Danielle ShaferSeptember 29, 2015

Acute Leukemia

Case #1

50 year old lady is diagnosed with AML. WBC 88K with 78% blasts and platelets of 3K. She reports profound fatigue. She received a unit of PRBCs for hemoglobin of 7 and developed dyspnea. Oxygen saturation is 80% with temperature to 38.2◦C. Electrolytes are OK.

Questions

Is the diagnosis leukostasis?What is the preferred treatment?How can blood transfusion be safely given?What is the optimal treatment for

asymptomatic patients with newly diagnosed or relapsed AML and a WBC of 100K?

Hyperleukocytosis (HL)

Present in ~5 to 20% of untreated AML patients

Commonly defined as WBC>100K but can occur below arbitrary threshold Association with monocytic AML subtypes Chromosomal MLL rearrangements FLT3-ITD mutations

Primary clinical manifestations: Leukostasis DIC TLS

HL

Pathogenesis Rapid blast proliferation Disruption in normal hematopoietic cell adhesion with

reduced affinity to bone marrow

Does HL matter?

Mortality up to 8% in first 24 hours and ~20% during first week

HL is negative prognostic factor with shorter OS – even when early deaths are excluded.

DIC

Decrease in platelets and fibrinogenElevation in D-dimersProlongation of PT and aPTT

Occurs in 30 to 40% of HL-AML

Treat with FFP/fibrinogenLook for APLInitiate treatment

TLS

Up to 10% of HL-AMLProphylaxis with IVF and allopurinolClose monitoring during first days of

treatmentRasburicase for marked hyperuricemia as

lowers uric acid level by enzymatic degradation

Leukostasis

Empirically diagnosed in patients with acute leukemia, HL and respiratory or neurologic symptoms.

~44 to 50% of AML patients with WBC>100K have high probability of leukostasis

Organs affected: lung, brain, kidneyTreatment: immediate cytoreduction

Symptoms of leukostasis

Organ Symptoms

Lung Dyspnea, hypoxemia, diffuse alveolar hemorrhage, respiratory failure

Central nervous system Confusion, somnolence, dizziness, headache, delirium, coma, focal neurologic deficits

Eye Impaired vision, retinal hemorrhage

Ear Tinnitus

Heart Myocardial ischemia/infarction

Vascular system Limb ischemia, renal vein thrombosis, priapism

Hydroxyurea

Effective as short term bridging strategyDoses up to 50 to 60 mg/kg per dayNo evidence it will reduce risk of tumor lysis

Leukapheresis

Rapidly removing excessive leukocytes by mechanical separation

Able to lower WBC count by 10 to 70% in single leukapheresis

Does not replace initiation of treatment Majority of disease burden is in marrow so rapidly

mobilized after leukapheresis No consistent clinical benefit has been demonstrated

Contraindications to Leukaphersis

Cardiovascular comorbiditiesHemodynamic instabilityCoagulation disturbancesAPL

Transfusion

Judicious as it can increase blood viscosity and aggravate leukostasis

If necessary, should be administered slowly during or immediately after leukapheresis

Case #2

23 year-old-man without significant history is diagnosed with pre-B ALL. WBC is 160K with 90% blasts and 450 neutrophils. Hemoglobin is 7.5 and platelets are 10K. His electrolytes and renal function are normal. Uric acid is 11; LDH is 1500.

Case #2 questions

What is the risk of TLS?What is the optimal treatment for preventing

TLS?What is the role of rasburicase and urine

alkalinization?

