Myeloid/NK cell acute leukemia

Myeloid/NK cell leukemia is distinct entity, being different from the myeloid/NK cell precursor acute leukemia and blastic NK cell lymphoma/leukemia in morphology and immunotypes. The entity is a more mature state than the latter. We reported a typical case with presentation, immunology and cytogenetic results. The patient went to see a doctor with leucocytosis, anemia and thrombocytopenia. There are no superficial lymph nodes and splenohepatomegaly. The morphology of leukemia cells in bone marrow was similar to that of acute promyelocytic leukemia. The leukemia cells express CD13, CD33, CD15, and CD56, not expressing CD34, HLA-DR and CD16. No abnormal cytogenetics were found. The patients were given chemotherapy as acute myeloid leukemia, and got complete remission.     

Myeloid/Natural Killer Cell Precursor Acute Leukemia Accompanied by Homozygous Protein C Deficiency

A patient with myeloid/natural killer (NK) cell precursor acute leukemia who was also homozygous for protein C deficiency was treated and showed a complete remission while he simultaneously received low molecular weight heparin. He presented with fever spikes, lymphadenopathy, and a bulky tumor of the anterior mediastinum. A bone marrow aspirate showed the infiltration of immature lymphoblastoid cells. The patient's diagnosis was determined to be myeloid/NK cell precursor acute leukemia by morphologic and immunophenotypic analysis (CD7(+)CD33(+)CD34(+)CD56(+)). The patient developed a thrombosis in his jugular vein on cannulation of the internal jugular vein. An examination of the serum levels and the activities of proteins C and S demonstrated a slight decrease in the protein C level but an undetectable protein C activity. The patient received the diagnosis of homozygous protein C deficiency, because both parents were found to have heterozygous protein C activity. Treatment of the patient's leukemia included induction chemotherapy (Ara-C and idarubicin) with concomitant administration of low molecular weight heparin for his homozygous protein C deficiency. He achieved a complete remission without expressing any thrombosis during the course of chemotherapy. To our knowledge, this is the first case ever described in which acute myeloid leukemia was complicated with homozygous protein C deficiency.     

CD7(+) acute myeloid leukemia (M0) associated with a mediastinal bulky mass lesion

A 41-year-old man visited his doctor in May 2000 because of a sore throat and high fever. His symptoms did not improve, despite administration of antibiotics and nonsteroidal anti-inflammatory drugs. Since a chest X-ray examination revealed an anterior mediastinal bulky tumor, he was referred and admitted to our hospital on June 21, 2000. The peripheral white blood cell count was 44,540/microliter with 74% myeloblasts. Bone marrow aspiration revealed a hypercellular marrow with 82% myeloblasts, which were negative for peroxidase and alpha-naphthyl butylate esterase staining. Blast cells were positive for CD7, CD13, CD33, CD34, and HLA-DR, and negative for CD56. A needle biopsy specimen of the mediastinal tumor consisted of myeloblasts. We diagnosed the patient as having CD7 (+) acute myeloid leukemia (AML) (M0) with a bulky mediastinal mass based on the surface marker analysis, although the clinical features resembled myeloid/NK precursor acute leukemia. The patient achieved a complete remission after two courses of induction therapy. We are planning an allogeneic stem cell transplantation during his first remission because of the high risk of relapse.     

髓系／NK前体细胞急性白血病1例并文献复习

目的:提高对髓系/NK前体细胞急性白血病的认识.方法:报道1例髓系/NK前体细胞急性白血病资料,并复习文献,总结该病临床及实验室检查特点.结果:患者以腹部症状起病,肝脾显著肿大.流式细胞仪免疫表型分析HLA-DR( )、CD11c( )、CD11b( )、CD13( )、CD33( )、CD38( )、CD56( )、MPO( ).经两疗程CHOP方案化疗,骨髓象部分缓解,但是髓外浸润加重,后改用VDP方案,最终因出现感染、DIC、多器官功能衰竭而死亡.结论:急性NK细胞白血病具有独特的临床、组织病理学和免疫表型特征,对现有化疗不敏感,预后恶劣.     

