Category Archives: Hematology and Oncology

Moffitt Pearls 7.10.17 – PD-1 Inhibitors & PCP Pneumonia

Pulmonary Report 7.10.17

Thank you to Ugo for presenting the case of an elderly male with widely metastatic melanoma refractory to PD1 inhibitors presenting with 1-2 weeks of fatigue, FTT, DOE found to have PCP pneumonia!

Top Pearls:

  • PD1 inhibitors are considered first-line therapy for metastatic melanoma.
  • Common toxicities of immune check point inhibitors include immune-mediated inflammation of virtually any organ system. See below for more details on PD1 inhibitors.
  • The risk for opportunistic infections w/ checkpoint inhibitors is related to the steroids that are generally given to treat the checkpoint inhibitor toxicities. A case report & paper (https://www.ncbi.nlm.nih.gov/pubmed/27501841) illustrating this risk.
  • Remember! For patients on steroids if > 20 mg/day of prednisone for > 2 weeks –> give PCP prophylaxis. (per expert opinion -> the rule of Dr. Jen B!)

Which patient that are immunocompromised get PCP?

  • HIV-positive patients (CD4 < 200)
  • Cancer, solid organ transplant, BMT – related to type & chemo intensity
  • Rheumatologic (GPA has intrinsic risk)
  • Chronic steroids (see Jen rule above)

Steroids for Rx of PCP in HIV-Negative patients??

  • Not well studied in HIV-negative patients, only a few retrospective studies
  • No mortality benefit, but may expidite recovery
  • Steroids are recommended in the AJT guidelines
  • 40-60 mg Prednisone BID x 5-7 days with 7-14 day taper

 

Table Comparing PCP in HIV Positive and Negative Patients (thanks Jen!)

table PCP

 

PD-1 Inhibitors (blast from the past)

pd1

Emerging data show that 20% of patients with melanoma treated with ipilimumab achieve long-term survival! See this associated review.

PD-1 (programmed cell death 1) and its association with the ligand (PD-L1) is a necessary step in stimulating apoptosis of T-cells, serving as an immune checkpoint. PD-L1 is generally expressed by native cells, signaling to the T-cell “I’m one of you! Don’t hurt me”.  Some tumors have been found to also express PD-L1, enabling them to evade destruction by T-cells.  In order to treat these malignancies, PD-1 inhibitors (pembrolizumab, nivolumab) serve to block the interaction between PD-1 and PD-L1, enabling T-cells to stay “programmed on”, and thus enable immune-mediated destruction of tumor.

Because of this mechanism of action, a common consequence is the upregulation of cell-mediated immunity and, unfortunately, inhibition of native tissues to turn off T-cells. As a result, we commonly see autoimmune-mediated inflammation manifested as new rash, diabetes, thyroid disease, pneumonitis, hepatitis, colitis, etc.

Common Immune-Mediated Toxicities Seen with Check-point Inhibition:

Organ System Manifestation Management
Skin & Mucosa Pruritic rash (most common!)

Alopecia

Vitiligo

Mucositis

Topical corticosteroids

Oral antipruritics

Consider oral steroids

GI Tract Diarrhea/colitis – presents ~6wks into treatment R/O infxn

Anti-motility agents

Steroids if severe

Liver Hepatitis (rate <5%, severe toxicity very rare) Stop therapy if moderate-severe.

Steroids + mycophenolate given rarely.

Lung Pneumonitis – (rate <5%, but occasionally fatal) Steroids common. Infliximab, cyclophosphamide also used, though patients requiring therapy beyond steroids have nearly 100% mortality.
Endocrine Hypophysitis

Autoimmune thyroid disease

Adrenal Insufficiency T1 DM

Hormonal replacement

Steroids

Less commonly reported immune-mediated adverse events include the following: acute renal injury, pancreatitis, neurotoxicity (GBS, myasthenia gravis, PRES, aseptic meningitis, autoimmune encephalitis), cardiotoxicity (myocarditis), hematologic (cytopenias), and ocular inflammation.

