Exploring Haematological Disorders in General Practice A/Prof James Morton AM (Icon South Brisbane & Icon Chermside)
Clinical Haematologist | Group Director of Haematology
Topic one| Urgent Haematological Cases – Interactive
Discussion
Topic two | Icon Doctor App
Dr Karthik Nath (Icon South Brisbane & Brisbane
South Private Hospital, Springwood)
Clinical Haematologist | Group Deputy Director of Cellular Therapy
Topic one | Iron Deficiency Latest Updates –Interactive Discussion
Topic two | CAR T-cell Therapies for Blood Cancer –Recent Advances
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Urgent Haematology Cases …and what to do. A/Prof James Morton AM
Clinical Haematologist | Group Director of Haematology
Icon Cancer Centre South Brisbane & Icon Cancer Centre Chermside
Case 1 71yo farmer
Increasing headaches and tinnitus last 2-3 months
PMH: Nil
OE: NAD
Bloods:
Hyperviscosity: Symptoms • CNS: Headaches, altered conscious state, Seizures
• Eyes: Visual deterioration, Haemorrhage, Thrombosis
• Ears: deafness, tinnitus, vertigo, balance change
• Lungs: Dyspnoea, Pulmonary Haemorrhage
• Vascular: Bleeding, Thrombosis, Priapism
Hyperviscosity: Causes • Paraprotein
• IgM > 30
• IgA > 50
• IgG > 70
• Leukostasis
• AML: especially Monocytic: WCC > 80
• CML: WCC > 200
• CLL: WCC > 400+
• Polycythemia
• Thrombocystosis
• CTD: RA, Sjogrens
Hyperviscosity: Treatment Apheresis
Protein: Plasma
WCC: Leukodepletion
PLT / Hb
Treatment underlying disorder
Flare Reaction
71yo farmer
Increasing headaches and tinnitus last 2-3 months
PMH: Nil
OE: NAD
Bloods:
BM: low level Waldestroms Macroglobulinemia
Treatment: Plasma-Exchange
Chemotherapy: BR, Acalabrutinib
Case 2: Neutropenia 34yo Medical Registrar
Routine bloods
Neutropenia Causes
Congenital
Acquired
Infection: Post Viral
Drugs
Immune: Chronic Idiopathic
LGL / RA / Felty’s S
Agranulocytosis
Hypersplenism
Nutritional
BM disease: Chemotherapy
MDS
Acute Leukaemia
Hairy Cell Leukaemia
Other
Remember: Spurious, Normal Variant
Neutropaenia Treatment: ATRA + Arsenic
Case 3: Severe Thrombocytopenia 35yo female
1w history: Fatigue, Headache, Fevers
1d: bruising, oral bleeding, PV bleeding
Hb 85
WCC 6: N diff
PLT 18
Case 3: Severe Thrombocytopenia • ITP
• Primary
• Secondary: Viral / Drugs / CTD / LPD
• TTP
• Amegakarocytic Thrombocytopenia
• Primary BM process
Case 3: Severe Thrombocytopenia • ITP: treatment
• Indication:
• PLT < 30
• PLT < 50 and bleeding
• PLT < 80-100: surgery, delivery
• Treatment:
• Prednisone
• IVIg
• Splenectomy
• TPO
• Other: Rituximab, BTKi etc
Case 3 35yo female
1w history: Fatigue, Headache, Fevers
1d: bruising, oral bleeding, PV bleeding
Hb 85 LDH 1123
WCC 6: N diff Cr 150
PLT 28 Bili 80
• ADAM-TS 13
• Pentad:
• TCP
• MAHA
• CNS
• Fevers
• Renal
• Treatment:
• Plasma-Exchange
• Steroids
• Rituximab
• Caplacizumab
Case 4: Back Pain 50yo Male Back Pain
OE: NAD
FBC: Normal
ELFT: Ca 2.8
SEPP: λ-FLC 1055
Treatment:
Surgical Decompression T4
Prophylactic nail Femur
Radiotherapy Thoracic Spine
Chemotherapy: VCD: CR
Melphalan autologous Transplant
Skeletal MRI: widespread lytic lesions
Large R Femoral shaft: cortical scalloping
BM: BMA 31% PC, BMB 80% PC
FISH: IgH/CCNDI: t(11;14)
Case 5: • 39yo Lady
• 3 weeks abdominal swelling
• USS: hepatomegaly, acites
• Headaches
Case 5 • CT + Duplex USS: Budd- Chiari Syndrome
• MRI-V: Sagittal Sinus Thrombosis
• JAK 2+
• Clotting: Factor V Leiden
• TIPPS procedure, Warfarin (Xarelto when available), Hydrea, Inderal, Lactulose
• Subsequent switch to Xarelto when available
• Trial PegIFN: not tolerated
