Blood & Cancer

Adam C. Cuker, MD, joins host David H. Henry, MD, to discuss recent findings regarding coagulation in COVID-19 patients. Both Dr. Cuker and Dr. Henry both practice at the Hospital of the University of Pennsylvania in Philadelphia.

Dr. Cuker cited data suggesting at least 25%-30% of patients with COVID-19 develop venous thromboembolism (VTE), despite receiving prophylactic anticoagulation. Furthermore, COVID-19 patients have presented with “lots of different thrombotic manifestations,” he said. This includes stroke and “COVID toes syndrome,” a condition in which patients present with ischemic toes, which appears to have a thromboembolic etiology.

Dr. Cuker suggested that all three aspects of Virchow’s triad may be at play in patients with COVID-19 who have thrombotic manifestations, including:

• Circulatory stasis (in patients who are immobilized/sedated/prone/paralyzed).
• Hypercoagulability (inflammation, high levels of factor VIII and fibrinogen, neutrophil extracellular traps).
• Endothelial injury (SARS-CoV-2 may infect endothelial cells via ACE2).

Dr. Cuker notes that high D-dimer correlates with disease severity and prognosis in COVID-19 patients. He also compares COVID-19 to heparin-induced thrombocytopenia (HIT), noting that both are associated with venous and arterial thromboses. And, like HIT patients, those with COVID-19 may require therapeutic-intensity anticoagulation to prevent clots.

Dr. Cuker says his hospital’s recommendations for anticoagulation in COVID-19 patients are as follows:

• Stable hospitalized patients should receive standard-intensity prophylaxis.
• ICU patients should receive intermediate- or therapeutic-intensity anticoagulation (at the discretion of the provider).
• On discharge, patients should receive low-dose rivaroxaban (Xarelto) at 10 mg daily for 30 days as prophylaxis.
• A nonhospitalized patient who has no risk factors for thrombotic events should not receive thromboprophylaxis.

Dr. Cuker also discusses two recent publications on thrombosis and anticoagulation in COVID-19 patients. In one study, thrombotic events occurred in 31% of COVID-19 patients admitted to the ICU at three Dutch hospitals (Thromb Res. 2020 Apr 10. pii: S0049-3848(20)30120-1).

Another study suggested that systemic anticoagulation may improve outcomes of patients hospitalized with COVID-19 (J Am Coll Cardiol. 2020 May 5. pii: S0735-1097(20)35218-9).

Show notes by Emily Bryer, DO, resident in the department of internal medicine, University of Pennsylvania, Philadelphia.

Disclosures:

Dr. Henry has no financial disclosures relevant to this episode.

Dr. Cuker has served as a consultant for Synergy CRO. His institution has received research support on his behalf from Alexion, Bayer, Pfizer, Novo Nordisk, Sanofi, Spark, and Takeda.

* *

For more MDedge Podcasts, go to mdedge.com/podcasts

Email the show: [email protected]

Interact with us on Twitter: @MDedgehemonc

David Henry on Twitter: @davidhenrymd

The million-dollar question in the treatment of chronic lymphocytic leukemia (CLL) is what to do after a patient relapses following treatment with venetoclax. Anthony Mato, MD, and Lindsey Roeker, MD, both of Memorial Sloan Kettering in New York, join podcast host David H. Henry, MD, of Pennsylvania Hospital, Philadelphia, to explore the evidence about this question and to review the initial patient work-up and treatment strategies.

In Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, discusses patients compliance and how clinician biases can influence compliance.

Practice points:

• For patients with CLL with unmutated immunoglobulin variable heavy chain gene (IgVH), novel agents are the first therapy.
• Evidence is limited about the best treatment approach after relapse on venetoclax.

* *

Initial work-up in patients with CLL

• The initial work-up for patients with CLL is often fluorescent in situ hybridization (FISH), looking for trisomy 12, as well as deletion of 13q, 17p, and 11q.
• Next-generation sequencing is used to look for mutations in TP53 and IgVH mutational analysis is done to recognize whether a patient is mutated.
• IgVH-mutated patients tend to respond better to therapy.