TLS

Primary TLS can occur before starting treatment in malignancies with high cell turnover

Secondary TLS, more common, can occur a short time after start of treatment

TLS Risk factors

Tumor burdenPotential for rapid cell lysisPreexisting nephropathy

Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus

British Journal of HaematologyVolume 149, Issue 4, pages 578-586, 16 MAR 2010 DOI: 10.1111/j.1365-2141.2010.08143.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2010.08143.x/full#f2

Cairo Bishop TLS (Lab)

Cairo Bishop TLS (Clinical)

TLS

Current patient at risk for TLSAggressive hydration (4000 to 5000 mL of

IVF started 24 to 48 hours before induction) to maintain urine output of 80 t0 100 ml/m2 per hour

Fix electrocytes Hyperkalemia Hyperphosphatemia Calcium if symptomatic

No evidence for urinary alkalinization

Tumour lysis syndrome: new therapeutic strategies and classification

British Journal of HaematologyVolume 127, Issue 1, pages 3-11, 22 JUL 2004 DOI: 10.1111/j.1365-2141.2004.05094.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2004.05094.x/full#f1

TLS Drugs

Allopurinol Reduces uric acid in 1 to 3 days

Rasburicase Promotes catabolism of uric acid to allantoin Single dose likely sufficient

Case #3

59 year-old lady presents with new onset diplopia. She has third nerve palsy and CT demonstrates left occipital and thalamic infarct. CBC shows hemoglobin of 10.5, WBC of 500 and platelets of 88K. Prothrombin time is slightly prolonged with INR of 1.3 and PTT is normal. Fibrinogen is 80. BM and molecular and cytogenetics establish diagnosis of APL.

Copyright © 2011 American Society of Hematology. Copyright restrictions may apply.

Marco Gambassi, ASH Image Bank 2011; 2011-5912

Promyelocytes with Auer rods - 01

Copyright © 2011 American Society of Hematology. Copyright restrictions may apply.

Peter Maslak, ASH Image Bank 2011; 2011-4233

APL - 2.

Case Continued

What is the best prophylaxis and emergent management of coagulopathy in APL?

Coagulopathy in leukemia

In thrombohemorrhagic syndrome: Symptomatic thrombus in ~5% Symptomatic hemorrhage in ~7%

Coagulopathy in APL DIC Primary and secondary fibrinolysis and

fibrinogenolysis Incidence of fatal hemorrhage in APL is 5%

Risks include high WBC, coagulopathy, age, PS and increased creatinine.

APL early death rates

Ravindra B. Kolhe et al. Blood 2013;122:5597

©2013 by American Society of Hematology

Treatment

Early recognitionInitiation of ATRAPlatelet goal of 50K for first few daysCryoprecipitate to maintain fibrinogen > 150

Case #5

A 35-year-old man with AML is treated with induction therapy. On day 16, he develops fevers, bloody diarrhea, and right lower abdominal pain followed a few hours later by an acute abdomen. He undergoes emergency explorative laparotomy and right hemicolectomy with temporary colostomy.

Case #5 Questions

Can neutropenic enterocolitis be prevented?Should this influence the decision regarding

further chemotherapy?

Neutropenic enterocolitis (NE)

AKA necrotizing colitis, ileocecal syndrome or typhlitis

Ill defined syndrome characterized by fever and abdominal pain in setting of neutropenia Bacteremia common

Reported incidence ~6.5%

Neutropenic enterocolitis (NE)

Pathogenesis linked to damaged GI mucosa from chemotherapy and neutropenia

CT findings with thickening of bowel wall and intramural edema +/- paracolonic fluid, free air or pneumatosis intestinalis Greater than 10-mm wall thickening linked to 60%

mortality

Treatment includes bowel rest, fluid resuscitation, NG suction, parenteral nutrition and broad spectrum antibiotics.

NE – Unanswered questions

Parenteral alimentation and NG suctionQuinolone prophylaxisKeratinocyte growth factors

A bit about AML

Incidence

Most common type of acute leukemia in adults

Median age at diagnosis around 70 but can occur at any age

Estimated 18,860 people in US diagnosed in 2014

Age-Specific Incidence of AML

Data from NCI, SEER database: accessed 11/2/14

Etiology

Substantial proportion related to toxin exposure Alkylating agents

Usually 5-10 years after drug Frequently with dysplasia in all 3 lineages Usually preceding myelodysplastic phase with typical

cytogenetic abnormalities including loss of chromosome 5 or 7 Topoisomerase II inhibitors

Latency period 1-3 years Monocytic differentiation common Often with 11q23 abnormality Less often with antecedent myelodysplasia

Benzene and radiation Down syndrome

Relative survival by time and age for acute myeloid leukemia based on SEER data.

