Treatmentrelated AML associated with balanced chromosome translocations

1
Treatment-related AML associated with balanced
chromosome translocations

• Amanda F. Cashen, M.D.
• May 26, 2006

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Patient Presentation

• 50 yo man with h/o MS was found to have WBC
  30,700 with circulating blasts.
• Initially presented June 2000 with several months
  of progressive arm numbness. Treated with Avonex
  (i.m. interferon ß1a).
• Symptoms progressed (diffuse numbness, fatigue).
  Started prednisone 3/02 with some improvement.
• 9/02, leg pain and right leg weakness. Given MP
  iv x 3d with only transient improvement.
• 1/03, daily pain, problems using keyboard. Felt
  to be in remission but with at least 3 relapses
  in past year. Started mitoxantrone.
• Mitoxantrone 12 mg/m2 q3mo x 4 then 5 mg/m2 q3mo
  x 2 (last dose 6/04)
• MRI 12/03 showed no new lesions and improvement
  in cervical and thoracic spinal cord
• Rebif (s.c. interferon ß1a) added 12/03.

3

• 10/24/05, presented to neurologist with c/o leg
  and low back pain, low grade fevers, bleeding
  from gums.
• WBC 30,700 /µl (68 blasts, 4 neutrophils), Hgb
  9.7 g/dl, platelets 15,000 /µl? admitted to BMT
  service
• PMH MS
• Meds Tylenol 3, Rebif 44 mcg sc tiw
• FH 3 sibs, father died of lymphoma
• SH married with 2 children, school
  superintendent
• PE no LAD or HSM, no bruising or rash CN
  intact, strength 4/5 L leg, 5/5 other limbs

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Initial Labs

• WBC 30.8 (72 blasts, 25 lymphs, 3 monos)
• Hgb/Hct 9.4/26.6
• Plt 15
• MCV 94
• CMP WNL
• LDH 736
• Fibrinogen 512
• PT/PTT WNL
• LVEF 64

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Hospital Course

• Bone marrow biopsy
• gt90 cellularity, 94 blasts
• AML-M1 (CD34, CD13, CD33, CD117)
• Started induction with cytarabine and idarubicin
  (73)
• Day 14 bone marrow negative for residual disease
• Cytogenetics t(821) in all metaphases

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• Day 37 marrow 20 cellularity, 1 blasts
  extensive marrow necrosis worrisome for
  recurrent/persistent disease, small amount of
  recovering hematopoiesis
• Cytogenetics t(821) in 2/20 metaphases t(45)
  in 1/20 metaphases
• FISH t(821) in 6.5 of nuclei
• 1/1/06, salvage with mitoxantrone/etoposide/ara-c
• 2/10/06, WBC 10.1 with 27 blasts
• 2/20/06, allo PBSCT from his sister, TBI/VP16/Cy
  conditioning
• ORSA sepsis post-transplant, mucositis, rash
  treated empirically with steroids
• Day 34 BM normal hematopoiesis, normal female
  karyotype, FISH for t(821) negative
• Day 88 BM hypocellular, normal hematopoiesis

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Mitoxantrone for MS

• Approved in 2000 for the treatment of
  relapsing-remitting and progressive MS
• Phase III multicenter, double-blind, placebo
  controlled trial in 188 patients with RRMS (50)
  or SPMS (50) Lancet 20023602018
• Treated with mitoxantrone 12 mg/m2 or 5 mg/m2
  q3mo x 2 yrs vs. placebo (methylene blue)
• Primary outcome was composite of 3 measures of
  disability, time to first attack requiring
  steroids, and median time to first attack
• Outcome of composite measure was better in the
  high-dose arm compared to placebo (plt0.0001)
• Change in MRI lesions was not different between
  groups
• Recommendation from the American Academy of
  Neurology Because mitoxantrone has modest
  clinical benefit and significant toxicity (esp.
  cardiac), mitoxantrone should not be used in
  preference to other immunomodulatory agents in
  the treatment of MS. Neurology 2003611332

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AML in patients treated with mitoxantrone

• In oncology series, patients treated with
  mitoxantrone have an incidence of t-AML of
  0.5-7.
• Case reports in patients with MS

