ASH 2019 Late-Breaking Abstracts Rundown

Children, adolescent and young adult (AYA) B-cell acute lymphoblastic leukemia (B-ALL) patients at first relapse currently face an unmet need. More efficacious therapies in this setting are necessary to quell the currently high rates of relapse and death that arise with the use of the chemotherapy standard of care. A Phase III trial(AALL1331; NCT02101853), presented by Patrick Brown, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, has demonstrated the superior efficacy of blinatumomab versus the chemotherapy standard.

The aforementioned unmet need is especially pertinent in children and AYAs with early relapse [or high-risk (HR), defined as <36 months from diagnosis or isolated extramedullary relapse <18 months from diagnosis] and those with late relapse and measurable residual disease (MRD) of ≥0.1% at the end of re-induction chemotherapy [intermediate risk (IR)].

Allogeneic hematopoietic stem cell transplant (HSCT) is the preferred treatment for this population. However, many patients are unable to proceed to HCST due to adverse events from chemotherapy and/or failure to achieve MRD negativity at second remission.

The CD3-CD19 Bi-specific T-cell engager (BiTE®), blinatumomab, offers a preferential toxicity profile in addition to efficacy as a standalone therapy. The two arms of this randomized Phase III study received either chemotherapy or blinatumomab following re-induction chemotherapy and prior to HSCT. All patients enrolled were HR/IR first relapse B-ALL patients aged 1-30 years.

With no currently approved treatments, the rare autoimmune hemolytic anemia cold agglutin disease (CAD) presents a real unmet need. CAD patients suffer from hemolysis driven anemia, an increased risk of thromboembolism,= and early mortality. The Phase III Cardinal study (NCT03347396), presented during the 61st ASH Annual Meeting and Exposition by Alexander Röth, MD, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, has demonstrated that sutimlimab presents an effective therapeutic approach for the management of CAD.

Sutimlimab is a first-in-class humanized monoclonal anti-C1 antibody. Through preventing the activation of the classical complement pathway (CP) via the selective inhibition of the C1 complex of complement, the monoclonal antibody prevents erythrocyte opsonization. The treatment offers a means to prevent hemolysis, significantly increase hemoglobin (Hb), and ultimately improve quality of life (QoL). The safety and efficacy of a potential treatment like sutimlimab is pertinent, considering the current lack of therapeutic options.

Patients with a confirmed diagnosis were enrolled, with an eligibility criteria of a baseline Hb ≤10 g/dL, an above-normal total bilirubin level, and one or more blood transfusions in the prior 6 months. Of the 24 patients enrolled 62.3% were female, and the mean age was 71.3 years. The study first followed patients for 26 weeks while receiving intravenous transfusions on days 0 and 7, followed by bi-weekly transfusions (part A) and an ongoing extension thereafter (part B).

The Phase III QUAZAR AML-001 trial (NCT01757535), presented by Andrew Wei, MBBS, PhD, Alfred Hospital and Monash University, Melbourne, Australia, evaluated an oral formulation of azacitidine (CC-486) in patients with acute myeloid leukemia (AML) in first remission following intensive induction chemotherapy (IC). The response to IC in patients is often short-lived and OS is poor. The lack of meaningful and lasting benefits necessitates improved maintenance therapies for such patients. This study evaluated the efficacy of CC-486 in extending the benefits of post-remission maintenance treatment (Tx) in older AML patients.

As mentioned previously, many elderly AML patients receiving Tx aren’t living significantly longer post-treatment as the benefits are temporary. CC-486 is an oral hypomethylating agent used to prolong drug exposure during Tx and is being evaluated as a potential combination therapy alongside IC treatment to provide meaningful improvements in such patients.

Patients admitted to the study had secondary or de novo AML and intermediate- or poor-risk cytogenetics. They also would have achieved first complete remission (CR) or CR with incomplete count recovery (CRi) after IC. Patients were randomized 1:1 receiving either 300mg of CC-486 or placebo on days 1-14 of 28-day repeated Tx cycles.

