1.
To the Editor:
The ongoing pandemic with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and resultant coronavirus disease 2019 (COVID‐19) is resulting in high mortality and morbidity worldwide.1, 2 While the exact impact of SARS‐CoV‐2 in cancer patients remains to be defined, early reports, especially from China, suggest an increased mortality in those older than 60 years, those with pulmonary compromise or hematological malignancies. 3 The virus SARS‐CoV‐2 uses the angiotensin converting enzymes‐related carboxypeptidase (ACE2) receptor to gain entry into cells, with these receptors widely expressed in the cardiopulmonary system, monocytes and monocyte‐derived macrophages. 4 Monocytes and macrophages frequently interact with ACE2‐expressing cells in various tissues, and ACE2 is also expressed by cells of the bone marrow (BM) niche, where it associates with the granulocyte‐colony stimulating factor (G‐CSF) receptor to negatively regulate hematopoietic progenitor cells mobilization (supplemental material for complete reference list in Data S1).
The cytokine profile of patients with COVID‐19 resembles that of patients with secondary hemophagocytic lymphohistiocytosis (HLH), with the excess production of interleukin 2 (IL‐2), IL‐6, G‐CSF, interferon gamma inducing protein 10, monocyte chemoattractant protein‐1 and tumor necrosis factor (TNF) alpha, among others.5, 6 Severe manifestations of SARS‐CoV‐2 are largely cytokine mediated and include cytokine release syndrome (CRS), respiratory failure secondary to acute respiratory distress syndrome (ARDS), and multiorgan dysfunction syndrome (MODS) (Figure S1).1, 2, 5 Note, IL‐6 is a prominent secreted cytokine and plays a critical role in the inflammatory cascade seen. 6 This has led to the use of IL‐6 and IL‐6 receptor (IL‐6‐R)‐directed monoclonal antibodies such as siltuximab (IL‐6) and tocilizumab/sarilumab (IL‐6‐R) in the management of CRS and ARDS in patients with COVID‐19.
The 2016 iteration of the World Health rganization (WHO) classification of myeloid neoplasms identifies four distinct sub‐types of adult onset myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), namely chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, BCR/ABL‐negative (aCML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN‐RS‐T), and MDS/MPN, unclassifiable (MDS/MPN‐U). 7 Among these, proliferative variants of CMML, MDS/MPN‐U and aCML tend to have persistent leukocytosis along with circulating immature myeloid cells. 8 Proliferative CMML in particular has a proinflammatory phenotype with elevated serum levels of cytokines including IL‐6, TNF‐alpha, monocyte colony stimulating factor (M‐CSF) and IL‐1RA 9 ; with CMML cells demonstrating an intrinsic hypersensitivity to GM‐CSF that is more prominent in RAS‐mutant samples. 10 Case series have described exaggerated leukemoid reactions, CRS, ARDS and MODS in CMML patients who have undergone surgery, or in response to infections/inflammation; given the abundance of ACE2 receptors experessed on monocytes and macrophages, we hypothesize that these patients are particularly susceptible to the cytokine‐related complications of SARS‐CoV‐2. 11
We describe a 69‐year‐old man with symptomatic (constitutional symptoms), proliferative, ASXL1, NRAS, TET2 mutated‐ CMML‐0 with a normal karyotype, who had a stable white blood cell count (WBC) of ~35 × 109/L for 6 months, regulated on hydroxyurea. A donor search for allogenic hematopoietic cell transplant had been initiated. Further dose increments in hydroxyurea to try to better control his leukocytosis were not tolerated, due to anemia and thrombocytopenia. The patient was admitted with high grade fever and hypoxic respiratory failure to his local hospital. His WBC on admission was 90 × 109/L with neutrophilic series left‐shift and he went on to develop ARDS and MODS, necessitating assisted ventilation. He was diagnosed with SARS‐CoV‐2 and died prior to the administration of anti‐cytokine directed therapies.
Given the paucity of evidence for the management of hematological malignancies during this pandemic and the proinflammatory milieu of proliferative MDS/MPN overlap neoplasms, we formed an ad hoc expert panel to help draft consensus emergency recommendations for the management of COVID‐19 in these patients. The committee also reviewed available cytokine‐directed clinical trials for SARS‐CoV‐2 and summarized details of therapies of particular interest to patients with proliferative MDS/MPN‐overlap neoplasms (Table 1).
TABLE 1.