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AML in MS patients treated with mitoxantrone

• From published case reports, incidence of t-AML
  in MS patients treated with mitoxantrone is 0.21
  (five in 2336 patients).
• Of 1378 pts treated with mitoxantrone in the
  three MS studies (mean cumulative dose of 60
  mg/m2 and mean follow-up of 36 months), one
  patient had t-AML, an observed incidence
  proportion of 0.07 95 confidence interval
  (CI)0.00 - 0.40. There were no cases of t-AML
  in published reports of nine additional studies
  of single-agent mitoxantrone therapy for MS.
  Multiple Sclerosis, 20028441-5

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Cytogenetics characteristic of t-MDS/AML

• Loss of 5q, 7q, or monosomy 5 or 7
• Characteristic of previous therapy with
  alkylating agents (latency of 3-6 years,
  preceding MDS)
• Poor prognosis, resistant to therapy
• Abnormalities of 7 are most common, often present
  with other abnormalities (t(321) is
  characteristics of t-MDS)
• Abnormalities of 5 usually have multiple other
  cytogenetic abnormalities, mutations of p53 are
  common.

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Cytogenetics characteristic of t-MDS/AML

• Balanced translocations
• Occur in 30 of t-AML cases
• Associated with prior therapy with a
  topoisomerase II inhibitor
• Present with overt AML
• Shorter latency (6 mo-5 years)
• Translocations involving 11q23 (MLL)
• Respond to antileukemic therapy but outcome is
  poor due to relapse
• Core binding factor AML t(821) and inv(16)
• Rare (t(821)? 3.4 of t-AML cases in literature)
• Best results with antileukemic therapy
• t-APL
• Respond to antileukemic therapy ATRA
• Normal karyotype
• 10-15 of patients with t-AML
• Present with overt AML
• Not a/w specific prior treatment

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Blood 2002991909
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Therapy-related AML with t(821), inv(16), and
t(816) A report on 25 cases and review of the
literature JCO,1993112370

• 26 patients with t(821) described
• Prior heme malignancy in 12, solid malignancy in
  14
• Median interval between prior cancer and t-AML
  was 33 mo. (9-120)
• 3 patients had an MDS phase
• 21 pts were treated with intensive antileukemic
  therapy
• 76 CR
• DFS 47 at 24 mo.

of cases
14
International Workshop on Balanced Chromosome
Aberrations in t-MDS and t-AL Genes,
Chromosomes, Cancer,200233

• Data on 511 patients with t-AL or -MDS a/w
  balanced chromosome translocations

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International Workshop on Balanced Chromosome
Aberrations in t-MDS and t-AL

• Prior therapy
• gt50 had received prior RT and CT
• 30 of t(1517) and 21 of inv(16) cases had
  received RT alone

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International Workshop on Balanced Chromosome
Aberrations in t-MDS and t-AL

• 11q23 group
• Contained the cases of t-ALL (12/13 cases had
  t(411)
• 12 t-MDS
• Shortest median latency (26 mo.)
• Lowest median age (b/c primary disease was ALL in
  16)
• A/w prior exposure to topoisomerase II inhibitors
• Median survival 7 mo.

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International Workshop on Balanced Chromosome
Aberrations in t-MDS and t-AL

• 21q22 group
• Translocations involved 8q22 (56), 3q26 (20),
  16q22 (5) and others
• 80 of t(821) and 37 of t(321) presented with
  t-AML
• t(321) was a/w more prior therapy and -7
• A/w prior exposure to topoisomerase II inhibitors
• Intermediate survival

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International Workshop on Balanced Chromosome
Aberrations in t-MDS and t-AL

• inv(16)/t(1517) group
• inv(16) short latency and long survival (45 at
  5 years) 85 CR rate
• t(1517) median survival 29 mo. 69 CR rate
• Best overall survival

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Summary

• t-AML is very rare in reported series of MS
  patients treated with mitoxantrone, but follow-up
  to-date is short.
• Balanced chromosomal translocations occur in a
  minority of t-AML cases and are associated with
  prior topoisomerase II exposure.
• Median survival is short for patients with
  translocations involving 11q23 (MLL).
• inv(16), t(1517), and t(821) have a generally
  good prognosis.