HAematology Flashcards
What is the most common cause of renal impairment in MM
Cast nephropathy
RF for MGUS turning to MM?
M protein >1.5g/dL
Non-IgG MGUS
Abnormal serum free light chain ratio
Patients with MGUS progress to a symptomatic plasma cell proliferative disorder or lymphoproliferative disorder at a **rate of 1 percent per year. **
What does prolonged repitilase time suggest?
Inherited dysfibrinogenaemia ( others: DIC, paraproteinemia)
Markers of AML?
CD13, 33, 24, 117, MPO
Independent RF for hodgkins:
low albumin <40
Anaemia <10.5
MALE
Stage IV
WCC>15
Lt<0.6
Age >45
Syndrome of VIPoma
profound and chronic watery diarrhea and resultant dehydration, hypokalemia, achlorhydria, acidosis, flushing and hypotension (from vasodilation), hypercalcemia, and hyperglycemia.
NDAPH
NADPH maintains glutathione in its reduced form, which acts as a scavenger for dangerous oxidative metabolites.
G6PD enzyme catalyses the oxidation of Glucose-6-phophate and reduction of NADP+ to NADPH
The pentose monophosphate shunt is the only source for NADPH in red blood cells.
Lab tests suggestive of intravascular haemolysis
haemoglobinuria, methaemalbuminaemia, and urinary haemosiderin
schistocytes, fragmented cells and helmet cells
Fanconi anemia (FA) is a hereditary DNA repair disorder characterized by progressive pancytopenia with bone marrow failure, variable congenital malformations and predisposition to develop hematological or solid tumors. Patients may develop acute myeloid leukemia, often preceded by myelodysplastic syndrome. Patients are also highly predisposed to solid tumors, of the head and neck or anogenital regions. This condition is typically inherited in an autosomal recessive fashion. It is associated with chromosomal fragility.
Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer development due to a mutation in P53. The classical LFS malignancies - sarcoma, cancers of the breast, brain, and adrenal glands - comprise about 80% of all cancers that occur in this syndrome.
OSLAM syndrome is a rare autosomal dominant hereditary disorder. Its name is an initialism of “osteosarcoma, limb anomalies, and erythroid macrocytosis with megaloblastic marrow syndrome”.
Gardner syndrome, also known as Gardner’s syndrome or familial colorectal polyposis, is a subtype of Familial Adenomatous Polyposis (FAP). Gardner syndrome is an autosomal dominant form of polyposis characterized by the presence of multiple polyps in the colon together with tumors outside the colon. The extracolonic tumors may include osteomas of the skull, thyroid cancer, epidermoid cysts, fibromas, as well as the occurrence of desmoid tumors in approximately 15% of affected individuals.
High risk features of ET
> 60 with JAK2 V617F mutation
Histroy of thrombosis at any age
Prognostic factors for CLL
Poor:
Unmutated IgH (CLL cells that haven’t gone through hypermutation of IgVH)
increased beta2 microglobulin
CD38+ve
MALE
Lymph doubling time <12Mo
Increased LDH
**17p deletion –> mutation in p53 **= resistance to chemo
Good:
13q del
Low CD38+ve
Low ZAD-70
Warm AIHA
Warm: most common 85%
Nucleated red cells may be seen in addition to spherocytes in warm AIHA.
IgG mediated
Haemolysis at body temp
extravascular
Causes:
- AI: SLE
- lymphoma, CLL
- Methyldopa, quinidine, penicillin
- pregnancy
Tx:
1. Supportive, folic acid and transfusion
2. Steroids
3. Rituximab
4. Splenectomy: outcomes of splenectomy are not as good as compared with ITP, with a 30-60% complete response.
Thromboembolism is common and therefore prophylactic anticoagulation should be considered
Cold AIHA
Less common
Temp <37
intravascular
Mediated by complement/IgM
Agglutination on blood film
Causes:
Infections: EBV, CMV, , mycoplasma. HCV, syphilis
Macroglobulinemia
infection tend to cause acute disease
Tx:
1. Warm, folic acid
2. Rituximab
3. PLEX (if IgM high)
4. Low dose alkylating agents (CYC or chlorambucil)
*not responsive to steroids
In warm antibody hemolytic anemia, IgG is nearly always present, and C3 (C3b and C3d) may be present as well. In cold antibody disease, C3 is present while IgG is usually absent. The test is ≥ 98% sensitive for autoimmune hemolytic anemia; false-negative results can occur if antibody density is very low or, rarely, if the autoantibodies are IgA.
Leukocyte alkaline phosphatase (LAP)
- found within mature WBC
- level increased in physiological response (leukemoid reaction) and pathologies that has **mature ** WBC (i.e. PV, ET, PMF)
- lower levels in conditions that have undeveloped WBC: CML, PNH, AML
What are rates of ICH in haemophilia?
low
What are rates of ICH in haemophilia?
low
Hereditary Spherocytosis
Autosomal Dominant defect of red blood cell cytoskeleton
- red blood cell survival reduced as destroyed by the spleen
- MCHC elevated
* jaundice, gallstones
* splenomegaly
* aplastic crisis precipitated by parvovirus infection
Degree of haemolysis is variable
Inx:
- EMA binding test and the cryohaemolysis test
- Osmotic fragility test was previously used
- To note you don’t neccesarily need these tests, if FHx and typical lab findings are seen
Tx:
Folate supplement
Splenectomy
Multiple myeloma
Poor prognostic markers for MM
High RISS score: (b2 microglobulin >5.5, albumin <35)
FISH:
17p del
p53 mutation
t4:14, 414:16, t16:20, 14:20, gain 1q, del 1p
Mantle cell lymphoma
Cyclin D1 nuclear expression
T11:14
CD 5+ 19+, 20+, FMC 7 positive
CD23-ve
Nuclear staining for cyclin D1 (BCL1) is present in >90 percent of cases
Mantle cell lymphoma and CLL are both CD5+ve
To differentiate these:
Mantle cell is** CD23-ve and CD200 -ve**
Alpha thalassaemia
Chr 11
4 genes
2 gene deletion: Cis: more common in asian and can be associated with fetal hydrops
Trans: N Hb with reduce MCV (more common in african)
3 gene deletion:
HbH (4 beta disease)
Low Hb, low MCV
Splenomegaly
nondeletional defect, such as a point mutation (ie, aa/–, where a represents the mutated alpha chain, such as hemoglobin Constant Spring). HbH disease tends to be more severe in patients with the nondeletional form.
Alpha thalassaemia
Chr 16
4 genes
2 gene deletion: Cis: more common in asian and can be associated with fetal hydrops
Trans: N Hb with reduce MCV (more common in african)
3 gene deletion:
HbH (4 beta disease)
Low Hb, low MCV
Splenomegaly
nondeletional defect, such as a point mutation (ie, aa/–, where a represents the mutated alpha chain, such as hemoglobin Constant Spring). HbH disease tends to be more severe in patients with the nondeletional form.
