Case Report: A 57 year old Filipino Man with a Hemoglobin of 3'3

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Case ReportA 57 year old Filipino Man with a
Hemoglobin of 3.3
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• The patient was in good health when he moved to
  the United States from the Philippines with his
  wife in the summer of 2008
• He noted DOE and SOB in January of 2009 which was
  worse when he was outside, and much worse over
  the past 2 weeks
• On the day of admission his SOB was so bad that
  he could barely walk to the bathroom, and went to
  an outside hospital

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Other Symptoms

• Fevers and night sweats for a few weeks
• Dark urine
• Dark skin
• No bleeding or dark stools

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Past Medical History

• Gout with arthritis requiring minor surgery to a
  finger
• No personal or family history of anemia, no prior
  blood transfusion
• Medications Colchicine and diclofenac prn gout
• Married smoked and drank ethanol until 1994

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Physical Exam

• T37.5, BP 120/70, P120, 100 O2 Sat
• Jaundiced
• Chest with rales ¼ way up chest
• III/VI systolic ejection murmur
• Enlarged spleen without hepatomegaly
• No palpable lymph nodes
• A deformed 2nd PIP joint on the right hand from
  gouty arthritis
• 1 edema of the legs

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Initial Labs at the Outside Hospital

• Hemoglobin 3.3
• MCV 91
• RDW 20
• Retic count 15.5 (5 days after admission)
• WBC 15.5 (74N, 12L, 15M)
• Platelets 215
• LDH 1145 (100-250)
• Creatinine 0.8
• AST 21
• ALT 26
• Total bilirubin 4.8 (0.3-1.1)
• Direct bilirubin 1.3 (0-0.3)
• Urine 1 Blood
• U/A No RBC

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• Direct Coombs
• IgG Negative
• C3
• Indirect Coombs anti-Big S
• PNH Negative
• Cold Agglutinin gt1512 (initial outside)
• Donath Landsteiner Negative
• B12 126 at outside hospital
• Ferritin 3369 (22-232)
• Haptoglobin lt6
• Warm SPEP Albumin 2.7, no paraprotein
• Erythropoietin 1282 (3-34)
• Fibrinogen 419
• Total complement 1 (63 to 145 done 1 day after
  rituxan)

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• Mycoplasma IgG (-) IgM
• CMV (-) for IgM
• EBV 11,000 copies/ml IgM (-)

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Cold Agglutinin Thermal Amplitude (Done 4-30-09
6 days after Plasmapheresis)
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Little i antigen Present on Fetal Cells
Big I antigen Present on Adult Cells
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Bone Marrow at Outside Hospital on 4-20-09

• Outside hospital reading
• Hypercellular BM with mild megakaryocyte
  hyperplasia, but no evidence of leukemia,
  myelodysplastic syndrome or abnormal
  proliferation of cells
• Flow showed 1 population of B cells that were
  lambda restricted and were CD19, CD20, CD38,
  HLADR, CD45, CD5(-), CD10(-) consistent with
  extranodal marginal zone lymphoma and/or
  lymphoplasmacytic lymphoma

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Therapy at Outside Hospital4-12-09 to 4-28-09

• Intubation for respiratory arrest with Hb of 3
• Glucocorticoids
• Approximately 16 units of PRBC
• Rituxan for 2 doses on 4-14-09 (reaction) and
  4-22-09 (no reaction)
• Danazol 300 mg p.o. bid on 4-15-09
• Plasmapheresis 4-16-09 to 4-24-09
• Cytoxan 100 mg qday on 4-17-09

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Therapy at BJC

• Transfusion
• Continued rituxan
• Another round of plasmapheresis
• Continued oral cytoxan
• D/C danazol
• Continued prednisone at 40 mg/day

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Possible Reasons for Failure to Respond to
Therapies

• Allo-antibodies
• Gave anti-Big S negative blood
• Tested for Kidd genes, and gave JK-A-negative
  blood (patients was JK-A-negative and JK-B
  positive)
• Rapid production of IgM from lymphoma

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Reading of outside BM at BJC

• BJC initial reading (4 working days after
  receiving the sample)
• Myelodysplastic syndrome
• BJC amended reading (6 working days after
  receiving the sample from OH)
• Large Non-Hodgkins B cell lymphoma with 5 CD20
  CD79a

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Repeat Bilateral Bone Marrow (done 5-7-09, 1 day
after Rituxan)

