Endotheliopathy is essential in COVID-19 associated coagulopathy

A notable feature of COVID-19 pathogenesis is hypercoagulability. The mechanisms that result in this phenomenon were investigated by George Goshua et al, MD of the Yale-New Haven Hospital, New Haven, CT. 1

The first COVID-19 related mortality at the Yale-New Haven Hospital occurred mid-March in a 45-year-old male and upon examination, a pulmonary embolism was discovered. Soon after, COVID-19 associated coagulopathy (CAC) was identified as a characteristic of COVID-19 disease progression worldwide, and therefore understanding the mechanism of coagulopathy is of utmost importance to tailor treatments to an individual patient.

Hemostatic markers of 48 ICU and 20 non-ICU patients with COVID-19 were measured and several conclusions were drawn from these results. Endogenous anticoagulants and fibrinolytic enzymes were preserved within the COVID-19 cohort which implies that CAC is distinct from disseminated intravascular coagulation. Furthermore, von Willebrand factor (VWF) and Factor VIII (FVIII) were found to be highly elevated within the patients in ICU, indicating endotheliopathy plays a significant role in CAC.

Due to the significance of endotheliopathy in CAC, endothelial cell and platelet markers were measured and soluble CD40 ligand and P-selectin were discovered to be significantly elevated in the COVID-19 positive ICU patients compared with COVID-19 negative controls. Whilst thrombomodulin was not determined to be significantly elevated in COVID-19 ICU patients, an exploratory analysis suggests that thrombomodulin can predict survival in all patients.

The results from this presentation have several therapeutic implications such as the administration of aspirin for all hospitalized patients with COVID-19 as well informing investigations into dipyridamole, defibrotide and eculizumab as potential therapies.

In summary, evidence of endotheliopathy was determined in patients with COVID-19, as characterized by elevated VWF and FVIII and signified a progression to critical illness. In addition, thrombomodulin segregates with mortality as determined in an exploratory analysis.

Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase III, randomized, open-label study

The phase III IKEMA study (NCT03275285), presented by Philippe Moreau, MD, Nantes University Hospital, Nantes, France, evaluated the use of isatuximab plus carfilzomib and dexamethasone (Isa-Kd) vs carfilzomib and dexamethasone (Kd) in patients with relapsed/refractory (R/R) multiple myeloma (MM).2

Isatuximab is an IgG1 monoclonal antibody targeting a transmembrane glycoprotein on CD38 and results in various cytotoxic effects, including antibody-dependent cell-mediated cytotoxicity, complement dependent cytotoxicity and antibody-dependent cellular phagocytosis. In addition, isatuxumab can induce direct apoptosis, immunomodulation and the inhibition of CD38 ectoenzyme activity.

Approximately 300 patients, treated with between one and three prior lines of therapy, were stratified and randomized to receive Isa-Kd (n=179) or Kd (n=123). The primary endpoint of the study was progression-free survival (PFS). Various secondary endpoints were evaluated, including overall response rate, minimal residual disease (MRD) negativity, and complete response rate.

The interim PFS analysis presented at EHA 2020, reported a median PFS in the Kd arm of 19.15 months (95% CI: 15.770-NE), which is similar to the results of an interim survival analysis of the ENDEAVOR trial that led to the approval of Kd for this indication.3 Isa-Kd significantly improved PFS with a hazard ratio of 0.531, corresponding to a 47% reduction in the risk of progression or death. Consistent improvements in PFS were observed across most patient subgroups and Isa-Kd also resulted in a notable delay in time to next treatment.

 

As measured by MRD, deeper responses were seen with Isa-Kd which was consistent with striking PFS improvements. The MRD negativity rate with Isa-Kd was approximately 30% in the ITT population compared with 13% in the Kd treatment arm.

The rate of ≥Grade 3 adverse events observed were higher in the Isa-Kd arm; however, there was no significant difference in the number of fatal events observed as well as no difference in the incidence of adverse events leading to discontinuation, suggesting that Isa-Kd has a manageable safety profile.

