The Immune System in Waldenstrom s Macroglobulinemia

Transcription

1 The Immune System in Waldenstrom s Macroglobulinemia Christine Chen Princess Margaret Cancer Centre Toronto, Ontario April 2018

2 Disclosures Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Scientific Advisory Board Celgene, Sanofi, GSK N/A Gilead, Janssen N/A N/A Celgene, Amgen, Abbvie, Janssen

3 Objectives 1. Understand the basics of the immune system 2. Discuss the immune defects seen in patients with WM 3. Review management of immune defects and prevention/treatment of infections in WM

4 The Immune System The basics

5

6 Innate immunity: Phagocytes Phagocytes include neutrophils, monocytes, macrophages, dendritic cells, and mast cells

7 Innate immunity: Natural killer cells

8 Adaptive immunity B cells microbe antibody B lymphocytes can mature into: plasma cells that produce antibodies that bind directly to microbes memory B cells that can remember microbes and lead to rapid immune response in case of re-infection

9 Adaptive immunity T cells microbe T lymphocytes: Are activated by other cells with ingested microbes to expand and kill other target cells with the microbe (do not bind directly to microbes) Can also activate B cells to secret antibodies and macrophages to destroy ingested microbes

10 Step-wise activation of the immune system to fight infections Patients with cancer can have defects anywhere along this step-wise process

11 Immune defects in cancer patients, including WM Management and prevention

12 Epithelial barrier breakdown Epithelial barriers: Natural shedding of skin removes bacteria In the lungs, infectious agents are removed by cilia and trapped by mucus Normal bowel flora (bugs) prevent pathogenic bugs from infecting Breakdown: Mouth sores, skin breaks or wounds, intravenous lines Particularly problematic are superbugs resistent to usual antibiotics (eg. MRSA (methicillin-resistent staph aureus) and C. difficile Prevention: Careful hygiene and avoidance of trauma/cuts Avoid smoking that stun cilia movement Use of probiotics (live bacteria) can help maintain a healthy gut Yogurt, kefir, (fermented dairy product), apple cider vinegar, supplements Avoid excess use of antibiotics that may lead to resistence

13 Low neutrophils (neutropenia) Less than 1.5 x 10 9 /L particularly at risk of infection if less than 0.5 (severe or grade 3) Usually chemotherapy-induced onset ~ 3-5 days after chemotherapy, duration varies with chemo type Can use G-CSF, a growth factor injection into skin, to hasten neutrophil recovery G-CSF (Neupogen or Grastofil)

14 Febrile neutropenia Fever (at least 38.0 o C) with neutrophils less than 0.5 Prone to infections: 80% derive from patient s own bugs (bowel) Others pneumonia, line infections (from skin) Must be treated urgently: High risk should be admitted for IV antibiotics Low risk can be treated as an outpatient with oral antibiotics (assess using MASCC score)

15 T cell dysfunction and depletion Inherent defects with underlying WM May also be due to therapy (particularly fludarabine or cladribine) Keating et al Blood 1998;62:1165

16 T cell dysfunction and depletion Types of infection (opportunistic): Viruses herpes (including shingles) Mycobacteria TB, MAC Pneumocystis (PJP) Fungi Prevention: Viruses - Acyclovir (typical dosing 400mg tablets twice daily) TB - patients from endemic areas may harbor latent TB that will reactivate with chemo skin test ± CT chest and if positive, treat with 9 months Isoniazid PJP - Septra (typical dosing double strength tablets 1-2 daily on MWF) or inhaled pentamidine Fungi Oral nystatin mouthwash; Fluconazole (typical dosing mg tablets daily) Keating et al Blood 1998;62:1165

17 Fungal infections Candidiasis (yeast) is common: Oral thrush sore mouth, white plaques treatment with mouthwashes (nystatin) or antifungal medications (fluconazole) Vaginitis vaginal itching, whitish discharge treatment with creams/vaginal suppositories or antifungal medications WebMD online

18 TB skin test Skin injection with tuberculin Read reaction hrs later positive negative Image from: Image from:

19 B cell dysfunction and depletion Common with B cell lymphomas inherent to disease and/or due to therapy (rituximab) Hypogammaglobulinemia (low antibodies) Common with CLL, WM, myeloma Predisposes to bacterial infections Prevention options: Antibiotics continual low dose Vaccinations IVIG (intravenous immunoglobulin) infusions

20 Recommended vaccinations prior to treatment No live vaccines New shingles vaccine (Shingrix) is now available more than 90% protective Inactivated (not live) Vaccinations

21 IVIG Intravenous Immunoglobulin - the antibody fraction of blood collected from donors - given every 3-4 weeks IV to prevent infections - side effects headache, fevers, chills, nausea, diarrhea - $2000 per dose - new subcutaneous formulation for self-administration

22 Rituximab-related infections Rituximab is a monoclonal antibody to CD20 (marker on B cells) causes depletion of B cells Commonly given in combination with chemotherapy or longterm as single agent maintenance therapy Patients on maintenance commonly complain of recurrent sinus infections, nasal drip, cough Lanini et al. BMC Infect Dis 2013;13:317

23 Rituximab-related hepatitis B Patients at risk are from areas where hepatitis B is endemic often transmitted from mother to baby at birth

24 Rituximab-related hepatitis B Patients should be screened prior to starting therapy (especially with rituximab) May need antiviral prevention during and after therapy Examples of antiviral agents: lamivudine, tenofovir

25 Take home messages As a patient, what can you do to protect yourself?

26 Before treatment: Good diet and general health maintenance, including dental care Vaccinations, including annual flu shot Screening for hepatitis and TB may need to see specialists from hepatology and infectious diseases During treatment: Good hygiene wash hands! Oral care may use preventive mouthwash for sores or thrush, avoid dental procedures due to risk of infection Diet wash fruit and veggies well, consider soft diet if mouth sore, avoid constipation (don t use suppositories) May receive preventive antibiotics or antiviral agents depending on therapy If at risk, may need TB or hepatitis therapy Get a thermometer and measure if chills, fevers, feeling unwell call/go to ER if temp >38.3 May use G-CSF injections to support neutrophil counts If recurrent severe infections, may receive IVIG monthly After treatment: Good diet and general health maintenance, including dental care Some may need ongoing antibiotics or antiviral agents depending on therapy May continue IVIG monthly reassess every 4-6 months

27 Thanks! Princess Margaret Cancer Centre Lymphoma/Myeloma faculty: Christine Chen Michael Crump John Kuruvilla Anca Prica Vishal Kukreti Rodger Tiedemann Robert Kridel Donna Reece Suzanne Trudel

28

29 Supplemental slides

30

31 Management of ibrutinib toxicities Opportunistic infections (Rogers #830) Retrospective single agent review of 566 patients (74% CLL) Median 3 prior lines (range 0-18), followed for median 2.7 yrs Opportunistic infections uncommon (4.7% at 5 yrs) Most common fungal (61%) with no PJP Ruchlemer #4323 reported 28 pts with invasive fungal infections (aspergillus, mucormycosis) on ibrutinib, not related to neutropenia or steroids, 46% with brain involvement should we prophylax?