In patients with beta thalassaemia, co-inheritance of alpha thalassemia trait ameliorates the severity of beta thalassemia by partially normalizing the alpha to beta globin ratio without greatly affecting the amount of total hemoglobin
Beta thalassaemia
Chr 11
2 genes
Minor:
- defect in one beta allele
- Microcytosis more profound cf Hb drop
-** HbA2 high**
+/- HbF
no Tx
Major:
Defect in both alleles
Autosomal recessive
I**ncreased HbF (90-100%, **HbA2 >2.5%
Hepatosplenomegaly
Increased risk of erythroid tumour and increased marrow cavity –> pathological fractures
Good prognostic factos in AML
t8:21, t15:17 (APML)
Inv16
Mutated NPM1 without or low FLT3-ILD
Biallelic mutated CEBPA
Poor prognostic for AML
Age, ECOG correlates to reduced OS and DFS
Cytogenetics:
del5 or del7
Del5q, abn. 3q
17p abnomality
TP53 mutation
t6:9, t9:22
Wt NPM1 with FLT3-ILD high
*if it was mutated WtNPM1 then it will be intermediate risk *
*FLT3-TKD doesn’t affect prognosis
CALR mutation in Myeloproliferative disorders
CALR mutation has the best prognosis
then isolated JAK2 mutation
Triple negative confers the worse prognosis
Which conditions are reversible in haemochromostosis
Cardiomyopathy
Dermal pigmentation
Irreversible complications of haemochromatosis
- diabetes
- cirrhosis
- hypogonadism
- arthropathy
Paraneoplastic pemphigus (PNP)
rare autoimmune blistering disorder that may occur in the setting of lymphoproliferative disorders and malignancies
he disorders most frequently linked to PNP are non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Castleman’s disease.
**Antibodies against periplakin and envoplakin **are strongly associated with PNP.
HbS
a valine is substituted for glutamic acid on the surface of the Hb S molecule in the sixth (or seventh, in the revised amino acid numbering convention) position of the beta globin chain (HBB glu6val)
HbS has the following properties:
- it is less negatively charged, due to the loss of glutamate for valine
- it polymerises with adjacent HbS
- the loss of the negative charge and the configuration of HbS makes it less soluble than HbA
- it has** lower affinity for oxygen (right-shift of the oxygen-dissociation curve)**, which increases the risk of desaturation, but improves the yield of oxygen to the tissues
- it is the result of a point mutation substituting glutamate for valine at position 6, and
it contains two α-like globins and two β-like globins and four haem molecules.
AIP
Acute intermittent porphyria
**Autosomal dominant **
defect in porphobilinogen deaminase (an enzyme involved in the biosynthesis of haem)
- results in the toxic accumulation of delta aminolaevulinic acid and porphobilinogen
Presentation: 20-40 yr old, FEMALE 5:1
Combination of abdominal, neurological and psychiatric symptoms:
abdominal: abdominal pain, vomiting
neurological: motor neuropathy
psychiatric: e.g. depression
hypertension and tachycardia common
Dx:
- Urine turns deep red on standing
- Raised urinary porphobilinogen (elevated between attacks as well)
- assay of red cells for porphobilinogen deaminase
- raised serum levels of delta aminolaevulinic acid and porphobilinogen
Tx:
- avoid triggers
- Acute attacks:
> IV haematin.haem arginate
> > IV glucose (carb load) if above not readily available
What is required for secondary haemostatis?
Negatively charged phopholypid surfce, coag factors, calcium, appropriate temp
Chimeric antigen receptor T cells (also known as CAR T cells) are T cells that have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy. Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are receptor proteins that have been engineered to give T cells the new ability to target a specific protein. The receptors are chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor. CAR-T cell therapy uses T cells engineered with CARs for cancer therapy. The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to more effectively target and destroy them. Scientists harvest T cells from people, genetically alter them, then infuse the resulting CAR-T cells into patients to attack their tumors
Option A describes Bi-specific T-cell engagers (BiTEs). BiTEs form a link between T cells and tumor cells. This causes T cells to exert cytotoxic activity on tumor cells by producing proteins like perforin and granzymes, independently of the presence of MHC I or co-stimulatory molecules. These proteins enter tumor cells and initiate the cell’s apoptosis.
Option C describes PARP inhibitors. PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). PARP1 is a protein that is important for repairing single-strand breaks (‘nicks’ in the DNA). If such nicks persist unrepaired until DNA is replicated (which must precede cell division), then the replication itself can cause double strand breaks to form. Drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and in tumours with BRCA1, BRCA2 or PALB2 mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that don’t replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2 still have homologous repair operating, which allows them to survive the inhibition of PARP.
Follicular lymphoma
- Histology and FISH
- nodular growth pattern and cell morphology consisting of a mixture of centrocytes and centroblasts is characteristic
- CD 19+, CD 20+
- CD5 -ve, CD 10+ve
- CD23 -ve
- BCL-6 +ve
Molecular gene rearrangements of the t(14;18) involving BCL2 can occur.
the majority has a normal serum lactate dehydrogenase (LDH) level.
PNH
- acquired disorder
- PNH is a clonal stem cell disorder resulting in deficiency of GPI-anchored proteins and intravascular haemolysis, cytopenias and thrombosis
Pathophysiology:
- GPI anchor protein to cell mb
- Complement regulating surface proteins (such as DAF) need GPI protein to attach to mb
- - thrombosis due to lack of CD59 –> platelet aggregation
- flow cytometry of blood to detect low levels of CD59 and CD55
Features:
- haemolytic anaemia
- red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopaenia may be present
- haemoglobinuria: classically dark-coloured urine in the morning (although has been shown to occur throughout the day)
- **thrombosis **e.g. Budd-Chiari syndrome
- aplastic anaemia may develop in some patients
Management:
- blood product replacement
- anticoagulation
- eculizumab, a monoclonal antibody directed against terminal protein C5 It has been shown in the TRIUMPH trial to **decrease blood product support requirements and improve quality of life **in PNH, but requires meningococcal vaccination prior to commencement and is not useful acutely.
- stem cell transplantation
Fact or fiction
Levels of VWf are lower in O blood group patients.
FACT
Ruxolitinib
selective inhibitor of Janus kinase (JAK) 1 and 2
significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and** improving overall survival**
Brentuximab vedotin
- antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma
- It selectively targets tumor cells expressing the **CD30 antigen, **a defining marker of Hodgkin lymphoma and ALCL.
The major side effects include cytopenias and peripheral neuropathy
DLBCL prognostication
Age>60, elevated LDH, poor functional status, stage III/IV disease and presence of extra-nodal sites are all adverse prognostic factors in DLBCL and are used in the IPI risk calculator.
Recently the use of DNA micro-analysis has been used to predict survival also - with three subtypes identified: Germinal center B cell like; Type 3; and Activated B cell like. The “activated B cell-like DLBCL” (ABC) group has a lower overall survival rate than the “germinal centre B cell-like DLBCL” (GCB) group, with type 3 somewhere in between
Aplastic anaemia
Aplastic anaemia causes a deficiency of all blood cell types (PANCYTOPENIA): red blood cells, white blood cells, and platelets.
It is more frequent in people in their teens and twenties, but is also common among the elderly.
