Case Conference 1/6/16

Case Conference 1/6/16

27 year old woman CC: bruising PMH: Healthy Meds: Multivitamin 4,000 IU vitamin D Fish oil Probiotic Allergies: none Family Hx: Maternal GF - Lung Ca & vasculitis Paternal GF - Heart disease Paternal GM - melanoma Maternal Uncle - melanoma Social Hx: Single Smoker - 5 yr pack hx Occasional ETOH Occasional marijuana use Server at Champs

HPI ROS Completed a detox diet ~ one month ago (no gluten, sugar, ETOH, or dairy for 2 weeks) 2 days later, she developed excessive bruising with large generalized areas of discoloration Bruising for the past month Also noted new menorrhagia, nose bleeds, & hematochezia + Fatigue and night sweats. No weight loss Hematochezia: streaks of blood on tissue, painless Menorrhagia: for the past 2 cycles, changes pads/ tampons q45 min Bleeding/Bruising: unprovoked, gums bleed with flossing Questions?

Exam Vitals: 98.7F BP 122/78 HR 104 RR 16 BMI 32.4 Gen: NAD, anxious HEENT: normal Resp: CTAB CV: tachycardic, regular, no murmur Abd: Non-tender Lymph: no palpable cervical or axillary adenopathy Skin: Bruising on truck, abdomen, arms, wrists, legs, and ankles + petechiae on face

What do you want next? 9.1 6.8 38 INR: 1.4 CBC report also commented that there was a scatter pattern suspicious for immature WBCs Trauma Infxn Neopl Cong Heme Endo Met Psych Vasc Inflam

ANW Admission PCP contacted Dr. Bloom the following day & hospitalization was recommended Additional history on admit: + nausea, poor appetite, loose stools, no herbal medications Exam was unchanged Labs were repeated: 8.3 6.6 29 MCV 106 Additional Labs: Albumin: 4.2 Tot/Direct Bili: 0.6 / 0.2 ALT & AST: 17 & 20 INR: 1.3 PTT: 25 Fibrinogen: 115 D Dimer >4

What would you like to order next? 1. Peripheral Smear 2. CT Chest/Abd/Pelvis 3. Haptoglobin 4. Iron Studies 5. BMP 6. Differential Several Concerns: - She had blasts: - Figure out what else is going on in the blood / marrow: get a diff and check a smear - She was Bleeding, her Fibrinogen & platelets were low, & INR was high - Think DIC, DIC, DIC 7. Other

141 107 10 3.6 21 0.75 Uric Acid: 6.1 LD: 531 Few elliptocytes, few tear drop cells, circulating blasts with auer rods What are you thinking now?

Oncology Consult Assessment: Circulating blasts + Auer rods highly suggestive of APL Clinical picture also consistent with DIC (due to leukemia) Plan: BM biopsy + cytogenetic testing - t(15;17) Begin ATRA (given high suspicion for APL) Follow for bleeding; transfuse cryo to keep fibrinogen >100 and platelets for counts <30. Start allopurinol to prevent tumor lysis

Hospital Day 2 BM confirmed APL with t(15;17) Felt to have good-intermediate risk disease (WBC 10,000) Plan Start induction chemo with ATRA + ATO (Arsenic Trioxide) & premeditate with dexamethasone Continue to follow counts and transfuse prn Observe for risk of differentiation syndrome & Torsades Differentiation Syndrome (retinoic acid syndrome) Potentially fatal complication of induction chemo in patients with APL Fever, edema, pulmonary opacities, hypoxemia, respiratory distress, hypotension, renal/hepatic dysfunction, rash, serositis (pleural & pericardial effusions) All due to cytokine storm - release of inflammatory cytokines from malignant promyelocytes Occurs in ~25% treated with ATRA or ATO

Hospital Course Responded to treatment well Only a few more episodes of bruising and gingival bleeding She required several platelet transfusions to keep platelets >30 WBC trended up (significantly) - by HD 10 her WBC had risen to 80,000 and she developed HA and left arm weakness. STAT MRI was negative for stroke. Hydroxyurea was started to try to decrease counts WBC rose to 91,000 by HD 11 and ATRA/ATO was held due to concern for differentiation syndrome WBC began trending down and treatment was restarted by HD 16 By HD 32 she was finally transfusion Independent and was able to discharge home She returned for ongoing ATO infusions and eventually started consolidation therapy She also developed significant pain all over and required dilaudid PCA - pain was attributed to marrow expansion