Many of the adverse events described above can be managed with continued use of PD-1 inhibitors if mild. However, for severe adverse reactions, PD-1 inhibitors are withheld and potential discontinued permanently.

Moffitt Pearls 7.5.17 – Wilson’s Disease & Hemolytic Anemia

Thank you to Vincent for presenting a challenging case of a young woman with anxiety and depression presenting with unexplained jaundice and cirrhosis, later representing with a severe, hemolytic anemia. Although similar to a prior case presented last month then this was a second presentation of possible Wilson’s disease

 Top Pearls:

  1. Acute alcoholic hepatitis is a chronic disease (despite the name!). Presentation is based on predominantly cumulative burden – a single binge in a patient with otherwise minimal alcohol intake is unlikely to cause severe alcoholic hepatitis.
  2. In a young patient (< 35 yo) with new diagnosis of cirrhosis, consider genetic causes including Wilson’s, hemochromatosis, alpha-1 antitrypsin disease, autoimmune hepatitis, PBC, PSC. Vascular disease and infectious hepatitis should also be considered.
  3. The combination of liver disease and hemolysis raises concern for Wilsonian Crisis, which can herald impending acute liver failure.

Laboratory Diagnosis of Tumor Lysis Syndrome

Alcoholic Hepatitis

The clinical syndrome of acute alcoholic hepatitis includes the following compilation of laboratory and clinical features:

  • Moderately elevated transaminases in a 2:1 ratio of AST/ALT
  • Typically less than 300, rarely greater than 500
  • Elevated bilirubin and Jaundice
  • Jaundice generally develops within 3 months prior to presentation
  • Fever & Neutrophilic Leukocytosis
  • Both should only be ascribed to alcoholic hepatitis after ruling out infection!
  • Right upper quadrant pain – can often palpate tender hepatomegaly
  • Clinical history of chronic drinking with or without recent bing
  • It’s not uncommon that patients have actually decreased their drinking in the weeks-months preceding acute alc hep due to the onset of symptoms with alcohol intake.

See this RCT from NEJM regarding pentoxifylline vs. prednisolone for the treatment of alcoholic hepatitis. Bottom line:  Acute alcoholic hepatitis is a profoundly morbid disease with very high mortality (30-40% in 6 months).  Prednisolone was associated with a reduction in 28-day mortality, but did not reach significance and there were no improvements in 90-day or 1 year mortality.

Autoantibodies Associated with Causes of Cirrhosis

 

Autoimmune hepatitis

IgG, ANA, antismooth muscle Ab, anti-liver-kidney microsome-1 Ab, anti-liver cytosol Ab-1

Primary biliary cirrhosis

ANA, anti-mitochondrial Ab

Primary sclerosing cholangitis

IgM (40-50%), p-ANCA (30-80%)

Wilson Disease (WD) & Hemolytic Anemia

  • Wilson’s disease (WD) is an inherent disease, caused by mutations in the ATP7B gene leading to decreased excretion of copper into the bile
  • Copper accumulation results in injury to the liver and the central nervous system (thank you Muazzum for you amazing neuro ROS)
  • WD presents in a fulminant form with hepatocellular dysfunction, hemolysis and various multiorgan failures (Wilson’s crises)
  • Wilson disease can cause a Coombs-negative hemolytic anemia WITHOUT schistocytes reported in the literature
  • The exact mechanism of the haemolytic process has yet to be defined. copper inhibits sodium potassium ATPase in the erythrocyte leading to haemolysis (and likely without schistocytes as in this case).
  • Medical treatment includes chelating agents and/or zinc, but these have not proved effective in fulminant liver failure, where only liver transplantation (LTx) is regarded as lifesaving.
  • Some limited data for plasmapheresis for rapid copper removal
  • Portends very poor prognosis, often leading to acute liver failure

 (see attached an article on a review of Wilson’s and Hemolytic anemia compliments of HH!!)

Blast from the past!!! Approach to Hemolytic Anemia (thank you Katie!!)