M=F
2 peaks: 20-25, 60
ASIANs
Causes:
- most common: Idiopathic - Autoimmune suppression of haematopoietic stem cells by T-cell mediated mechanism
- Radiation, chemotherapy, SLE
- Toxins: benzene
- Medications: Chloramphenicol, gold, sulfonamides, phenytoin, carbamazepine, quinacrine, tolbutamide
- Post- viral hepatitis
- Non-hepatitis virus: parvovirus, EBV, CMV, echovirus 3
- Pregnancy
- PNG
- Malignancy: large granular lymphocytic leukemia
- congenital: defects in telomere length (dyskeratosis congenita) or DNA repair (fanconi)
- linked to both the initiation of bone marrow failure and the propensity to later progress to myelodysplasia, PNH, or AML
Symptoms:
- hepatosplenomegaly, lymphadenopathy, or bone tenderness should not be present, and their presence should lead to questioning the diagnosis.
- will have the classic sx and signs of pancytopenia
Lab:
- pancytopenia (could be any number)
- may have: reticulocytopenia, macrocytosis,
- BM biopsy/aspirate: Hypocellular marrow
Treatment:
1. Mild: supportive care (EPO or filgrastim), transfusion, abx
2. Severe:
- defined as Nt <0.5, plt <20, reticulocyte <1%, bone marrow cellularity <20%
- young (<40y): allogeneic BMT (if you have HLA matched sibling, it’s safer)
- Old (>40y):
> ATG + cyclosporin
> Eltrombopag, a thrombopoietin mimetic, is now being added to ATG plus cyclosporine with tri-lineage hematologic responses as high as 90%.
> ATG should be used in combination with corticosteroids (prednisone or methylprednisolone 1–2 mg/kg/day orally for 1 week, followed by a taper over 2 weeks) to avoid ATG infusion reactions and serum sickness.
Cyclosporine and eltrombopag are maintained at full doses for 6 months and then stopped in responding patients.
full benefit of immunosuppression take 4mo
- 1/3 will replase after IS treatment
- Clonal hematologic disorders, such as PNH, AML, or myelodysplasia, may develop in one-quarter of patients treated with immunosuppressive therapy after 10 years of follow-up.
- Factors that predict response to ATG-cyclosporine therapy are patient’s age, reticulocyte count, lymphocyte count, and age-adjusted telomere length of leukocytes at the time of diagnosis
Polychromasia
The term ‘polychromasia’ suggests that the red cells are being stained many colours. In practice, it means that some of the red cells stain shades of bluish grey (Fig. 5-62) – these are the reticulocytes. Cells staining shades of blue, ‘blue polychromasia’, are unusually young reticulocytes. ‘Blue polychromasia’ is most often seen when there is either an intense erythropoietic drive or when there is extramedullary erythropoiesis, as, for instance, in primary myelofibrosis or carcinomatosis. It should be noted that in certain circumstances the absence of polychromasia is significant; in a patient with severe anaemia it indicates that the bone marrow response is inadequate (e.g. in aplastic anaemia and pure red cell aplasia).
What causes pancytopenia with normocellular marrow?
SLE
disseminated infection
hypersplenism
B12/folate def
MDS
Hairy cell leukemia
Hairy cell leukemia is a rare malignancy of hematopoietic stem cells differentiated as mature B lymphocytes with hairy cytoplasmic projections.
- V600E mutation in the BRAF gene is recognized as the causal genetic event of hairy cell leukemia
- median age at presentation is 55 years, 5:1 male predominance.
- Hairy cell leukemia is usually an indolent disorder whose course is dominated by pancytopenia and recurrent infections, including mycobacterial infections.
- hepatosplenomegaly
Lab:
- pancytopenia
- “hairy cells” are usually present in small numbers on the peripheral blood smear and have a characteristic appearance with numerous cytoplasmic projections.
- dry tap on BM
- immunophenotype:
> CD11c, CD20,22
> CD25
> CD103, CD123
- marked infiltration of the red pulp
Tx: indicated for symptomatic disease
1. nucleoside analog: cladribine or pentostatin
single course: 70-95% remission
2. Rituximab in relapse setting (with ot without 1)
3.** BRAF inhibitor vemurafenib** exhibits ~100% overall response rate in patients with refractory/relapsed hairy cell leukemia, with 35–40% complete remissions.
In TRALI, host neutrophils are activated by a factor in the blood product. Activation is associated with the release from neutrophils of cytokines, reactive oxygen species, oxidases, and proteases that damage the pulmonary capillary endothelium. This damage causes inflammatory (non-hydrostatic) pulmonary edema. Transfused factors responsible for host neutrophil activation can include antibodies in the blood component directed against recipient antigens, or soluble factors such as bioactive lipids that can activate neutrophils. Donor anti-leukocyte antibodies can bind to antigens on recipient neutrophils or possibly to other cells such as monocytes or pulmonary endothelial cells.
which enzymes are involved in error-free homologous recombinant repair pathway
BRAC1, BRCA 2, PALB2
Myeloproliferative disorder
General
- disease of the elderly
- includes ET, PV, IMF and CML
- Possible causative factors: **ionising radiation **
- Mutations:
JAK2, CALR, MPL
JAK2 V617F on Exon 14
if negative –> ET or MF –> check CALR + MPL –> if negative clonal testing
if negative. –> if PV: 3% JAK2 on exon 12, 13
CALR
somatic mutation on Exon 9
associated with myeloid neoplasm with thrombocytosis
Mutation of calreticulin –> activates MPL –> activates JAK/STAT pathway
Types:
1: deletion: IMF, M>F
2. Insertion: ET, younger pt, low risk of thrombosis, ^^ platelets
PV
Increased Hb and Hct +/- panmyelosis
Criteria:
Major:
1, Hb >165 (m), >160 (f)
or Hct >49% or 48%
or >25% ^ in RCM
- BM: increased cellularity with panmyelosis
- JAK2 V617F or JAK2 on Exon12
Minor:
reduced EPO
** Clinical:**
1. Hyperviscosity syndrome: parasthesia, HA, HTN, dizzy, SOB, tinnitus, visual
2. Thrombotic: DVT, PE, Budd Chiari, Stroke/TIA, MI
Arterial > Venous, RF: prior hx, >60, Leuc >15, HTN
- Bleeding
- Erythromelalgia: associated with plt >400
- Prutitus (esp. with warm shower) - mast cell degranulation and histamine release
- Epigastric sx and PUD (due to increased histamine from tissue basophils and change in gastric BF due to hyperviscosity
- gout
- Plethora
- Splenomegaly>hepatomegaly
Investigations:
1. If EPO is elevated, must exclude secondary causes:
- OSA, COPD, Pulm HTN, Smoking
- high altitude
- Eisenmenger sx
