Hematologic Malignancies 2024 PDF

Qzlet 226 HEMATOLOGIC MALIGNANCIES Laura Blanchard, PA-C Department of Medicine Division of Hematology UNC Cancer Center problem is happening in the bone marrow Platelets LEUKEMIAS ○ ○ ○ ○ ○ AML ALL CLL Hairy Cell Leukemia CML – leukemia in the name but technically a myeloproliferative disor...

Qzlet 226 HEMATOLOGIC MALIGNANCIES Laura Blanchard, PA-C Department of Medicine Division of Hematology UNC Cancer Center problem is happening in the bone marrow Platelets LEUKEMIAS ○ ○ ○ ○ ○ AML ALL CLL Hairy Cell Leukemia CML – leukemia in the name but technically a myeloproliferative disorder ACUTE MYELOID LEUKEMIA (AML) ACUTE MYELOID LEUKEMIA ○ Clonal proliferation of immature myeloid cells (“Blasts”) with inability to differentiate into mature cells Immature ------------------------------------ Mature (Blast) (Neutrophil) CLASSIFICATION ○ Previously used….no longer relevant CLASSIFICATION ○ WHO (World Health Organization) AML with recurrent genetic abnormalities ● AML with myelodyplasia-related changes ● ○ ● Therapy-related AML ○ ● Arises from MDS Alkylating agents and radiation AML, not otherwise classified AML CONT… Fun facts ● ● ● ● ● Most common acute leukemia in adults ~ 1% of adult cancer deaths Median age 65 years old Incidence increases with age Male:Female ratio is 5:3 Clinical manifestations Fever, infections (of any kind) ● Pale, fatigue, shortness of breath ● Bleeding from gums/nose, hematoma, DIC AND/OR ● Vision changes, headache, chest pain, SOB, stroke like symptoms ● Bone pain ● Rash (Leukemia cutis) ● Mental status changes, numbness ● *Symptoms usually present for days/weeks* AML CONT… Exam ● ● Labs ● ● ● Petechiae, raised skin lesion, pale Cranial nerve palsies, altered mental status CBC with differential ○ Pancytopenia (or leukocytosis with anemia/thrombocytopenia) CMP ○ Tumor lysis syndrome (H potassium, H LDH, H phosphorus, H uric acid, L calcium) ○ AKI Peripheral blood smear ○ +/- Blast present Diagnosis * >20% myeloid blasts OR any blast % with t(8;21), inv(16), APL* ● ● ● ● Bone marrow biopsy ○ Hypercellular with >20% blasts ○ Auer rods Flow Cytometry Cytogenetic analysis Myeloid mutation panel AML CONT… ○ Risk stratification ● ● ● ○ Favorable: 60% chance of cure with chemotherapy alone Intermediate: 40% chance of cure Adverse: 10% chance of cure Treatment ● ● Induction, Consolidation, Salvage Therapy types: ○ ○ ○ ○ ○ ○ ○ Cytotoxic Chemotherapy Hypomethylating agents Targeted therapy Apoptosis regulators Antibody drug conjugates Stem cell transplant (allogenic) Clinical Trials AML CONT ---- APL ○ Acute Promyelocytic Leukemia ● Clinical manifestations ○ ○ ● Exam ○ ● Based on WBC and coagulopathies Labs/Diagnostic ○ ○ ○ ○ ● Low or elevated WBC DIC (bleeding and clotting) CBC with differential Peripheral smear ○ “sliding plate” or “dumbbell” appearance BMBx Cytogenetic/FISH ○ t(15;17) – aka “PML-RAR” pathognomonic Treatment ○ ○ ATRA (all-trans retinoic acid) – pushes the cells to differentiate Arsenic – damages PML-RAR (15;17) fusion HIGHLIGHTS – AML ○ ○ Older adults Non-specific HPI/Exam ● ○ ○ Fatigue Pancytopenia OR Elevated WBC with anemia/ thrombocytopenia BMBx >20% blasts ● Auer Rods ● ○ Chemotherapy within days of presentation Low cure rate ○ APL = DIC ○ ACUTE LYMPHOBLASTIC LEUKEMIA ALL ○ Clonal proliferation of immature Lymphoid cells (“lymphoblasts”) that can affect B-cell or T-cells ● ○ B cell and T cell ALL differ in their prognosis and treatment but have similar presentations Fun Facts ● ● 2/3 of cases are B-cell types Disease of children ○ ○ ● 75% of cases in children <6 yo ○ 90% survival rate children ○ 60-70% survival in AYA ○ 30-40% survival in adults Second peak of cases >65 yo Cause is unknown ○ Could be associated with radiation or infectious causes CLASSIFICATION ○ Philadelphia (Ph) chromosome positive ALL T(9;22) also know as “BCR-ABL” ● 2-4% of childhood cases; 25% of adult cases ● ○ ○ Incidence increases with age (~50% of pt >60 yo) Ph “like” ALL Gene expression resembling Ph+ disease, but cells lack t(9:22) translocation ● ○ Ph negative ALL ● Various gene mutations ALL CONT… ○ Clinical Manifestations ● ● ● Similar to AML due to bone marrow involvement Fever, infections (of any kind), Pale, fatigue, shortness