Quiz #2 - Malignant Heme Flashcards Preview

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Flashcards in Quiz #2 - Malignant Heme Deck (66):
1

Leukemia

Lymphoid or myeloid neoplasm with widespread involvement of bone marrow. Tumor cells are usually found in peripheral blood.

2

Lyphoma

Discrete tumor mass arising from lymph nodes. Presentations often blur definitions.

3

Hodgkin vs non‑Hodgkin lymphoma

Both may present with constitutional (“B”) signs/symptoms: low-grade fever, night sweats, weight loss (patients are Bothered by B symptoms).

HL:
--Localized, single group of nodes; contiguous spread (stage is strongest predictor of prognosis). Overall prognosis better than that of non-Hodgkin lymphoma.
--Characterized by Reed-Sternberg cells
--Bimodal distribution–young adulthood and > 55 years; more common in men except for nodular sclerosing type.
--Associated with EBV

NHL:
--Multiple lymph nodes involved; extranodal involvement common; noncontiguous spread.
--Majority involve B cells; a few are of T-cell lineage
--Can occur in children and adults.
-- May be associated with HIV and autoimmune diseases

4

Hodgkin Lymphoma

Contains Reed-Sternberg cells: distinctive tumor giant cells; binucleate or bilobed with the 2 halves as mirror images (“owl eyes” A). 2 owl eyes × 15 = 30. RS cells are CD15+ and CD30+ B-cell origin.

Subtype
--Nodular sclerosis --> Most common
--Lymphocyte rich --> Best prognosis
--Mixed cellularity --> Eosinophilia, seen in immunocompromised patients
--Lymphocyte depleted --> Seen in immunocompromised patients

5

Burkitt Lymphoma

NHL

Adolescents or young adults
t(8;14)—translocation of c-myc (8) and heavy-chain Ig (14)

“Starry sky” appearance, sheets of lymphocytes with interspersed “tingible body” macrophages

Associated with EBV.
Jaw lesion in endemic form in Africa; pelvis or abdomen in sporadic form.

6

Diffuse Large B-cell Lymphoma

NHL

Usually older adults, but 20% in children
Alterations in Bcl-2, Bcl-6
Most common type of non-Hodgkin lymphoma in adults.

7

Follicular Lymphoma

NHL

Adults t(14;18)—translocation of heavy-chain Ig (14) and BCL-2 (18)
Indolent course; Bcl-2 inhibits apoptosis.
Presents with painless “waxing and waning” lymphadenopathy

8

Mantle Cell Lymphoma

NHL

Adult males
t(11;14)—translocation of cyclin D1 (11) and heavy-chain Ig (14), CD 5+
Very aggressive, patients typically present with late-stage disease.

9

Marginal Zone Lymphoma

Adults
t(11;18)

Associated with chronic inflammation (eg, Sjögren syndrome, chronic gastritis [MALT lymphoma]).

10

Primary CNS Lymphoma

Adults

Most commonly associated with HIV/ AIDS; pathogenesis involves EBV infection

Considered an AIDS-defining illness.

Variable presentation: confusion, memory loss, seizures. Mass lesion(s) (may be ring-enhancing in immunocompromised patient) on MRI, needs to be distinguished from toxoplasmosis via CSF analysis or other lab tests.

11

Adult T-cell Lymphoma

Adults Caused by HTLV (associated with IV drug abuse)

Adults present with cutaneous lesions; common in Japan, West Africa, and the Caribbean.

Lytic bone lesions, hypercalcemia.

12

Mycosis fungoides/ Sézary syndrome

Adults
Mycosis fungoides: skin patches D/plaques (cutaneous T-cell lymphoma), characterized by atypical CD4+ cells with “cerebriform” nuclei and intraepidermal neoplastic cell aggregates (Pautrier microabscess).

May progress to Sézary syndrome (T-cell leukemia).

13

Multiple Myeloma

Monoclonal plasma cell (“fried egg” appearance) cancer that arises in the marrow and produces large amounts of IgG (55%) or IgA (25%). Bone marrow > 10% monoclonal plasma cells. Most common 1° tumor arising within bone in people > 40–50 years old. Associated with:
ƒ increased susceptibility to infection
ƒ Primary amyloidosis (AL)
ƒ Punched-out lytic bone lesions on x-ray A
ƒ M spike on serum protein electrophoresis
ƒ Ig light chains in urine (Bence Jones protein)
ƒ Rouleaux formation B (RBCs stacked like poker chips in blood smear) Numerous plasma cells C with “clock-face” chromatin and intracytoplasmic inclusions containing immunoglobulin.