CD56-positive acute lymphoblastic leukemia

We report a patient with lung cancer who developed CD56-positive acute lymphoblastic leukemia. He was referred to our hospital for thrombocytopenia. Atypical cells were found in the blood and the bone marrow. These cells were immunophenotypically positive for CD3epsilon, CD56, and terminal deoxynucleotidyl transferase, and negative for surface CD3, CD4, CD19, CD33, and myeloperoxidase. A small proportion of leukemic cells express CD13. There were no rearrangements of T-cell receptor (TCR)-beta, TCR-gamma, or immunoglobulin heavy chain. No Epstein-Barr virus was detected. Systemic examination did not detect any tumors other than pulmonary adenocarcinoma, and the patient was diagnosed as having acute natural killer (NK) cell leukemia. Chemotherapy was effective, and he achieved complete remission. The course of the disease was complicated by a lung abscess, and the patient died 3 months after the diagnosis. We considered that the diagnosis was blastic NK cell lymphoma/leukemia subtype. However, it actually was myeloid/NK cell precursor leukemia subtype that weakly expressed CD13.     

Transplantation of highly purified CD34+ progenitor cells from unrelated donors in pediatric leukemia

Unrelated donors are commonly used for hematopoietic stem cell transplants, but graft-versus-host disease (GVHD) is a major problem. We investigated whether transplantation of purified mobilized peripheral-blood CD34(+) stem cells from unrelated donors would prevent acute and chronic GVHD in pediatric patients with leukemia and avert the need for pharmacologic immunosuppression. Thirty-one pediatric patients with acute lymphoblastic leukemia (ALL, n = 16), acute myeloid (n = 7), chronic myeloid (n = 6), or juvenile myelomonocytic leukemia (n = 2) underwent transplantation. The median purity of CD34(+) cells after positive magnet-activated cell sorting was 98.5%. Patients received a median of 8.0 x 10(6) CD34(+) cells and 6 x 10(3) CD3(+) T lymphocytes per kilogram, with no posttransplantation pharmacologic immunosuppression. Primary acute GVHD > or = grade II was seen in only 10% of patients (n = 3) and occurred only after human herpesvirus 6 (HHV 6) infection. Two patients had limited chronic GVHD. Engraftment occurred in all patients (primary engraftment, n = 26; engraftment after reconditioning, n = 5). The 2-year survival estimate was 38% for all patients and 63% for patients with ALL in complete remission. Patients with myeloid malignancies had a poor outcome. In comparison to a historical control group who received unmanipulated bone marrow, our patients had a lower incidence of GVHD (P <.001). No difference was observed in the probability of relapse or survival. Study patients with ALL in remission showed a trend toward better survival (P =.07). Transplantation of purified peripheral-blood CD34(+) cells from unrelated donors effectively minimizes GVHD and may be a good therapeutic option for patients with relapsed ALL.     

CD7+ and CD56+ myeloid/natural killer cell precursor acute leukemia treated with idarubicin and cytosine arabinoside

We describe a 69-year-old Japanese male with acute leukemia with a CD7+ and CD56+ immunophenotype presenting with multiple lymphadenopathy. He was treated with idarubicin and cytosine arabinoside. Although the leukemia showed partial response, the patient did not achieve complete remission. He died of sepsis due to severe neutropenia after the third course of chemotherapy. His autopsy revealed blast infiltration in the lymph nodes, liver, spleen and vertebral bone marrow. Recently, CD7+ and CD56+ myeloid/natural killer precursor acute leukemia has been associated with a poor prognosis. Our case illustrates that myeloid/natural killer cell precursor acute leukemia shows some response to intensive chemotherapy for acute myeloid leukemia, but such therapy is insufficient to effect a cure. To overcome the resistance of this disease to chemotherapy, further studies should explore other treatment strategies.     