- Methemoglobunemia
- inappropriate EPO producing tumour: RCC, HCC, pheo, uterine leiomyoma, ovarian tumour, cerebral hemangioblastoma
- Leucocyte ALP will be increased, ESR will be reduced
Treatment:
Phlebotomy: aim** hct<45%**
+ daily aspirin
Low risk: <60, no thrombosis
- if microvascular sx, CV RF, leucocytosis then can consider increasing aspirin to BD
High risk: >60, hx of thrombosis: (other RF: plt >1500, WCC >15, splenomegaly, uncontrolled sx
- consider HC or IFN alpha
- if arterial thrombosis: aspirin BD
- if venous thrombosis: VKA (reduces recurrence, lifelong if splanchnic, cerebral, unprovoked proximal
- also to note, MPN pts are at higher riks of bleeding
Ruxolitinib: selective JAK1/2 inhibitor
use of failed on HC tx with splenomegaly
shown to reduce spleen size, improve sx, and reduce the need for phlebotomy
Poor prognostic factors:
- >61y
- thrombosis hx
- WCC >10.5
- abnormlal karyotype
leukaemic transformation risk: 2.3% in first 10 years, 7.9 in first 20yrs
Essential thrombocytopenia
Part of MPN
it has the best OS out of the MPN
Increase in platelet in the abscence of recognisable stimulus
- megakaryocyte proliferation
F>M (2:1)
- risk increases with age, and in older people there is no difference between genders
Diagnostic criteria:
Platelets >450
BM: mainly megakaryocyte hyperplasia and hyertrophy without other lineage increase
should not meet criteria for other MPN
Most have mutations JAK2 V617F, CALR, MPL
remember bleeding time will be prolonged
Essential thrombocytopenia
Causes of secondary thrombocytosis
infection, inflammation
malignancy
haemorrhage
iron deficiency
Haemolytic anaemia
post splenectomy
post chemo
Drugs (Vinca-alkaloids)
Essential thrombocytopenia
Indication for starting aspirin
> 60
CV RF
JAK2 V617F mutation
Contraindications:
- Extreme thrombocytosis
- ab vWF
- low risk: CALR mutation
Essential thrombocytopenia
Symptoms
Vasomotor
Erythromelalgia (burning sensation in hands)
-thrombosis
-bleeding
splenomegaly is rare
Risk of transformation to AML or MF
Hyperviscosity sx
Essential thrombocytopenia
Indication for chemoreductive therapy
High risk:
**>60 **and JAK2 mutation
>prior thrombosis
Other relative indications:
Plt >1500 ??11 x 10^9
uncontrolled ET sx
Uncontrolled myeloproliferation - splenomegaly
Essential thrombocytopenia
Chemoreductive therapy
- HC
- rIFN a
Pegylated interferon alfa-2 can induce significant hematologic responses and can potentially target the malignant clone in CALR-mutant cases. haematological remission (80%) and free from phlebotomy (60%), reduced thrombosis, improved pruritis
Second line:
- Anagrelide (PDEi): low dose, as high dose has complications - HA, peripheral oedema, HF
- Busulfan (alkaylating agent) not used in younf pt’s due to risk of transformation
- Peg- IFN in PV and ETL
○ 80% haematological response
○ 60% freedome from phlebotomy
○ Reduces thrombosis
○ Improved pruritus
○ Molecular response
○ ADR is common
○ Not curative
Essential thrombocytopenia
Poor prognostic factors
> 60
Leucocyte >11 x 10^9
thrombosis hx
Male
increased LDH
non-driver mutation
survival of patients younger than age 50 years does not appear different from matched controls.
There is a 10–15% risk of progression to myelofibrosis after 15 years, and a 1–5% risk of transformation to acute leukemia over 20 years
PMF
Primary myelofibrosis
- Primary myelofibrosis is a myeloproliferative disorder characterized by clonal hematopoiesis that is often but not always accompanied by JAK2, CALR, or MPL mutations
- BM shows fibrosis
- splenomegaly
- leukoerythroblastic peripheral blood picture with teardrop poikilocytosis.
MF can also occur secondary to ET or PV - fibrosis occurs in response to increased secretion of platelet-derived growth factor (PDGF) and possibly other cytokines.
Sx:
- 20% don’t have sx
- 80% have symptoms
○ Low blood counts:
§ Anaemia - fatigue, weakness, or SOB
§ Frequent infection
§ Easy bruising or bleeding
○ Splenomegaly related abdominal discomfort the liver is enlarged in ~50% of patients
○ Bone pain
○ Constitutional symptoms
§ Anorexia, unexplained weight loss, night sweats
○ Gout
Hematopoiesis in the liver leads to portal hypertension with ascites, esophageal varices, and occasionally transverse myelitis caused by myelopoiesis in the epidural space.
Lab/Histology:
- Fibrosis at this stage is detected by a silver stain demonstrating increased reticulin fibers.
- ANAEMIA
- WCC can be low, normal or elevated
- Plt - variable, become thrombocytopenic in later disease
- Periperal blood: tear drop poikilocytosis, nucleated red cells, myeloid series is shifted
- triad of teardrop poikilocytosis, leukoerythroblastic blood, and giant abnormal platelets is highly suggestive of myelofibrosis.
- DRY TAP
early in disease: hypercellular with marked increased in megakaryocytes
JAK2 is mutated in ~65% of cases, and MPL and CALR are mutated in the majority of the remaining cases; 10% of cases are “triple-negative.”
PMF
Treatment
Observation is adequate unless:
- Significant symptoms
- Anaemia
- Splenomegaly (>10cm)
- Leucocytosis (>25 x 10^9)
- Marked thrombocytosis (PLt >1000)
- Anaemia: transfusion Anemia can also be controlled with androgens, prednisone, thalidomide, or lenalidomide.
- First-line therapy for myelofibrosis-associated splenomegaly is hydroxyurea 500–1000 mg/day orally, which is effective in reducing spleen size by half in approximately 40% of patients.
- Both thalidomide and lenalidomide may improve splenomegaly and thrombocytopenia in some patients. Splenectomy is not routinely performed but is indicated for medication-refractory splenic enlargement causing recurrent painful episodes, severe thrombocytopenia, or an unacceptable transfusion requirement.
Patients with high-risk or intermediate-2–risk disease on the DIPSS-plus, or those patients harboring high-risk mutations such as ASXL1 or SRSF2, should be considered for allogeneic stem cell transplant, which is currently the only potentially curative treatment modality in this disease.
If not for AlloHSCT: Ruxolitinib
JAK inhibitor
improves:
- spleen size
- constitutional symptoms (promotes wt gain, improves pruritis)
- may reduce thrombosis risk
- ADR: anaemia, thrombocytopenia, increase infection risk (Herpes zoster, UTI, RTI)
type 1/like CALR mutations, compared to their counterparts with other driver mutations, displayed significantly better survival.