CRAB
HyperCalcemia
Renal involvement
Anemia
Bone lytic lesions/Back pain


14

Monoclonal gammopathy of undetermined significance (MGUS)

monoclonal expansion of plasma cells (bone marrow < 10% monoclonal plasma cells), asymptomatic, may lead to multiple myeloma. No CRAB findings. Patients with MGUS develop multiple myeloma at a rate of 1–2% per year.

15

Waldenström macroglobulinemia

Ž M spike = IgM
Ž hyperviscosity syndrome (eg, blurred vision, Raynaud phenomenon);

no CRAB findings.

16

Myelodysplastic Syndromes

Stem-cell disorders involving ineffective hematopoiesis
--> defects in cell maturation of nonlymphoid lineages.

Caused by de novo mutations or environmental exposure (eg, radiation, benzene, chemotherapy). Risk of transformation to AML.

Pseudo–Pelger-Huet anomaly—neutrophils with bilobed (“duet”) nuclei. Typically seen after chemotherapy.

17

Leukemia

Unregulated growth and differentiation of WBCs in bone marrow --> marrow failure --> anemia (decreased RBCs), infections (decrease mature WBCs), and hemorrhage (decrease platelets).

Usually presents with increased circulating WBCs (malignant leukocytes in blood); rare cases present with normal/low WBCs.

Leukemic cell infiltration of liver, spleen, lymph nodes, and skin (leukemia cutis) possible.

18

Acute lymphoblastic leukemia/lymphoma

Most frequently occurs in children; less common in adults (worse prognosis). T-cell ALL can present as mediastinal mass (presenting as SVC-like syndrome).

Associated with Down syndrome.

Peripheral blood and bone marrow have INCRESAED lymphoblasts

TdT+ (marker of pre-T and pre-B cells), CD10+ (marker of pre-B cells). Most responsive to therapy. May spread to CNS and testes.

t(12;21) --> better prognosis.

19

Chronic lymphocytic leukemia/small lymphocytic lymphoma

Age > 60 years. Most common adult leukemia.

CD20+, CD23+, CD5+ B-cell neoplasm.

Often asymptomatic, progresses slowly; smudge cells B in peripheral blood smear; autoimmune hemolytic anemia.

CLL = Crushed Little Lymphocytes (smudge cells).

Richter transformation—CLL/SLL transformation into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL).

20

Hairy cell leukemia

Adult males.

Mature B-cell tumor.

Cells have filamentous, hair-like projections (fuzzy appearing on LM ).
Peripheral lymphadenopathy is uncommon. Causes marrow fibrosis -->  dry tap on aspiration.
Patients usually present with massive splenomegaly and pancytopenia.

Stains TRAP (tartrate-resistant acid phosphatase) ⊕. TRAP stain largely replaced with flow cytometry.

Treatment: cladribine, pentostatin.

21

Acute myelogenous leukemia

Median onset 65 years.
Auer rods ; myeloperoxidase ⊕ cytoplasmic inclusions seen mostly in APL (formerly M3 AML);
lots of circulating myeloblasts on peripheral smear; adults.

Risk factors: prior exposure to alkylating chemotherapy, radiation, myeloproliferative disorders, Down syndrome.

APL: t(15;17), responds to all-trans retinoic acid (vitamin A), inducing differentiation of promyelocytes;

DIC is a common presentation.

22

Chronic myelogenous leukemia

Occurs across the age spectrum with peak incidence 45–85 years, median age at diagnosis 64 years.

Defined by the Philadelphia chromosome (t[9;22], BCR-ABL) and myeloid stem cell proliferation.

Presents with dysregulated production of mature and maturing granulocytes (eg, neutrophils, metamyelocytes, myelocytes, basophils ) and splenomegaly.

May accelerate and transform to AML or ALL (“blast crisis”).

Very low LAP as a result of low activity in malignant neutrophils (vs benign neutrophilia [leukemoid reaction], in which LAP is high).

Responds to bcr-abl tyrosine kinase inhibitors (eg, imatinib, dasatinib).

23

Chronic myeloproliferative disorders

The myeloproliferative disorders (polycythemia vera, essential thrombocythemia, myelofibrosis, and CML) are malignant hematopoietic neoplasms with varying impacts on WBCs and myeloid cell lines.

Associated with V617F JAK2 mutation.

24

Polycythemia vera

Primary polycythemia.

Disorder of increased RBCs.

May present as intense itching after hot shower.

Rare but classic symptom is erythromelalgia (severe, burning pain and red-blue coloration) due to episodic blood clots in vessels of the extremities.

Low EPO (vs 2° polycythemia, which presents with endogenous or artificially High EPO).

Treatment: phlebotomy, hydroxyurea, ruxolitinib (JAK1/2 inhibitor).