• 5 to 10 of the cells were CD20 with large
  mononuclear cells with coarse nuclear chromatin
  and promiment nucleoli consistent with
  Non-Hodgkin Large B cell lymphoma
• Flow of aspirate (hemodiluted) showed no CD20()
  cells
• 1 of cells on flow (hemodiluted) were
  lambda-restricted with CD20(-), CD5(-), CD23(-),
  CD10(-)

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Bone Marrow on 5-7-09 Done 24 hours after
Rituxan
Anti-CD20
H and E
Leder
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Anti-CD20
H and E
Leder
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Chromosome Analysis

• Complex karyotype
• Inv(5) (q22 q31)
• Der (8) t(3 8) (t21 p21)
• 9
• 18
• 18
• Del (22) (q13) (CP3)/46
• XY 17

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Issues to Discuss

• Therapy of cold agglutinin disease
• Effect of plasmapheresis on rituxan

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Interpretation of Coombs Test
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Structure of Antibodies
IgG
IgM
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Diseases associated with Cold Agglutinin Disease

• Lymphoproliferative diseases
• Non-Hodgkins lymphoma (1 to 4 of patients)
• Waldenström macroglobulinemia
• CLL
• Infections
• Mycoplasma pneumonia
• Infectious mononucleosis

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Therapy for Cold Agglutinin Disease

• Avoid the cold (put the room at 82 degrees)
• Plasmapheresis
• 95 of IgM is intravascular
• Remove 80 of IgM with one plasmapheresis
• Short term efficacy
• Rituxan effective in 54
• Oral alkylating agents (chlorambucil, cytoxan)
• Glucocorticoids not usually effective
• Splenectomy
• Classically ineffective
• Effective in some patients with lymphomas with
  large spleens
• Treat underlying neoplasm

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Mechanism of Rituxan
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Response of Cold Agglutinin Disease to
RituximabSchollkopf et al. Leukemia and Lymphoma
47253, 2006
Patients with cold agglutinin disease (13
idiopathic, and 7 due to lymphoproliferative
disease) All get 4 doses of rituximab at 375
mg/m2 given once a week
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Berentsen et al. Rituximab forprimary chronic
cold agglutinin disease a prospective study of
37 courses of therapy in 27 patients.
Blood200410329258

• 37 courses of rituximab administered
  prospectively to 27 patients with primary chronic
  CAS.
• 14 of 27 patients responded to their first
  course of rituximab and 6 of 10 responded to
  re-treatment
• Overall response rate of 54.
• Responders achieved a median increase in
  hemoglobin levels of 40 g/L (4 g/dL)
• Median time to response was 1.5 months, and
  median observed response duration was 11 months

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Rituxan

• Best drug for cold agglutinin disease
• Effect of plasmapheresis?
• 145 kD protein with the constant region of human
  IgG and the variable region of a mouse anti-CD20
  antibody
• Affinity for CD20 of 8 nM
• Serum halflife of 76 hours (3 days) after the 1st
  infusion and 206 hours (9 days) after the 4th
  infusion
• Peak concentration of 500 ug/ml (3.44 microM)
  after the 4th dose
• The patients BM was still positive for CD20 cells
  at 24 hours after rituxan when blood was negative
  for CD20

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Are there more rapid therapies for Cold
Agglutinin Disease?

• Eculizumab anti-C5 antibody that blocks
  activation of C5 and completion of complement

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Complement-mediated Destruction of RBC
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Use of Eculizumab in Cold Agglutinin Disease Roth
et al., Blood 1133885-3886, 2009
Patient with idiopathic Cold agglutinin
disease Responded to rituxan initially Treated
with eculizumab with Some effect
Eculizumab was dosed at 600 mg intravenously
every 7 days for 4 weeks, at 900 mg 7 days
later, and then chronically at 900 mg every 14
days
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Reasons Eculizumab Solaris was not Used

• Haptoglobin was detectable after plasmapheresis
  in this patient
• Not on the hospital formulary
• Alexion would not give on a compassionate basis
• Costs 20,000 per dose

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Continued Cytoxan and Prednisone with Rituxan

• Beneficial effect of rituximab in combination
  with oral cyclophosphamide in primary chronic
  cold agglutinin disease Vassou et al., Int J
  Hematol. 2005 Jun81(5)421-3
• Prednisone at 40 mg could have a beneficial effect

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Therapy for Non-Hodgkins Large B cells Lymphoma

• R-CHOP
• Rituxan
• Cytoxan
• Adriamycin Hydroxydaunorubicin
• Vincristine Oncovin
• Prednisone

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Follow up

• Discharged with a Hb of 6
• 2 weeks later was doing well, with follow-up
  scheduled in Illinois