Prefibrotic MF vs ET
higher risk of bleeding
Higher risk of transformation to over-MF or AML
shorter OS
no difference in thrombosis rate
Prefibrotic MF vs PMF
Constitutional sx in 20%, significantly lower than over PMG
Better OS
Tx is similar to PMF
CML
Increased proliferation of grranulocytic line of cells without affecting their capacity to differentiate (but they are dysfunctional)
Median age 57-60
MEN >W
t9:22, BCR-ABL, Philadelphia, proto-oncogene, TK activity in excess
low leuc ALP activity
Presentation (60-70 years)
* anaemia: lethargy
* weight loss and sweating are common
* splenomegaly may be marked → abdo discomfort
* an increase in granulocytes at different stages of maturation +/- thrombocytosis
○ Leukocytosis/L) shift
* decreased leukocyte alkaline phosphatase
may undergo blast transformation (AML in 80%, ALL in 20%)
Inx:
Increased WCC, increased basophil (if you see basophils in peroipheral blood - think CML)
Blood film with leucocytosis ith L) shift and basophils
Clinical phases:
> chronic: 85% at dx
- <10% of blast in peripheral blood
- +/- increased eosinophils and basophils
- no significant sx
- risk of transformation without tx is 20-25%
> Accelerated phase:
- impaired neutrophil differentiation
- basophils in peripheral blood
- Circulatin blasts 10-19%
- plt <100
- Clonal evolution in cytogenetics
- Worsen splenomegaly and constitutional sx
> Blast Crisis
- >20% blasts in peripheral blood or BM
- –> Acute leukaemia
- 1/3 ALL, 2/3 AML
CML
Treatment
1st line: TKI inhibitors
- Imatinib (improved OS and PFS cf alpha IF and cytarabine)
> ADR: fluid retention, weight gain, muscle pain, GI, skin rash and fatigue
> very high response rate in chronic phase CML
Dasatinib:
- Second gen TKI
- More potent
- Rapid and deeper molecular response
- Similar PFS and OS cf imatinib
SE: pleural effusion and Pulm HTN
Nilotinib: second gen TKI
○ More potent that imatinib
○ More rapid and deeper molecular response
○ Similar OS
○ SE:** CV and pancreatitis **
* If resistant to initial therapy: ○ BCR-ABL kinase domain mutation analysis ○ **315I mutation** requires either **ponatinib** or **Asciminib ** § Ponatinib: 3rd Gen TKI, SE: CV risk § Asciminib: **Novel allosteric inhibitor of BCR-ABL** □ Binding site is not in the kinase domain SE: pancreatitis, fatigue, nausea, HA If resistant to above tx: HSCT - cure ~70%
ALL TKI are contraindicated in pregnancy (at all stages)
Hydroxyurea can be used in palliative setting to reduce WCC
CML
prognostic factors
Good: Philly chrosome
Bad: complex chromosomal or karyotype abnormality
Monitoring:
BCR-ABL-1: <0.01% = treatment free remission
MMR (major molecular response) <0.1%
if MMR is lost after TFR, this indicates failure
ALL
ALL
Mostly childred
bimodal distribution
Children have better DFS cf adults
Malignant proliferation of lymphoid precursor - B or T cell
associated with down’s
other RF:
- ionising radiation
- Cancer drugs
- Hodgkin’s
- MM
- Benzene
Clinical presentation is similar to AML
- bleeding, anaemia, infection
- accumulation of blasts in marrow –> bone pain
- Hepatosplenomegaly
- leucostasis and hyperleucocytosis sx is less common in ALL
- Gout, TLS, increased phosphate and K+
- look at table for AML (big) vs ALL (small)
> PAS and Tdt postive in ALL
Common site of relapse is CNS and testes
Investigations:
- >20% blasts in BM or blood (lymphoblasts obviously)
- Flow/cytogenetics:
>early or Pro T: cytoplasmic CD3, and CD2,5,7,38
>common thymocyte: CD1a, sCD3, CD4/CD8
CD1a positive and lack of CD13 = better survival
>Late thymocyte: CD4 or CD8 single positive
Blood:WCC >100, Nt/Hb/Plt reduced
Check:
TLS, DIC, mediastinal mass, LP once peripheral blasts cleared
HIV, HepB/C, CMV sb
BCR-Able
ALL
Treatment
Induction:
- Antracycline, prednisone, Vincristine
- High dose MTX for CNS prophylaxis
Maintenance:
Low dose oral chemo
Philly +Ve:
- TKI + chemo or TKI + steroids in elderly
HSCT - improves outcome by 25%
Inotuzumab ozogamicin is an antibody-drug conjugate used to treat B-cell precursor acute lymphoblastic leukemia (ALL).
CD22+ b-cells
Blinatumomab
is an antineoplastic antibody used to treat CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in relapsed and refractory patients, as well as those in first or second complete remission with minimal residual disease (MRD).
Blinatumomab recruits and activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on both benign and malignant B cells.6 By bringing T-cells and tumor cells together, blinatumomab induces an immune response that leads to T-cell activation and proliferation
ALL
Prognostic factors
Good:
- female
- t12:21
- hyperploidy
- Age 4-11
- Pre-B lymphocyte
- reduced or normal WCC
- Del 9p
Poor:
- MAle
- Male B or early T
- Hypoploidy
- WCC >50
- t4:11 –>MLC-AF4 fusion gene
-** Philly +Ve**
CNS involvement
- Abnormal TP53 (Chr17)
- <1 years
- Non-caucasion
ALL
Prognostic factors
Good:
- female
- t12:21
- hyperploidy
- Age 4-11
- Pre-B lymphocyte
- reduced or normal WCC
- Del 9p
Poor:
- MAle
- Male B or early T
- Hypoploidy
- WCC >50
- t4:11 –>MLC-AF4 fusion gene
-** Philly +Ve**
CNS involvement
- Abnormal TP53 (Chr17)
- <1 years
- Non-caucasion
Multiple myeloma
Median age 68
M>F
Maori are at high risk of advanced disease
CD56, CD 38
Myeloma specific Ab: BCMA, FcRH5
Usually single clone of plasma cells:
- 95% produce M-protein: IgG 50%, IgA 20%, IgD 2%, IgM 0.5%
- 20% have abnormal free light chains; the important thing is the ratio
- **Kappa>lambda = better prognosis **
- 5% non-secretory
SLiM CRAB:
S: 60% plasma cell in BM
Li: light chain ratio >100
M: 2or more lesion MRI lytic lesion >0.5cm
C: calcium
R: renal
A: anaemia
B: bony lesions
Frequency of symptoms:
1. Anaemia (75%)
2. Bony pain 60%
3. Renal impairment 50%
4. Fatigue 30%
5. Calcium 30%
6. Weight loss 25%
Other complications of MM:
- hyperviscosity
- infection
- bleeding +/- acquired vWD
- Amyloidosis
Multiple myeloma
MGUS/Smoldering/MM
MGUS:
- asymptomatic
- M-protein <30
- Clonal BM plasma <10%
- urine monoclonal protein <500mg/24h
- 0.3-1% develop haem. malignancy:
> increased risk if M-protein >15 or abnormal FLC ratio
> Increased risk if IgM or IgA
Smoldering:
- asymptomatic
- M-protein >30g/L
- Clonal BM plasma cells >10-60%
- Urine monoclonal protein >500mg/24h
- no CRAB or MDE
MM:
- symptomatic
- M protein in serum or urine >30
- >10% plasma cells in BM
- SLiMCRAB
MM
What is most cause of renal impairment in MM?