Cytokine signaling‐associated clinical trials for COVID patients
| NCT number | Drug name | Mechanism of action | Phase | Enroll # | Arms | Dosage | Location | Recruitment status |
|---|---|---|---|---|---|---|---|---|
| NCT04322773 | Tocilizumab vs. Sarilumab | IL‐64 antagonists | 2 | 200 | Tocilizumab | Single Dose 400 mg (IV) | Denmark | Yes |
| Tocilizumab | Single Dose 2 × 162 mg (sc) | |||||||
| Sarilumab | Single Dose 1 × 200 mg (sc) | |||||||
| NCT04324073 | Sarilumab | IL‐6R antagonist | 2,3 | 240 | Sarilumab | Single Dose 1 × 400 mg (IV) | France | Yes |
| NCT04327388 | Sarilumab | IL‐6R antagonist | 2,3 | 300 | Sarilumab | Single Dose 1 concentration (IV) | Canada, France, Italy, Spain | Yes |
| Sarilumab | Single Dose 2 concentration (IV) | |||||||
| NCT04341870 | Sarilumab | IL‐6R antagonist | 2,3 | 60 | Sarilumab in combo with ( a ): | Single Dose 400 mg (IV) on D1 | France | Not open yet |
| a Azithromycin | Oral, 500 mg on D1, 250 mg D2‐D5 | |||||||
| a Hydroxychloroquine | Oral, 600 mg QD (200 mg TID) on D1‐D10 | |||||||
| Sarilumab alone | Single Dose 400 mg IV | |||||||
| NCT04315298 | Sarilumab | IL‐6R antagonist | 2,3 | 400 | Sarilumab | Single Dose (IV) low dose | US | Yes |
| Sarilumab | Single Dose (IV) high dose | |||||||
| Placebo | Single Dose (IV) to match Sarilumab | |||||||
| NCT04329650 | Siltuximab | IL‐6 antagonist | 2 | 100 | Siltuximab | Single Dose (IV) 11 mg/Kg | Spain | Not open yet |
| Methylprednisolone | 250 mg/24 h (IV) × 3 d followed by 30 mg/24 h × 3 d | |||||||
| NCT04331795 | Tocilizumab | IL‐6R antagonist | 2 | 50 | Tocilizumab (with risk factors) | Single Dose 200 mg (IV)‐ 2nd dose if needed | US | Yes |
| Tocilizumab (without risk factors) | Single Dose 80 mg (IV)‐ 2nd dose if needed | |||||||
| NCT04315480 | Tocilizumab | IL‐6R antagonist | 2 | 38 | Tocilizumab | Single Dose (IV) 8 mg/kg | Italy | Active, not recruiting |
| NCT04335071 | Tocilizumab | IL‐6R antagonist | 2 | 100 | Tocilizumab | Single Dose (IV) 8 mg/kg | Switzerland | Not open yet |
| Placebo | Single Dose (IV) 100 mL of NaCl 0.9% | |||||||
| NCT04320615 | Tocilizumab | IL‐6R antagonist | 3 | 330 | Tocilizumab | Single Dose by IV | US, Canada, Denmark, France, Germany, Italy, UK, Spain | Yes |
| Placebo | Single Dose by IV | |||||||
| NCT04317092 | Tocilizumab | IL‐6R antagonist | 2 | 400 | Tocilizumab | Single Dose 8 mg/kg (IV) | Italy | Yes |
| NCT04332094 | Tocilizumab | IL‐6R antagonist | 2 | 276 | Tocilizumab in combo with ( a ): | Two Doses on Day 1: 162 mg (sc) 12 h apart | Spain | Yes |
| a Azithromycin | Oral, 500 mg on D1‐D3 | |||||||
| a Hydroxychloroquine | Oral, 400 mg/12 h D1,200 mg/ 12 h for D2‐D6 | |||||||
| Azithromycin with ( a ): | Oral, 500 mg on D1‐D3 | |||||||
| a Hydroxychloroquine | Oral, 400 mg/12 h D1, 200 mg/12 h for D2‐D6 | |||||||
| NCT04335305 | Tocilizumab with Pembrolizumab | IL‐6R antagonist (Toc); Immune check point block (Pem) | 2 | 24 | Tocilizumab with ( a ): | Single Dose 8 mg/kg (IV) | Not open yet | |
| a Pembrolizumab | Single Dose 200 mg (IV) | |||||||
| NCT04339712 | Anakinra vs. Tocilizumab | IL‐1R antagonist (Ana) | 2 | 20 | Tocilizumab | In case of immune dysregulation: single dose 8 mg/kg (IV) | Greece | Not open yet |
| IL‐6R antagonist (Toc) | Anakinra | Incase of MAS: 200 mg × 3 daily for 7 d (IV) | ||||||
| NCT04330638 | Anakinra, Anakinra with Siltuximab, Tocilizumab, Tocilizumab with Anakinra | IL‐6 antagonist (Sil); IL‐1R antagonist (Ana); IL‐6R antagonist (Toc); | 3 | 342 | Anakinra | Daily 100 mg (sc) for 28 d | Belgium | Yes |
