Therapy-related T/myeloid mixed phenotype acute leukemia in a patient treated with chemotherapy for cutaneous diffuse large B cell lymphoma.
The patient is a 63-year-old woman with a history of diabetes and hypertension who, in 2008, presented with several large cutaneous lesions that on biopsy were consistent with primary cutaneous diffuse large B cell lymphoma (DLBCL). DLBCL represents 20 percent of primary cutaneous B-cell lymphomas and 4 percent of all primary cutaneous lymphomas. A staging work-up did not reveal bone marrow involvement or any other extracutaneous spread. General first-line therapy of CD20+ DLBCL consists of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The overall long-term survival rate is 40 percent. (3) Given the size and number of lesions and the poor prognosis of primary cutaneous DLBCL, the patient was treated with systemic chemotherapy, which consisted of 6 cycles of R-CHOP. She remained in clinical and radiological remission for 4 years. In 2012, the patient re-presented with shortness of breath, night sweats, and weakness; she denied fevers, chills, weight loss, or bruising. On physical exam, the patient was found to have palpable lymphadenopathy.
Labs were significant at this time for a hemoglobin of 6.8 g/dL (normal reference: 13.5-17.5 g/dL), platelets of 14,000/[micro]L (normal reference: 150,000-450,000/[micro]L), a white blood cell count of 7,600/[micro]L (normal reference: 4,500-11,000/[micro]L), lactate dehydrogenase of 582 units/L (normal reference 110-275 units/L), and uric acid of 7.4 mg/dL (normal reference: 3.5-7.0 mg/dL). Computed tomography of the chest, abdomen, and pelvis were significant for diffuse lymphadenopathy of the mediastinal, axillary, abdominal, and pelvic lymph nodes, the largest of which measured 3.3x2.1cm. The laboratory findings were concerning for recurrent lymphoma.
Peripheral blood smear review revealed circulating atypical mononuclear cells, the precise lineage of which was difficult to determine by morphology. Flow cytometry of peripheral blood revealed 10 percent CD34+ blasts with co-expression of CD117 and CD7, but negative expression of surface CD3. These findings were concerning for an acute leukemic process so a bone marrow biopsy and aspirate was performed. The bone marrow biopsy showed a hypercellular marrow (80-90 percent) replaced almost entirely by sheets of blasts, which accounted for 80-90 percent of the bone marrow cellularity (Figures 1A, 1B). By immunohistochemistry the blasts showed variable positivity for CD34, CD117, CD3, CD7, myeloperoxidase, and terminal deoxynucleotidyl transferase (TdT), consistent with a T/myeloid mixed phenotype acute leukemia (T/M-MPAL) (Figures 1C, 1D). The blasts were negative for CD5, CD20, and CD79a. The bone marrow aspirate smears were suboptimal; however, numerous medium to large sized mononuclear cells with round to irregular nuclei, finely dispersed chromatin, and prominent nucleoli consistent with blasts were seen. Flow cytometric analysis of the bone marrow aspirate showed an approximately 20 percent population in the blast gate positive for CD34, CD117, bright CD7, cytoplasmic CD3, and myeloperoxidase but negative for surface CD3, consistent with a T/M-MPAL (Figure 2); there was no immunophenotypic evidence of recurrent DLBCL. Cytogenetic studies on the aspirate material were notable for a 46, XX, t(8,12) (q22, p13) karyotype in all 20 metaphases examined with a normal AML/MDS FISH panel. Molecular analysis for nucleophosmin (NPM1) and Fms-Related Tyrosine Kinase (FLT3) mutations were negative. Four days after the bone marrow biopsy, an enlarged inguinal lymph node was excised to rule out the possibility of recurrent lymphoma not seen in the bone marrow. Flow cytometry of the inguinal lymph node revealed a 25 percent blast population with immunophenotypic findings similar to those seen in the bone marrow, consistent with involvement by a T/myeloid mixed phenotype acute leukemia. Histologic analysis of the lymph node showed intact architecture with an expanded paracortex consisting almost entirely of blasts forms immunohistochemically consistent a T/myeloid mixed phenotype acute leukemia. (Figures 3A-F). Given the findings seen in the peripheral blood, bone marrow, and inguinal lymph node, and the history of prior R-CHOP chemotherapy for primary cutaneous DLBCL, a diagnosis of therapy-related mixed phenotype acute leukemia (t-MPAL), T/myeloid, not otherwise specified (NOS) was rendered.