25

Essential thrombocythemia

Characterized by massive proliferation of megakaryocytes and platelets. Symptoms include bleeding and thrombosis. Blood smear shows markedly increased number of platelets, which may be large or otherwise abnormally formed B. Erythromelalgia may occur.

26

Myelofibrosis

Obliteration of bone marrow with fibrosis due to increased fibroblast activity. Often associated with massive splenomegaly and “teardrop” RBCs . “Bone marrow is crying because it’s fibrosed and is a dry tap.”

27

Chromosomal Translocations

t(8;14) Burkitt (Burk-8) lymphoma (c-myc activation)

t(9;22) (Philadelphia chromosome) CML (BCR-ABL hybrid), ALL (less common, poor prognostic factor)

Philadelphia CreaML cheese. The Ig heavy chain genes on chromosome 14 are constitutively expressed. When other genes (eg, c-myc and BCL-2) are translocated next to this heavy chain gene region, they are overexpressed.

t(11;14) --> Mantle cell lymphoma (cyclin D1 activation) t(14;18) --> Follicular lymphoma (BCL-2 activation)
t(15;17) --> APL (M3 type of AML) Responds to all-trans retinoic acid.

28

Langerhans cell histiocytosis

Collective group of proliferative disorders of dendritic (Langerhans) cells. Presents in a child as lytic bone lesions and skin rash or as recurrent otitis media with a mass involving the mastoid bone.

Cells are functionally immature and do not effectively stimulate primary T cells via antigen presentation.

Cells express S-100 (mesodermal origin) and CD1a.

Birbeck granules (“tennis rackets” or rod shaped on EM) are characteristic B.

29

Tumor Lysis Syndrome

Oncologic emergency triggered by massive tumor cell lysis, most often in lymphomas/leukemias. Release of K+-->  hyperkalemia, release of PO43– --> hyperphosphatemia, hypocalcemia due to Ca2+ sequestration by PO43–. increased nucleic acid breakdown --> hyperuricemia --> acute kidney injury. Prevention and treatment include aggressive hydration, allopurinol, rasburicase.

30

Antimetabolites - Azathioprine, Cladribine, and Cytarabine

all act on S phase --> DNA synthesis

Azathioprine, 6-mercaptopurine
- mach: Purine (thiol) analogs --> decrease de novo purine synthesis. Activated by HGPRT. Azathioprine is metabolized into 6-MP.
- use: Preventing organ rejection, rheumatoid arthritis, IBD, SLE; used to wean patients off steroids in chronic disease and to treat steroid-refractory chronic disease.
- AEs: Myelosuppression; GI, liver toxicity. Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have increased  toxicity with allopurinol or febuxostat.

Cladribine
- mech: Purine analog -->  multiple mechanisms (eg, inhibition of DNA polymerase, DNA strand breaks).
- used in Hairy cell leukemia. Myelosuppression, nephrotoxicity, and neurotoxicity.

Cytarabine (arabinofuranosyl cytidine)
- mech: Pyrimidine analog --> DNA chain termination. At higher concentrations, inhibits DNA polymerase.
Use: Leukemias (AML), lymphomas.
AEs: Myelosuppression with megaloblastic anemia. CYTarabine causes panCYTopenia.

31

Antimetabolities: 5-fluorouracil and Methotrexate

5-fluorouracil
- mech: Pyrimidine analog bioactivated to 5-FdUMP, which covalently complexes with thymidylate synthase and folic acid. Capecitabine is a prodrug with similar activity. This complex inhibits thymidylate synthase ---> decresed  dTMP --> decreased DNA synthesis.
-Use: Colon cancer, pancreatic cancer, actinic keratosis, basal cell carcinoma (topical). Effects enhanced with the addition of leucovorin.
- AEs: Myelosuppression, palmarplantar erythrodysesthesia (hand-foot syndrome).

Methotrexate
- mech: Folic acid analog that competitively inhibits dihydrofolate reductase --> decreased dTMP --> decreased DNA synthesis.
- use: Cancers: leukemias (ALL), lymphomas, choriocarcinoma, sarcomas. Non-neoplastic: ectopic pregnancy, medical abortion (with misoprostol), rheumatoid arthritis, psoriasis, IBD, vasculitis.
- AEs: Myelosuppression, which is reversible with leucovorin “rescue.” Hepatotoxicity. Mucositis (eg, mouth ulcers). Pulmonary fibrosis. Folate deficiency, which may be teratogenic (neural tube defects) without supplementation. Nephrotoxicity (rare).

32

anti-tumor antibiotics

Bleomycin
- Induces free radical formation --> breaks in DNA strands.
- use: Testicular cancer, Hodgkin lymphoma.
- AEs: Pulmonary fibrosis, skin hyperpigmentation. Minimal myelosuppression.
G2 phase: blocks double check repair

Dactinomycin (actinomycin D)
- Intercalates into DNA, preventing RNA synthesis.
- Use: Wilms tumor, Ewing sarcoma, rhabdomyosarcoma. Used for childhood tumors.
- AEs: Myelosuppression.