cast nephropathy
Multiple myeloma
Treatment
Class of treatment:
- Steroids: Dex or pred
- Alkylating: Cyclophosphamide, Melphan
- IMiDs: Thalidomide, lenalinomide
- Proteasome inhibitor: Bortezomib *renal impairment and biochemical improvement *
- Mabs: Daratuzumab (Anti-38), Elotuzumab
- Other: ABT199 (selective BCL-2inhibitor - t11:14)
Ideal initial therapy:
Transplant candidates:
- CyBorD + Lenolidomide
- 1st ASCT, if high risk , then 2nd ASCT
- otherwise, RVD: Velcade, Revlimid, and dexamethasone
- then **lenolidomide maintenance **
Non-transplant:
CyBorD +/- thalidomide or CTD or MPT
Other facts:
- adding Bortezomib improved PFS and OS. it causes neuropathy
- PFS increases with autologous SCT
- Lenolidomide maintenance improves OS and PFS, but increases risk of other cancers
- Daratuzumab improves PFS
- CAR-T therapy: BCMA-Tcell (Cilatacatpagene)
- Drug congugate: Belantumab-Mefadotin (to BCMA )
- BiTE cell:
Multiple myeloma
Treatment
Class of treatment:
- Steroids: Dex or pred
- Alkylating: Cyclophosphamide, Melphan
- IMiDs: Thalidomide, lenalinomide
- Proteasome inhibitor: Bortezomib *renal impairment and biochemical improvement *
- Mabs: Daratuzumab (Anti-38), Elotuzumab
- Other: ABT199 (selective BCL-2inhibitor - t11:14)
Ideal initial therapy:
Transplant candidates:
- CyBorD + Lenolidomide
- 1st ASCT, if high risk , then 2nd ASCT
- otherwise, RVD: Velcade, Revlimid, and dexamethasone
- then **lenolidomide maintenance **
Non-transplant:
CyBorD +/- thalidomide or CTD or MPT
Other facts:
- adding Bortezomib improved PFS and OS. it causes neuropathy
- PFS increases with autologous SCT
- Lenolidomide maintenance improves OS and PFS, but increases risk of other cancers
- Daratuzumab improves PFS
- CAR-T therapy: BCMA-Tcell (Cilatacatpagene)
- Drug congugate: Belantumab-Mefadotin (to BCMA )
- BiTE cell:
Autologous SCT
Indications:
- MM
- Mantle cell lymphoma
- T-cell lymphoma
- Hodgkins lymphoma, DLBCL, Follicular lymphoma
Risks:
- risk of death 1%
- Early complications:
> Sepsis: influenced by length of neutropenia, central access, mucositis/enterocolitis, debilitation
> Mucositis:
> idiopathic pulomanary sx, engraftment sx
> Sinusoidal obstructive sx
Late complications:
- Infection: Viral, PJP
- Secondary cancer:
MDS/AML (2-5y)
Skin, solid cancers
Waldenstrom
Lymphoplasmacytic lymphoma
MyD88
IgM - pentamer
Median age 65
Weaknessm fatigue, bleeding, wt loss, recurrent infection, dyspnoea, CHF
Neuro sx
Peripheral neuropathy
Cerebrak dysfunction
Triad of anaemia, hyperviscosity, plasma vol. expansion
Associated with:
HBV, HCV
cold AIHA
Raynaud’s
Tx:
Bendamustine, Rituximab
Tx: HCV
Steroids, PLEX
MGUS decreases life expectancy - is that true?
yes, and increases risk of osteoporosis, autonomic necropathy, vertebral # - independent of other conditions
Risk:
Mprotein >15
non-IgG isotype
FLC <0.2 or >1.65
POEMS syndrome
Polyneuropathy
Organomegaly
Endocrinopathy
Monoclonal gammopathy
Skin changes
It is associated with a chronic overproduction of pro-inflammatory cytokines (small molecules that act as messengers between cells to promote inflammation). These include IL-1b, IL6, TNFα and vascular endothelial growth factor (VEGF – a powerful vasodilator that may cause leaky blood vessels).
Causes sclerotic lesions
Differntiation syndrome
You get with ATRA/Arsenic treatment for M3 AML
Fever, Pulm. infiltrate, effusion, wt gain, hepatorenal dysfunction
Tx: WH ATRA/Arsenic –> Dex 10mg BD
Independent RF for thrombosis in aPLs
MALE
Lupus anticoagulant
Constantly positive anticardiolipin
which 2 conditions give you raised APTT and TCT?
Heparin and DIC
Gaisbock’s syndrome
Interferon alpha 2b tx for ET is CI in which conditions?
Thyroid and mental disorders
Indicated in high risk, pregnant women
AML
AML
Most common leukaemia in adults
Median age 60
incidence 4/100,000
M>F
Acute leukaemia is >20% blast is peripheral blood
Causes:
Transformation from other haematological malignancies: MDS, MPS, or fanconi anaemia
Chemotherapy exposure:
- Alkylating agents - cyclophosphamide (associated with Chr 5 or 7 abnormality
- Topoisomerase 2 inhibitors: etoposide, anthrocycline - associated with MLL gene abnormality on Chr 11
- Benzene
- Ionising radiation (increases risk of AML, ALL, CML)
- Germline
AML: big cells and lack of deformability –> leukostasis. This increases risk of ischaemia, increases ICH, 80% will be febrile
S/S: over weeks
- anaemia, infection, bleeding
- bony tenderness - esp sternum due to accumulation of blasts in marrow
- Organ infiltration: Gingival hypertrophy (esp. myelomonocytic), liver/spleen, LN, gonas, eyes
Increased risk of TLS: increased uric acid –> gout/renal, increases phosphate, reduced calcium, nephropahty, low mg
Increased procoagulant –> DIC
Blood film: Auer rods, large circulating blasts (can fit 4 RBCs)
BM aspirate:** Blasts >20% (normal** <5%)
Flow cytometry: blasts less scatter, mod CD45+
Cytogenetic for haematopoetic cells
Haematopoietic precursors:
CD34, HLA-DR, CD45, TdT
Myeloid: CD33, 13, MPO (lineage specific)
Lymphoid:
- B-cell: CD22, CD79a, CD19, 10
- T-cell: CD3 (lineage specific), 2, 5, 7,8
Gemtuzumab ozogamicin
AntiCD33 drug conjugate
AML
Definition of response
Complete response: CR
Blasts<5%
ANC >1
Plt >100
No circulating blasts or blasts with aeur rods, no extramedullary disease
Partial:
- 5-25% blasts with atleast 50% reduction from baseline
Primary Refractory:
- no CR after 2 years of induction
Progressive disease: >50% increase in blasts from baseline
Relapse: >5% blast after CR
AML classification
M0: undifferentiated
M1: without maturation
M2: with granulocytic maturation
M3: Acute promyelocytic
M4: Granulocytic and monocytic maturation
M5: Monocytic
M6: Erythroleukaemia
M7: megakaryoblastic
AML
Treatment
Standard:
- Anthrocycline (Daunorubicin) + Cytosine arabinoside (cytarabine) “7+3”
Novel:
ATRA and Arsenic for M3
Liposomal Ara-C and Daunorubicin
Gemtuzumab ozogamicin is a monoclonal anti-CD33 antibody used to treat CD33-positive acute myeloid leukemia. Increases the risk of VOD of the liver
Midostaurin is an antineoplastic agent used to treat high-risk acute myeloid leukemia (AML) with specific mutations (FLT3), aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematologic neoplasm (SM-AHN), or mast cell leukemia (MCL).