of breath, weight loss, swollen lymph nodes, bleeding Neuropathic or meningeal symptoms ○ ○ Exam ● ● ● ○ High association with CNS disease; ~50% will relapse in CNS Painless lymphadenopathy Splenomegaly Easy/spontaneous bruising/bleeding Labs/Diagnostic tests ● CBC with differential ○ ● Peripheral blood smear ○ ● ● ● High WBC or Low WBC, pancytopenia Lymphoid blasts Bone marrow biopsy +/- Lymph node biopsy (excision/core needle) Cytogenetics ○ ○ ○ FISH ○ Look for t(9;22) Flow cytometry ○ Look for B cell expression markers (CD19, CD20) Hyperdiploidy/Hypodiploidy ○ Prognostic factor ALL CONT…. ○ Risk Stratisficaiton Ph + : Historically considered poor prognostic factor; improved outcomes with development of TKIs ● Ph like: poor outcomes ● Ph –: best prognosis; 90% cure rate in children and 60% cure rate in adults ● ○ Treatment ● Induction, CNS prophylaxis, Consolidation, Maintenance ○ ● ● Treatment lasting 2-3 years Salvage therapy at time of relapse Therapy types: ○ ○ ○ ○ ○ ○ ○ ○ ○ Cytotoxic Chemotherapy Steroids Vinca Alkaloid Asparaginase +/- Tyrosine kinase Inhibitors (TKIs) Stem cell transplant (allogenic) Immunotherapy CAR-T Clinical Trials HIGHLIGHTS - ALL ○ ○ ○ Children Ph+ or Ph – (Philadelphia chromosome) Non-specific HPI/exam ● ○ BMBx/blood smear/lymph node biopsy ● ○ ○ ○ Fatigue, current fevers, painless lymphadenopathy, and easy bruising (kids hurt themselves more than adults so more common presentation in kids) Lymphoblasts Chemotherapy within days of presentation (2-3 years of therapy) CNS prophylaxis High cure rate CHRONIC LYMPHOCYTIC LEUKEMIA CHRONIC LYMPHOCYTIC LEUKEMIA ○ ○ Progressive accumulation of functionally incompetent monoclonal B lymphocytes. Fun Facts: Most common leukemia in adults (25-30% of all leukemias) ● Median age 70 yeas old ● ○ Incidence increases rapidly with age Male > Female ● Genetic factors are the most likely cause as they present similar throughout the world ● CLL CONT ○ Rai Staging Stage Characteristics Median survival 0 Only lymphocytosis in peripheral blood and bone marrow > 12 years I Lymphadenopathy > 8 years II Hepatosplenomegaly >5 years III Anemia 1-2 years IV Thrombocytopenia 1-2 years CLL CONT ○ Clinical manifestations ● Typically asymptomatic ○ ● ● Can have waxing and waning painless lymphadenopathy that doesn’t completely clear 5-10% will have typical “B” symptoms ○ ○ Elevated WBC found on routine blood work Weight loss, fever, drenching night sweats, fatigue Exam ● Lymphadenopathy ○ ○ ○ ● ● ● Present in 50-90% of patients Most common sites cervical, supraclavicular and axillary Firm, round, non tender and freely mobile Splenomegaly Hepatomegaly Macules, papules, plaques, nodules, ulcers (leukemia cutis) CLL CONT ○ Work up ● CBC with differential ○ ○ ● Peripheral smear ○ ● Smudge cells (also referred to as basket cells) Flow cytometry ○ ● Elevated WBC count >20K with elevated lymphocyte count ○ ALC >5, many patient present with >100 Anemia and Thrombocytopenia (in advanced stages) Looking for B cell antigen markers on cells Lymph node biopsy ○ Specific changes in the architecture CLL CONT When to treat??? ○ Not all patients require treatment at time of diagnosis: Subsets can have survival rates similar to normal population ● CLL is not curative ● Rai Stage <3 = observation with q3 month blood work “Active disease” = treatment ● Worsening anemia AND/OR thrombocytopenia ● Massive or progressive symptomatic splenomegaly or hepatomegaly ● >50% increase in lymphocytosis in 2 months ● “B” symptoms ● ○ ○ Treatment ● ● ● Targeted agents Chemotherapy Immunotherapy Used in combination or as single agent * Monitor for transformation to aggressive form of lymphoma HIGHLIGHTS - CLL ○ ○ ○ Most common leukemia in adults Older adults Non-specific HPI/exam ● ○ High WBC ● ○ ○ High lymphocyte count (usually >100) BMBx ● ○ Fatigue, +/- lymphadenopathy (waxing/waning painless) Smudge cells Can observe some patients Not curable HAIRY CELL LEUKEMIA HAIRY CELL LEUKEMIA ○ ○ Chronic B cell lymphoproliferative disorder (lymphoid neoplasm) resulting in accumulation of small mature B lymphoid cells with "hairy" projections within the peripheral blood, bone marrow, and splenic red pulp Fun Facts: ● ● ● ● ● ● Pathophysiology not