When to treat

• Henry recommends the “if it bothers you, it bothers me” approach, noting that indications for treatment include fever, chills, night sweats, lumps and bumps in the neck, large liver and spleen, and high creatine.

Progression

• If a patient is IgVH unmutated, that takes chemoimmunotherapy combinations off the table, regardless of whether the patient is young or fit. Instead, they are on a pathway to receive a novel agent as first therapy.
• The choices for novel agents keep expanding. Some standards include ibrutinib plus or minus obinutuzumab, venetoclax plus obinutuzumab, and acalabrutinib plus or minus obinutuzumab.
• Each of these combinations has different adverse event profiles and dose schedules. Patient preferences and comorbidities should drive decision making on novel combinations.

Relapse

• The million-dollar question: What is the best treatment following relapse on venetoclax?
• The answer is unclear but there are generally two choices: Re-treat with the same regimen or switch to a Bruton’s tyrosine kinase (BTK) inhibitor.
• There are limited data on re-treatment and emerging data on BTK inhibitors after venetoclax that points to success.

Disclosures

Dr. Anthony Mato reported research funding from DTRM Biopharma and Gilead; consultancy and research funding from Genentech, Pharmacyclics, TG Therapeutics, Adaptive, Sunesis, AstraZeneca, Abbvie, LOXO, and Johnson & Johnson; and consultancy with Verastem, Acerta, Janssen, and Celgene.

Dr. Lindsey Roeker reported minority ownership interest in Abbvie and Abbott Laboratories, ASH grant funding.

Dr. Henry and Dr. Yurkiewicz reported no relevant financial conflicts.

* *

For more MDedge Podcasts, go to mdedge.com/podcasts

Email the show: [email protected]

Interact with us on Twitter: @MDedgehemonc

David Henry on Twitter: @davidhenrymd

Ilana Yurkiewicz on Twitter: @ilanayurkiewicz

In this episode, we review how immune checkpoint inhibitors and COVID-19 have changed the management of non-small cell lung cancer (NSCLC). Jeffrey Crawford, MD, and Susan Blackwell, PA, both of Duke Cancer Institute, join host David H. Henry, MD, to discuss the use of pembrolizumab in NSCLC, two studies of PD-1 inhibitors presented at ESMO 2020, and how COVID-19 has affected NSCLC care, particularly the use of granulocyte colony-stimulating factor (G-CSF). Diagnosis and treatment of NSCLC What information should be obtained from a biopsy?

• Is this lung cancer?
• If so, what kind of lung cancer is it: Small-cell lung cancer or NSCLC? Which subtype?
• Molecular studies for targets, including ALK, KRAS, EGFR, PD-L1.

Treatment with pembrolizumab:

• If, for example, a patient has NSCLC and is positive for PD-L1, the treatment of choice is pembrolizumab.
• A multidisciplinary approach is essential to provide comprehensive education and care to patients taking pembrolizumab (and other immunotherapies).
• Pembrolizumab can have many side effects, including itching, fatigue, thyroiditis progressing to hypothyroidism, hypophysitis, or another off-target “-itis.”
• Ms. Blackwell and Dr. Crawford recommend listening to patients, checking the thyroid routinely, and checking cortisol based on index of suspicion.

NSCLC studies presented at ESMO 2020 KEYNOTE-024 5-year OS update: First-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%.

• The 5-year survival is greater than 30% with pembrolizumab in this study.
• Historically, 5-year survival has been 1% to 2% in patients treated with chemotherapy alone, Dr. Crawford said.
• In the control arm of this study, patients received chemotherapy and then crossed over into the pembrolizumab arm, so overall survival was 16% at the 5-year mark.
• The results suggest immunotherapy should be used first-line if patients meet criteria, Dr. Crawford said.
• Source: Abstract LBA51. https://bit.ly/3mMYLTK.

EMPOWER-Lung 1: Phase III first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%.

• Cemiplimab improved overall and progression-free survival in NSCLC patients when compared with chemotherapy alone.
• Abstract LBA52. https://bit.ly/3mLT6xb.

