Bone Marrow Transplantation (2011) 46, 904–905
& 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11
www.nature.com/bmt
LETTER TO THE EDITOR
Failure of front-line autologous transplant in anaplastic lymphoma
kinase-positive diffuse large B-cell lymphoma
Bone Marrow Transplantation (2011) 46, 904–905;
doi:10.1038/bmt.2010.206; published online 6 September 2010
Anaplastic lymphoma kinase (ALK)-positive diffuse large
B-cell lymphoma (DLBCL) is an uncommon clinicopathological entity first described in 1997,1 although the actual
incidence may be significantly underestimated because of
the potential for confusion with plasmablastic lymphoma
or poorly differentiated carcinoma.2 The optimal therapy
for advanced disease is not known for this aggressive subset
of DLBCL. In this study we describe the challenges in the
diagnosis and treatment of a patient we recently treated for
ALK-positive DLBCL. Front-line autologous hematopoietic SCT with chemosensitive disease was inadequate for
disease control, highlighting the very aggressive nature and
poor prognosis of this subset of DLBCL.
Our patient, a 60-year-old man, presented with a mass at
the base of his tongue in 2005. The tongue mass was excised
and showed a plasma cell neoplasm composed predominantly of mature plasma cells (Figure 1a), although mitotic
figures were frequent (circle) and some areas showed
plasmablastic differentiation. Evaluation for a systemic
plasma cell disorder was negative. The patient was diagnosed
with extramedullary plasmacytoma and received radiation
with 50 Gy to the tongue base over a 5-week period in 25
fractions and 30 Gy to lymphatics in 15 fractions.
One year later, he developed severe low back pain and leg
weakness. Evaluation including magnetic resonance imaging (MRI) of the lumbar spine revealed numerous spine
metastases including L5 without cauda equina compression. Biopsy of L5 demonstrated a poorly differentiated
malignancy with cytologic features suggestive of metastatic
adenocarcinoma. The neoplastic cells were positive for
CD138, a marker that can be expressed in both carcinoma
and plasma cell neoplasms. There was no history of
carcinoma or clinical findings to suggest a primary site.
Because of his history of plasmacytoma as well as retroperitoneal lymphadenopathy visible on his lumbar spine
MRI, we performed positive emission tomography (PET),
which showed multiple hypermetabolic lymph nodes above
and below the diaphragm, intense activity in the spleen and
several additional bony hypermetabolic foci. A hypermetabolic right axillary lymph node was excised. The lymph
node demonstrated infiltration by large, immunoblast-like
cells with round nuclei and a single, central nucleolus
(Figure 1c). The atypical cells stained positive for CD45,
CD138, ALK, epithelial membrane Ag and MUM1
(multiple myeloma oncogene 1). FISH with a break-apart
probe to 2p23 showed separation of the ALK locus. With
this new information, we stained his previous tongue lesion
for ALK, which was diffusely positive (Figure 1b). Lactate
dehydrogenase (LDH) at this time was 383 U/L.
Given the worsening neurological symptoms, he received
corticosteroids and underwent urgent radiation of 36 Gy in
12 fractions to L5, followed by combination CHOP
chemotherapy. After six cycles of chemotherapy, only a
few hypermetabolic foci remained in his spleen. He
completed two more cycles of CHOP chemotherapy and
then proceeded with autologous hematopoietic SCT as
front-line therapy for chemosensitive disease. His initial
(diagnosis) marrow was negative for lymphomatous
involvement, as was his pretransplant marrow. He successfully mobilized 4.21 106 CD34 þ cells/kg after G-CSF
priming. After conditioning with BEAM, he was infused
with his collected stem cells and engrafted without serious
complications. His day-15 post transplant lymphocyte
count failed to reach 500 cells/mL, a negative prognostic
factor.3
Fewer than 100 days after his transplant, he developed
fevers, bone pain, hepatosplenomegaly and pancytopenia.
