Submitting Author: Nakashima, Megan Okumoto, MD
Institution: Cleveland Clinic
Additional authors:Heesun J. Rogers, M.D., Ph.D.
Session: B Lymphoblastic Leukemia/Lymphoma

The patient is a 66 year-old woman with a history of “uterine cancer” treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy, brachytherapy, and external radiation therapy in 1998.

In November of 2010 she was diagnosed with follicular lymphoma, Grade 1-2 on a biopsy of a submandibular lymph node. At that time her disease was stage III. She was treated with bendamustine and rituximab, with improvement, but therapy was stopped after four cycles due to persistent neutropenia (March 2011).

Three months later (June 2011) she developed new axillary lymphadenopathy; biopsy showed diffuse large B-cell lymphoma (DLBCL) with translocations involving both BCL2 and MYC. She was treated with 6 cycles of R-CHOP, again requiring dose-reductions due to cytopenias (neutropenia, anemia and borderline thrombocytopenia). After 6 cycles (November 2011) she was clinically felt to be in complete remission, and was then initiated on bimonthly rituximab maintenance.

In late November 2012 she developed dyspnea on exertion, malaise, and spontaneous bruising, and CT scan demonstrated new lymphadenopathy in multiple mesenteric and retroperitoneal nodes. Complete blood count (11/30/2011) showed WBC 44.01 k/uL, Hgb 8.0 g/dL, platelets 6,000 /uL. Manual differential showed 93% atypical lymphoid cells with prominent nucleoli (Figure 1). Due to her history of DLBCL she was initially treated with ifosfamide, etoposide, and cytarabine. Flow cytometry performed on the bone marrow aspirate showed an immature B-cell phenotype and FISH studies were negative for BCL2 and MYC translocation.

A diagnosis of B lymphoblastic leukemia/lymphoma was rendered and vincristine and prednisone were added. She achieved remission on this regimen, confirmed by negative bone marrow biopsy and normal WBC without blasts, and is currently awaiting allogeneic bone marrow transplant.

The Wright-stained aspirate smear obtained from the posterior iliac crest shows an expansion of small to medium-sized blasts with high nuclear:cytoplasmic ratios, slightly basophilic cytoplasm, large round to convoluted nuclei, relatively finely clumped chromatin and visible nucleoli (Figure 2). No Auer rods are seen.

A posterior iliac crest core biopsy, fixed in zinc formalin and decalcified, shows a hypercellular marrow diffusely replaced by mononuclear cells with round to irregular nuclei and occasionally prominent nucleoli, consistent with blasts (Figures 3-6). Residual trilineage maturation is markedly decreased. A formalin-fixed aspirate clot section shows similar morphology.

Flow cytometry, bone marrow aspirate: 91% blasts (Figures 7 and 8)

Positive: CD19, CD38, CD45, CD65, CD123, TDT (dim, subset), HLA-DR

Negative: CD10, CD20, CD34, CD117, surface immunoglobulin light chains, cytoplasmic and surface IgM.

Immunohistochemical stains, bone marrow core biopsy: Blasts (Figures 9 and 10)

Positive: CD79a, PAX5, BCL-2, TDT (weak), cMYC (weak, 30% of blasts)

Negative: CD10, CD34, BCL-6, MUM1, surface immunoglobulin light chains, myeloperoxidase.

47,XX,+X,t(4;11)(q?21;q?23)[3] (figure 12)

B-cell clonality studies performed by polymerase chain reaction (BIOMED-2 primers) on DNA extracted from the bone marrow aspirate showed clonal rearrangement of IGH FR1, IGH FR2, and IGH FR3.

Fluorescence in situ hybridization (FISH) performed on the aspirate showed 11q23 rearrangement in 178/200 cells (89%) using an MLL dual-color, break-apart probe (Abbott Molecular, Abbott Park, IL; figure 11) confirming conventional karyotype.

FISH studies were negative for MYC (8q24) translocation (dual color, break apart probe, Abbott Molecular) and BCL2 (18q21) translocation (dual color, break-apart probe, Abbott Molecular).

This is an interesting case of a patient with follicular lymphoma which transformed to diffuse large B-cell lymphoma with BCL2 and MYC translocation (so-called “double-hit” lymphoma). Her lymphoma was treated with chemotherapy including alkylating agents (bendamustine, cyclophosphamide) and a topoisomerase II inhibitor (doxorubicin); she also had a remote history of pelvic irradiation. Approximately 2 years after her follicular lymphoma diagnosis (1 year after initiation of doxorubicin therapy), she developed new lymphadenopathy of mesenteric and retroperitoneal nodes and leukocytosis with increased atypical lymphoid cells. These atypical cells showed an immature B-cell phenotype including weak TDT positivity, but lacking CD10. FISH analysis and conventional cytogenetics demonstrated a balanced MLL translocation, but no translocations involving MYC or BCL2.

Therapy-related myeloid neoplasms are known to present in patients previously treated with alkylating agents and/or ionizing radiation and topoisomerase II inhibitors. The latter is often associated with balanced translocations including those involving MLL. Rare cases of therapy-related lymphoblastic leukemia have been reported, but are not as well-characterized as the myeloid neoplasms.

B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged, likely therapy-related

Therapy-related B-acute lymphoblastic leukemia/lymphoma, with t(4;11)(q?21;q?23); MLL rearrangement

Case 96