Blinatumomab Superior to Chemotherapy as Post-Reinduction Therapy in High-Risk Child & AYA B-ALL Patients at First Relapse

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.

Disease-free survival (DFS) represented the primary aim, with AEs, MRD response, overall survival (OS) and the ability to proceed to HSCT comprising the secondary aims. Considering both primary and secondary aims, this study found compelling evidence supporting the establishment of blinatumomab as a new standard of care.

Sutimlimab Effectively Prevents Hemolysis in Patients with CAD by Inhibiting Activation of the Classical Complement Pathway (CP)

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).

Response rate was measured by Hb increase and represented the primary endpoint of the trial, while secondary endpoints were comprised of changes in hemolytic markers from baseline (e.g. bilirubin) and QoL. The study reported Hb levels sustained > 11 g/dL following the third week, prevention of hemolysis and improved QoL, providing support for the use of sutimlimab for the treatment of CAD.

CC-486 (Oral Azacitidine) Prolongs the Benefits of Induction Therapy in Elderly AML Patients

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 primary endpoint was OS and secondary endpoints comprised of health-related QoL, relapse-free survival (RFS) and drug safety. They also tested measurable residual disease (MRD). CC-486 demonstrated clinically and statistically significant improvements in RFS and OS in AML patients following IC, and a safety profile generally consistent with injectable azacitidine; making it a promising option as a new therapeutic standard for patients with AML in remission.

Prognostic Mutation Constellations in AML and MDS

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 PTPN11IDH1/2RAD21 and SMC1A.

Three gene expression clusters accounted for an additional 9% of cases with mutual exclusive mutations in RUNX1, TP53 and CEBPA and co-occurring with a combination of mutations in DNA methylation, splicing and signaling genes.

In summary, the integration of mutational and expression data from a large cohort of adult pan-myeloid leukemia cases allowed for the definition of subtypes and constellations of mutations which have prognostic significance not previously considered in prior gene panel-based classification schemas.

Inducing Sustained Expression of Fetal Hemoglobin using Post-Transcriptional Gene Silencing

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.

 

 

The results for all three subjects in this adult cohort showed reduced numbers of red blood cells (RBCs) with significant Hb polymer compared with two hydroxyurea-responsive treated comparators, and significantly less Hb polymer per sickled RBC than a third highly responsive hydroxyurea-treated comparator. The successful and sustained engraftment of three adult patients treated with LVV-delivered shmiR technology targeting BCL11A was demonstrated by this study. Early results suggest an acceptable safety profile, and confirmation of BCL11A as an effective target in the mitigation of SCD cellular pathology.

Candor: KdD vs. Kd for MM

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.

PFS was met after a median follow-up of 16.9 mo and 16.3 mo for the KdD and Kd arms while median PFS was not reached for the KdD arm vs. 15.8 mo for the Kd arm. Similarly, PFS was not met in the LEN-Exposed group in the kdD arm vs. 11.1 mo in the Kd arm. Additionally, the MRD-negative complete response rate at 12 mo was 12.5% for KdD vs. 1.3% for Kd.

This study demonstrated in this patient population that KdD resulted in a favorable efficacy and was generally well tolerated. With a 37% reduction in the risk of progression or death KdD represents an efficacious new regimen of R/R MM.

References

Brown P, Lingyun J, Ji L et al. A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in High and Intermediate Risk (HR/IR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs) Demonstrates Superior Efficacy and Tolerability of Blinatumomab: A Report from Children’s Oncology Group Study AALL1331. Blood. 2019 Nov; 134(Supplement_2): LBA-1.

Roeth A, Barcellini W, D’Sa S et al. A Study to Assess the Efficacy and Safety of BIVV009 (Sutimlimab) in Participants With Primary Cold Agglutinin Disease Without A Recent History of Blood Transfusion (Cadenza Study). Blood. 2019 Feb 28;133(9):893-901.

Wei A, Döhner H, Pocock C et al. Efficacy of Oral Azacitidine Plus Best Supportive Care as Maintenance Therapy in Subjects With Acute Myeloid Leukemia in Complete Remission (QUAZAR AML-001). Future Oncol. 2019;12(3):293-302.

Iacobucci I, Meggendorfer M, Nadarajah N et al. Integrated Transcriptomic and Genomic Sequencing Identifies Prognostic Constellations of Driver Mutations in Acute Myeloid Leukemia and Myelodysplastic Syndromes. Blood. 2019 Nov: 134 (Supplement_2): LBA-4.

Esrick EB, Achebe M, Armant M et al. Validation of BCL11A As Therapeutic Target in Sickle Cell Disease: Results from the Adult Cohort of a Pilot/Feasibility Gene Therapy Trial Inducing Sustained Expression of Fetal Hemoglobin Using Post-Transcriptional Gene Silencing. Blood. 2019 Nov; 134(Supplement_2): LBA-5.

Usmani S, Quach H, Mateos MV et al. Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor (NCT03158688). Blood. 2019 Nov; 134(Supplement_2): LBA-6.

 

Written by Thomas Southgate and Marjon Karimee

Edited by Cally Cameron Smith

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