Acute Leukemias

AML Group of hematopoietic neoplasms involving precursor cells committed to the myeloid line of cellular development These precursor cells proliferate, but have reduced capacity to differentiate into more mature cellular elements This leads to: Accumulation of immature forms/blasts in BM, peripheral blood & other tissues Decreased RBC, platelets, & neutrophils Anemia, Bleeding, & Infection

Epidemiology Most common type of acute leukemia in adults Average age of 65 Men > Women Incidence increases with age: 1.3/100,000 in those <65 12.2/100,000 in those >65 Incidence is similar between races

Risk Factors

What is true about the presentation of AML? 1. Fevers are usually due to an underlying infection Fever is almost always due to an infection 2. Lymphadenopathy is a common finding on exam Palpable lymphadenopathy is rare 3. Hepatosplenomegaly is common finding on exam Organomegaly is present in only 10% of cases (& often from evolution of MPD into AML) 4. 1&2 are true

Signs & Symptoms Related to complications of BM failure / pancytopenia Weakness/fatigue Infections Hemorrhagic findings (gingival bleeding, ecchymoses, epistaxis, menorrhagia) Bone pain infrequent When present, due to expansion of medullary cavity by leukemic process Oropharyngeal Signs Gingival Hypertrophy Oral candidiasis Herpetic lesions

Extramedullary Disease Myeloid Sarcoma: solid tumor composed of Immature WBCs that occurs outside the BM (virtually any organ or tissue) <1% will have prominent extramedullary disease Most common presentations (usually with BM involvement) Cutaneous Infiltration leukemia cutis (violaceous non-tender cutaneous plaques) Sweet syndrome (acute neutrophilic dermatosis) Gingival infiltration

Complications and their treatments Commonly due to high cellular turnover & bone marrow infiltration Anemia, infection, & Bleeding 1. Thrombocytopenia 2. Abnormal Platelet Function 3. DIC Common in Malignancy Common in APL Leukostasis (mainly CNS & Resp Sx) Leukapheresis or Hydroxyurea Tumor Lysis Syndrome (High Phos, Uric Acid, and K & low Ca) Fluids & Allopurinol +/- Rasburicase High # of WBCs can also interfere with certain labs (spuriously high K or low glucose) Transfusions prn for anemia & DIC ATRA for DIC from APL Increased WBC (>50,000) > leads to WBC plugs in microvasculature - 10-20% of new AML cases - Diagnosed Empirically - Untreated Mortality is 20-40%

Diagnosis Presumptive: circulating blasts May not have leukocytosis Definitive: BM aspirate & biopsy Marrow infiltration (20% of the cells from aspirate must be blasts) Need to have both to make the diagnosis Leukemic cells must be of myeloid origin OR - peripheral blood can have 20% blasts

Peripheral smear 75% will have platelets <100 25% will be <25 Median leukocyte count 15 25-50% will be < 5 > 95% will have circulating blasts detectable on smears +/- Auer rods Depends on AML Subtype

Classification of AML Once AML is diagnosed, it should be classified into the appropriate subtype based on WHO classification scheme Probably more familiar with FAB (next slide)

Type Name % of cases Mo acute myeloblastic leukemia, minimally differentiated 5 M1 acute myeloblastic leukemia, w/o maturation 15 M2 acute myeloblastic leukemia, with granulocytic maturation 25 M3 acute promyelocytic leukemia (APL) 10 M4 acute myelomonocytic leukemia 20 M4eo myelomonocytic together w BM eosinophilia 5 M5 acute monoblastic leukemia (M5a) or acutemonocytic leukemia (M5b) 10 M6 acute erythroid leukemias, including erythroleukemia (M6a) and very rare pure erythroid leukemia (M6b) 5 M7 acute megakaryoblastic leukemia 5

Poor Prognostic Factors Advanced age pts >55 y/o Poor performance status Eastern Cooperative Oncology Group (ECOG) scale used by oncologists Cytogenetic / Molecular genetic findings in tumor cells Hx of prior cytotoxic agents or radiation Hx of prior myelodysplasia or other hematologic disorders such as myeloproliferative neoplasms

