Acute Leukemia and Intracerebral Hemorrhage

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Acute Leukemia and Intracerebral Hemorrhage

• Tanya Wildes
• April 22, 2006

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Disclosure Tanya Wildes, M.D.
Dr. Tanya Wildes has no relevant financial
interests to disclose.
3
Disclosure ltinsert namegt, M.D.
Tanya Wildes, M.D. has financial interests to
disclose. Potential conflicts of interest have
been resolved.

• Research Support / Grants None
• Stock/Equity (any amount) None
• Consulting / Employment None
• Speakers Bureau / Honoraria None
• Other None

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Case 1

• 31 year old female with AML M5 presents with
  neutropenic fevers after her first cycle of
  consolidation chemotherapy.
• She also complains of intermittent headaches
  since she underwent intrathecal chemotherapy two
  weeks ago. Headaches are aching, bifrontal, worse
  when supine.

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Case 1

• Physical Exam
• Temp 38.6 P 116
• Neuro exam was nonfocal
• Labs
• WBC 0.1
• Hgb 9.3
• Plt 22
• PT 15.3
• PTT 36.0

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Brain MRI
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Case 1

• MRI demonstrates parenchymal hemorrhage left
  frontal lobe that measures 10 x 7 mm x 7 mm.
• Neurosurgery was consulted they recommended
  transfusion of platelets with goal platelet count
  over 100,000.
• Neutropenic fevers were treated with cefepime and
  supportive care.
• Follow-up head CT two weeks later showed no
  increase in the size of hemorrhage.
• The patient was discharged home once neutropenic
  fevers resolved.

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Case 2

• 42 year old female with HTN, DM presented with 1
  week of headache.
• No history of trauma.
• She was conversant and neurologically intact upon
  arrival to ED.

• Initial labs
• WBC 218.4
• Hgb 9.7
• Platelet 20
• PT 19.0
• PTT 39.9

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Head CT
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Head CT

• IMPRESSION
• 1. SMALL (10.7 x 8.5 mm) PARENCHYMAL HEMORRHAGE
  AT THE LEFT PARIETAL GREY-WHITE MATTER JUNCTION.
• 2. SUGGESTION OF VERY MILD EDEMA IN LEFT
  HEMISPHERE WITH 5MM MIDLINESHIFT TOWARDS THE
  RIGHT.

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Case 2

• Patient was transferred to BJH BMT service.
• On arrival, patient was conversant with normal
  vital signs.
• Peripheral smear revealed abundant blasts, some
  with bilobed nuclei, minimal granulation,
  occasional auer rods.

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Case 2

• Neurosurgery was consulted.
• They recommended correction of her
  thrombocytopenia and coagulopathy.
• Within 3 hours of arrival, the patients level
  of consciousness declined.
• She was intubated for airway protection.
• A repeat head CT was performed.

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Head CT
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Head CT

• FINDINGS
• Intraparenchymal hemorrhage in the right parietal
  lobe has intervally increased in size, measuring
  approximately 5 cm x 3.3 cm with extensive
  surrounding vasogenic edema.
• Interval development of a new, smaller foci of
  intraparenchymal hemorrhage within the bilateral
  frontal lobes and right temporal lobe, as well.
• Mass effect upon the left ventricle, with near
  effacement of the temporal and occipital horns.
  There is slight rightward midline shift.

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Case 2

• Neurosurgery then recommended recombinant
  activated factor VII.
• Despite aggressive medical intervention, the
  patient expired within hours of her initial
  presentation.

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Clinical questions

• How common is intracranial hemorrhage among
  leukemia patients?
• What clinical factors account for differences in
  severity of intracranial hemorrhage?
• Is there evidence to support the use of
  recombinant factor VII in our patient population?