In summary, IKEMA met its primary endpoint and Isa-Kd represents a potential new standard of care for patients with relapsed/refractory multiple myeloma.

Subcutaneous daratumumab + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly-diagnosed light chain (AL) amyloidosis: primary results from the phase III ANDROMEDA study

Systemic light chain (AL) amyloidosis is a rare disease characterized by insoluble amyloid fibril deposition in tissues and organs. No therapies are currently approved by health authorities for the treatment of AL amyloidosis; however, outcomes have improved due to the use of novel bortezomib-based myeloma therapies such as cyclophosphamide, bortezomib and dexamethasone (CyBoRD). Sustained hematologic responses are required in AL amyloidosis to reverse amyloid-mediated organ dysfunction and improve overall survival.

Efstathios Kastritis, MD, of the University of Athens School of Medicine, Athens, Greece, presented results from the randomized phase III ANDROMEDA study (NCT03201965) of subcutaneous daratumumab (DARA Sc) plus CyBorD vs CyBorD alone for newly diagnosed AL amyloidosis patients.4 DARA is a CD38 targeted antibody used as an anti-plasma cell therapy. The efficacy and safety profile of DARA Sc is well characterized in multiple myeloma and shows promising single-agent activity in AL amyloidosis.

Patients were randomized 1:1 to receive CyBorD weekly with or without DARA Sc. The primary endpoint of ANDROMEDA was overall hematologic complete response (CR) rate. Secondary endpoints included major organ deterioration (MOD) event free survival (MOD-EFS), organ response rate and MOD progression-free survival (PFS).

The hematological CR at 6 months was 50% with DARA-CyBorD vs 14% with CyBorD alone, and median time to CR was also less in the DARA-CyBorD arm. Furthermore, improvements in CR in the DARA-CyBorD arm was seen across all patient subgroups.

Treatment with DARA-CyBorD substantially improved MOD-EFS with delays in major organ deterioration, hematologic progression and death observed. Cardiac and renal responses also doubled with the addition of DARA, and DARA-CyBord exhibited an acceptable safety profile.

In conclusion, the addition of DARA Sc to CyBorD was superior to CyBorD alone and resulted in deeper and more rapid hematologic responses as well as delayed MOD-PFS, improved MOD-EFS and improved organ response rate.

Positron emission tomography-guided omission of radiotherapy in early-stage unfavorable Hodgkin lymphoma: final results of the international, randomized Phase III HD17 trial by the GHSG

Since the German Hodgkin Study Group (GHSG) HD14 study, where 2+2 (2 x eBEACOPP + 2 x ABVD) was shown to be a more superior regimen than two cycles of ABVD, 2+2 plus radiotherapy (RT) consolidation has been the standard treatment for early-stage, unfavorable Hodgkin lymphoma (HL).5

However, 2+2 plus RT leads to more severe hematological toxicities, an increased incidence of primary malignancies and fertility issues. Therefore, evaluating the omission of RT is of importance in preventing treatment-related unfavorable incidences.

Peter Borchmann, MD, of University Hospital Cologne, Cologne, Germany, presented data from the phase III HD17 study (NCT01356680), evaluating whether RT can be omitted in patients achieving a complete metabolic response after 2+2 chemotherapy without a loss of efficacy.6

Patients were subsequently assigned combined modality treatment with 4 cycles of chemotherapy followed by 30Gy involved-field RT or PET-guided treatment, omitting RT in PET-negative patients. The primary endpoint measured was the difference in 5-year progression-free survival (PFS) between the two arms.

There was a 2.2% difference in 5-year PFS between the two arms, with a PFS of 97.3% in the standard group and 95.1% in the PET-guided omission group. Furthermore, sensitivity analyses in the PET-negative patients showed no significant difference in 5-year PFS between the two arms.

Therefore PET-guided treatment of early stage unfavorable HL using the 2+2 backbone is non-inferior to chemotherapy-radiotherapy treatment using 2+2 and Gy consolidation radiotherapy.