Gilteritinib is an AXL receptor tyrosine kinase inhibitor used to treat relapsed or refractory acute myeloid leukemia. with FLT3 mutation
**Ivosidenib **is an isocitrate dehydrogenase-1 inhibitor used to treat acute myeloid leukemia and cholangiocarcinoma in adults with a susceptible IDH1 mutation.
Enasidenib is an isocitrate dehydrogenase-2 inhibitor used to treat relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation (IDH2 mutation)
BCL-2 inhibitor: Venetoclax
What’s special able M3 AML
Acute promyelocytic
t15:17 (translocation of RARalpha gene - PML:RAR-a)
Young patients (~25)
RISK of **DIC **, thrombocytopenia
Generally present with pancytopenia
**++++Auer rods **
**eXquisitely sensitive to anthrocycline **
Responds to ATRA
if ATRA doesn’t work: Arsenic trioxide as salvage
HAs 85% haem remission
SE: QT prolongation –> Torsades
Prognostic factors of APL:
WCC>10,000 = bad
WCC<10,000 and Plt>40,000 = low risk
WCC <10,000 and plt<40,000 = intermediate
AML
Who would you feel is unfit for chemo?
Age >70
>60 with organ dysfunction, ECOG 2-3, EF <50%, DLCO <0.65, CrCl <45
Age-related clonal haemopeoiesis (CHIP)
Acquired somatic mutations occur in the blood of haematologically normal individual with ageing:
- DNMT3, TET2, ASXL1, TP53
- Showed 11 fold increase risk of hematological cancers and increased risk of CVD
MDS
- Slower development of symptoms (months) cf. AML
- Bone marrow failure with peripheral blood cytopenia
- Cells are hypofunctional
○ i.e hypo granular neutrophil
- Pancytopenia (often macrocytic) with metamyelocytes
Diagnosis:
- MDS with single lineage dysplasia
○ Blasts <5%
○ With rign sideroblasts (>15% ringed sideroblasts)
- MDS with multilineage dysplasia
○ Dysplasia >1 linease, blasts <5%
○ With rign sideroblasts (>15% ringed sideroblasts)
- MDS with excess blasts
○ Blasts 5-19%
Isolated del 5q abnormality
Prognosis:
- Blasts %
- Karyotype
○ Good: del 5q, del20q
○ Int: other
○ Poor: complex >3, ot chr 7 anomalies
Cytopenia, <10, <1.5, <100
Low risk patients:
- Maintain QoL
- Supportive therapy (consider iron chelation after 20 units of RBC)
Trial drug: Luspatercept (reduce RBC transfusion, as this drug targets RBC maturation, commonly used fro beta thalasaemia)
High risk patients:
- Azacitidine therapy
○ Low intensity
○ OS improvement
○ Delayed tf to AML
○ Improvement cytopenias
○ It’s a slow acting cycle (usually needs 4 months)
- Allogenic BMT
5q minus syndrome:
- Hypoplastic anaemia, normal or elevated platelets, atypical marrow megakaryocytes
- indolent clinical course
- Del 5Q: targerted therapy with **lenalidomide **(thalidomide derivative)
CLL
indolent, incurable
Proliferation of mature B-cell
Age>70
M>F
Clinical features
- 25% asymptomatic
- 5-10% get B-symptoms
- Gout
- Hyperviscosity
- Lymphadenopathy
- Liver and spleen enlargement
-** Immune dysregulation**:
>AIHA (warm)
>ITP
>Hypogammaglobulinemia +/- neutropenia –> infection
Causes of cytopenia:
- spleen sequeatration
- Ab mediated
- Marrow infiltration
BM failure: late stage
Secondary skin cancers: BCC, SCC
Which bone marrow infiltration pattern causes the worse prognosis in CLL?
Diffuse
CLL
Diagnostic clues
Blood film: small, mature lymphocytes
SMUDGE cells (lab artifect), thrombocytopenia, spherocytes
Flow cytometry/Cytogenetics:
CD5+, CD19+, CD23+
CD20 dim, LC restriction
CBC: clonal popn of B-lymphocytes >5 x 10^9/L
CLL
What is richter’s transformation?
CLL transformation to DLBCL
CLL
When to treat?
Worsening anaemia, or Plt <100
Massive or progressive or symptomatic splenomegaly
Progresive lymphocytosis:
- more than 50% increase in <2mo or LDT <6mo
AIHA/ITP not responsive to steroids
Symptomatic extranodal involvement
CLL
Treatment
Are they less than 60:
if yes: 17p del or unmutated IgH
If yes:
1. Ibrutinib or Venetoclax
remember with venetoclax there is increased risk of TLS, thus gradually increase dose, add rituximab after 5 weeks
If no:
- FCR: Fludarabine, cyclophosphamide and rituximab
Over 60:
1. Obinutuzumab (Anti CD20)
PLUS: Chlorambucil (alkylating agent) must have CrCl >30, CIRS>6
Second line:
Ibrutinib: ADR: bruising, diarrhoea, fatigue
Venetoclax
**Idelalisib: PI3 kinase inhibitor ** (increased risk of RSV, CMV infection
CLL
Staging
RAI:
0 = increased Lt = mild
I: increased Lt with adenopathy = mod
II: increased Lt with hepatosplenomegaly = mod
III: anaemia = High
IV: reduced platelet = High
Binet:
A: Hb >10, Plt >100, LN <3
B: Hb >10, Plt >100, LN >3
C: Hb <10, Plt <100
What do you call if there is solid LN mass in CLL?