Doxorubicin, daunorubicin
- Generate free radicals. Intercalate in DNA --> breaks in DNA --> decreased replication. Interferes with topoisomerase II enzyme.
- Use: Solid tumors, leukemias, lymphomas.
- AEs: Cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia. Dexrazoxane (iron chelating agent), used to prevent cardiotoxicity.

33

alkylating agents

Busulfan
- Cross-links DNA.
Used to ablate patient’s bone marrow before bone marrow transplantation.
- Severe myelosuppression (in almost all cases), pulmonary fibrosis, hyperpigmentation.

Cyclophosphamide, ifosfamide
- Cross-link DNA at guanine. Require bioactivation by liver. A nitrogen mustard.
- Solid tumors, leukemia, lymphomas.
- Myelosuppression; SIADH; hemorrhagic cystitis, prevented with mesna (thiol group of mesna binds toxic metabolites) or adequate hydration.

Nitrosoureas
- Require bioactivation. Cross blood-brain barrier --> CNS. Cross-link DNA.
- Brain tumors (including glioblastoma multiforme).
- CNS toxicity (convulsions, dizziness, ataxia).

Procarbazine
- Cell cycle phase–nonspecific alkylating agent, mechanism not yet defined.
- Hodgkin lymphoma, brain tumors.
- Bone marrow suppression, pulmonary toxicity, leukemia.

34

microtubule inhibitors

Paclitaxel, other taxanes
Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur).
Ovarian and breast carcinomas. Myelosuppression, neuropathy, hypersensitivity. Taxes stabilize society.

Vincristine, vinblastine
- Vinca alkaloids that bind β-tubulin and inhibit its polymerization into microtubules -->  prevent mitotic spindle formation (M-phase arrest).
- Solid tumors, leukemias, Hodgkin (vinblastine) and non-Hodgkin (vincristine) lymphomas.

Vincristine: neurotoxicity (areflexia, peripheral neuritis), constipation (including paralytic ileus). Crisps the nerves.

Vinblastine: bone marrow suppression. Blasts the bone marrow.

35

Other cancer drugs

Cisplatin, carboplatin
- mecHanism Cross-link DNA. clinical
-Use Testicular, bladder, ovary, and lung carcinomas.
adVeRse eFFects Nephrotoxicity, peripheral neuropathy, ototoxicity. Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride (saline) diuresis.

Etoposide, teniposide
- mecHanism Inhibit topoisomerase II --> increased DNA degradation.
-clinical Use Solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas.
- adVeRse eFFects Myelosuppression, alopecia.

Irinotecan, topotecan
-mecHanism Inhibit topoisomerase I and prevent DNA unwinding and replication.
- clinical Use Colon cancer (irinotecan); ovarian and small cell lung cancers (topotecan).
- adVeRse eFFects Severe myelosuppression, diarrhea.

Hydroxyurea
- mecHanism Inhibits ribonucleotide reductase --> decreased DNA Synthesis (S-phase specific).
- clinical Use Myeloproliferative disorders (eg, CML, polycythemia vera), sickle cell (increased HbF).
- adVeRse eFFects Severe myelosuppression.

36

Common Chemotoxicities

Cisplatin/Carboplatin Ž ototoxicity
Vincristine Ž peripheral neuropathy
Bleomycin, Busulfan Ž pulmonary fibrosis
Doxorubicin Ž cardiotoxicity
Trastuzumab (Herceptin) Ž cardiotoxicity Cisplatin/Carboplatin Ž nephrotoxicity
CYclophosphamide Ž hemorrhagic cystitis

37

epigenetics

 the  study  of  heritable  changes  in   cellular  function  or  gene  expression  that  can  be   transmitted  from  cell  to  cell  (and  possibly  even   generation  to  generation)  as  a  result  of  chromatin-­ based  signals  that  do  not  alter  the  nucleotide   sequence  of  the  DNA.

The main currencies of epigenetic information = enzymatic chemical modifications on the DNA and histones

Transcriptional coactivators have activities that modify chromatin, to increase access to the DNA

38

epigenetics & leukemia

Disorganization  of  epigenetic  information  is  prevalent  in   leukemia,  leading  to  changes  in  gene  expression.  i.e.   global  DNA  demethylation and  increased  DNA  methylation   in  promoters  of  tumor  suppressor  genes.
• Leukemias also  have  altered  histone  modification  and   microRNA  modulation.
• Many  leukemias have  mutations  in  the  enzymes  that   regulate  epigenetic  information.    
• Epigenetic  changes,  unlike  genetic  changes,  can  be   reversed  by  therapeutics.  