The effects of COVID-19 on NSCLC care

Logistically, it’s more difficult to see patients during the pandemic, Dr. Crawford noted, but the many potential side effects of immunotherapy make it necessary to see patients regularly in person. How has COVID-19 affected the concern of febrile neutropenia and the use of G-CSF? Dr. Crawford said the pandemic has heightened the concern about infection risk. Prior guidelines for G-CSF:

• Before the pandemic, guidelines suggested routine prophylactic G-CSF in patients with a greater than 20% risk of febrile neutropenia.
• In patients with 10% to 20% risk, the recommendation was to consider the use of G-CSF based on the patient population and risk factors.

Pandemic-specific guidelines for G-CSF:

• The National Comprehensive Cancer Network (NCCN) recommended relaxing guidelines during the pandemic.
• If the risk is greater than 20%, NCCN still recommends giving G-CSF.
• If the risk is 10% to 20%, NCCN recommends giving G-CSF even in the absence of additional risk factors.
• Dr. Crawford noted that lung cancer patients receiving chemotherapy are typically in the 10% to 20% risk category.
• Download the COVID-specific NCCN guidelines: https://bit.ly/3jQIco5.

G-CSF biosimilars

• The most common complaint with biosimilars is bone pain.
• Ms. Blackwell advises first treating bone pain with acetaminophen or ibuprofen and warm blankets.
• For refractory pain, she suggests a low-dose narcotic or dexamethasone.
• Consider an antihistamine for prophylaxis, as patients report this can help with symptoms.

Show notes written by Ronak Mistry, DO, a resident at Pennsylvania Hospital, Philadelphia.

Disclosures: Dr. Crawford is on advisory boards at Amgen and Merck, makers of Onpro/Neulasta (pegfilgrastim) and Keytruda (pembrolizumab). Ms. Blackwell and Dr. Henry have no conflicts of interest.

* *

For more MDedge podcasts, go to mdedge.com/podcasts...

How do patients fare when they have cancer and COVID-19? Researchers developed the COVID-19 and Cancer Consortium (CCC19) and the National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) to gain some insight.

In this episode, Brian Rini, MD, a professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and host of The Uromigos podcast, explains what CCC19 and NCCAPS are. He also discusses findings from CCC19 that were presented at the European Society of Medical Oncology Virtual Congress 2020.

NCCAPS (NCT04387656)

• NCCAPS is a natural history study of COVID-19 in patients with active cancer.
• It is a prospective study, funded by the National Cancer Institute, that is open at more than 500 centers.
• The study is open to U.S. adults who are receiving active cancer treatment and either have COVID-19 or are awaiting a SARS-CoV-2 test result.
• Researchers collect blood samples and other data from patients enrolled.
  • Blood is collected at baseline and at regular intervals incorporated into patients’ normal oncology follow-up.
  • The samples will be used to assess things like genomics, cytokine abnormalities, and coagulation parameters.
• No data from NCCAPS have been released to date, but more than 100 patients have been enrolled.
• For more information, visit the NCCAPS webpage: https://bit.ly/3ck8nBb.

CCC19 (NCT04354701)

• CCC19 is a retrospective database that includes information on patients with active cancer or a history of cancer who have been diagnosed with COVID-19, with or without a confirmatory test.
• Health care providers or their proxies from the United States, European Union, Argentina, Canada, Mexico, and United Kingdom can report cases through the CCC19 website.
• All data are deidentified.
• More than 100 institutions are now part of CCC19.
• Data from CCC19 were presented in two abstracts at ESMO 2020:
  • Wise-Draper TM et al. Abstract LBA71. https://bit.ly/3iUarm2
  • Grivas P et al. Abstract LBA72. https://bit.ly/33OKttP
• The data from LBA72, which includes nearly 4,000 patients, suggest cancer-specific factors are associated with a greater risk of 30-day all-cause mortality, including:
  • Progressive cancer (adjusted odds ratio, 2.9).
  • Hematologic malignancy (aOR, 1.7).
  • Receiving cancer therapy within the past 3 months (aOR, 1.2).
• It still isn’t clear if certain cancer treatments increase the risk of mortality, Dr. Rini said, but researchers are investigating that.
• For more information on CCC19, visit https://ccc19.org/.

Disclosures:

Dr. Rini and Dr. Henry have no relevant conflicts of interest.