An intact gut microbiome protects genetically predisposed mice against leukemia

In B-cell precursor acute lymphoblastic leukemia (pB-ALL), it is already established that a second hit drives conversion of a pre-leukemic clone into leukemia and that infection could be this driver for change. Carolina Vicente-Dueñas, PhD, Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain, presented data describing how an intact gut microbiome can protect genetically predisposed mice against leukemia.7

Using Pax5+/- mice either developed in a specific pathogen-free (SPF) facility or a conventional facility (CF), CF Pax5+/- mice were more likely to develop pB-ALL. Furthermore, a lower number of B-cells were detected in gut-associated lymphoid tissue of Pax5+/- mice developed in CF. Therefore, the gut microbiome may interact with gut associated lymphoid tissue in a way that can modulate development of pB-ALL.

Subsequently, they investigated the gut microbiome of Pax5+/- and wild-type mice developed in SPF and CF environments as well as co-housing experiments. As anticipated, the gut microbiome was found to be different between SPF and CF reared mice; however, Pax5+/- mice have a distinct microbiome that was found to be independent of microenvironmental factors.

Furthermore, the incidence of genetic predisposition could be accurately predicted using a matched learning analysis with an accuracy of 96%, suggesting the microbiome can be used as a biomarker for genetic predisposition.

To further analyze the role of the gut microbiome, Pax5+/- mice were treated with antibiotics to elucidate its effect on pB-ALL progression. Antibiotic treated mice in both SPF and CF conditions had a significant increase in pB-ALL incidence, from 0% to 47.82% in CF Pax5+/- mice, and from 21.95% to 62.96% in SPF Pax5+/- mice. Leukemia arising in Pax5+/- mice were also phenotypically similar to their human counterparts, further highlighting the value of this model.

In conclusion, the gut microbiome profile provides a biomarker that could be used to identify predisposed carriers at risk of developing leukemia, and gut microbiome deprivation via antibiotic treatment early in life is a risk factor for leukemia development in predisposed carriers.

Fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: follow-up of efficacy and safety results from the multicenter, open-label, randomized Phase III CLL14 trial

The CLL14 trial (NCT03201965) aimed to evaluate fixed-duration venetoclaxobinutuzumab for previously untreated chronic lymphocytic leukemia (CLL). At EHA 2020, Othman Al-Sawaf, MD, of the University Hospital of Cologne, Cologne, Germany, presented follow-up efficacy and safety results from the study that was first published in 2019.8

In CLL14, untreated patients with co-existing medical conditions were randomized 1:1 to receive venetoclax-obinutuzumab or chlorambucil–obinutuzumab. The primary endpoint of the study was progression-free survival (PFS).

Follow-up efficacy analyses showed a 3-year PFS of 81.9% in the venetoclax-obinutuzumab cohort versus 49.5% in the chlorambucil–obinutuzumab arm. Furthermore, this continued PFS benefit included patients with mutant IGHV and TP53 mutations or deletions.

Following 18 months of treatment cessation, 47.2% of patients in the experimental arm had undetectable minimal residual disease (uMRD), compared with only 7.4% of patients treated with chlorambucil–obinutuzumab. Next generation sequencing analysis of MRD identified a subset of patients undergoing MRD conversion and this was more frequent in the chlorambucil–obinutuzumab arm. Interestingly, characteristics of patients with deep responses showed that the traditional prognostic markers for high-risk CLL, including TP53 mutational status, complex karyotypes and CLL-IPI risk group did not necessary predict poor response when treated with venetoclax-obinutuzumab.

Follow-up safety analyses showed a slight increase in the incidence of secondary malignancies in patients treated with venetoclax-obinutuzumab, 6.4% of patients compared to 1.9% in the chlorambucil–obinutuzumab arm.

To conclude, follow-up analyses of CLL14 confirms the indication of venetoclax-obinutuzumab for previously untreated CLL patients. Promisingly, approximately half of patients treated with venetoclax-obinutuzumab maintained uMRD almost two years after treatment cessation. However, further follow-up of second primary malignancy frequency is warranted.