| Siltuximab | Single Dose 11 mg/kg (IV) | |||||||
| Anakinra with ( a ): | Daily 100 mg (sc) for 28 d (or until discharge) | |||||||
| a Siltuximab | Single Dose 11 mg/kg (IV) | |||||||
| Tocilizumab | Single Dose 8 mg/kg (IV) | |||||||
| Anakinra with ( a ): | Daily 100 mg (sc) for 28 d | |||||||
| a Tocilizumab | Single Dose 8 mg/kg (IV) | |||||||
| NCT04341584 | Anakinra | IL‐1R antagonist | 2 | 240 | Anakinra | 2 × 200 mg (IV) on D1‐D3, 2 × 100 mg (IV) on D4, 1 × 100 mg (IV) on D5 | France | Not open yet |
| NCT04324021 | Emapalumab or Anakinra | IFN‐γ inhibitor (Ema); IL‐1R antagonist (Ana) | 2,3 | 54 | Emapalumab | D1: 6 mg/kg (IV), D4, D7, D10, D13 3 mg/kg (IV) | Italy | Yes |
| Anakinra | 400 mg/kg (V) 4 × daily for 15 d | |||||||
| NCT04337216 | Mavrilimumab | GM‐CSFR α monoclonal | 2 | 10 | Mavrilimumab | Single Dose (IV) | US | Not open yet |
| NCT04326920 | Sargramostim | Recombinant GM‐CSF | 4 | 80 | Sargramostim | Inhalation via nebulizer (125μg) for 5 d ‐continue with IV if patient requires mechanical ventilation | Belgium | Yes |
| NCT04331899 | Peginterferon Lambda‐1 alpha | IFN‐α mimetic | 2 | 120 | Peginterferon Lambda‐1 alpha | Single Dose (sc) 180μg | US | Not open yet |
| NCT04320238 | rHu interferon α‐1b with or without thymosin alpha 1 | rHu IFN‐α1b Immune modulator(Thy) | 3 | 2944 | rHu IFN‐α1b | Nasal drops: 2‐3 per nostril × 4 times a day | China | Yes |
| rHu IFN‐α1b with ( a ): thymosin alpha 1 | Nasal drops: 2‐3 per nostril × 4 times a day sc 1 × per week | |||||||
| NCT04280588 | Fingolimod | Sphingosine‐1‐phosphate receptor modulator | 2 | 50 | Fingolimod | Oral 0.5 mg daily × 3 d | China | Yes |
| NCT04275245 | Meplazumab | humanized anti‐CD147 Ab | 2 | 20 | Meplazumab | 10 mg (IV) × 2 d, once per day | China | Yes |
| NCT04268537 | PD‐1 blocking Ab | Immune check point block | 2 | 120 | PD‐1 blocking Ab | Single Dose 200 mg (IV) | China | Not open yet |
| Thymosin | 1.6 mg sc qd, × 5 d | |||||||
| NCT04317040 | CD24Fc | Inflammatory cytokine inhibitor | 3 | 230 | CD24Fc | Single Dose 480 mg (IV) | US | Yes |
| NCT04333472 | Piclidenoson | Inflammatory cytokine inhibitor | 2 | 40 | Piclidenoson | Oral, 2 mg every 12 hs for up to 21 d | Israel | Not open yet |
| NCT04338802 | Nintedanib | Tyrosine kinase inhibitor | 2 | 96 | Nintedanib | Oral, 150 mg 2 × daily for 8 weeks | China | Not open yet |
| NCT04340232 | Baricitinib | JAK inhibitor | 2,3 | 80 | Baricitinib | Oral, 2 mg once daily for 14 d | US | Not open yet |
| NCT04320277 | Baricitinib in combo with Ritonavir | JAK inhibitor (Bar) anti‐viral (Rit) | 3 | 60 | Baricitinib (mild cases) | Oral, 4 mg once daily × 2 weeks; Ritonavir 600 | Italy | Yes |
| Baricitinib (moderate cases) | Oral, 4 mg once daily × 2 weeks; Ritonavir 600 | |||||||
| NCT04331665 | Ruxolitinib | JAK inhibitor | NA | 64 | Ruxolitinib | Oral, 10 mg twice daily D1‐D14, 5 mg twice daily D15‐D16, 5 mg once daily on D17 | Canada | Not open yet |
| NCT04338958 | Ruxolitinib | JAK inhibitor | 2 | 200 | Ruxolitinib | Oral, 2 × 10 mg per day with defined response adapted dose escalation up to 2 × 20 mg for 7 d | Germany | Not open yet |
| NCT04334044 | Ruxolitinib | JAK inhibitor | 1,2 | 20 | Ruxolitinib | Oral 2 × 10 mg per day for 14 d | Mexico | Not open yet |
| NCT04332042 | Tofacitinib | JAK inhibitor | 2 | 50 | Tofacitinib | Oral, 10 mg twice daily for 14 d | ITaly | Not open yet |
| NCT04321993 | Baricitinib | JAK inhibitor (Bar) | 2 | 1000 | Baricitinib | Oral, 2 mg once a day for 10 d | Canada | Not open yet |
| Sarilumab | IL‐6R antagonist (Sar) | Sarilumab | Single Dose 200 mg (sc) | |||||