The patient was treated initially with induction with 7/3 Ara-C and Idarubicin. During treatment, the patient developed multiple complications including neutropenic fever with Urinary Tract Infection and shortness of breath. She underwent brocoscopy for evaluation of pulmonary consolidation that was negative for infection and malignancy. She also underwent thoracentesis. Pleural fluid cytology revealed atypical cells, which were immunophenotypically consistent with the patient's known diagnosis of T/M-MPAL by flow cytometry. At day 14, bone marrow was consistent with persistent disease. However, given the prior complications she did not undergo repeat induction. In addition, the patient did not undergo consolidation due to poor performance status. Eventually the patient was treated with decitabine as palliative therapy in a patient with poor performance status. She remained transfusion-dependent and continued to have a poor performance status. After 5 cycles of decitabine, the patient's bone marrow continued to show refractory disease. At that time, palliative care was chosen in favor of further chemotherapy.
Generally, acute leukemias can be classified as either lymphoid or myeloid based on the lineage of the blastic cells, but rarely blasts of both lineages can be present (so-called bilineage acute leukemias) or blasts can express antigens of more than 1 lineage (so-called biphenotypic acute leukemias). (4) In 2008 the World Health Organization combined bilineage and biphenotypic acute leukemias under the general classification of MPALs (7) MPAL comprises 2-5 percent of acute leukemia in all age groups, but it should be noted that the true incidence might not be known given the challenges of diagnosis and classification. (8) Cytogenetic abnormalities including complex karytotypes are seen in a third of cases of MPAL with certain cytogenetic alterations including t(9; 22)(q34; q11.2); BCR-ABL1 and 11q23 rearrangements defining specific MPAL subtypes. Cases of MPAL without specific cytogenetic abnormalities are classified as B/myeloid or T/myeloid, not otherwise specified (NOS), depending on the expression of T-lineage or B-lineage specific markers along with myeloid lineage specific markers. The overall prognosis of MPAL is poor, with a median survival of 11- 18 months in adults. (4) MPAL, T/myeloid, NOS represents approximately a third of MPAL and comprise less than 1 percent of all leukemias. Diagnosis is generally made by demonstrating dual expression of T-lineage and myeloid lineage specific markers, in particular cytoplasmic CD3 and myeloperoxidase. FLT3 mutations are often associated with MPAL, T/myeloid, NOS, which gives hope for targeted treatment with FLT3 inhibitors. (4) In general, MPAL, T/myeloid, NOS is more common in children than in adults. (8)
No specific genetic finding is specific to MPAL, T/myeloid, NOS; however, non-specific abnormalities including deletions of 5q, 6q, and 12p (as noted in the present case) can be seen. (8) Abnormalities of chromosome 12p have also been identified in 5 percent of cases of acute nonlymphocytic leukemias (ANLL) and myelodysplastic syndromes (MDS). 12p abnormalities have been associated with prior exposure to mutagenic compounds, and are often associated with a poor prognosis. An ETV6 gene was recently described on 12p13 that has been implicated in leukemogenesis. Therapy-related leukemia is often associated with 12p abnormalities. (6)