AML  and  CLL  have  one  of  the  lowest  number  of   mutations  per  case  of  any  adult  cancer

HDAC  inhibitors  also  reactivate  gene  expression

MLL protein fusions target the super elongation complex (SEC) or DOT1 complex (DotCom) to MLL target genes, leading to expression of pro-leukemia genes
AFF1

39

DNA  methylation  inhibitors


Azacitidine(VidazaR):  a  CTP   analogue  that  cannot  be   methylated
DNA
 methyl
 transferase (DNMT)
 inhibitors
FDA
 approved
 for
  myelodysplastic syndromes
 and
  AML
 treatment
 

40

Common features of AML, ALL, and MDS

Abnormal Blood Counts
• Cytopenias (low blood cell counts) MDS, ALL, AML
• Leukocytosis (high WBC count) some ALL & AML

✦ Incomplete or Aberrant Differentiation of hematopoietic cells.

Cause of death:
Related to the cytopenias resulting from the disease rather than as a direct effect of the neoplastic cells (in contrast to solid tumors).
- Infection Neutropenia (v. common) Neutrophil Dysfunction (common)
Other immune suppression (ALL)
✦ Bleeding Thrombocytopenia (v. common) Coagulopathy (less common)

41

AML

The vast majority of AML is Sporadic (no causal linkage)
✦ Known Risk Factors - Ionizing radiation (occupational, therapeutic, atomic bomb) - Prior chemotherapy with DNA damaging agents (alkylating agents, topoisomerase II inhibitors) - Antecedent Hematologic Disorder (MDS, MPDs) - Certain Congenital disorders (Fanconi Anemia, Down Syndrome, Bloom Syndrome, Congenital Neutropenia) - Smoking (~2x risk) - Benzene exposure

Most signs and symptoms are attributable to bone marrow failure/cytopenias. - Bleeding -Minor: skin, nose, gums; Major: GI tract, Lungs, CNS (thrombocytopenia) - Fevers, flu-like symptoms, infections (neutropenia) - Palor/Fatigue/Generalized Weakness/ Shortness of Breath (anemia)

Diagnostic Criteria:
✦ Blood or Bone Marrow with ≥20% Blasts - Blasts = Myeloblasts ~ Myeloid Blasts ~MPO+ Blasts ~ Sudan Black+ Blasts ~ NSE+ Blasts
✦ Blasts are cells with the Morphology of very immature hematopoietic cells. Normally, there are ≤ 3-5% in Bone Marrow and none in Blood.
✦ Major Diagnostic Branch: ALL vs AML - Flow Cytometry, Histochemistry and Immunohistochemistry used.

M3: Acute Promyelocytic leukemia (APL)

AML is highly aggressive and generally fatal. It is better to be young than old. Molecular Features are used for treatment decisions and predict survival

42

Core-binding Factor Leukemias

t(8;21) AML1-ETO & inv(16) CBFβ-MYH11

CBF is a heterodimeric transcription factor composed of α and β subunits. ‣ RUNX1 (aka CBFα, AML1 & PEBP2a)-Chr 21 ‣ CBFβ (aka PEBP2b) - Chr 16

✦ Knockout Mice deficient in either RUNX1 or CBFβ fail to develop definitive hematopoiesis & are non-viable. Essential for Hematopoiesis.

✦ Knockin Mice Engineered with AML1-ETO or CBFβ-MYH11 fusion genes are not viable due to hematopoietic failure. Fusions are dominant inhibitors of native gene function.

43

APL

8% of AML (~25% in Latinos) ‣ ~1000 cases per year in US ‣ Younger patients (median age ~40), no increased incidence with age
✦ Fulminant DIC common at presentation
✦ Typically presents w/ pancytopenia
✦ Originally described in 1957 as a particularly lethal form of AML (survival months)
✦ Now ~80-90% patients cured with ATRAbased therapy ‣ APL is the most curable form of AML.

***All Phases of Treatment Differ from other AML

ATRA syndrome: Fever, weight gain, dyspnea, hypoxemia, edema, pleuropericardial effusions. 3846
- treat with steroids
- called differtiation syndrome

44

MDS

Clonal hematopoietic disorders characterized by: •ineffective myelopoiesis
•progressive cytopenias
•morphologic abnormalities of erythroid, granulocytic and megakaryocytic lineages
•propensity to transform to AML (1/3 of cases)

Median Age: 70 yrs (risk increases with age) - Most common heme malignancy of elderly - & likely vastly under-diagnosed.