| Hydroxychoroquine sulfate | Inflammatory cytokine inhibitor (Hyd) | Hydroxychoroquine sulfate | Oral, 2 × 200 mg daily for 10 d | |||||
| Lopinavir/ritnavir | Protease inhibitor (Lop) | Lopinavir/Ritnavir | Oral, 2 × 200 mg/50 mg daily for 10 d | |||||
| NCT04341675 | Sirolimus | mTOR inhibitor | Sirolimus | Oral, 6 mg once on D1, 2 mg once a day D3‐D13 | US | Not open yet | ||
| FDA approved compassionate use | Lenzilumab | anti‐GM‐CSF antibody | Pre‐3 | Approved Apr 2, 2020 | Sponsor: Humanigen, Inc. | US | https://apnews.com/ACCESS WIRE/738d3526740dee777dacee2b6b8a836f |
Abbreviations: Terminology Key: NCT, national clinical trial; IV, intravenously; sc, subcutaneous injection; IL‐6, interleukin‐6; IL‐6R, interleukin‐6 receptor; IFN‐γ, interferon gamma; GM‐CSFR α, granulocyte‐macrophage colony‐stimulating factor receptor alpha; rHu, recombinant human; IFN‐α1b, interferon alpha 1b; CD147, cluster of differentiation 147; Ab, antibody; JAK, janus kinase; D1, Day 1; NaCl, sodium chloride; mg/kg, milligram per kilogram; MAS); μg, microgram; qd, once a day; bid, twice a day.
All trials were identified from https://www.clinicaltrials.gov using filter criteria: COVID, 2019‐nCOV, SARS‐CoV‐2.
Permissive leukocytosis in these pateints to a degree that may be reasonable in other settings may put patients at increased risk for complications in the COVID‐19 era, and tighter regulation of the WBC is a worthwhile consideration. This has to be carefully balanced with the potential need for additional blood draws and clinic visits, including blood product transfusions for worsening cytopenias. In a clinically suspected case of SARS‐CoV‐2 in an MDS/MPN patient, frequent monitoring of CBC, with use of additional doses of hydroxyurea to control an evolving leukemoid reaction may be beneficial, though this is unclear. The use of corticosteroids as antinflammatory agents is somewhat controversial, given concerns of potentially increasing ACE‐2 expression and viral replication/decreasing viral clearance, and should be used with caution. In the event of CRS or ARDS, treating physicians should consider potential early access to clinical trials or off‐label use of anti‐IL‐6 therapies (Table 1). This recommendation is of particular importance in CMML, given that TET2, which is the most frequently mutated gene in CMML (60%), encodes a protein involved in the negative regulation of IL6 gene expression. This suggests that TET2‐mutant patients may not be able to down‐regulate IL‐6 once the inflammatory cascade has been initiated. 12
IL‐6 signals through three pathways: (a) cis signaling in immune cells, where it binds to membrane‐bound IL‐6‐R in a complex with gp30 and activates JAK‐STAT3, (b) trans signaling, where IL‐6 binds to soluble IL‐6‐R and then forms a complex with gp130 on potentially all cell surfaces, especially the endothelium, activating JAK‐STAT3 (cytokine storm and endothelial dysfunction), and (c) trans presentation, where IL‐6‐R binds to gp130 on T‐helper cells (Th17) leading to accentuated T cell signaling. 13 Current evidence points towards IL‐6‐R antagonists’ being superior to IL‐6 neutralizing antibodies, due to the ability of the former in blocking trans presentation of IL‐6, an important mechanism in the development of acute lung injury and ARDS. 13 Preliminary data from China in SARS‐CoV‐2 with tocilizumab seems encouraging, with oxygen requirements being reduced in 75% of tocilizumab‐treated patients (n = 21). Clinical trials with sarilumab and siltuximab continue to accrue.