clearly understood Uncommon (~2% of all leukemias) Slow growing, indolent course Median age 50 years old Male predominance 4:1 Incidence is 3x higher in Caucasians than Blacks HCL CONT ○ Clinical manifestations ● ● ● ● ● ○ Asymptomatic (25%) Fatigue, weakness (25%) Bleeding - gingival, bruising, etc (25%) Abdominal fullness (25%) Usually do NOT have “B” symptoms Exam ● Splenomegaly (80-90%) ○ ○ Extending more than 8 cm below left costal margin in 25% Due to expansion of the red pulp by tumor cells HCL CONT ○ Diagnostic work up ● CBC with differential ○ ● Pancytopenia Peripheral smear ○ “Hairy” cell make up <20% of WBC ○ Irregular cytoplasm and cytoplasmic outlines give the “hairy” appearance BMBx ● Flow Cytometry ● ○ ● Looking for B cell antigen markers on cells Genetic testing ○ BRAF mutation ○ Helpful but not diagnostic HCL CONT ○ Treatment ● Observation ○ Asymptomatic – can observe for months or years with routine blood work (q3 -6 months) When to treat?? ● Cytopenias, Symptomatic splenomegaly, Fatigue or weight loss What to use?? ● Cladribine ○ ○ Daily infusion x 5 days Remission rate in the 90% with 9-11 year disease free survival HIGHTLIGHTS – HAIRY CELL ○ ○ ○ ○ ○ ○ Rare Slow growing disease Asymptomatic with splenomegaly “hairy” projections on cells Can observe some patients Not curable REVIEW – LEUKEMIA Most likely test questions: most common acute leukemia in adults is AML % blasts needed for diagnosis AML is 20% auer rods are seen in AML leukemia that presents with DIC APL most common acute leukemia in children is ALL Fatigue is a common presentation with leukemia most common adult leukemia is CLL (overall, not just acute) CLL presents with a waxing and waning lymphadenopathy CLL has smudge cells in smear Hairy cell leukemia has irregular projections MYELOPROLIFERATIVE DISORDERS Platelets MYELOPROLIFERATIVE DISORDERS ○ ○ ○ ○ Chronic Myelogenous Leukemia - WBC Polycythemia Vera - RBC Essential Thrombocythemia – Platelets Myelofibrosis – scar tissue all of them are specific to a cell line but all of them are slow growing *These are a group of slow growing blood cancers in which the bone marrow makes too many cells within the myeloid linage with relatively normal differentiation. CHRONIC MYELOID LEUKEMIA ○ Uncontrolled proliferation and production of granulocytes (WBC) with fairly normal differentiation ● ○ Philadelphia Chromosome t(9;22) is pathognomonic Fun Facts ● ● ● ● AML = stuck in blast phase, CML = multiple ton of mature 15-20% of all adult leukemias Median age 50-60 years old Slight male predominance Only known risk factor is ionizing radiation Normal smear CML smear CML CONT ○ Clinical course – 3 phases ● Chronic phase (85% of patients) ○ ● Accelerated phase ○ ○ ○ ● <10% blasts; usually asymptomatic 10-20% blasts Plt <100K (not related to therapy) Cytogenetic changes Blast phase ○ ○ >20% blasts Extra medullary disease CML CONT Clinical manifestations *Symptoms vary depending on phase of disease at presentation ○ Asymptomatic ● Fatigue, Weight loss, Sweats ● Abdominal fullness ● Bleeding ● ○ Exam Normal ● Splenomegaly ● Pale ● CML CONT ○ Diagnostic work up ● CBC with differential ○ ○ ○ ● Bone marrow biopsy ○ ● WBC >100K Increased basophils and eosinophils Normal OR Elevated platelet count (>600K) To calculate blast count Cytogenetic/FISH ○ Philadelphia chromosome present (~95% of patients) CML CONT ○ Treatment Chronic phase: ○ TKIs : Imatinib and dasatinib ○ Multiple generation of drug available ○ Drug choice - patient specific based on side effect profile Accelerated phase ○ ○ TKIs ○ If previously treated with TKIs, send TKI mutation testing (resistance) – requiring different generation TKI for tx Stem cell transplant Blast phase ○ ○ AML induction chemotherapy + TKIs Stem cell transplant *Hydrea: Used to decrease WBC count while awaiting diagnosis HIGHLIGHTS - CML ○ ○ ○ ○ High WBC Philadelphia chromosome 3 phases of disease Non-specific HPI/Exam ● ○ Fatigue, splenomegaly Treatment = Imatinib (Gleevec) POLYCYTHEMIA VERA (PV) ○ Clonal proliferation of myeloid cells resulting in elevated red blood cells. ● ○ Characterized by a JAK2 mutation Fun Facts: Median age 60 years old ● Slight male predominance ● Risk factors unknown ● PV CONT ○ Clinical Manifestation ● ● ● ● ● ○ Asymptomatic (found incidentally) Headache, dizziness, vision changes Itching (usually post-bath) GI complaints (early satiety, ulcers) Complications of clotting (CVA, MI, DVT, PE, superficial thrombophlebitis) Exam Normal ● Hypertension ● Splenomegaly ● Excoriation of the skin ● Major Criteria PV CONT ○ Diagnostic work up ● CBC with differential ○ ● ● ● Elevated Hgb >16 EPO level (low) JAK2 mutation analysis +/- Bone marrow biopsy ○ Used when diagnosis is questionable 1. Hgb/Hct > 16.5/49 in male; 16/48 in female OR Increased red cell mass 2. BMBx: hypercelluar; trilineage growth; varying size of mature megakarycytes 3. Presence of JAK2 mutation Minor Criteria 1. Subnormal serum EPO levels Diagnosis of PV requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion *Diagnosis made by sustained elevation in hgb/hct, a low EPO level AND a JAK2 mutation* ○ Treatment ● Phlebotomy ○ ● Low dose Aspirin (unless contraindicated) ○ ● To prevent thrombosis Hydrea ○ ● Maintain hematocrit <45% (titrate to needs; starting once weekly) Decreases bone marrows ability to make RBCs Ruxolitinib (JAK2 inhibitor) HIGHLIGHTS – PV ○ ○ ○ ○ Older adults Elevated Hemaglobin Itching after shower Phlebotomy + ASA ESSENTIAL THROMBOCYTHEMIA (ET) ○ ○ Clonal proliferation of myeloid cells resulting in elevated platelets. Fun Facts 90% of cases have JAK2, CALR or MPL mutation ● 1/3 of all myeloproliferative disorders ● Life expectancy is near normal population ● Female predominance ● ● Median age 60 years old; increases with age Normal smear Essential thrombocythemia ET CONT ○ Clinical manifestations ~50% are found incidentally ● Headache, dizziness, vision changes ● Thrombosis events and bleeding ● First trimester fetal loss ● ○ Exam Normal ● Splenomegaly (moderate size) ● ET CONT ○ Diagnostic work up ● CBC with differential ○ ○ ● CMP ○ ● Elevated platelets >450K (median count 1 million) ○ Platelet size varies RBC and WBC usually normal To rule out other causes BMBx ○ ○ Genetic testing ○ JAK2 mutation 65% Megakaryocytes Diagnostic Criteria Major Criteria 1. Platelet count ≥450 × 109/L 2. BMBx with increased megakaryocytes 3. Not meeting criteria CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms 4. Presence of JAK2, CALR, or MPL mutation Minor Criteria 1. Presence of a clonal marker or absence of evidence for reactive thrombocytosis ET CONT Treatment Low risk: ○ Observation ● Low-dose Aspirin (optimal dosing unknown) ● ○ Avoid in patient with acquired von Willebrand disease (thrombocytosis may alleviate aVWD and reduce bleeding) High and intermediate risk: ● Hydrea ○ Cytoreduction to target plt 100K – 400K Others: ● Platelet pheresis (take away plt from circulation) ○ ● Used in extreme thrombocytosis prior to cytoreduction as the intervention is temporary Ruxolitinib (JAK2 inhibitor) HIGHLIGHTS – ET ○ ○ ○ ○ Older adults Elevated platelets Blood clots/bleeding issues Observation  ASA  Hydrea MYELOFIBROSIS ○ ○ Clonal proliferative disorder with abnormal megakaryocytes (platelets) and bone marrow fibrosis (scarring) resulting in impaired hematopoiesis Fun Facts: Rare ● Median age 65 years old ● Familial occurrence have been reported ● MF CONT ○ Clinical manifestations Asymptomatic (~30%) ● Fatigue (~70%), weight loss, bone pain, night sweats ● ○ Exam Normal ● Splenomegaly ● Hepatomegaly ● MF CONT ○ Diagnostic work up ● CBC with differential ○ ○ ● Peripheral smear ○ ○ ○ ● Anisocytosis (varying RBC size) Poikilocytosis (varying RBC shape) Teardrop- shaped RBCs BMBx ○ ● Anemia (usually hgb <10) WBC and platelets can be mildly increased or decreased Reveals fibrosis (scarring) Genetic testing ○ JAK2, MPL and CALR MF CONT ○ Treatment ● Blood transfusion PRN ○ ● Clinical trials ○ ● JAK2 inhibitor Hydrea ○ ● Need better treatment options Ruxolitinib ○ ● Given progressive anemia Controls proliferation Stem cell transplant (allogenic) ○ Only chance of cure HIGHLIGHTS - MF ○ ○ ○ ○ ○ ○ Rare Older adults Cell lines don’t function well due to bone marrow scarring Teardrop cells BMBX= scarring Treatment = stem cell transplant MYELODYSPLASTIC SYNDROME ○ Group of diverse blood disorders characterized by abnormal development (dysplastic) and ineffective production in one or more blood/marrow