Flashcards in Quiz #2 - Malignant Heme Deck (66):
Lymphoid or myeloid neoplasm with widespread involvement of bone marrow. Tumor cells are usually found in peripheral blood.
Discrete tumor mass arising from lymph nodes. Presentations often blur definitions.
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).
--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
--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
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.
--Nodular sclerosis --> Most common
--Lymphocyte rich --> Best prognosis
--Mixed cellularity --> Eosinophilia, seen in immunocompromised patients
--Lymphocyte depleted --> Seen in immunocompromised patients
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.
Diffuse Large B-cell Lymphoma
Usually older adults, but 20% in children
Alterations in Bcl-2, Bcl-6
Most common type of non-Hodgkin lymphoma in adults.
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
Mantle Cell Lymphoma
t(11;14)—translocation of cyclin D1 (11) and heavy-chain Ig (14), CD 5+
Very aggressive, patients typically present with late-stage disease.
Marginal Zone Lymphoma
Associated with chronic inflammation (eg, Sjögren syndrome, chronic gastritis [MALT lymphoma]).
Primary CNS Lymphoma
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.
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.
Mycosis fungoides/ Sézary syndrome
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).
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:
increased susceptibility to infection
Primary amyloidosis (AL)
Punched-out lytic bone lesions on x-ray A
M spike on serum protein electrophoresis
Ig light chains in urine (Bence Jones protein)
Rouleaux formation B (RBCs stacked like poker chips in blood smear) Numerous plasma cells C with “clock-face” chromatin and intracytoplasmic inclusions containing immunoglobulin.
Bone lytic lesions/Back pain
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.
M spike = IgM
hyperviscosity syndrome (eg, blurred vision, Raynaud phenomenon);
no CRAB findings.
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.
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.
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.
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).
Hairy cell leukemia
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.
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.
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).
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.
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).
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.
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.”
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.
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.
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.
Antimetabolites - Azathioprine, Cladribine, and Cytarabine
all act on S phase --> DNA synthesis
- 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.
- 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.
Antimetabolities: 5-fluorouracil and Methotrexate
- 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).
- 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).
- 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.
- 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.
- Cross-links DNA.
Used to ablate patient’s bone marrow before bone marrow transplantation.
- Severe myelosuppression (in almost all cases), pulmonary fibrosis, hyperpigmentation.
- 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.
- Require bioactivation. Cross blood-brain barrier --> CNS. Cross-link DNA.
- Brain tumors (including glioblastoma multiforme).
- CNS toxicity (convulsions, dizziness, ataxia).
- Cell cycle phase–nonspecific alkylating agent, mechanism not yet defined.
- Hodgkin lymphoma, brain tumors.
- Bone marrow suppression, pulmonary toxicity, leukemia.
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.
- 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.
Other cancer drugs
- 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.
- mecHanism Inhibit topoisomerase II --> increased DNA degradation.
-clinical Use Solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas.
- adVeRse eFFects Myelosuppression, alopecia.
-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.
- 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.
Vincristine peripheral neuropathy
Bleomycin, Busulfan pulmonary fibrosis
Trastuzumab (Herceptin) cardiotoxicity Cisplatin/Carboplatin nephrotoxicity
CYclophosphamide hemorrhagic cystitis
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
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
DNA methylation inhibitors
Azacitidine(VidazaR): a CTP analogue that cannot be methylated
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)
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)
✦ 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
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.
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
Clonal hematopoietic disorders characterized by: •ineffective myelopoiesis
•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
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
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
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
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
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
Favorable (variable definitions exist)
• No bulky disease
• No B-symptoms
• < 3 sites
• No extranodal sites
• ESR < 50 mm/h
– 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
– abbreviated chemo
• Advanced – chemo alone
• Chemo: ABVD
* 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
• 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
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
Hairy Cell Leukemia
o CD19+, CD20+, CD25+, CD11c+, CD103+ o TRAP resistant
• Treatment o Cladribine or Pentostatin +/-rituximab
o Vemurafenib (BRAF inhibition)
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
• Alopecia • Nausea/vomiting • Myelosuppression – Neutropenia • Cardiac toxicity • Neuropathy
5y OS = 60%
Lymph Node Compartments and Functions
Mantle zone: naïve cells meet antigen
Germinal center: proliferating cells (centroblasts) differentiate into antigen-specific B cells (centrocytes)
Memory B cells
MEDULLA B cell area: accumulation of plasma cells
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
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
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
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+
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 !!
- Non-GC: NFkB/Rel pathway inhibitors
- GC: BCL6 inhibitors
“Double Hit” Lymphomas (High-grade B-cell lymphoma with MYCand BCL2 and/or BCL6 rearrangements)
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.
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)
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)
Myelosuppression Mucositis Diarrea
Resistance: • Increased DNA repair • Decreased drug permeability • Production of “trapping” agents (thiols) • Increased expression of the aldehyde- dehydrogenase (ALDH)
Bleomycin main SE
estrogen receptor agonist: Increased
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
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.
• 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.
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