Case 5 • 8/20: bone pain, night sweats, fatigue
Case 5 Dx Myelofibrosis
Rx Ruxolitinib
DNR Search: VUD options
Discussion
1. Masked Polycythemia Rubra Vera due to iron deficiency
2. Unusual Thrombosis: consider PRV: JAK 2 testing
3. Management: VS to Hct 0.43: produce iron deficiency
4. Don’t give Iron
5. Transformation PRV to MF
Case 6 Mr LB
69yo Male
4w increasing abdominal girth, night sweats
PMH: Gout, BP, Polyps, GERD, Cholesterol
ED: Ascitic tap and discharged
Represented 1w feeling worse
Tumour Lysis Tumour Lysis Syndrome Tumour Lysis Syndrome Management • Forced diuresis
• Rasburicase
• Pre-Phase Vincristine – Prednisone
• Hyperfiltration for Calcium –Phosphate crystalluria
• Treatment: DA-EPOCH-R
The Urgent Haematology Case • Cytopenia: Hb < 80, PLT < 30, ANC <1
• Haemolytic anaemia
• Paraprotein (FLC / Band): viscosity, bone pain or lytic lesion, Hb/Ca/Cr
• Lymphadenopthy, Splenomegaly, B symptoms, Mediastinal mass
• Tumour Lysis: Urate, Cr, LDH
• Abnormal film: blasts, MDS changes, Leucoerythroblastic film, Hyperviscoity
Iron Deficiency Anaemia Karthik Nath
MBBS (Hons), BSc, FRACP, FRCPA, PhD
Clinical Haematologist – Icon Cancer Centre South Brisbane
Deputy Director of Cellular Therapy
Visiting locations: Springwood Health Hub, Brisbane South Private Hospital
Friendlies Medical Suites, Bundaberg
Can this patient have Iron Deficiency? • Microcytic anaemia – Yes (classic presentation)
• Not microcytic but anaemic (~ 50% of IDA) - Yes
• Microcytic, but not anaemia - Yes
• Not microcytic, not anaemic - Yes Fatigue Thrombocytosis (↑ PLT) Pica (craving for ice)
Restless Legs syndrome
Change in Fatigue in Non-Anaemic Women with Low Ferritin Randomized to Iron vs Placebo Treatment Multifaceted Role of Iron Interpretation of Iron Studies • TIBC (μg/dL) = transferrin (g/L) × 25.2
• TSAT = ([serum iron ÷ TIBC] x 100)
Q: Ferritin cut-offs: What do I do with normocytic anaemia when ferritin is 50-100? • If no other cause is apparent, time-limited trial of iron repletion warrants consideration.
Q: Ferritin Cut-offs: Should I use the same ferritin cut-offs for all adult patients? • Use higher cutoffs for: • CKD (especially on EPO)
IBD • CHF
Oral Iron Formulations Oral Iron Formulations • Avoid slow-release formulations
Does Vitamin C Improve the Absorption of Iron Tablets? • Randomized Controlled Trial found no significant benefit
• Avoid taking with a glass of OJ (may be fortified with Ca, which lessens absorption). Suggest taking on empty stomach with water.
Li et al, JAMA Network Open,
Alternate day PO Iron in non-anaemic, iron deficient patients Q: What starting dose do I recommend? • Typically start with once daily
• If GI side effects can go to every other day.
• If ongoing intolerance, discuss IV iron.
Q: Response to oral Iron? • Haemoglobin normalizes in 4-6 weeks with oral iron (if no ongoing losses)
• Repletion of iron stores takes 4-6mo
Q: When should I consider IV Iron ? • Inability to tolerate oral iron
• Highly symptomatic with anaemia
• Ongoing blood loss (cannot get ahead of it)
• Unable to absorb PO iron (gastric bypass, coeliac disease, ESRD)
• Inflammatory states: Advanced CKD, Heart Failure
• Potential harm from oral iron (IBD)
Commonly used IV Iron Formulations Infusion time Diluted in normal saline and infused over 1530min Diluted in normal saline and infused over 2030min
Q: Determining how much IV Iron to administer: Management of Signs/Symptoms of Reaction During Infusion: Q: Potential Side Effects of IV Iron • Skin staining with extravasation (<1%)
• Anaphylaxis (rare)
• Transient flu-like symptoms -Self-resolves.