Phase I/II ALEXANDER study of AUTO3, the first bicistronic chimeric antigen receptor (CAR) targeting CD19 and CD22 with pembrolizumab in patients with relapsed/refractory diffuse large B-cell lymphoma

The onset of CD19 CAR T-cell therapies in diffuse large B-cell lymphoma (DLBCL) has improved patient outcomes; however, an unmet need in this patient group still remains as only 29–37% of patients have a durable complete response. This may be attributed to PD-L1 upregulation contributing to CAR-T exhaustion as well as CD19 antigen loss to promote antigen escape. Wendy Osborne, MBBS (Hons), MRCP, FRCPath, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK, presented preliminary results from the Phase I/II study investigating AUTO3, a bicistronic CAR targeting both CD19 and CD22 in combination with pembrolizumab in a bid to improve CAR-T outcomes in DLBCL.9

The initial dose-escalation study enrolled 23 relapsed/refractory DLBCL patients who were dosed with either 50, 150 or 450 x 106 CAR T-cells. Patients received AUTO3 alone, or with 3 doses of pembrolizumab 200 mg every 3 weeks starting on day 14 or with a single dose of pembrolizumab 200 mg on day -1. The primary endpoints of the study were the incidence of Grade 3–5 toxicities within 75 days of AUTO3 infusion and the frequency of dose-limiting toxicities.

The incidence of treatment-related adverse events were mainly hematological and reversible and did not contribute to dose-limiting toxicities. The majority of cases of cytokine release syndrome (CRS) were Grade 1, with no Grade 3 incidences observed. Furthermore, only 17% of patients required tocilizumab therapy for their CRS. In addition, there was only one incidence of neurotoxicity which may have been due to an unrelated factor.

At all dose levels, complete responses were observed at a rate of 48%. For patients treated with day -1 pembrolizumab, there was a 63% complete response rate observed. Moreover, 10/11 patients maintained durable complete responses at 12 months.

This study demonstrated that AUTO3 warrants further exploration as a CAR T-cell therapy for DLBCL. This bicistronic approach is accompanied with a tolerable safety profile as well as an induction of complete responses without severe CRS or neurotoxicity in the majority of patients.

Written by Solyana Yohannes

References

  1. Goshua G, Pine A, Meizlish M et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. The Lancet Haematology. 2020
  2. Moreau P, Dimopoulos M, Yong K et al. Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design. Future Oncology. 2020;16(2):4347-4358.
  3. Dimopoulos M, Goldschmidt H, Niesvizky R et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. The Lancet Oncology. 2017;18(10):1327-1337.
  4. Palladini G, Kastritis E, Maurer M et al. Daratumumab Plus CyBorD for Patients With Newly Diagnosed AL Amyloidosis: Safety Run-in Results of ANDROMEDA. Blood. 2020
  5. Gillessen S, Plütschow A, Fuchs M et al. Dose-Intensification in Early Unfavorable Hodgkin Lymphoma: Long-Term Follow up of the German Hodgkin Study Group (GHSG) HD14 Trial. Blood. 2019;134(Supplement_1):129-129.
  6. Borchmann P. Position Emission Tomography-Guided Omission of Radiotherapy in Early-Stage Unfavorable Hodgkin Lymphoma: Final Results of the International, Randomized Phase III HD17 Trial by the GHSG. EHA. 2020
  7. Vincente-Dueñas C, Janssen S, Oldenburg M et al. An Intact Gut Microbiome Protects Genetically Predisposed Mice Against Leukemia. EHA. 2020
  8. Al-Sawaf O, Zhang C, Tandon M et al. Fixed-duration venetoclax-obinutuzumab for previously untreated patients with chronic lymphocytic leukemia: Follow-up of efficacy and safety results from the multicenter, open-label, randomized, phase III CLL14 trial. Journal of Clinical Oncology. 2020;38(15_suppl):8027-8027.
  9. Osborne W, Marzolini M, Tholouli E et al. Phase I Alexander study of AUTO3, the first CD19/22 dual targeting CAR T cell therapy, with pembrolizumab in patients with relapsed/refractory (r/r) DLBCL. Journal of Clinical Oncology. 2020;38(15_suppl):8001-8001.

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