* *

For more MDedge Podcasts, go to mdedge.com/podcasts

Email the show: [email protected]

Interact with us on Twitter: @MDedgehemonc

David Henry on Twitter: @davidhenrymd

In this episode, we review three hematology cases. One case illustrates the work-up and treatment of immune thrombocytopenia (ITP).

Another case demonstrates how to diagnose and manage heparin-induced thrombocytopenia (HIT). And the final case is a patient who presented with anemia, a new mitral valve murmur, and mild splenomegaly.

Host David H. Henry, MD, reviews these cases with three residents from Pennsylvania Hospital in Philadelphia – Sheila De Young, DO; Ronak Mistry, DO; and Debika Shinohara, MD, PhD.

Case 1: Suspected ITP with Sheila De Young, DO

Patient presentation: A 50-year-old female with no past medical history and incidental platelet count of 4,000/microL (normal 150,000-450,000/microL [150-450 x 109/L]).

On physical exam, there was no lymphadenopathy, and the spleen was nonpalpable. She had obvious petechiae on her legs. A urine pregnancy test was negative. Her hemoglobin and white blood cell counts were normal via complete blood count.

• ITP definition:
  • Acquired thrombocytopenia caused by autoantibodies against platelet antigens.
  • One of the most common causes of thrombocytopenia in otherwise asymptomatic adults.
• To consider: Increased destruction, decreased production, and pseudothrombocytopenia
  • To ensure the platelet count is not falsely low (in the case of pseudothrombocytopenia), looking at a peripheral smear is helpful. If red blood cells and white blood cells appear normal, we can exclude pseudothrombocytopenia.
• Work-up:
  • We need to rule out secondary causes of thrombocytopenia such as HIV, hepatitis C, chronic lymphocytic leukemia, systemic lupus erythematosus, etc.
• Management/treatment:
  • In the acute setting, the treatment for ITP is intravenous immunoglobulin and steroids.
  • Long-term management of ITP includes steroids, splenectomy, thrombopoietin receptor agonists (romiplostim/eltrombopag), and rituximab.
• Case conclusion:
  • This patient was found to have ITP. Shared decision-making led to the patient receiving a thrombopoietin receptor.

Case 2: Possible HIT with Ronak Mistry, DO

Patient presentation: A male with ischemic leg and creatinine phosphokinase greater than 4,000 units/L. His platelet count was 101,000/microL on admission, 70,000/microL on the second day, and 60,000/microL on the third day.

The patient was on prophylactic subcutaneous heparin for 48 hours, so the surgery team considered HIT to explain the drop in platelets.

• HIT definition:
  • A life-threatening complication of exposure to heparin.
  • Results from autoantibody directed against endogenous platelet factor 4 (PF4) in complex with heparin.
• To consider:
  • Determine baseline platelet count, what type of heparin the patient received, and look at when the heparin was administered in relation to when the platelet count dropped.
  • HIT is far less common in patients who receive subcutaneous heparin versus intravenous heparin.
  • Typically, we see a 50% decrease in platelet count 5-10 days following exposure to heparin.
• Work-up:
  • In the inpatient setting, it is important to consider other causes that predispose patients to thrombocytopenia (i.e., critical illness, medications).
  • Thrombocytopenia can represent a consumptive process of platelets secondary to tissue injury in the setting of elevated creatine phosphokinase.
• Diagnosis:
  • Enzyme-linked immunosorbent assays (ELISAs) can detect the presence of PF4-heparin antibody.
  • ELISA should be followed by a confirmatory test. The serotonin release assay is preferred among diagnostic tests for HIT.
• Management/treatment:
  • Stop heparin immediately.
  • Giving more platelets is not the solution. It increases a person’s risk for thrombotic events.
  • The patient needs to be placed on different anticoagulation, such as argatroban or fondaparinux, to carry them through this procoagulant time frame.
• Case conclusion:
  • HIT was ruled out in this patient.

Case 3: Anemia case with Debika Shinohara, MD, PhD

Patient presentation: A female, age 45 years, with a 4-month history of intermittent fevers and unintentional weight loss.

Her hemoglobin was 8 g/dL, but she had otherwise unremarkable blood work. On physical exam, she was found to have a new mitral valve murmur and mild splenomegaly.

• To consi...