Given the inherent hypersensitivity of CMML cells to GM‐CSF (granulocyte macrophage), additional anti‐cytokine therapy using anti‐GM‐CSF monoclonal antibodies such as lenzilumab may also be considered. Of note, lenzilumab has been shown to abrogate neurotoxicity and CRS by neutralizing GM‐CSF in chimeric antigen receptor T‐cell mice models. 14 In addition, a recent phase 1 study of lenzilumab in CMML demonstated clinical benefit in 27% of patients, without any drug‐related grade 3 or 4 adverse events. 10 Mavrilimumab, a GM‐CSF receptor alpha directed mononclonal antibody is also being considered for the management of CRS in SARS‐CoV‐2. Additional cytokine‐directed clinical trials that might have value in the context of SARS‐CoV‐2 induced CRS include studies with anakinra (IL‐1beta receptor antagonist), empalumab (monoclonal antibody to interferon gamma, currently approved for HLH) and JAK inhibitors (ruxolitinib, pacritinib) (Table 1). We continue to closely watch these studies for safety and efficacy signals. We recommend that all providers consider documenting any patients with hematological malignancies infected with SARS‐CoV‐2 in the American Society of Hematology (http://www.ashresearchcollaborative.org/covid-19-registry) and COVID19 and Cancer Consortium (CCC19 http://ccc19.org) registries.
2. CONFLICT OF INTEREST
A.M.Z. received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer‐Ingelheim, Trovagene, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. A.M.Z participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer‐Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Trovagene, Takeda, Ionis, Amgen, Janssen, Epizyme, and Tyme. A.M.Z served on steering and independent data review committees for clinical trials for Novartis and Janssen. A.M.Z received travel support for meetings from Pfizer, Novartis, and Trovagene.
Supporting information
Data S1: Supporting information references.
Figure S1 CMML patients are at even higher risk of a hyper‐inflammatory reaction and CYTOKINE STORM. CMML cells exhibit GM‐CSF hypersensitivity which pre‐primes the environment for inflammatory respossnse. Background concentrations of pro‐inflammatory cytokins (IL‐6, IL‐10, IL‐1b, TNF‐α) are increased in CMML patients compared with healthy controls. IL‐6, interleukin 6; IL‐8, interleukin 8; IL‐10, interleukin 10; IL‐1b, interleukin 1 beta; TNF‐α, tumor necrosis factor alpha; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor.
ACKNOWLEDGEMENTS
Current publication is supported in part by grants from the “The Henry J. Predolin Foundation for Research in Leukemia, Mayo Clinic, Rochester, MN, USA”. A.Z. is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a NCI’s Cancer Clinical Investigator Team Leadership Award (CCITLA). Research reported in this publication was in part supported by the National Cancer Institute of the National Institutes of Health under Award Number P30 CA016359. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. M.S. is a Leukemia and Lymphoma Society Scholar in Clinical Research. David Steensma is supported by the Edward P. Evans Foundation.
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Associated Data
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Supplementary Materials
Data S1: Supporting information references.
Figure S1 CMML patients are at even higher risk of a hyper‐inflammatory reaction and CYTOKINE STORM. CMML cells exhibit GM‐CSF hypersensitivity which pre‐primes the environment for inflammatory respossnse. Background concentrations of pro‐inflammatory cytokins (IL‐6, IL‐10, IL‐1b, TNF‐α) are increased in CMML patients compared with healthy controls. IL‐6, interleukin 6; IL‐8, interleukin 8; IL‐10, interleukin 10; IL‐1b, interleukin 1 beta; TNF‐α, tumor necrosis factor alpha; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor.