Download APL, isolated extramedullary relapse (small bowel)

Society for Hematopathology/
European Association for
Haematopathology
Case 211
Rachel Ochs, MD
Adam Bagg, MD
Hospital of the University of Pennsylvania
Philadelphia, PA
Clinical History - Presentation
• 41-year-old man, presented with pancytopenia
and disseminated intravascular coagulation in
June 2002
• Diagnosed with morphologically classical
hypergranular t(15;17)(q24;q12)–positive APL
• Metaphase cytogenetic studies in the bone
marrow were normal, but the PML-RARA fusion
was detected by both FISH and qualitative
reverse-transcription polymerase chain reaction
(RT-PCR)
Clinical History - Treatment
• All-trans-retinoic acid (ATRA) therapy was
initiated
– pt developed differentiation syndrome
• Induction therapy with cytarabine, daunorubicin,
and ATRA
– subsequent attainment of molecular and hematologic
remission
• Consolidation chemotherapy: idarubicin
alternating with mitoxantrone
Disease course
• 2004: Relapse, molecular only in bone marrow
– Treatment: Arsenic followed by autologous stem-cell transplant
• 2005: Relapse, peripheral blood and CNS involvement
– Treatment: ATRA, intrathecal cytarabine, and CNS radiation
– After the attainment of a second remission (by RT-PCR), he
underwent nonmyeloablative 9/10 allele-matched unrelateddonor stem-cell transplantation in March 2006
• 2006 (December): Relapse, bone marrow (morphologically
evident)
– Treatment: ATRA and donor lymphocyte infusion
– Molecular studies on bone marrow showed full engraftment for
15 months, as well as negativity for PML-RARA
Disease course (cont.)
• 2008: Presented with bowel obstruction and ascites,
found to have large small bowel mass
– Tandem peripheral blood engraftment studies showed
100% donor DNA, and bone marrow examination showed
no morphologic or cytogenetic evidence of disease
– RT-PCR (ascites fluid and peripheral blood) was positive for
a PML-RARA fusion
– Small bowel mass was resected
Extramedullary APL, small bowel (5X)
Extramedullary APL, small bowel (40X)
APL, ascites fluid
Gran
Mono
Lymp h
Bla st
CD45-
Flow cytometry, ascites fluid
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Gel electrophoresis following analysis with PML-bcr3 primer, lane 5, arrowed
Lane 1 = size markers; lane 10 = positive control for PML-bcr3; lane 11 = positive control for
PML-bcr1; lane 8 = non-specific band; all other lanes = negative specimens and negative controls
Proposed Diagnosis
• Acute promyelocytic leukemia, isolated
extramedullary relapse (small bowel) without
bone marrow involvement
Consensus Diagnosis
• Acute promyelocytic leukemia, with
t(15;17)(q24.1;q21.2), PML-RARA, involving
only small intestine (myeloid sarcoma) at
relapse
Extramedullary relapse:
Targeted therapy
• Extramedullary relapse (EMR) rates may be increasing in
the era of targeted therapy
• Possible causes:
– Patients are surviving longer
– Sanctuary sites in which ATRA and arsenic do not reach
therapeutic concentrations?
– ATRA and arsenic increase the expression of adhesion molecules
in leukemic cells (eg, CD11b, CD11c, CD18, and CD56), which
could allow those cells to access numerous different tissues
– ATRA may induce expression of multiple CC chemokines, which
may result in increased chemotaxis into tissues
– Differentiation syndrome allows leukemic cells to infiltrate
different organ tissues (known risk factor for EMR)
Extramedullary relapse:
Bone marrow transplant
• Suggested that graft vs. leukemia effect is more
potent in bone marrow, and may help suppress bone
marrow relapse more than extramedullary relapse in
patients with chronic GVHD
• CD8-positive T cells and natural killer cells are present in
higher numbers in BM than in EM tissues
• Patients with haplo-stem cell transplant may have higher
rates of extramedullary relapse (GVL effect elicited by HLA
disparity occurs preferentially in bone marrow?)
Follow-up
• Arsenic attempted as salvage therapy,
however there was disease progression and
the patient expired shortly (<1 month) after
presentation with granulocytic sarcoma