA, showed an excellent overall response rate of 83% with manageable safety in RMM with 4 out of 5 responders being triple refractory (Abstract 181). Similarly, REGN5458, a BCMA x CD3 bispecific monoclonal antibody, induced deep and durable responses in patients with RRMM Myeloma (Abstract 291). The first-in-human study of Talquetamab, a bispecific antibody targeting GPRC5D-expressing myeloma cells showed excellent ORR of 78% for iv and 67% for sq dosing in RRMM (Abstract 290) while FcRH5 directed bispecific antibody cevostamab revealed 53% ORR in heavily pre-treated RRMM with 41% RR in pentarefractory patients (Abstract 292).

Daratumumab continues to improve outcomes in myeloma as noted in APOLLO trial in RRMM patients who received the subcutaneous formulation along with pomalidomide and dexamethasone (Abstract 412) as well as in the frontline setting as a part of a quadruplet regimen based on the updated results of the GRIFFIN trial (Abstract 3243). 

Hodgkin Lymphoma: Brentuximab continues to impress in Hodgkin lymphomas including frontline use in older adults (Abstract 471) and brentuximab + nivolumab consolidation following transplant in high-risk disease (Abstract 472). Camidanlumab tesirine, a novel anti-CD25 targeted antibody drug conjugate demonstrated high response rates among heavily pretreated relapsed/refractory Hodgkin lymphoma patients, including patients not eligible for transplant (Abstract 474).

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