AN APPROACH TO “BAD BLOOD” AKA

ACUTE LEUKEMIA

Arif Ali Awan – R2 JGHNovember 27th, 2014IM Teaching

DISCLAIMER

Just a Resident

CASE

52F Nurse, 3 sisters

PMHx: HTN, hysterectomy

Meds: Hctz 12.5; NKDA

No family history

Presents with 6 week history of intermittent fever (upto 38.5), sore throat, malaise, muscle pains, mild dyspnea went to GP, given NSAID’s and antibiotics

Developed small red dots especially on legs, gingival bleeding, worsening fatigue

Presented to Santa Cabrini WBC 279,000, Hgb 80 MCV = 90, Plat 25; 60% peripheral blasts

Transferred to JGH.

THE FIRST THINGS YOU HAVE TO DO

Make sure patient not in DIC, TLSSymptomatic leukostasis!AML/APL or ALL

ACUTE LEUKEMIA

A disease in which immature heterogenous white blood cells multiply or accumulate uncontrollably

Circulating “clonal” white blood cells.

Need to distinguish between AML (60-70%)/APL (5-8% of AML), ALL (~20%)

Hematologic emergency: fatal in weeks to months (Infection, bleeding)

AML: 16000 cases yearly in US, median age 70 y, 3-5/100,000 person-yr

ALL: total 6000 cases yearly in US, minority in adults

HISTORY Common: fatigue, infection, bruising, bleeding

Leukostasis: Neuro (CN, altered MS), Resp, CVS

MSK: bone pain

Cardiac history, co-morbidities

Prior transfusions and pregnancies: allo antibodies

Drug allergies

Prior herpes simplex: prophylaxis

Pregnancy/menses: OCP; fertility preservation

Siblings?

Extramedullary: anywhere, gingiva

Skin (leukemia cutis or Sweet syndrome)

Performance status

RISK FACTORS

Risk factors: MDS Myeloproliferative disorder Prior chemotherapy IR Trisomy 21 Rare congenital syndromes (Klinefelter’s, Fanconi, dyskeratosis congenita) Smoking RR 1.4 CT scans RR 1.2-1.7 Family history

Not cell phones!

PHYSICAL EXAM

Fever: treat as infection

Eyes: hemorrhages and or exudates up to half have ocular involvement.

Oropharynx: gingival involvement, dental caries, oral thrust

Organomegaly and LNs: uncommon in AML - think of ALL or CML in blast crises

Neuro: CN palsies, Altered MS.

Skin: pallor, infiltrative lesions, petechiae and echymoses, leukemia cutis (10-15%), Sweet Syndrome

LEUKEMIA CUTIS

SWEET SYNDROME AKA ACUTE FEBRILE NEUTROPHILIC DERMATOSIS

AML CNS INVOLVEMEMENT

uncommon ( 5-7%): high circulating blast count, M5

defer LP if high blast count and asymptomatic to avoid contamination defer LP to consolidation

IDENTIFYING LINEAGE: AML/APL, ALL Morphology not always helpful Flow cytometry Immunostains Cytogenetics

AML DIAGNOSIS

Blood and marrow (aspirate and biopsy)

Auer rods: rod like filaments of aggregated primary azurophilic granules (most seen in M1 and M2)

> 20% blasts in BM/peripheral or recurrent cytogenetic abnormality

Special stains distinguish myeloid (MPO) from lymphoid (TdT)

Flow cytometry: help to distinguish lymphoid from myeloid (CD13, 33, 34, 117); establishes maturation

DO CYTOGENETICS!

ROUTINE LAB TESTING

CBC with differential and blood film

BUN, creatinine, lytes, uric acid, glucose

Liver enzymes, LDH

calcium profile

PT, PTT, fibrinogen, FDPs or D dimers

flow cytometry if blasts in blood

Beta-HCG

Type and Screen

Defer HSCT testing: HLA, CMV, Hep A/B/C/HIV/HTLV

LABORATORY FINDINGS

WBC: 20% > 100,000, 50% normal or reduced

Pancytopenia

Watch out for tumor lysis syndrome (hypoCA, HyperPhos, Acidosis, hyperK, increased LDH, increased Uric Acid, renal failure).