PET scan demonstrated dramatic hypermetabolic activity
in his marrow as well as in spleen and liver (Figure 2). His
LDH had risen to 5100 U/L. BM biopsy now demonstrated
near-replacement by ALK-positive DLBCL, now with
complex structural and numeric cytogenetic abnormalities
in all 20 metaphases examined. The abnormalities included
structural rearrangements of both chromosomes 2: the first
translocated an intact ALK gene region onto chromosome
15q; the second represented an apparently balanced
t(2;17)(p23;q23). Metaphase FISH verified ALK gene
disruption associated with this 2;17 translocation. The
t(2;17)(p23;q23) has been previously defined in DLBCL and
may indicate involvement of the CLTC (clathrin heavy chain)
gene.4 We attempted salvage with high-dose corticosteroids to
bridge him to other novel therapies; however, he did not
respond. He deteriorated rapidly, and LDH rose further to
15 200 U/L. The patient elected at this point to receive comfort
measures only and died 6 days after relapse diagnosis.
Our experience with this patient is congruous with
previous reports of this lymphoma subtype carrying a
dismal prognosis in the advanced stage setting. Therapeutic
options for aggressive lymphomas, including front-line
autologous transplant,5 may be inadequate for long-term
disease control and survival with ALK-positive DLBCL.
Conflict of interest
The authors declare no conflict of interest.
Letter to the Editor
905
a
b
Figure 2 Maximum intensity projection of F-18 fluorodeoxyglucose
positron emission tomography at relapse.
SG Holtan1, AL Feldman2, RA Knudson3, RP Ketterling3
and LF Porrata1
1
Department of Medicine, Division of Hematology, Mayo
Clinic Graduate School of Medicine, Rochester, MN, USA;
2
Department of Laboratory Medicine and Pathology,
Division of Hematopathology, Mayo Clinic Graduate School
of Medicine, Rochester, MN, USA and
3
Department of Laboratory Medicine and Pathology,
Division of Cytogenetics, Mayo Clinic Graduate School of
Medicine, Rochester, MN, USA
E-mail: [email protected]
c
Figure 1 Immunohistochemical staining. (a) Tongue lesion with tumor
cells showing mature plasmacytic differentiation but with frequent mitoses
(circle, hematoxylin and eosin (H&E),6 100). (b) Tongue lesion showing
tumor cells with plasmablastic differentiation with cytoplasmic ALK
staining ( 100). (c) Lymph node infiltrated with large immunoblast-like
cells (H&E, 40).
References
1 Delsol G, Lamant L, Mariame B, Pulford K, Dastugue N,
Brousset P et al. A new subtype of large B-cell lymphoma
expressing the ALK kinase and lacking the 2;5 translocation.
Blood 1997; 89: 1483–1490.
2 Laurent C, Do C, Gascoyne RD, Lamant L, Ysebaert L,
Laurent G et al. Anaplastic lymphoma kinase-positive diffuse
large B-cell lymphoma: a rare clinicopathologic entity with poor
prognosis. J Clin Oncol 2009; 27: 4211–4216.
3 Porrata LF, Inwards DJ, Ansell SM, Micallef IN, Johnston PB,
Gastineau DA et al. Early lymphocyte recovery predicts
superior survival after autologous stem cell transplantation in
non-Hodgkin lymphoma: a prospective study. Biol Blood
Marrow Transplant 2008; 14: 807–816.
4 De Paepe P, Baens M, van Krieken H, Verhasselt B, Stul M, Simons
A et al. ALK activation by the CLTC-ALK fusion is a recurrent
event in large B-cell lymphoma. Blood 2003; 102: 2638–2641.
5 Milpied N, Deconinck E, Gaillard F, Delwail V, Foussard C,
Berthou C et al. Initial treatment of aggressive lymphoma with
high-dose chemotherapy and autologous stem-cell support.
N Engl J Med 2004; 350: 1287–1295.
6 Gascoyne RD, Lamant L, Martin-Subero JI, Lestou VS, Harris
NL, Muller-Hermelink HK et al. ALK-positive diffuse large
B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Blood 2003; 102: 2568–2573.
Bone Marrow Transplantation