elements (RBCs, WBCs or platelets). ● Can develop after: ○ ○ ○ ○ ○ Chemotherapy (alkylating agents) ○ Associated with 5q- and 7q- (deletions) Environmental (benzene) Radiation (therapeutic or accidental) De novo Fun Facts: ● ● ~10,000 cases diagnosed annually in the US Median age >65 years old ○ ○ ● ● Younger if treatment related Incidence increases with age Male predominance Sometimes referred to as “pre-leukemia” MDS CLASSIFICATION ○ ○ MDS with single lineage dysplasia – <5% MDS with ring sideroblasts - <5% ● ○ ○ MDS with multilineage dysplasia – 70% MDS with excess blasts – 25% ● ○ ○ Previously called “refractory anemia with ring sideroblasts” Previously called “refractory anemia with excess blast 1 and 2 MDS with isolated del(5q) - <5% MDS, unclassified - <5% MDS CONT ○ Clinical manifestations Asymptomatic ● Fatigue, dizziness ● Infection ● Easy bruising or bleeding ● ○ Exam Normal ● Pale ● Petechiae ● MDS CONT ○ Diagnostic work up ● CBC with differential ○ ○ ○ ● Peripheral smear ○ ● Pancytopenia (anemia, neutropenia, thrombocytopenia) Can have isolated anemia ○ Low reticulocyte response <20% blasts >10% Dysplasia BMBx MDS CONT MDS CONT ○ Treatment ● Supportive Care ○ ○ ● Low intensity ○ ● Antibiotics for infections Blood/platelet transfusions Hypomethylating agents (Decitabine) High intensity ○ ○ Combination chemotherapy Stem cell transplant (allogenic) HIGHLIGHTS – MDS ○ ○ ○ Older adults Abnormal (dysplastic) development of cells in one or more blood cell lines Difficult to treat REVIEW – MYELOPROLIFERATIVE AND MDS Philadel - CML CML stages (chronic, accelerated, blasts) CML therapy is inmatinib (spelling……) elevated red cells only PCV itching in PV elevation in platelets ET tear drop cells and scarring of marrow myelofibrosis chemo therapy treatments can cause the developement of MDS several years later JAK2 mutation present in PV, ET, myelofibrosis HODGKIN LYMPHOMA HODGKIN LYMPHOMA ○ Lymphoid neoplasm caused by the proliferation of malignant Hodgkin/Reed-Sternberg cells mixed with non-malignant inflammatory cells and a variable degree of fibrosis ● Classification: ○ ○ ○ Classical Hodgkin Lymphoma (90%) ○ Nodular sclerosis cHL most common subtype Nodular Lymphocyte-predominant HL (10%) Fun Facts: ● ● ● 10% of all Lymphomas 8500 new cases annually Bimodal age distribution ○ ● Esptein-Barr Virus (EBV) linked to pathogenesis ○ ● ~20 years old and ~70 years old Although risk of HL following EBV is very small Geography, HIV infections, immunosuppression and family history also play a role HL CONT ○ Clinical manifestations Non-tender lymphadenopathy ● “B” symptoms/Constitutional symptoms ● ○ Fever, night sweats, weight loss, fatigue Generalized itching ● Cough, Chest discomfort and SOB ● ○ ○ Due to mediastinal mass Exam ● Non-tender, firm, rubbery lymphadenopathy ○ ● Cervical and supraclavicular nodes most common Splenomegaly Lymph node regions in lymphoma HL CONT ○ Diagnostic work up ● CBC with differential ○ ● ESR (erythrocyte sedimentation rate) ○ ● Identify sites of disease for biopsy and staging Lymph node biopsy ○ ● High risk marker in localized disease CT scan /PET scan ○ ● Often normal Excisional or core BMBx ○ Morphology ○ Reed-Sternberg cells ● ○ “Owl’s eyes” appearance Flow cytometry ○ B cell markers and EBV antigens HL CONT ○ Lymphoma Staging Stage Involvment I Single lymph node region or lymphoid structure II Two or more lymph node regions/structure on the SAME side of the diaphragm III Lymph node regions/structures on BOTH sides of the diaphragm IV Diffuse involvement of one or more extranodal organ/tissue HL CONT ○ Treatment ● ABVD + Radiation ○ ○ ○ Doxorubicin (anthracycline), Bleomycin, Vinblastine, Dacarbazine Site involvement radiation Monitoring PET scan within 3 months of therapy to document negative disease ● CT scan at 6, 12 and 24 months ● F/u visits every 3-6 months for 1-2 years, then every 6-12 months until 3 years, then annually ● HIGHLIGHTS – HODGKIN ○ ○ ○ ○ ○ ○ Bimodal age (20s and 70s) Linked to EBV Non tender, firm, mobile lymphadenopathy in the neck “B” symptoms Reed Sternberg cells (owls eyes) Chemotherapy + radiation NON-HODGKIN LYMPHOMA NON- HODGKIN’S DISEASE ○ Group of malignant neoplasms that derive from progenitor and mature B