Patients typically present with cytopenias. - Mild Anemia is most common
✦ Years may elapse between the first recognition of a cytopenia and an MDS diagnosis.
✦ When signs and symptoms are present they are generally attributable to cytopenias.
- Bleeding -Minor: skin, nose, gums; Major: GI tract, Lungs, CNS (thrombocytopenia)
- Fevers, infections (neutropenia)
- Palor/Fatigue/Generalized Weakness/ Shortness of Breath (anemia)

- Goals of Therapy ✓Improve Cytopenias ✓Reduce AML transformation ✓Improve Survival
- New Drugs: ✓DNA Hypomethylating Agents (reactivate epigenetically silenced genes) ✓Lenalidomide for del(5q) ✓New growth factors (romiplostim - TPO to add to EPO and GCSF) ✓Kinder, gentler Allo-BMT methods

45

CLL

Most  common  type  of   leukemia  in  North  America   incidence:  ~20,000  cases/year   prevalence:  ~  200,000  cases • More  common  in  Western   Europe  and  North  America • Median  age  =  72  years  old   • Peripheral  blood  smear   demonstrates  mature,  resting   B-­cells  and  smudge  cells

Diagnosis:
absolute  B-­lymphocyte  count  in  peripheral  blood   >5,000/µl
– small  lymphocytic  lymphoma  (SLL)  <  5,000/µl,  with   lymphadenopathy  or  splenomegaly
• 30%  of  bone  marrow  involved  with  lymphocytes
• co-­expression  of  CD5,  CD19/20,  &  CD23  surface   proteins
• Dim  expression  of  CD20  and  surface  Ig(sIg) ˗ exception:  Trisomy  12

Presentation: – Asymptomatic  at  diagnosis
  – Frequently  diagnosed  on  “routine”  blood  work;;  adds   to  shift  towards  earlier  stage
– Painless  lymphadenopathy – Occasional  B  symptoms
– Initial  treatment  strategy  =  Watch  and  Wait

46

CLL Clinical course

Symptoms  occur  secondary  to:
1. Accumulation  of  lymphocytes: lymphadenopathy,  hepatosplenomegaly,  anemia,   thrombocytopenia

2. Immune  dysregulation autoimmune  complications  in  ~25%  of  patients:   AIHA,  ITP

3. Immunodeficiency hypogammaglobulinemia present  in  75%  of  patients T  cell  defect  present  as  well

Richter’s  Syndrome: – Evolution  of  CLL  into  an  aggressive  lymphoma – Occurs  in  ~10%  of  patients – Two  types:
• clonally  related  (80%):  acquire  TP53,  c-­myc
• clonally  unrelated  (20%) – Risk  Factors:  NOTCH1  mutation,  VH4-­39 – Treated  as  if  it  were  a  large  cell  lymphoma:  RCHOP

47

indications for treating pts w/ CLL

• progressive  bone  marrow  failure (worsening  anemia  and/or  thrombocytopenia,   i.e.  Rai  Stage  III  or  IV)
• massive,  progressive,  or  symptomatic  LAD
• massive,  progressive,  or  symptomatic   splenomegaly • lymphocyte  doubling  time  of  <  6  months
• AIHA  or  ITP  poorly  responsive  to  steroids
• disease  related  symptoms:  weight  loss,  fevers,   fatigue

48

CLL treatment & toxicities

1. Alkylating  agents: • chlorambucil   • cyclophosphamide • bendamustine

2. Purine  analogues: • fludarabine  (Fludara) • cladribine  (Leustatin,  2-­Cda) • pentostatin(Nipent)

3. Monoclonal  antibodies: • rituximab  (Rituxan) • alemtuzumab  (Campath) • ofatumumab  (Arzerra) • obinutuzumab  (Gazyva)

4. BCR  Antagonists: • ibrutinib  (Imbruvica)   • idelalisib  (Zydelig)

5. Small  Molecule  Inhibitors • venetoclax  (Venclexa)

6. CAR  T  cells

Novel Treatment Tox:
1. BTK  Inhibitors 1. Diarrhea 2. Bleeding 3. Thrombocytopenia 4. Atrial  fibrillation

2. PI3  Kinase  Inhibitors 1. Diarrhea 2. Colitis 3. Transaminitis 4. Pneumonitis

3. Bcl-­2  Mimetics 1. Tumor  lysis  syndrome

49

Hodgkins Lymphoma

Favorable  (variable   definitions  exist)
• No  bulky  disease
• No  B-­symptoms
• <  3  sites
• No  extranodal sites
• ESR  <  50  mm/h

Unfavorable:
– Age  > 45
– Male  sex
– Stage  IV
– Serum  albumin  <  4  g/dL
– Hb <  10.5  g/dL
– WBC  count  > 15,000   cells/mm3
– Lymphocyte  count  <  600   cells/mm3