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Fatal Intracranial Hemorrhage in Blast
CrisisNEJM 1957

• Case series N100
• 81 deaths
• 18 deaths due to intracranial hemorrhage (22)

Fritz, RD, et al. The association of fatal
intracranial hemorrhage and blastic crisis in
patients with acute leukemia. NEJM 1959 261(2)
59-64.
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Fatal Intracranial Hemorrhage in Blast
CrisisNEJM 1957
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ICH in the contemporary era

• Autopsy series of 3426 patients with non-CNS
  cancer
• 453 patients with leukemia were autopsied
• 69/453 (15.2) patients with leukemia had ICH
• 71 of ICH were symptomatic
• 7 (9/129) of ALL patients had ICH
• 55.5 were petechial or small hemorrhages
• 22.4 (43/192)of AML patients had ICH
• 23.3 were petechial or small hemorrhages

Graus F, et al. Cerebrovascular complications in
patients with cancer. Medicine 1985 64(1)
16-35.
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Symptoms

• Petechial or small (lt2cm) hemorrhages
• Usually asymptomatic
• Large (gt2cm) hemorrhages
• Single
• Acute headache, vomiting, focal deficits,
  obtundation, transtentorial herniation
• Multiple
• Sudden lethargy without focal deficits

Graus F, et al. Cerebrovascular complications in
patients with cancer. Medicine 1985 64(1)
16-35.
22
Graus F, et al. Cerebrovascular complications in
patients with cancer. Medicine 1985 64(1)
16-35.
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Summary

• Patients with high WBC count at diagnosis and
  hemorrhage tend to have higher platelet counts
  and multiple hemorrhages.
• Pathophysiology likely related to leukemic
  infiltration with ischemic, hypoxic vasodilation
  and vessel rupture.
• Patients who develop hemorrhage after diagnosis
  tend to do so in the setting of sepsis, fever and
  marked thrombocytopenia they tend to have
  solitary hemorrhages.
• Pathophysiology likely related to multiple
  abnormalities of coagnulation.

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Subdural Hematoma

• 25/453 (5.5) patients with leukemia suffered
  subdural hematomas
• Acute confusion and lethargy were the presenting
  signs on all patients
• Thrombocytopenia with or without DIC and sepsis
  were present in all patients with leukemia and
  SDH
• None were diagnosed pre-mortem
• 3/25 had meningeal leukemic infiltration

Graus F, et al. Cerebrovascular complications in
patients with cancer. Medicine 1985 64(1)
16-35.
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Treatment

• Randomized controlled trials
• rFVIIa for intracranial hemorrhage in patients
  with normal coagulation parameters
• rFVIIa for bleeding following hematopoietic stem
  cell transplantation
• Prospective
• Bleeding times after rFVIIa in thrombocytopenic
  patients
• Case reports
• rFVIIa for intracranial hemorrhage in patient
  with refractory ITP
• rFVIIa for subdural hemorrhage in AML patient
  with platelet alloimmunization

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TreatmentRCT rFVIIa in intracranial hemorrhage

• N399
• Inclusion criteria
• Age gt18
• ICH documented by CT within 3 hours of symptom
  onset

• Exclusion criteria
• Thrombocytopenia
• Coagulopathy or DIC
• Sepsis
• Planned surgical evacuation
• Known AVMs, trauma, aneurysm
• Use of oral anticoagulants
• Thrombosis (MI, DVT, CVA) within 30 days

Mayer SA, et al. Recombinant activated factor VII
for acute intracerebral hemorrhage. NEJM 2005
352(8) 777-785.
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TreatmentRCT rFVIIa in intracranial hemorrhage

• Intervention
• Patients randomized to 40 mcg/kg rFVIIa, 80
  mcg/kg rFVIIa, 160 mcg/kg rFVIIa or placebo
• Dose was given within 1 hour of CT scan and no
  more than 4 hours after symptom onset
• Endpoints
• Hematoma size by head CT at 24 hours and 72 hours
• Clinical Assessment
• Glasgow Coma Scale
• Rankin Scale global outcomes
• National Institutes of Health Stroke Scale
  neurologic impairment
• Barthel Index activities of daily living
• Extended Glasgow Outcomes Scale ability for
  self-care and independence

Mayer SA, et al. Recombinant activated factor VII
for acute intracerebral hemorrhage. NEJM 2005
352(8) 777-785.
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TreatmentRCT rFVIIa in intracranial hemorrhage
Mayer SA, et al. Recombinant activated factor VII
for acute intracerebral hemorrhage. NEJM 2005
352(8) 777-785.
30
TreatmentRCT rFVIIa in intracranial hemorrhage

• Results
• Clinical Outcomes
• Mortality in placebo arm 29 vs 18 in treatment
  arm
• Patients treated with rFVIIa showed
  dose-dependent improvement in outcomes on all
  four outcomes scales (Rankin Scale, National
  Institutes of Health Stroke Scale, Barthel Index
  and Extended Glasgow Outcomes Scale).
• Thromboembolic events occurred in 2 of placebo
  treated patients and 7 of rFVIIa treated patients

Mayer SA, et al. Recombinant activated factor VII
for acute intracerebral hemorrhage. NEJM 2005
352(8) 777-785.
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rFVIIa in thrombocytopenic patients

• Mayer study of rFVIIa in intracerebral hemorrhage
  patients may not be applicable to our patients as
  they excluded patients with thrombocytopenia,
  coagulopathy and sepsis.
• What evidence is there for efficacy of rFVIIa in
  thrombocytopenic patients?

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TreatmentrFVIIa in thrombocytopenia

• N74
• Group A 47 patients with decreased platelet
  production
• Group B 27 patients with immune destruction
• Dose 50mcg/kg or 100mcg/kg
• Positive response Decrease in Bleeding time gt2
  minutes between 2 hours before and 30 minutes
  after rFVIIa

Kristensen, et al. Clinical experience with
recombinant factor VIIa in patients with
thrombocytopenia. Haemostasis 1996 26S1159-164.
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TreatmentrFVIIa in thrombocytopenia
Kristensen, et al. Clinical experience with
recombinant factor VIIa in patients with
thrombocytopenia. Haemostasis 1996 26S1159-164.
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TreatmentrFVIIa in thrombocytopenia

• Median reduction in bleeding time
• Decreased platelet production 14 minutes
• Increased platelet destruction 5 minutes
• 8 patients had thrombocytopenia and active
  bleeding
• Bleeding stopped in 6 patients
• Theory
• Though thrombocytopenic patients have an intact
  intrinsic coagulation pathway, exogenous FVIIa
  ensures that the few platelets available are
  maximally activated.

Kristensen, et al. Clinical experience with
recombinant factor VIIa in patients with
thrombocytopenia. Haemostasis 1996 26S1159-164.
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Treatment rFVIIa in hematopoietic stem cell
transplant patients with bleeding

• Prospective, randomized trial of patients
  undergoing autologous or allogeneic transplant
• N100
• Inclusion Mild bleeding (score 2) x 3 days or
  severe to serious bleeding (score 3 or 4)
• Exclusion atherosclerotic disease, stroke or DVT
  within 3 months, DIC, thrombotic microangiopathy,
  VOD, active AML M3, M4 or M5 or recent
  granulocyte infusion.

Pihusch M, et al. Recombinant activated factor
VII in treatment of bleeding complications
following hematopoietic stem cell
transplantation. 2005 31935-1944.
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Treatment rFVIIa in hematopoietic stem cell
transplant patients with bleeding

• Treatment
• rFVIIa dose 40, 80 or 160 mcg/kg or placebo IV q
  6 hours x 6 doses
• Standard management practices
• RBC transfusion if Hgblt8
• Platelet transfusion if plt lt20x 109
• If diffuse alveolar hemorrhage or hemorrhagic
  cystitis, platelets were transfused if lt75 x 109
• Use of antifibrinolytic agents was discouraged

Pihusch M, et al. Recombinant activated factor
VII in treatment of bleeding complications
following hematopoietic stem cell
transplantation. 2005 31935-1944.
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Treatment rFVIIa in hematopoietic stem cell
transplant patients with bleeding

• Primary endpoint change in bleeding score 2
  hours after final dose of rFVIIa
• Secondary endpoints
• change in bleeding score at 24, 48, 72 and 96
  hours after initial dose
• RBC, platelet and FFP transfusion requirements
  during 96 hour follow-up

Pihusch M, et al. Recombinant activated factor
VII in treatment of bleeding complications
following hematopoietic stem cell
transplantation. 2005 31935-1944.
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Treatment RCT rFVIIa in hematopoietic stem cell
transplant patients with bleeding
Pihusch M, et al. Recombinant activated factor
VII in treatment of bleeding complications
following hematopoietic stem cell
transplantation. 2005 31935-1944.
40
Treatment RCT rFVIIa in hematopoietic stem cell
transplant patients with bleeding
Pihusch M, et al. Recombinant activated factor
VII in treatment of bleeding complications
following hematopoietic stem cell
transplantation. 2005 31935-1944.
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TreatmentCase report rFVIIa in ITP patient with
ICH