cells and T cells and rarely natural killers cells. B-Cell Lymphoma T-cell Lymphoma NK cell Lymphoma Follicular Peripheral T-Cell Extranodal NK-Cell Marginal Zone Breast Implant-Associated Anaplastic Large Cell Mantle Cell T-Cell Large Granular Lymphocytic Diffuse Large B-Cell Adult T-Cell Burkitt T-Cell prolymphocytic AIDS-Related B-Cell Hepatosplenic Gamma-Delta T-Cell Lymphoblastic Post-Transplant Lymphoproliferative disorders Castleman’s Small Lymphocytic Lymphoma/CLL NHL CONT Divided into Aggressive and Indolent lymphomas ○ Highly Aggressive ● ○ Burkitt Lymphoma Aggressive Diffuse Large B cell Lymphoma (DLBCL) ● AIDS-Related B cell Lymphoma ● Post-Transplant Lymphoproliferative disorder (PTLD) ● Peripheral T cell Lymphoma ● ○ Indolent Follicular lymphoma ● Marginal Zone Lymphoma ● Mantle Cell Lymphoma ● BURKITT LYMPHOMA BURKITT LYMPHOMA Highly aggressive germinal center B-cell lymphoma characterized by the translocation 8;14 of the MYC gene. ○ Fun Facts: Clinically divided into 3 forms: ○ - Endemic (African) - - Sporadic (non-endemic) - - Incidence is ~50-fold higher than US Accounts for 30-50% of all childhood cancers in Africa EBV positive US and Western Europe Accounts for 30% of childhood lymphomas and <1% of adult NHL Peak age is 11 years, with adult median age of 30 More common in Caucasians Male predominance 4:1 Immunodeficiency-associated - HIV patients with high CD4 counts (all other forms of HIV-associated lymphoma have low CD4 counts) Incidence has NOT decreased with advance in HIV treatment BL CONT ○ Clinical manifestations +/- “B” symptoms ● Rapidly growing mass ● ○ ● ○ Develop in days Electrolyte disturbances (from Tumor lysis syndrome) Exam ● Mass ○ ○ ○ African: Jaw or facial bone tumor Sporadic: Abdominal, Jaw/facial bones, bone marrow, CNS Immunosuppressed: lymph node, bone marrow, CNS BL ○ Diagnostic Work up ● CBC w differential ○ ● CMP, uric acid, LDH ○ ○ ● ● ○ ○ ○ Disease involvement Testicles are “sanctuary sites” for disease with high association for CNS involvement Ki-67 nearing 100% (very aggressive) Flow Cytometry ○ ● “Moth-eaten” appearance (low power) “starry-sky” pattern Proliferation index ○ ● Staging (Lymphoma staging I-IV) Disease involvement BMBX/Lumbar Puncture ○ ● “Starry-sky” pattern Tissue Biopsy ○ ● TLS Organ dysfunction HIV testing PET/CT scan ○ ● cytopenias B- Cell antigens Cytogenetics/FISH ○ Myc translocation; t(8;14) most common BL CONT ○ Lymphoma Staging Stage Involvment I Single lymph node region or lymphoid structure II Two or more lymph node regions/structure on the SAME side of the diaphragm III Lymph node regions/structures on BOTH sides of the diaphragm IV Diffuse involvement of one or more extranodal organ/tissue BL CONT ○ Treatment ● TLS prophylaxis ○ ● Pre-phase steroids ○ ○ ● ● AFTER tissue biopsy Reduce tumor burden which decreases risk of TLS Clinical trials Intensive chemotherapy ○ ○ ● Sevelamer, allopurinol, IV fluids R-CODOX-M (4 cycles) ○ Rituxan, Cyclophophamide, Vincristine, Doxorubicin, HDMethotrexate Dose adjusted R-EPOCH (6 cycles) ○ Rituxan, Etoposide, Prednisone, Vincristine, Doxorubicin, Cyclophosphamide ○ Used in older adults, less fit patients or HIV – related Intrathecal chemotherapy ○ CNS prophylaxis (1-2 IT treatments per cycle) HIGHLIGHTS – BURKITT ○ ○ ○ ○ ○ Young adolescents Fast growing abdominal mass (US) or Jaw mass TLS Starry sky appearance on biopsy Chemotherapy with CNS prophylaxis DIFFUSE LARGE B CELL LYMPHOMA DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) ○ ○ A diverse group of tumors consisting of large B cells with diffuse pattern and high proliferation rates. Fun Facts: ● Most common subtype of Non-Hodgkin lymphoma ○ 25% of all cases Highest incidence in Blacks ● Median age 65 yo ● Male predominance ● Can arise from other indolent lymphomas or de novo ● DLBCL CONT ○ Clinical manifestation Rapidly growing lymphadenopathy ● +/- “B” symptoms ● Symptoms of obstructive mass ● ○ ○ Abdominal pain, SOB, swelling, SVC syndrome Exam ● Mass ○ ● Neck, abdomen or mediastinal most common but can be anywhere Evidence of obstructive Mass ○ bowel obstruction, JVD, edema, SVC syndrome DLBCL CONT ○ Diagnostic work up ● CBC w differential ○ ● CMP, uric acid, LDH ○ ○ ● ○ ○ ○ Ki-67: 