Small lymphocytic leukaemia
Lymphoma
Malignancy of mature lymphocytes
look like normal cells on FNA
An Arbor staging:
1: on side of diaphram, with one LN
2. on one side of diaphragm with multiple LN (2 or more)
3. both side of diaphragm LN
4. Extranodal involvement
Translocations and lymphoma:
8:14 - burkitt’s, c-myc activation
14:18: follicular, BCL-2 activation
11:14: mantle cell, increase Cyclin D1
11:18 MALT (malt 1 activation)
2:5: anaplastic - ALK1 mutation
Majority is NHL (66-90%) - DLBCL, and Follicular are more common
Follicular is the most indolent
ECOG:
0 fully active
1 restricted physical activity - light house work
2 >50% up and about, not working, ok with self care
3 limited self care, <50% up and about
4 Confined to bed
5 DEAD
B-symptoms:
-Temp >38
- Wt loss >10% in 6/12
- Night sweats for >2/52
Flow cytometry:
1. CD5+, CD 10 -: CLL, Mantle
but CLL is CD200 + and CD23+
- CD5-, CD10+: Follicular, DLBCL, Burkitts
- CD5-, CD10-: Marginal, Waldenstrom, Hairy cell
But Hairy cell is CD103+, CD123+
** PET is highly sensitive in HL, DLBCL, Follicular**
Mycosis fungoides
T-cell lymphoma of the skin
PTCL- NOS, Anaplastic large cell
T-cell lymphoma that do not respond well to therapy
DLBCL
Peak 60s
Large transformed B-cell: **prominent nucleoli, basophilic cytoplasm **
**Loss of follicular structure **
CD19, 20, 22, 79a +ve
Hgih Ki-67 (fraction of proliferating cells, >45%)
2 subtype:
- germinal center: good prognosis
- Activated B-cell= poor prognosis
FISH:
BCL2, BCL6, MYC : if triple postive = poor prognosis
DLBCL
Prognostic index
Age >60
PS 2-4
LDH: high
Extranodal >1 site
Stage 3 or 4
Activated B-cell type
triple positive on FISH BCL2,6, MYC
DLBCL
Treatment
- R-CHOP: 60% cure
Cyclophosphamide - alkylating agent
Doxorubicin: cardiac toxicity
Vincristine: M-phase, sensory neuropathy, constiaption
Prednisone
ADR:
- cytopenia d7-11
- febrile neutropenia
- Hair loss
- N/V
PET to monitor interim progress
Chemosensitive disease responds to ASCT
Novel:
BiTE: Glofitamab: CD20/CD3
Tafasitamab: Anti CD19
CAR-T: can cause cytokine release sx: tx with toci and steroids
Palatuzumab vedotin: CD79a Ab conjugate
Poor prognostic factors in Hodgkin’s Lymphoma
Lymphocyte deplete
B-symptoms
Age >45
Hb <10.5
Lt count <600 or <8%
MALE
Albumin <40
WCC >15,000
When both B12 and foalte are low, which one do you replace first
B12, to avoid SACD
Leucocyte ALP
High:
- PV
- Myelofibrosis
- Leukamoid reactions
- Infections
- Steroids
- Cushing’s
- Pregnancy
- OCP
Low:
- CML
- Pernicious anaemia
- PNH
- Infectious Mononucleosis
Hairy Cell
Ondolent B-cell lymphoma
M:F, 5:1
Splenomegaly/pancytopenia
BRAF V600E mutation: MEK-ERK pathway
Tx: Vemurafenib
TRAP+
Immunophenotype:
CD19, 20 (common B cell antigen)
CD 103+, 123+, 11c+, 25+
>90%CR with Cladarabine
Mantle Cell
INCURABLE
t11:14, increased Cyclin D1
CD19, 20, 5+
CD23-ve, CD10-ve, CD200 -ve
MALE 4:1
~70y
Usually presents in advanced stage
Tx:
>60: Ritux + Bendamustine
<60:
Ritux + DHAP + ASCT
Dex, Cytarabine (inhibit at S-phase), Cisplatin, Ritux
Maintenance Ritux after ASCT improves OS
Ibrutinib: for relapsed disease
- improves CR and PFS by 14 mo
Follicular Lymphoma
T14:18 - BCL2 activation
From germinal centre
Median age 60
Indolent
CD10+, CD5-
CD19,20+ve
BCL2/6+
Can wax and wane
Can also spontaneously regress
Can transform into DLBCL
Median survival ~20y based on centrocyte/centroblasts
Follicular Lymphoma
Treatment
- Wait and watch
- Rituximab or Obintuzumab ^ + CVP (Cyc, Vincrine, Pred) - treatment in elderly, fraily, poor EF
- Rituximab/Obintuzumab + Bendamustine (++ IS - alkylating agent and a purine analogue)
- significantly reduced CD4 cells and neutrophils cf CHOP, but less alopecia.
- Prolonged immunosuppression upto 2 yrs
- - not suitable for pt >70, can have fatal toxicities - Ritux/Obin + CHOP (increased alopecia and IS)
- RT only for localised disease
For recurrence:
- Chemo - Ritux, then Ritux maintenance: improved PFS, not OS
- Add anthrocycline if not used previously
- Obin/Benda if early or multiple relapses
- SCT for young pt
- Idelalisib: PI3 kinase inhibitor
- Lenalinomide
- CAR-T cell therapy
^: obintuzumab is superior to Rituximab in treatment of indolent NHL in terms of PFS
MALT lymphoma
Extra-nodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue
- 50% is gastric lymphoma
- Hx of chronic inflammatory or AI disorder:
> H. pylori associated chronic gastritis
> Chlamydia psittaci in conjunctival MALT
> Sjogren sx
> Hashimoto thyroiditis
Tx:
1. Gastric: treat the H.pylori
2. Orbit: Local RT
waldeyer’s ring
A ring of lymphoid tissue found in the throat
Hodgkin’s Lymphoma
There are 4 types
Contiguous LN involvement
LN pain exacerabated by alcohol
Pel-ebstein fever- cyclic fever
Classically it’s a B-cell that has lost it’s B-cell antigen
Reed sternberg - multinucleated
EXPRESS:
CD15+, CD30, TARC, MUM1
Bimodal distributation
Pref. cervical nodes (75%)
Mediastinal nodes 60%
B-sx: 40%
Hodgkin’s
Unfavourable in early disease
- Bulky mediastinal disease
- > 4 nodal areas
- B-symptoms
- Age >50 or extranodal disease
- Elevated ESR
Hodgkin’s
Treatment
- ABVD: Doxorubicin, Bleomycin, Vinblastine, Decarbazine
- 95% cure rate in early disease - Escalated BEACOPP: only in <50y
-Bleo: inhibit DNA/RNA synthesis, lung damage
-etoposide: inhibits DNA topoisomerase II, S phase
- doxorubicin
- Cyclophosphamide
- Vincristine
- Procarbazine
- Prednisolone
Esc. BEACOPP:
- more intense
- more sterility
- more premature menopause
- increased long term risk of AML/MDS
Acute: more hair loss, more infections, more Gd3/4 cytopenia
Subacute: Azospermia, amenorrhoea
RT for involved sites: - no role in advanced disease
- it increases the risk of breast, thyroid, lung ca
- Increased artherosclerosis and valvular heart dx
- increase pulm fibrosis
Interim PET
- if negative, then can drop the bleo. This reduces the risk of lung toxicity without reducing OS
- Can also avoid RT
Relapse disease:
High dose D-HAP (D – dexamethasone (a steroid) HA – high-dose cytarabine (Ara-C)
P – cisplatin (platinum). or ICE (ifosfamide, carboplatin, and etoposide phosphate.) then ASCT
New agents:
- Brentuximab: Anti CD30 conjugate with MMAE (tubulin toxin) ADR: reversible neuropathy (median onset 12/52) not for first line
- Pembrolizumab
T-cell lymphoma
Aggressive
Poor survival
Poor response to tx
Anaplastic large cell:
- if CD30+ can given brentuximab-MMAE (Cell cycle arrest in G2/M phase –> apoptosis
PTCL:
- CD3+ (T-cell)
- CD 3- (NK cell)
- Post thymic so express TdT or CD1 antigen
- More cutaneous disease, eosinophilia