ADDITIONAL INTERVENTIONS CXR

ECG

TTE if risk factors

LP if symptomatic

BM asp and biopsy with cytogenetics and flow cytometry (subclassification, prognosis, tailoring treatment): KIT, FLT3, NPM1, CEBPA

Broviac placement

Fertility preservation

Dentistry consultation if poor oral hygiene

Oncology/transplant nurse

Psychosocial support

AML - FAB

FAB subgroups based on the predominant cell type and to define the leukemia’s cell position in the maturation sequence of that specific lineage, less common use nowadays

M0-M7

M0 Minimal differentiation (3%)M1 Without maturation (15–20%)M2 Maturation (25–30%)M3 Acute promyelocytic leukemia (5–10%) M4 Acute myelomonocytic leukemia (20%) M4Eo Acute myelomonocytic leukemia with abnormal eosinophils (5–10%)M5 Acute monocytic leukemia (2–9%)M6 Erythroleukemia (3–5%)M7 Acute megakaryocytic leukemia (5%)

AML

WHO

AML with recurrent genetic abnormalities t(8;21)- AML/ETO With abnormal bone marrow eosinophils and inv16 or t(16;16) 11q23 abnormalities

AML with multilineage dysplasia

AML and MDS-therapy related

AML not otherwise categorized

++ atleast 20 different subtypes

AML TREATMENT

Goal: stabilize patient and then rapid restoration of normal BM function.

Induce Remission: Induction: reduces leukemia cell population from 1012 to 109 (MRD)

Prevent Relapse: Consolidation: 1-3 or more courses of chemo or BMT to eradicate residual leukemia and allow for cure

Complete Remission: normal blood counts (ANC>1000, plt > 100,000, no pRBC transfusion needs) and BM cellularity with < 5% blasts without leukemic phenotype

Cure?: relapse and death rates low after 3-4 years remission; 40% age < 60

Clinical trials

AML TREATMENT INDUCTION 7+3 1) Cytarabine (Ara C )

-continuous infusion x 7 days

-<60 yo 200 mg/m2; >60 yo 100 mg/m2

- Myelosuppresion: biphasic nadir 7-9 D, 15-24D, Rash, conjunctivitis, Mod. N/V, increased LFT’s, ulceration, neurotoxicity (cerebellar dysfunction)

2) Anthracycline

-Daunorubicin 60-90 mg/m2 IV x 3 days

-Dose reduce with hepatic dysfunction (bilirubin)

- Myelosuppresion: nadir 10-14 D, cardiac toxicity, mucositis, red/orange urine, Mod. N/V, increased LFT’s,

?? D14 Marrow

SUPPORTIVE CARE DURING INDUCTION Febrile Neutropenia: treat find source otherwise prophylaxis (Levofloxacin) RR 0.66 reduced mortality. NNT 30’ 60% identified source, 6% mortality (15% of cases fungal, 15% mixed, 5% bacteria)

IPA prophylaxis posaconazole NNT 20 mortality

Herpes Simplex Prophylaxis

Nutrition

HLA matched CMV neg, irradiated, leukodepleted transfusions (plt > 50000 APL)

?G-CSF no survival benefi

TLS: Allopurinal nearly all; Rasburicase if WBC > 100,000, T-ALL but not if G6PD def.

Beware transfusions with leukostasis.

Psychosocial

AML TREATMENT CONSOLIDATION High dose cytarabine/Ara-C (HiDAC)

3g/m2 x 6 doses

For 3-4 cycles

No proven role for maintenance therapy in AML compared to ALL

If relapse: salvage chemotherapy, re-induction, clinical trial, ?autologous transplant

HSCT/TRANSPLANT

Allogenic matched related donor better than unrelated donor

Unfavourable prognosis – 20% increased survival 27 vs 7 % at 5 year

Intermediate risk – 6 to 10% increased survival

COMPLICATIONS: LEUKOSTASIS WBC > 50,000 (AML > ALL)

Neurological: visual disturbance, headache/dizziness, TIA/CVA

CVS: MI

Resp: dyspnea, infiltrate on chest X-ray

Treatment: hydroxyurea, chemo, leukapheresis

TUMOR LYSIS SYNDROME

ALL > AML

First sign incr. LDH, low Ca

Then hyperkalemia, hyperphosphatemia, increased uric acid, renal failure, cardiac arrhythmias