Treatment:
• Early:  
– abbreviated  chemo
– XRT
• Advanced – chemo  alone
• Chemo:  ABVD

Problems:
* AML—related  to  chemotherapy – Latency  3-­5  years
• Solid  tumors—related  to  RT – Lung  cancer.  High  risk  in  smokers – Breast  cancer.  Young  women – Others:  sarcoma,  skin,  salivary
• Cardiac:   – Doxorubicin  and  RT  contribute
• Infertility:   – Uncommon  with  ABVD
• Hypothyroidism   – Cervical  XRT
• Xerostomia – XRT  to  salivary  glands

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Follicular Lymphoma

• Second  most  common  lymphoma  in  US  and  Europe
• Usually  occur  in  older  patients
• Indolent  clinical  course
• Often  disseminated,  with  lymphadenopathy,  bone  marrow,  liver   and  splenic  involvement
• Propensity  to  transform  to  more  aggressive  subtype   • Natural  course  of  untreated  disease  is  prolonged;;  patients   often  die  of  other  causes

Prongostic Factors:
Age  >  60  years
Stage  III  or  IV  disease
Serum  LDH  levels  >  ULN
Hemoglobin  levels  <  12  g/dL
Involvement  of  >  4   extranodal sites

Rituximab  is  a  monoclonal  antibody  that  targets   CD20  on  the  surface  of  B-­lymphocytes

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Hairy Cell Leukemia

• Pathology
o CD19+,  CD20+,  CD25+,   CD11c+,  CD103+ o TRAP  resistant
o BRAF

• Presentation
o Splenomegaly
o Cytopenias

• Treatment o Cladribine or  Pentostatin +/-­rituximab
o Vemurafenib (BRAF   inhibition)

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Diffuse  large  B  cell  lymphoma

• Most  common  subtype  of  NHL
• Represents  approximately  30%  adult  NHL
• Aggressive  clinical  course  if  left  untreated

Prognostic  factors  (APLES)
• Age  60  years
• Performance  status   1  
• LDH   1× normal • Extranodal sites   1
• Stage  III  or  IV

Risk  Category   • Low  (L) 0  or  1
• Low  intermediate  (LI) 2
• High  intermediate  (HI) 3
• High  (H) 4  or  5

DLBCL  Therapy: R-­CHOP
Side  effects
• Alopecia • Nausea/vomiting • Myelosuppression – Neutropenia • Cardiac  toxicity • Neuropathy
5y  OS  =  60%

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Lymph Node Compartments and Functions

FOLLICLE
Mantle zone: naïve cells meet antigen
Germinal center: proliferating cells (centroblasts) differentiate into antigen-specific B cells (centrocytes)

MARGINAL ZONE
Memory B cells

MEDULLA B cell area: accumulation of plasma cells

PARACORTEX
Mainly T cell area Site of entrance of all lymphoid cells and of accessory cells -T / B cell interaction

SINUS Macrophage area: “sieve”functions


follicles - B only
Diffuse - T or B

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Important Immunophenotypic Markers

CD45 All leukocytes
Ig ( / ) B cells (surface); plasma cells (cytoplasmic)
CD20 Most B cells
PAX5 Most B cells
CD10 Progenitors; Germinal center B cells
CD3 All T cells
CD5 All T cells; some B cells
CD4/CD8 T helper / cytotoxic cells
CD23 Activation / dendritic cells / CLL/SLL
CD15 Granulocytes; Reed-Sternberg cells
CD30 Act. lymphs; Reed-Sternberg cells
BCL2 Anti-apoptotic protein
BCL6 Germinal center cells
Ki67 Proliferation

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Important Genotypic Markers

Clonal IgH rearrangement --- B cell lymphoma
Clonal Ig Kappa rearrangement --- B cell lymphoma
Clonal TCR rearrangement ---T cell lymphoma
t(14;18); IgH/BCL2 ---- Follicular lymphoma
t(11;14); CCND1/IgH --- Mantle cell lymphoma
t(8;14); MYC/IgH ---- Burkitt lymphoma

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Follicular Lymphoma

Grade I (our case): Mostly centrocytes
Grade II: Mixed centrocytes and centroblasts
Grade III: Mostly centroblasts (MOST AGGRESSIVE)

(CD20+, CD10+, BCL6+ CD21+ FDC meshworks)

Malignant Follicle: No tingible body macrophages No zonation (“montonous”) Loss of mantle cell zone
No dark zone
No light zone
No tingible body macrophages
Mantle zone – thin, attenuated
Neoplastic B cells BCL2+
t(14;18)

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Types of DLBCL

Germinal center type (GCB)
Translocations of BCL2 Amplifications of CREL Mutations in EZH2 and GNA13 genes