 

 

https://www.evernote.com/shard/s307/sh/16c1d172-fb95-4da7-93b0-d85e5c25854f/3768012329b5e8d8e358cacd312f033a

ZSFG Morning Report 6.12.2017 – High Flow Oxygen and PD-1 inhibitors

Thank you to the ICU team and Bennett Caughey for presenting the case of a middle-aged woman with advanced metastatic SCC of the lung, who presented with hypoxia and respiratory distress after esophageal stent placement.

Take Home Points

  • Escalating hi-flow oxygen needs should warrant ICU evaluation.
  • Differential for noninfectious causes of cavitary lung lesions includes neoplasm. SCC is the primary lung malignancy most likely to cavitate.
  • PD-1 inhibitor therapy can cause pneumonitis, but is a diagnosis of exclusion; infection and malignancy should be excluded. Median duration of treatment prior to development of pneumonitis is 2.8 months.

……………………………………………………………

High flow oxygen

  • What is it? Heated and humidified air that allows for comfortable delivery of higher flow oxygen
  • No specific threshold that absolutely warrants ICU level care (institution dependent) but an escalating requirement is worrisome and should prompt ICU evaluation
  • Liters per minute (LPM) and FiO2 are the two variables that can be manipulated, again this is institution dependent
  • High flow oxygen also provides a small amount of positive pressure. Also found to have decreased 90-day mortality in pts with nonhypercapnic acute hypoxemic respiratory failure.

What you need to know about PD-1 inhibitors:

  • PD1 stands for programmed cell death 1, and is involved in check point signaling pathway
  • PD1 inhibitors block normal inhibition response, and therefore boost immune response against cancer cells.
  • Nivolumab and pembrolizumab: currently being used in pts with advanced melanoma and non-small cell lung cancer.
  • The most common immune-related adverse events are typically transient, but can occasionally be severe or fatal. The most commonly implicated organ systems are dermatologic, diarrhea/colitis, hepatotoxicity, and endocrinopathies.
  • Overall incidence of PD-1 inhibitor related pneumonitis is ~5%
  • In general, mild symptoms can be observed and PD-1 therapy can be withheld. In more severe cases, checkpoint inhibitor therapy should be permanently discontinued, and consider use of steroids.

MOFFITT ENDOCRINE REPORT PEARLS 5/17/17: Hypercalcemia of Malignancy and PTHrP!

Hey Everyone! Thanks to Vaibhav for presenting the case of an older woman with newly diagnosed bladder cancer who presented with weight loss and failure to thrive, found to have severe hypercalcemia with workup pending. We suspected she might have PTHrP-mediated hypercalcemia, a known association with urothelial carcinomas. Pearls on PTHrP below!

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Top Pearls:

  1. PTHrP is the most common cause of hypercalcemia in non-metastatic solid tumors
  2. PTHrP-related hypercalcemia is typically a finding in advanced disease with poor prognosis
  3. PTHrP acts primarily on bone and kidneys to cause hypercalcemia, not the GI tract

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For those who want more info:

Check out Myung’s pearls on hypercalcemia:

https://ucsfmed.wordpress.com/2017/02/15/hypercalcemia/

*Important general pearls on hypercalcemia of malignancy: 1) It occurs in 10-30% of patients with advanced tumors. 2) It is the most common cause of hypercalcemia in the inpatient setting. 3) Prognosis is poor (up to 50% 30-day mortality).

Now some more specific info on PTHrP!

What is PTHrP?

  • Normal gene product expressed in several tissues
  • Also called humoral hypercalcemia of malignancy (HHM)
  • The most common cause of hypercalcemia in patients with non-metastatic solid tumors
  • Most often in patients with advanced disease and poor prognosis (not usually an early finding)
  • Solid tumor associations: SCC, renal/bladder, breast, ovarian
  • Liquid tumor associations: NHL, CML (blast phase), T-cell leukemia/lymphoma

How is PTHrP related to PTH?