The medical community has gained a deeper understanding of the pathogenesis of myeloid malignancies, such as AML and myelodysplastic syndrome (MDS), thanks to recent genomic sequencing studies. While this information has proven beneficial, there is a gap in knowledge where specific subgroups and/or targeted DNA-sequencing have been analyzed. A recent study, conducted by Ilaria Iacobucci, PhD, St. Jude Children’s Research Hospital, Memphis, TN, has performed a genome-wide mutational/transcriptomic analysis of a large cohort of adult AML and MDS samples to accurately define subtypes of diagnostic, prognostic and therapeutic significance.

This study performed unbiased whole genome sequencing (WGS) and transcriptome sequencing (RNA-seq) in 1,304 adult individuals consisting of 598 AML and 706 MDS patients. Somatic and presumed germline sequence mutations, chimeric fusions and structural complex variations were incorporated into this analysis. From this investigation, associations between genetic variants, gene expression groups and outcome were studied.

TET2 (more frequent in MDS than AML) and DNMT3A (more frequent in AML than MDS) were the most frequently mutated genes. Interestingly, mutations in these genes promoting clonal hematopoiesis were significantly enriched in the subgroup with NPM1 mutations. Overall, NPM1 mutations occurred in 27.4% of AML and 1% of MDS, and were characterized by four expression signatures with a different combination of cooperating mutations in cohesin and signaling genes and outcome.

Co-occurring NPM1 and FLT3 mutations conferred poorer outcomes compared to only NPM1; in contrast, co-occurring mutations with cohesin genes had preferable outcomes. Additional mutations that significantly co-occurred with NPM1 were in PTPN11, IDH1/2, RAD21 and SMC1A.

Sickle cell disease (SCD) remains a considerable burden for patients, with just 50% surviving beyond their fifth decade. Controlling the expression of gamma (γ)-globin locus, BAF chromatin remodeling complex subunit (BCL11A) regulates the fetal-adult hemoglobin switch and hence represents an appealing therapeutic for SCD. A pilot/feasibility trial has assessed the use of BCH-BB694-transduced autologous CD34+ cells in severe SCD patients.

This open-label, non-randomized, single-center trial (NCT03282656), presented at the 61st ASH Annual Meeting and Exposition by David Williams, MD, Dana-Farber/Boston Children’s Cancer & Blood Disorders Center, Boston, MA, reports on a patient cohort consisting of three patients ≥18 years old with severe SCD. Plerixafor mobilization was used to collect autologous CD34+ cells, which were then transduced ex vivo with a BCH-BB694 shmiR lentiviral vector (LVV). After testing and release, gene-modified cells were infused into patients who had received busulfan conditioning.

17 months post-infusion, patients have experienced no adverse events related to the gene therapy product. Vector copy number has been stable in the bone marrow (BM) and peripheral blood (PB) in all cell lineages for the duration of the study, with the most recent data showing 0.45-2.85 copies per cell in erythroid progenitor cells.

Effective and selective knockdown of BCL11A in erythroid progenitors with no reduction in BCL11A expression in B lymphoid cells was found upon BCL11A protein level evaluation by immunoblot in subject BCL002 at 30 days (PB) and six months (BM) post-infusion.

Lenalidomide (LEN) and bortezomib have provided improved survival outcomes in newly diagnosed multiple myeloma (MM) patients undergoing continuous or maintenance therapy. Despite this, toxicity presents an issue and subsequent treatment discontinuation in this population has highlighted the need for more tolerable, efficacious and novel regimens. Carfilzomib and daratumumab have been investigated as therapeutic options in the Phase III Candor trial (NCT03158688). Saad Usmani, MD, FACP, University of North Carolina School of Medicine, Chapel Hill, NC, presented the late-breaking data at the 61st ASH Annual Meeting and Exposition.

In this open-label study, a comparison was made between carfilzomib, dexamethasone, and daratumumab (KdD) vs. carfilzomib and dexamethasone (Kd) in relapsed/refractory (R/R) MM patients. Patients who had undergone 1–3 prior lines of therapy, with partial response or better to ≥1 line of therapy were eligible and were randomized 2:1 to KdD or Kd.

Progression-free survival (PFS) represented the primary endpoint, while secondary endpoints were comprised of overall response rate (ORR), minimal residual disease (MRD) negative-complete response at 12 months (mo), overall survival (OS), time to response, and safety.

Of the 466 patients enrolled, 42.3% and 90.3% received previous LEN- and BTZ-containing regimens, respectively, and 33% of patients were LEN-refractory.