AML PROGNOSIS

Age (> or <60); > 60 worse secondary AML blast count > 100,000 response to induction chemotherapy APL better prognosis

CYTOGENETICS

Karyotype Molecular modifications

Favourable t(15,17), t(8,21); inv(16)/t(16:16)

NPM1 (FLT3 neg), CEBPA (biallelic)

Intermediate

Normal; includes -y, +8, +21, +22,

CEBPA

Poor -5/del(5q), -7/del (7q), t(6,9), 11q23, 3 or more abnormalities

FLT3

Over 23 genes mutated

AML PROGNOSIS

55-70% achieve CR with induction

50-70% will relapse during the first 18-24 months

allogeneic transplant an option in select few with sibling (preferable)

no role for maintenance chemotherapy

APL

Excellent prognosis once treatment started (higher mortality prior), younger ~ 30’s

Remember DIC/severe thrombocytopenia/CNS bleeding

t (15;17); t(11;17): PML-RAR α aberrant fusion protein blocks myeloid differentiation.

Treated with:

Induction: All-trans retinoic acid (ATRA) + anthracycline (nearly all patients CR)

Consolidation: ATRA or Arsenic trioxide (ATO)

Maintainence: ATRA, 6-Mercapto-purine, oral methotrexate

Auto-HSCT if relapse.

APL - 2

Watch out for differentiation syndrome (25-40%): fever, edema, stomatitis, Hypotension dyspnea, ARDS renal/liver failure Treated with high dose steroids (Dex 10 mg IV BID), temporary cessation ATRA/ATO

Other AE: electrolyte imbalances, QT prolongation, rash, pain, increased LFT’s, hearing loss (ATO)

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)Only ~ 1000 adult cases/year in US

Similar presentation to AML

Hepatosplenomegaly and LNs more common

Leukocytosis less common

CNS involvement (15%) and relapse more common

Mediastinal mass in T cell ALL: CXR, CT chest

TLS more common than AML, can be spontaneous

TdT stain (ALL), MPO (AML)

LP, testicular exam

Philadelphia chromosome

ALLB-cells (~80%): CD10, 19, 20

L1=Early Precursor B-ALL

subtype represents 25-30% of adult cases

L2= Pre-B ALL

representing 70% of cases

L3/Burkitt’s=B-ALL

subtype accounts for 1-2% of adult cases

T-ALL (~ 20%): CD2, 3, 5, 7, 4, 8, 38

Particularly aggressive

ALL TREATMENT

Borrowed from pediatric protocols

Overall survival 40%

PH chromosome ALL in 30%: poor prognosis

treatment 4 components over 2-3 years: Induction, consolidation, CNS prophylaxis and maintenance Mainly outpatient Allo BMT for PH + ALL or relapsed disease

Prognosis:

Good: children, pre-B WBC < 30,000, T-ALL < 100,000, rapid CR, t(12,21), hyperdiploidy

Bad: Ph chromosome changing with TKI-inhibitors, t(4,11), MLL/11q34 translocation

BACK TO OUR PATIENT

AML with leukemia cutis, FLT3 negative, intermediate cytogenetics

Given hydroxyurea (4g/day) initially

LP positive blasts

Induction chemotherapy complicated by:

1) Febrile neutropenia secondary CLA-BSI with VRE bacteremia

2) Severe Mucositis: MMW, pink lady, dilaudid

3) 15% weight loss: nutrition

4) Mild increased in liver enzymes

Day 28 bone marrow: CR

Received consolidation

Awaiting Allo-HSCT

FUTURE DIRECTIONS

Autologous Chimeric antigen receptor T-cells targeting CD19

Used in relapsed/refractory ALL: CR 90%, sustained response 67% of patients and response seen up to 24 months.

SUMMARY

Acute leukemia: emergency

AML/APL vs ALL

Leukostasis: symptomatic ?urgent treatment

Treatment: Feb. Neut, TLS, transfusions, Anti-microbial prophylaxis

Watch out for adverse effects due to chemotherapy

REFERENCES

DynaMed: AML, ALL, APL

Pocket Oncology 2014