  • First 13 N-terminal amino acids are homologous to PTH (PTH = 84 AAs, PTHrP =139-173 AAs)
  • Binds to same PTH-1 receptor as PTH: bone resorption, renal Ca reabsorption/phos wasting
  • Structural divergence after first 13 amino acids: less likely to stimulate 1,25 vit D production, does not increase intestinal Ca absorption
  • Thus, PTHrP hyperCa is from bone/renal only, while PTH hyperCa is also from GI
  • Lab findings in PTHrP hyperCa: 1) elevated PTHrP, 2) low PTH, 3) normal/low 1,25-vit D

How is measurement of PTHrP useful (aside from diagnosis)?

  • Tumor marker: helps to assess treatment response
  • Prognostic marker: worse survival if PTHrP level > 12 pmol/L, which predicts less robust response of hyperCa to bisphosphonate therapy

HyperCa Malignancy

Evernote: https://www.evernote.com/shard/s272/sh/f935a1b0-b47f-45e7-8ef0-611a9c5c1e55/ba948d973b82ab3470b7c86533c6a7d7

 

Have a great day everyone!

SamMy

MOFFITT HEME/ONC REPORT PEARLS 5/12/17: Warfarin-Related Bleeding!

Hey Everyone! Thanks to Matt for presenting the case of an elderly man with heart failure and valve replacement on warfarin presenting with a fall and found to have severe vital sign abnormalities and INR of 13! Pearls below:

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Top Pearls:

  1. 1st steps in warfarin-related bleeding: stabilize and give IV vitamin K.
  2. PCC is generally preferred over FFP where available. Give IV vitamin K too!!

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For those who want more info:

Rachel Stern wrote excellent pearls on supratherapeutic INR in patients on warfarin, see below:

https://ucsfmed.wordpress.com/2017/02/04/warfarin-supra-therapeutic-inr/

Here’s some additional info on warfarin reversal agents:

If no bleeding:

IV agents should only be needed if bleeding is present. Otherwise, you can get by with just holding the warfarin, and giving PO vitamin K if INR is very elevated. In the updated 2012 ACCP guidelines, the threshold for giving PO vitamin K for an elevated INR in the absence of bleeding was changed from >9.0 to >10.0.

If bleeding:

IV vitamin K: Works within 12-24 hours. IV and PO vitamin K reverse INR equally effectively, IV just works faster. **ALWAYS give IV vitamin K ASAP if bleeding on warfarin.**

Dosing: 5-10 mg IV no faster than 1 mg/min to reduce anaphylaxis risk. Can repeat every 12 hours if INR remains elevated.

PCC: Prothrombin complex concentrates, contain clotting factors, protein C/S and low doses of heparin to prevent premature clotting factor activation. Corrects INR faster than FFP and with less volume, often within 10 minutes. Effect is transient (hours) so must administer IV vitamin K simultaneously. 5x more expensive than FFP.

  • Kcentra: 4 factor unactivated (II, VII, IX, X)
  • Bebulin: 3 factor unactivated (II, IX, X)
  • FEIBA: 4 factor activated (II, VII, IX, X) [“factor eight inhibitor activity bypassing agent”] used primarily in hemophilia patients or DOAC reversal, not used routinely in warfarin bleeding.

No great evidence directly comparing 4 vs 3 factor concentrates, but generally 4 factor concentrates are preferred. Can be thrombogenic.

Dosing: Fixed dosing non-inferior to weight-based dosing; give 1500-2000 IU at 100 IU/min.

*Pearl: ACCP 2012 guidelines recommend PCC over FFP for warfarin-associated bleeding.

FFP: Fresh frozen plasma, contains all clotting factors at physiologic concentrations. Takes 30 mins or more to give one unit, so takes several hours to administer whole dose. Must be ABO compatible. Effect is transient (hours) so must administer IV vitamin K simultaneously.

Dosing: Start with 4 units (1L volume), up to 8 units are often required for full reversal.

rFVIIa: Recombinant activated factor 7. Works within 10 minutes. Effect is transient (hours) so must administer IV vitamin K simultaneously. Not typically given as monotherapy because does not replace other factors. Can be thrombogenic.