Treatment Symptomatic Transfusions, allopurinol, hydroxyurea, etc Chemotherapy Cure rates of 30-40% Induction Chemo ( 7 and 3 ) 7d cytarabine + concomitant 3d anthracycline Goal is complete remission Consolidation Chemo follows (vs. allogenic HSCT) Goal is to eradicate residual disease If young + favorable risk disease > 3-4 courses of high dose cytarabine Adverse risk disease > allogenic HSCT after induction chemo

APL M3 subtype Presence of (15;17) gene translocation Creates the promyelocytic leukemia - retinoic acid receptor alpha fusion transcript Arrests leukemic cells at promyelocyte stage Landark APL0406 Trial (NEJM 2013, 3069 (2), 111-121 Compared ATRA + ATO to ATRA + Anthracycline Chemo is specifically tailored to this gene translocation ATRA is added to induction & consolidation Binds a nuclear receptor to decrease proliferation & increase differentiation (maturation) of APL cells Cure in up to 80% Arsenic trioxide (ATO) can also induce differentiation ATRA + ATO demonstrated a 100% CR with 97% disease free survival at over 2 yrs of f/u with no deaths during induction This is a recently adopted category 1 treatment option for APL

Warning ATRA & Arsenic Trioxide may produce a differentiation syndrome Fever, dyspnea w or w/o pulmonary infiltrates, edema & hypotension Treatment: dexamethasone & temporarily stop the drugs

Board Question A 40yo W undergoes f/u evaluation after a 5 wk hospital stay. She was recently diagnosed with AML, with studies revealing a 5q- chromosomal deletion and 5 unrelated cytogenetic abnormalities. She was treated with induction chemo and is now experiencing full remission. The patient s brother is a complete HLA-matched donor. The physical examination, including vital signs, is normal. Lab studies, including CBC, are normal. Which of the following is the most appropriate treatment? 1. Allogenic HSCT 2. Autologous HSCT 3. Azacitidine 4. High-dose cytarabine She has high risk/adverse disease (5q-); thus, need induction and then allogenic HSCT (which has shown improved disease free survival) Studies using allogenic HSCT are not consistent - no definite proven benefit High Dose-C: only for favorable disease

ALL Malignancy of B or T lymphoblasts Cytochemical stains and Flow cytometry will differentiate T from B cell Often get lumped as lymphoma/ leukemia so here s a few tips: Lymphoma if a mass in mediastinum or elsewhere and < 25% blasts in BM If >25% blasts in BM (mass or no mass) -> it s leukemia

All presentation Similar symptoms to AML due to marrow failure fatigue, dyspnea, bleeding, infection/fever) BUT unlike AML, lymphadenopathy & organomegaly are common CNS involvement is common (HA, lethary, N/V, nuchal rigidity, CN palsy, or radiculopathy) TLS is common at time of diagnosis Poor prognosis: advanced age, adverse cytogenetics, B cell disease, and high WBC (>30,000): High risk: hypodiploidy & Philadelphia chromosome t(9;22)

Chemotherapy 30-40% cure rate for adults using standard chemo For young adults: Induction: anthracycline, vincristine, L-asparaginase, & corticosteroid If CR achieved > more intensive chemo with multiple agents for several months then 2-3 years of maintenance chemo Intrathecal chemo/radiation is also routinely given due to high risk for CNS disease If high risk disease, healthy, and donor available > allogeneic HSCT in first remission If Philadelphia chromosome + > BCR-ABL inhibitors are also given

Care of the adult survivor of childhood leukemia Fairly morbid cohort of pts And not uncommon over 300,000 survivors of childhood cancer as of 2010 ALL is most common childhood cancer Majority of long-term issues related to treatment of prior leukemia (some iteration of R-CHOP regimen) Important to collaborate with pt s oncologist OR survivor clinic to clarify prior treatments

Care of the adult survivor of childhood leukemia Cardiotoxicity (from anthracyclines) Echo rec d q3-5 yrs after establishing follow-up More cancer (!) Especially in pts that had received craniospinal radiation (brain, thyroid, parotid, sarcoma) Nearly 8x risk for AML compared to healthy population others can develop MDS Sustained bone demineralization