• 16 y.o. F with ITP refractory to IVIg, steroids,
  cyclophosphamide anti-CD20 and anti-TNFalpha
  monoclonal antibiodies
• Presented with severe headache, N/V x 36 hours
  no trauma.
• Platelet count - 4 x 109
• HCT demonstrated large intraparenchymal
  hemorrhage.
• Treated with platelet transfusion, FFP, IV
  tranexamic acid.
• Started on rFVIIa 122mcg/kg q 2 hours, weaned to
  q 8 hours, then q day x 5 days.
• Despite transfusion of 98 u of plt, highest
  platelet count was 35.
• Serial neuro-imaging demonstrated no further
  hemorrhage. She was discharged after 3 weeks
  with no residual neurologic deficits.

Barnes, C. Recombinant FVIIa in the management of
intracerebral haemorrhage in severe
thrombocytopenia unresponsive to
platelet-enhancing treatment. Transfusion
Medicine 2005 15 145-150.
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Treatment Case report rFVIIa in platelet
refractory AML patient with ICH

• 27 y.o. F with MDS evolved into AML. She was
  refractory to platelets at time of induction
  chemotherapy
• Day 7 Subdural Hemorrhage
• Treated with tranexamic acid and platelet
  transfusion
• Day 21 Head CT with stable hematoma
• Day 23 hemoptysis, periorbital hematoma
• Day 27 left hemiparesis head CT demonstrated
  progression of SDH

Vidarsson B. Recombinant Factor VIIa for bleeding
in refractory thrombocytopenia. Thromb Haemost
2001 83634-5.
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Treatment Case report rFVIIa in platelet
refractory AML patient with ICH

• Day 32-33 rFVIIa 100 mcg/kg q 2 hours x 5
  doses, then q4 hours x 6 doses.
• Day 33 headache resolved, periorbital
  hematomas stable, no left sided weakness
• Patient had no further bleeding for remainder of
  her course.
• Patient died on Day 81 of persistent disease.

Vidarsson B. Recombinant Factor VIIa for bleeding
in refractory thrombocytopenia. Thromb Haemost
2001 83634-5.
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Summary

• Intracerebral hemorrhage is common in acute
  leukemia
• Blast crisis related to leukostasis
• Coagulopathy
• Mainstay of treatment is supportive therapy
• Further study needed to determine the role of
  rFVIIa in patients with leukemia and
  intracerebral hemorrhage

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References

• Barnes, C. Recombinant FVIIa in the management of
  intracerebral haemorrhage in severe
  thrombocytopenia unresponsive to
  platelet-enhancing treatment. Transfusion
  Medicine 2005 15 145-150.
• Fritz, RD, et al. The association of fatal
  intracranial hemorrhage and blastic crisis in
  patients with acute leukemia. NEJM 1959 261(2)
  59-64.
• Graus F, et al. Cerebrovascular complications in
  patients with cancer. Medicine 1985 64(1)
  16-35.
• Kristensen, et al. Clinical experience with
  recombinant factor VIIa in patients with
  thrombocytopenia. Haemostasis 1996 26S1159-164.
• Mayer SA, et al. Recombinant activated factor VII
  for acute intracerebral hemorrhage. NEJM 2005
  352(8) 777-785.
• Pihusch M, et al. Recombinant activated factor
  VII in treatment of bleeding complications
  following hematopoietic stem cell
  transplantation. 2005 31935-1944.
• Quinones-Hinojosa, et al. Spontaneous
  intracerebral hemorrhage due to coagulation
  disorders. Neurosurg Focus 2003 15(4) 1-17.
• Vidarsson B. Recombinant Factor VIIa for bleeding
  in refractory thrombocytopenia. Thromb Haemost
  2001 83634-5.

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Fatal Intracranial Hemorrhage in Blast
CrisisNEJM 1957

• Of those with WBCgt300, there were 2 distinct
  subgroups
• Subgroup A WBC exceeded 300 gt8 days before ICH,
  peaked at 450-850
• Subgroup B WBC rose abruptly lt2 days before ICH.