Dosing: 20 mcg/kg bolus

See summary table below:

Warfarin bleeding

 

Evernote: https://www.evernote.com/shard/s272/sh/93445eda-f71a-4bee-952e-b6ffacd966db/8899e5c0b3e5e16ee2500ff81a9293f9

Have a great day everyone!

SamMy

MOFFITT MORNING REPORT PEARLS 5/5/17: Cavitary Lung Lesions and Castleman Disease!

Hey Everyone! Thanks to Braden for presenting a super interesting case of a middle-aged man with multicentric Castleman disease who was incidentally found to have a cavitary pulmonary nodule! We discussed an extensive differential for cavitary lung nodules and reviewed Castleman disease. Pearls below!

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Top Pearls:

  1. The ddx of cavitary lung lesions is broader than just TB/fungal/cancer! See below.
  2. Unicentric Castleman disease is usually curable while multicentric has a variable prognosis.
  3. Steroids predispose to infection with aspergillus, cryptococcus, nocardia, PCP, and legionella.

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For those who want more info:

Cavitary lung lesions:

Here’s the differential we discussed with Harry’s help!

  • Infection! TB, NTM, fungal (crypto, dimorphics, molds, rarely PCP), bacterial (staph, strep, nocardia, actinomyces, rhodococcus), strongyloides, rarely viral (CMV, VZV)
  • Malignancy! Primary lung cancer, metastases, lymphoma, rarely Kaposi sarcoma
  • Rheumatologic! Vasculitis (GPA, rarely MPA), sarcoidosis
  • Emboli! Bland or septic

 

Castleman disease:

Now a review of Castleman disease. Or maybe your first time learning about it. That’s ok too. 🙂

Castleman disease, aka angiofollicular lymph node hyperplasia! Obvi.

Commonly associated with HIV and HHV-8 but not always! Our patient today was negative for both.

Divided into unicentric and multicentric Castleman disease, which have very different prognoses (hint, unicentric is more favorable…).

Unicentric (UCD):

  • Lymphoproliferative disorder of young adults
  • Usually asymptomatic, enlarged lymph node discovered incidentally on exam or imaging
  • Node/mass is most often in mediastinum or lung
  • Biopsy shows polyclonal expansion (ie. NOT a monoclonal disorder!)
  • PET/CT rules out involvement of other sites
  • Complete resection of the involved lymph node is curative with excellent prognosis
  • If resection not possible, systemic therapy as in MCD (see below)

Multicentric (MCD):

  • Lymphoproliferative disorder (usually plasma cells) presenting in 5th or 6th decade of life
  • Peripheral lymphadenopathy and systemic symptoms
  • Biopsy shows polyclonal expansion (ie. NOT a monoclonal disorder!)
  • PET/CT demonstrates involvement of multiple sites
  • Treatment depends on HIV/HHV-8 status and disease aggression
  • HIV/HHV-8 neg without organ failure: anti-IL-6 immunotherapy (siltuximab or tocilizumab)
  • HIV/HHV-8 neg with organ failure: etoposide + rituximab
  • HIV/HHV-8 pos: ARVs + ganciclovir + rituximab, with etoposide if aggressive disease
  • Prognosis is variable, worse with HIV infection in which a rapidly progressive form can lead to death within weeks!

There is a strong association between MCD and POEMS syndrome; 15-50% of patients with POEMS also have MCD. POEMS stands for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.

RCT showing efficacy of siltuximab in MCD leading to FDA approval. Side effects included pruritis, weight gain, rash, hyperuricemia, URI, fatigue, night sweats, and anemia. Serious adverse events included pneumonia, anaphylaxis, and sepsis. https://www.ncbi.nlm.nih.gov/pubmed/25042199

*Harry pearl: High dose steroids predispose to five infections in particular- aspergillus, cryptococcus, nocardia, PCP, and legionella!

 

Evernote: https://www.evernote.com/shard/s272/sh/c22fc556-a0e2-48db-9acb-1c4e4c1e9aad/19a8b86aeffd850429a8e38c0d6c64cd

Have a great day everyone!