• Can rarely exacerbate RA symptoms. - Pretreatment with steroids can mitigate
• Avoid in 1st trimester of pregnancy
• Avoid if acutely bacteraemic
Q: Potential Side Effects of IV Iron Determine Cause of Iron Deficiency • Inadequate Iron Intake
- Poor diet, vegan diet
• Malabsorption
• Coeliac disease, PPI Rx, H. pylori, gastritis, gastric surgery, IBD
• Bleeding
• Menorrhagia, epistaxis, GI lesions
• Increased Demand
• Pregnancy/breast feeding, EPO treatment
Endoscopic Workup is Important Introduction to CAR T-cell Therapy Karthik Nath
MBBS (Hons) BSc FRACP FRCPA PhD
Clinical Haematologist | Icon Cancer Centre South Brisbane Deputy Director of Cellular Therapy
Visiting locations: Springwood Health Hub, Springwood Friendlies Medical Suites, Bundaberg
Objectives • Overview of CAR T-cell therapy
• Indications for CAR T-cell therapy in blood cancers
• Unique Toxicities of CAR T-cell therapy
• Future Developments – Immune-effector cell (IEC) therapies
The process of autologous chimeric antigen receptor (CAR) T-cell therapy Cappell, Kochenderfer,
Killer activity of CAR T-cells Cancer Cell CAR T-cell
CD19, BCMA
CAR T-cells are a ‘Living drug’
Day 10 biopsy showing anti-CD19 CAR-T infiltrating into site of disease (and no residual B-cell lymphoma) CD3 “T-cell marker”
PAX-5 “Lymphoma marker”
CD4 “T-cell marker”
CD8 “T-cell marker”
Objectives • Overview of CAR T-cell therapy
• Indications for CAR T-cell therapy in blood cancers
• Unique Toxicities of CAR T-cell therapy
• Future Developments – Immune-effector cell (IEC) therapies
CAR T-cell therapy is approved for use in relapsed/refractory blood cancers.
US FDA-approved CAR T-cell therapies Inpatient (Kite, Gilead)
Inpatient (Kite, Gilead)
Outpatient (Novartis)
Outpatient (BMS)
Inpatient (BMS)
Outpatient (J&J)
• r/r CLL or MCL ≥ 2 prior lines (2024)
MM after ≥ 2 lines of therapy (2024)
MM after ≥ 1 line of therapy (2024)
Kochenderfer, Nat Revs Clin Oncol, 2024 (modified)
The curative potential of CD19 CAR in relapsed/refractory lymphoma BCMA-directed CAR T-cell therapy 5th line therapy for multiple myeloma Objectives • Overview of CAR T-cell therapy
• Indications for CAR T-cell therapy in blood cancers
• Unique Toxicities of CAR T-cell therapy
• Future Developments – Immune-effector cell (IEC) therapies
Relative timescale for the onset and duration of Cytokine Release Syndrome (CRS) and Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) Pathogenesis of Cytokine Release Syndrome (CRS) • Phase 1. CAR T-cell trafficking to tumor site
• Phase 2. CAR T-cell activation/proliferation; cytokine production; activation of endogenous immune cells
• Phase 3. ↑ cytokines → systemic inflammatory response
• Phase 4. Diffusion of CAR-T, cytokines, activated monocytes into CSF (ICANS)
• Phase 5. Resolution phase
Pathogenesis of Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) Nature Reviews, 2022
Infections are an important cause of death after CAR T-cell therapy Objectives • Overview of CAR T-cell therapy
• Indications for CAR T-cell therapy in blood cancers
• Unique Toxicities of CAR T-cell therapy
• Future Developments – Immune-effector cell (IEC) therapies
Clinical trials using IEC therapies in solid tumours in last 3-years Gastric adenocarcinoma Auto CAR T-cell Claudin 18.2
Renal cell carcinoma Allo CAR T-cell CD70
Prostate cancer Auto CAR T-cell PSMA
Gastric adenocarcinoma Allo NK T-cell -
Synovial sarcoma TCR T-cell -
Melanoma TIL -
Melanoma + lung cancer IL15 secreting TIL -
Mesothelioma Auto CAR T-cell Mesothelin
Auto, autologous; allo, allogeneic; TCR, T-cell receptor; TIL, tumor infiltrating lymphocyte
CD19 CAR-T in Autoimmune Disease Activity and Outcomes of Stem Cell Transplantation at Largest provider of ASCT in Queensland Favorable survival outcomes with ASCT compared to national registry data
ASCT, autologous stem cell transplant
Acknowledgments Icon Cancer Centre
Ian Irving
James Morton
Kerry Taylor
Jason Butler
Simon Durrant
Icon Cellular Therapy Lab
Debra Taylor
Icon Cancer Foundation
Leanne Hardymann
Icon Group – Research
Icon Pharmacy
Memorial Sloan Kettering Cancer Center, NYC
Jae Park
Sham Mailankody
Translational Research Institute
Maher Gandhi
QIMR Berghofer
Steven Lane
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