Klepin H D et al. JCO 2014;32:2541-2552

©2014 by American Society of Clinical Oncology

Ten-year relative survival curves obtained by model-based projections for 2006–2010 (black solid lines), period analysis for 2001–2005 (black dashed curves), and cohort analysis for

cohorts of patients diagnosed during 1991–1995 (gray solid lines).

D. Pulte et al. Ann Oncol 2009;21:335-341

© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

XIE et al, Nature Medicine 19 Oct 2014

Percentage of Patients in Cytogenetic Risk Groups by Age (SWOG)

Appelbaum F R et al. Blood May 2006

Byrd, J. C. et al. Blood 2002;100:4325-4336

Prognosis in AML-CytogeneticsPrognosis in AML-Cytogenetics

Breems D A et al. JCO 2008;26:4791-4797

Prognosis in AML-CytogeneticsPrognosis in AML-CytogeneticsMonosomal karyotype (MK)Monosomal karyotype (MK)

MK positive (MK+). MK refers to ≥ two autosomal monosomies or one autosomal monosomy with at least one structural abnormality

Treatment Outcome in Cytogenetically Treatment Outcome in Cytogenetically Normal AML-age < 60Normal AML-age < 60

4 year OS (%)

NPM +ve/FLT3 –ve 60

CEBPA +ve 62

FLT3 +ve 24

Wild type 33

Schlenk et al. N Engl J Med 2008;358:1909-18

Intensive Induction Options

Idarubicin (12mg/m2) IV d1-3 + Cytarabine (100-200mg/m2) CI d1-7

Daunorubicin (60mg/m2 or 90mg/m2) IV d1-3 + Cytarabine (100-200mg/m2) CI d1-7

Metaanalysis

10 studies have randomized patients to Dauno vs. Ida

N=4060 Age had a significant interaction with CR and OS

Bottom line, likely IA better in younger patients, not necessarily in older patients.

Wang et al, PLoS 2013 April

Intensive Induction in >60

Lowenberg et al. NEJM. September 24, 2009

High dose vs standard dose Daunorubicin

• 813 eligible patients.• Median follow up: 40 months. • 26% of the patients were > 71 years of age• Only 10% underwent HCT• No differences in:

• 30-day mortality (12% vs 11%), • Hospitalization• Rate of death during induction• SAE

Lowenberg et al. NEJM. September 24, 2009

SurvivalSurvival

CR 2yr OS MortalityStandard Dose 54 26 11High dose 64 31 12

Lowenberg et al. NEJM. September 24, 2009

Survival by Age

60-65

CR 2yr OS

SD 54 23

HD 64 38

66-70

CR 2yr OS

SD 59 29

HD 58 29

Lowenberg et al. NEJM. September 24, 2009

Other Options for AML therapy

Clinical trials – should be first choice in older patients, especially when not fit for intensive induction

Also Decitabine – but randomized studies indicate not

better for OS compared to supportive care Azacitadine Clofarabine

Less Intensive therapies: AMLStudy Combination N Med OS

CR rate

Other

AML 14UKMRC Burnett et al.Cancer 2007

LD-ARAC 103 <6mo 18%

OS 66 days if no CR;

565 days if CR

HU & BSC 99 <4mo 1%

MDAnderson et al.

Kantarjian et al.JCO 2012

Decitabine 242 7.7 mo 17.8%

Treatment Choice

LDARAC243 5.0 7.8%

French ATURetrospecti

veThepot et al.Blood 2009

Azacitadine Phase II

138 10.2 mo 14%

MD Anderson

Retrospective

Quintas-Cardama Blood 2012

Epigenetic therapy

both Dec and AZA

114 6.5 mo 28%

Dec > AZA with re to

OS8.8 v. 5.5