SamMy

MOFFITT ONCOLOGY REPORT PEARLS 4/14/17: Lymphomas!!

Hey Everyone! Crazy oncology report today with Andrew and Josh presenting the case of a middle-aged man with shortness of breath and fevers, found to have endobronchial B-cell lymphoma almost completely obstructing the entire airway! Eek! We watched an awesome video of the interventional pulmonologists freezing and removing the endobronchial masses. Pearls below:

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Top Pearls:

  1. DLBCL is the most common non-Hodgkin lymphoma.
  2. Lymphoma causing oncologic emergency (e.g. airway compromise) should be treated promptly with steroids with monitoring and prophylaxis for tumor lysis syndrome.
  3. Hodgkin and many non-Hodgkin lymphomas are curable in the majority of patients. Mantle cell lymphoma portends the worst prognosis of the group.

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For those who want more info:

Lymphoma Classification:

Lymphomas can be divided into Hodgkin and non-Hodgkin lymphoma. The most common non-Hodgkin lymphomas are: DLBCL (25%), mantle cell, Burkitt, CLL/SLL, follicular, lymphoplasmacytic, and marginal zone.

Lymphoid neoplasm classification was updated in 2016, including a lot of genetic markers to help with subclassification:

http://www.bloodjournal.org/content/bloodjournal/127/20/2375.full.pdf

 

A brief primer on the five major categories of mature lymphoid neoplasms:

Hodgkin lymphoma is its own group including classical and nodular Hodgkin lymphoma.

Mature B-cell neoplasms include CLL, marginal zone lymphoma, hairy cell leukemia, myeloma, MALT lymphoma, follicular lymphoma, mantle cell lymphoma, DLBCL, Burkitt lymphoma, and many others.

Mature T and NK neoplasms include T cell leukemia/lymphoma, mycosis fungoides, Sezary syndrome, cutaneous T cell lymphoma, anaplastic large cell lymphoma, and others.

Post-transplant lymphoproliferative disorder (PTLD) is its own group.

Histiocytic and dendritic cell neoplasms include Langerhans cell histiocytosis, Erdheim-Chester disease, and others.

*Pearl: There is an “unclassifiable” B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin, so not all tumors may fit perfectly into a clear category.

 

Treatment:

Treatment of Hodgkin lymphoma = ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)

Treatment of most non-Hodgkin lymphoma = R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)

What to do overnight for an oncologic emergency due to lymphoma (e.g. airway obstruction)?

  • Steroids!!
  • Check tumor lysis labs and LDH and start prophylaxis.
  • Some chemo (cytoxan and rituximab) may be started as path is pending (call oncology!)
  • Call relevant consultants (ENT for airway, neurosurg for spine, etc).

 

*Pearl: There are case reports of steroids causing tumor lysis syndrome in high risk patients! Start TLS prophylaxis even if you are just treating with steroids!

*Pearl: All DLBCL is at least intermediate risk for tumor lysis syndrome and should receive allopurinol (in addition to hydration and monitoring). Bulky DLBCL or LDH >2x ULN (and all Burkitt lymphoma) is high risk and merits rasburicase!

 

Prognosis:

There are different prognostic scoring systems for each of the different lymphomas.

As an example, for DLBCL, risk factors for poor prognosis are older age, elevated LDH, poor performance status, advanced stage disease, and number of extra nodal disease sites. But the risk factors may differ slightly for each type of lymphoma.

Hodgkin: 5 year survival 98% for low risk, 67% for high risk.

DLBCL: 5 year survival 90% for low risk, 50% for high risk.

Burkitt: 5 year survival 90% in younger patients, 54% overall.

Follicular: 5 year survival 91% for low risk, 52% for high risk.

Marginal zone: 5 year survival 83% for low risk, 56% for high risk.

Mantle cell: 5 year survival 60% for low risk, 20% for high risk (worst prognosis).

 

Evernote: https://www.evernote.com/shard/s272/sh/04aead8c-7491-426c-a0bf-515d1a5938e8/39eb8d959478c360c2d9ea442fc5c02c

 

Have a great day everyone!

SamMy