Therapy-related acute leukemias are usually myeloid (AML), with acute lymphoblastic leukemia (ALL) being less common. Therapy-related MPAL (t-MPAL) are extremely rare: a review from 2011 reports only 3 other known cases of t-MPAL secondary to chemotherapeutic agents. Therapeutic agents used in these cases included cyclophosphamide, methotrexate, 5-florouracil, cisplatin, etoposide, bleomycin, doxorubicin, and radiation. Therapy-related acute leukemias in general have been attributed to topoisomerase II inhibitors and alkylating agents. (1) Patients with therapy-related acute leukemias from alkylating agents generally show a latency of 3-7 years from exposure to the alkylating agent and often have an insidious course, with the development of MDS prior. In contrast, patients with therapy-related acute leukemias from topoisomerase II inhibitors generally have a latency of 2-3 years and present more acutely, without MDS prior. (5) Therapy-related mixed phenotype acute leukemia, T/myeloid, NOS has been described in one patient with multiple sclerosis treated with Mitoxantrone. (2)
At the time of this writing, there is currently no consensus on the most appropriate therapy for MPAL. Some studies suggest protocols for AML, while others treat as ALL. There is no consensus for the appropriate induction or consolidation regimens for either protocol in MPAL. (8)
We have presented a case of t-MPAL T/myeloid, NOS likely secondary to cyclophosphamide and/or doxorubicin in a patient who received R-CHOP chemotherapy for primary cutaneous DLBCL four years prior. To the best of our knowledge, this is only the second case of therapy-related mixed phenotype acute leukemia, T/myeloid, NOS and the first associated with RCHOP. To the best of our knowledge, the only other reported case of therapy-related mixed phenotype acute leukemia, T/myeloid, NOS occurred in a patient with multiple sclerosis treated with Mitoxantrone; no cases of therapy-related mixed phenotype acute leukemia, T/myeloid, NOS associated with chemotherapy in cancer patients have heretofore been reported. Our patient is also unique in that she is an older adult with a diagnosis of mixed phenotype acute leukemia, T/myeloid, NOS; mixed phenotype acute leukemia, T/myeloid, NOS is more common in children. Finally, our patient exhibited an abnormal karyotype of 46, XX, t(8,12) (q22, p13). To the best of our knowledge, this karyotype has not yet been described in the literature for patients with mixed phenotype acute leukemia, T/myeloid, NOS.
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(2.) Estey E, Donner, H. Acute myeloid leukemia. Lancet 368:1894-1907.
(3.) Mauritzon N, Albin M, Rylander L, Billstrom R, Ahlgren T, Mikoczy Z, Bjork J, Atromberg U, Nilsson PG, Mitelman F, Hagmar, L, Johansson B. Pooled analysis of clinical and cytogenic features in treatment-related and de novo adult acute myeloid leukemia consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 19742001. Leukemia 16:2366-2376.
(4.) Michelis SD, McKenna RW, Arthur DC, Bruning RD. Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases. Blood 65:1364-1372.
(5.) Pedersen-Bjergaard J, Christiansen DH, Desta F, Andersen MK. Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. 2002 Leukemia 20:1943-1949.
(6.) Rowley JD, Olney HJ. International workshop on the relationship of prior therapy to balanced chromosome aberrations in therapy-related myelodysplastic syndromes and acute leukemia: overview report. Gene Chromosome Canc. 2002; 33:331-345.
(7.) Singh ZN, Huo JD, Anastasi J, Smith SM, Karrison T, LeBeau MM, Larsen RA, Vardiman, JW. Therapy-related myelodysplasric syndrome: morphologic subclassification may not be clinically relevant. 2007 Am J Clin Path. 127:197-205.
(8.) Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater R. 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. 2002. Gene Chromosome Canc 33:379-394.
Dr. Roberts and Dr. Schmieg are associated with the Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA . Dr. Oncale is associated with the Department of Medicine, Tulane University, New Orleans, LA. Dr. Safah is associated with the Department of Oncology and Medical Hematology, Tulane University, New Orleans, LA.
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|Author:||Roberts, Evans, III; Oncale, Melody; Safah, Hana; Schmieg, John|
|Publication:||The Journal of the Louisiana State Medical Society|
|Article Type:||Clinical report|
|Date:||Jan 1, 2016|
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