Activated B cell type (ABC) Constitutive activation of the NF-κB pathway Chronic active B-cell receptor signalling by activating mutations in receptor constituents: CD79B, CARD11 or CD79A, and/or MYD88 L265P (implying TLR pathway activation)

Gene Expression Profiling: GC vs non-GC (Prior to Rituxan) GC better !!
Immunohistochemistry:
- Non-GC: NFkB/Rel pathway inhibitors
- GC: BCL6 inhibitors

“Double Hit” Lymphomas (High-grade B-cell lymphoma with MYCand BCL2 and/or BCL6 rearrangements)

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Methotrexate

Folic  Acid  Analogs:  

MTX:  a  folic  acid  analog  that  binds  with  high  affinity  to  the   active  catalytic  site  of  dihydrofolatereductase (DHFR) and  interferes  with  the  synthesis  of  tetrahydrofolate(THF) THF:  the  key  one-­carbon  carrier  for  enzymatic  processes   involved  in  de  novo  synthesis  of  thymidylate,  purine   nucleotides,  and  the  amino  acids  serine  and  methionine.   Inhibition  of  these  metabolic  processes  interferes  with  the   formation  of  DNA,  RNA,  and  key  cellular  proteins.  

Side Effects:
Myelosuppression
Mucositis
Renal
 toxicity

Resitance:
Decreased  drug  transport  into  the  cell
• Altered  dihydrofolate reductaseenzyme
 -­lower  affinity  for   methotrexate
• Quantitative  increase  in  dihydrofolate reductase enzyme   concentration  in  the  cell  (gene  amplification,  increased  message)

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5-­Fluorouracil  

pyrimidine analog:
resistance:
Alteration  of  drug  influx
• Efflux,  enhancement  of  drug  inactivation  and  mutation  of   the  drug  target
• High-­level  expression  of  TS
• Increased  activity  of  deoxyuridine triphosphatase
• Methylation  of  the  miss  match  repair  MLH1  gene
• Overexpression  of  bcl-­2,  bcl-­xl,  and  mcl-­1  proteins   (apoptosis  proteins)

Side Effects:
Myelosuppression
Mucositis
Diarrea
Hand-­‐Foot syndrome

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Cyclophosphamide

DNA alkylating

SEs:
Myelosuppression Mucositis Diarrea
Cystitis

Resistance: • Increased  DNA  repair • Decreased  drug  permeability • Production  of  “trapping”  agents  (thiols) • Increased  expression  of  the  aldehyde-­ dehydrogenase  (ALDH)

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Bleomycin main SE

pulmonary fibrosis

62

Tamoxifen

estrogen receptor agonist: Increased
 risk
 for
 Endometrial
 Neoplasia

63

Clinical staging of Lymohoma

The clinical staging system:
Stage Area of Involvement
I Single lymph node group
II Multiple lymph node groups on same side of diaphragm
III Multiple lymph node groups on both sides of diaphragm
IV Multiple extranodal sites or lymph nodes and extranodal disease
X Bulk > 10 cm
B symptoms: weight loss > 10%, fever, drenching night sweats

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Marginal Zone Lymphoma

1. Splenicmarginal zone* lymphoma -20%
2. Extranodalmarginal zone B cell lymphoma (or MALT lymphoma for "mucosa-associated lymphoid tissue") - 70%
3. Nodalmarginal zone B cell lymphoma (NMZL) -10%

• Mucosa-associated lymphoid tissue (MALT) can develop in nearly every organ as a result of chronic infection or an autoimmune process. If there is prolonged lymphoid proliferation, a malignant clone can emerge and a MALT lymphoma could follow.
• Certain infections have been associated with MALT lymphomas:
• There is H. pylori infection in 85-90% of gastric MALT lymphomas.
• Chlamydophila psittaci has been identified as a possible causative agent in ocular adnexal lymphomas.[4]
• Borrelia burgdorferi infection has been linked to skin MALT lymphomas.
• Campylobacter jejuni has been linked to small bowel MALT lymphomas.
• There is also a possible link between hepatitis C and HIV and MALT lymphomas.
• Autoimmune diseases such as Hashimoto's thyroiditis and Sjögren's syndrome have also been linked to MALT lymphomas in the thyroid and salivary glands.

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Mantle Zone Lymphoma

what is the typical rearrangement in MCL?
t (11;14) IgH:Cyclin D1(BCL1) this results in inappropriate “on” status of cyclin D1

Non-nodal: Less often exhibits complex karyotype
Non-nodal: More SHM
TP53mutations: Worse Prognosis

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AIDS related lymphomas

• Diffuse large B-cell lymphoma (DLBCL), centroblastic
• DLBCL, immunoblastic
• Burkitt lymphoma