40-90% (aggressive) Flow Cytometry ○ ● Staging CNS disease Proliferation index ○ ● Excisional or less preferred core biopsy Morphology reveals Large cells in diffuse pattern BMBx/Lumbar puncture ○ ● Staging (Lymphoma staging I-IV) Disease involvement Tissue Biopsy ○ ● TLS Organ dysfunction PET/CT scan ○ ● Cytopenias can occur B- Cell antigens Cytogenetics/FISH DLBCL DLBCL CONT ○ Lymphoma Staging Stage Involvment I Single lymph node region or lymphoid structure II Two or more lymph node regions/structure on the SAME side of the diaphragm III Lymph node regions/structures on BOTH sides of the diaphragm IV Diffuse involvement of one or more extranodal organ/tissue DLBCL CON ○ Treatment ● Limited stage disease (Stage I or II) ○ ○ ● R-CHOP (Rituxan, Cyclophosphamide, Doxorubicin, Vincristine and prednisone) Radiation to affected area Advance stage disease (Stage III or IV) – based on molecular subtype ○ ○ R-CHOP DA-R-EPOCH HIGHLIGHTS – DLBCL ○ ○ ○ ○ Most common NHL Older adults Lymphadenopathy Tissue biopsy ● ○ Large cells in a diffuse pattern Chemotherapy FOLLICULAR LYMPHOMA FOLLICULAR LYMPHOMA ○ ○ Indolent lymphoma of the follicle center with germinal center expressed B cell markers Fun Facts: ● ● ● ● ● Most common indolent lymphoma 35% of all NHLs Caucasian predominance Incidence increases with age; median age 65 years old 85% have the t(14:18) FL CONT ○ Clinical manifestation Painless adenopathy that waxes and wanes ● “B” symptom (20%) ● Asymptomatic ● ○ Exam ● Lymphadenopathy ○ Cervical, axillary, inguinal and/or femoral regions FL CONT ○ Diagnostic work up ● CBC with differential ○ ● Tissue biopsy ○ ● Staging Characteristic nodules close together and varying in size and shape Flow cytometry ○ ○ ● Lymph node of FL Morphology ○ ● Excision or core BMBx ○ ● Usually normal Germinal center B cell phenotype Cytoplasm positive for BCL2 (80-90%) Cytogenetic/FISH ○ t(14;18) FL CONT ○ Treatment Observation (stage I or II) ● Chemotherapy (stage III or IV) -75% of patients ● ○ ○ ○ ● R-CHOP Rituxan + Bendamustine Stem cell transplant +/- Maintenace therapy ○ Rituxan q2 months x 2 years (controversial) – no prolonged overall survival HIGHLIGHTS – FOLLICULAR ○ ○ ○ ○ Most common indolent lymphoma Older adults Slow growing Asymptomatic for years ● ○ Tissue biopsy ● ○ +/- waxing and waning lymphadenopathy Multiple nodules of varying size Observation or chemotherapy based on stage REVIEW – LYMPHOMA MULTIPLE MYELOMA MULTIPLE MYELOMA ○ Proliferation of plasma cells producing a monoclonal immunoglobulin ● ○ One immunoglobulin (IgM, IgA, IgG) is over produced MM is a continuum ● MGUS (Monoclonal gammopathy of unknown significance) ○ ○ ○ ○ ● Smoldering MM ○ ○ ○ ○ ● >10% plasma cells in bone marrow Asymptomatic; no end-organ damage >3 g/dL of serum monoclonal protein Observation MM ○ ○ ○ ○ ● <10% plasma cells in bone marrow Asymptomatic; no end-organ damage <3 g/dL of serum monoclonal protein Observation >10% plasma cells in bone marrow Symptomatic; end-organ damage (CRAB) Any spike of serum monoclonal protein Treatment Plasma Cell Leukemia ○ ○ Any amount of circulating serum plasma cells Treatment MM CONT ○ Proliferation of plasma cells producing a monoclonal immunoglobulin ● ○ One immunoglobulin is over produced (IgA or IgG most common) Fun Facts: ● ● ● ● ● Accounts for 1-2% of all cancers and 17% of hem malignancies Incidence is 2-3 times higher Blacks than Whites Male predominance Median age 66 years old Small set of familial cases (not well understood) An Antibody – which are effected in MM MM CONT ○ Clinical manifestation ● ● Fatigue Bone fracture with minimal trauma (slamming the door) ○ ● Bone pain ○ ● ○ Usually from thoracic or lumbosacral areas Possible cord compression Hyperviscosity (thick blood) – rare ○ ○ Usually back or chest Numbness/tingling ○ ● “pathologic fractures” Bleeding, headache, vision change, etc Exam ● ● ● Pain over bone Pale Paresthesias, weakness, loss of bowel/bladder control MM CONT ○ Diagnostic work up ● CBC with differential ○ ○ ● CMP ○ ○ ● ○ Determines type (ex: IgG Kappa) BMBx ○ ● M-spike Urine dipstick is usually negative for protein Immunofixation ○ ● Monoclonal spike “M-spike” UPEP (urine protein electrophoresis) ○ ● Rouleaux formation – “stacking poker chips” SPEP (serum protein electrophoresis) ○ ● Elevated Creatinine Hypercalcemia Peripheral smear ○ ● Cytopenia Plasma cells in peripheral blood = plasma cell leukemia >10% plasma cells Imaging ○ ○ Skeletal survey (X-ray) ○ “Punched out” lesions CT, MRI or PET (more sensitive) Rouleaux formation MM CONT Diagnosis….. CRAB criteria Clonal plasma cell population + One disease related end organ impairment (CRAB) ○ C – hyperCalcemia R – Renal insufficiency A - Anemia B - Bone lesions MM CONT ○ Staging ● ISS (Internataion Staging system) ○ ○ ○ ● Stage I – Beta-2 Microglobulin <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II - neither stage I nor stage III Stage III – Beta-2 Microglobulin ≥5.5 mg/L Median overall survival ○ ○ ○ Stage I - ~5 years Stage II - ~3.5 years Stage III - ~2.5 years MM CONT ○ Treatment Bortezomib, Lenalidomide, Dexamethasone ● Stem Cell Transplant (autologous) ● Lenalidomide maintenance therapy ● ○ Supportive Care Radiation ● Surgery (fractures) ● Bisphosphonates (bone strength) ● *Several other therapy regimens for relapsed disease or Non-transplant candidates HIGHLIGHTS - MM ○ ○ ○ ○ ○ Older adults with pathologic fracture Plasma cell problem >10% plasma cells in bone marrow CRAB criteria SPEP/UPEP ● ○ ○ ○ ○ M-spike (monoclonal spike) Rouleaux formation Punched out lesion Chemotherapy Not curative WALDENSTROM MACROGLOBULINEMIA (WM) – AKA LYMPHOPLASMACYTIC LYMPHOMA ○ ○ Chronic, slow growing lymphoproliferative disorder which affects B cells causing them to overproduce abnormal IgM proteins Fun Facts: Rare – 3 per million people per year ● Median age 70 years ● Large Caucasian predominance ● Familial cases in up to 20% ● WM CONT ○ Clinical manifestations Asymptomatic ~25% ● Weakness, fatigue, weight loss, oozing blood from gums ● Anemia, lymphadenopathy, hepatosplenomegaly ● ○ ● Hyperviscosity, peripheral neuropathy – common ○ ○ Bone marrow/organ infiltration IgM monoclonal protein Exam Normal ● Lymphadenopathy ● Hepatosplenomegaly ● WM CONT ○ Diagnostic work up ● CBC with differential ○ ● Peripheral smear ○ ● Rouleaux SPEP/Immunofixation ○ ● Anemia M spike (from IgM) BMBx ○ >10% plasma cell differentiation Serum IgM Symptoms Bone marrow involvement Waldenstrom Macroglobulinemia High levels Present – lacks bone involvement >10% MGUS Low levels Absent <10% Multiple Myeloma Rare (<0.5%) Present - CRAB >10% WM CONT ○ Treatment ● Chemotherapy + Immunoglobulin ○ ○ ● Bendamustine + Rituximab Bortezomib + Dexamethasone + Rituximab Stem cell transplant (Autologous) HIGHLIGHTS - WM ○ ○ ○ Rare Older adults SPEP/immunofixation ● ○ M-spike - IgM NO bone involvement or CRAB symptoms AMYLOIDOSIS ○ Extracellular tissue protein deposits (fibrils) which clump together to become insoluble ● Several types, most common: ○ ○ ○ AL amyloidosis – plasma cell dyscrasia by light chain fragments AA amyloidosis – recurring inflammation results in production of amyloid A protein which forms amyloid deposits Fun Facts: Can be hereditary (rare types) ● ~2,000 cases per year ● Median age ~65 years old ● Male predominance ● AMYLODI CONT ○ Clinical manifestation ● Skin changes, Edema, Speech changes, etc *All symptoms are related to location and amount of protein deposits ○ Exam ● ● ● Waxy thickening of skin Pleural effusion Enlarged muscles (tongue, deltoids) ○ ● ● ● “Shoulder pad sign” Heart failure (edema, arrhythmias) Neuropathy Bleeding (abnormal liver function) AMYLOIDOSIS CONT ○ Diagnostic work up ● Work up to rule out other causes… ○ CXR, EKG, Thoracentesis, etc Tissue biopsy ● Urine analysis ● ○ Increased protein BMBx ● Pathology ● ○ Congo red stain ○ Results in apple-green birefringence with polarized light microscopy AMYLOID CONT ○ Treatment ● Stem cell transplant (autologous) ○ ● Generally without induction treatment Bortezomib + Cyclophosphamide + Dexamethasone (CyBorD) ○ Transplant delayed or no eligible HIGHLIGHTS – AMYLOID ○ ○ ○ ○ ○ ○ RARE Older adults Protein depositions (enlarged tongue or heart) Tissue biopsy Not curative High mortality rate REVIEW – MM, WM AND AMYLOIDOSIS REFERENCE ○ Flow Cytometry REFERENCE Protein Electrophoresis/ Immunofixation ○ FLURESENCE IN SITU HYBRIDIZATION (FISH) REFERENCE ○ Lymph node architecture REFERENCE Risk stratification ELN 2017 ○