An unusual case of CD4+ CD7+ CD56+ acute leukemia with overlapping features of type 2 dendritic cell (DC2) and myeloid/NK cell precursor acute leukemia

Type 2 dendritic cell (DC2) acute leukemia has been recently described. We report here an unusual case of a 17-yr-old adolescent with overlapping features of DC2 and myeloid/NK cell precursor acute leukemia as defined by Suzuki et al. The patient presented with lymphadenopathy and hepatosplenomegaly without extranodal manifestations in skin or elsewhere. The morphologic, cytochemical and immunophenotypic features were compatible with those described in DC2 acute leukemia, with co-expression of CD4, CD56 and CD123 antigens. The novel markers BDCA-4 and BDCA-2 considered specific for DC2s were co-expressed. However, bright CD7 positivity along with a dim expression of CD33 (57%) and CD117 (27%) were also noted. Additionally, there was bright expression of NG2 monoclonal antibody 7.1, a frequent finding in myeloid/NK cell precursor acute leukemia. The interpretation of the immunophenotypic profile leads to the hypothesis on the existence of borderline cases between DC2 and myeloid/NK cell precursor acute leukemia. Still, other hypotheses can not be overlooked, such as the possibility for a kind of variant monoblastic leukemia or of another rare entity of acute unclassified leukemia.     

Myeloid/natural killer cell precursor blast crisis of chronic myelogenous leukemia with two Philadelphia (Ph-1) chromosomes

We report on a 30-year-old patient with blast crisis of a chronic myelogenous leukemia (CML) that shows immunophenotypic features similar to those of the myeloid/natural killer (NK) cell precursor leukemia previously described. Expression of CD13/CD33/CD65 as well as MPO+/LF- blasts was classified as a myelogenous blast crisis of a CML. In addition, the blasts were positive for CD7/CD56. Other lymphoid markers were not expressed. Cytogenetic and molecular cytogenetic examinations showed two Philadelphia (Ph-1) chromosomes and a trisomy 8. Similar to expression of the myeloid/NK cell precursor phenotype in acute myelogenous leukemia (AML), it is possible to exhibit this phenotype in Ph-1-positive CML. Only one case report of myeloid/NK precursor phenotype blast crisis of CML was found in the literature. Therefore, it is not clear whether this phenotype is a distinct biologic and clinical disease entity of CML, as is the case in the respective AML phenotype.     

Association of natural killer cell immune recovery with a graft-versus-leukemia effect independent of graft-versus-host disease following allogeneic bone marrow transplantation

 There is good evidence that T lymphocytes play an important role in the graft-versus-leukemia (GVL) effect following allogeneic bone marrow transplantation (BMT) for hematologic malignancies. However, the role of natural killer (NK) cells in GVL is less clear. To further investigate a possible association of NK cells with GVL we studied 15 patients undergoing BMT for chronic myeloid leukemia (CML), correlating T-cell (CD4+ and CD8+) and NK-cell (CD16+56+) recovery with relapse and graft-versus-host disease (GVHD). Patients were studied on three occasions up to 9 months after BMT, for lymphocyte surface phenotype and for spontaneous and IL-2-stimulated (LAK cell) cytotoxic function. Circulating CD8+ and NK but not CD4+ cell numbers were significantly lower in five patients who relapsed compared with those remaining in remission after BMT (mean 0.03 vs 0.32×10⁹/l, p=0.002 for CD8+ cells; mean 0.03 vs 0.11×10⁹/l, p=0.002 for NK cells). There was no correlation of CD4+, CD8+, or NK cell numbers and development of grade-II or more acute GVHD. Spontaneous NK cytotoxic function rose to within the normal range in the first month after BMT. LAK function remained low during the study period. These results link NK cell recovery more closely with a GVL than with a GVH effect. Received: 1 May 1996/Accepted: 19 September 1996     

Cyclosporine-induced autologous graft-versus-host disease in patients with acute myeloid leukemia undergoing non-myeloablative chemotherapy without progenitor cell reinfusion

To determine the incidence and severity of cyclosporine-induced graft-versus-host disease following non-myeloablative chemotherapy without progenitor cell reinfusion in patients with acute leukemia, 17 adults with refractory acute myeloid leukemia (14) or blastic phase of chronic myeloid leukemia (3) were treated with etoposide 2400 mg/m2 and cyclophosphamide 120 mg/kg followed by cyclosporine (CsA) 2.5 mg/kg i.v. daily and interferon gamma 0.025 mg/m2 subcutaneously every other day until day 28. Skin biopsies were obtained on days 14 and 28, or on the appearance of a skin rash, and graded for GVHD. Blood samples were examined at baseline and weekly starting on day 14 for natural killer (NK) cell and T cell lymphocytic changes. Post-treatment lymphocytes from select patients were assessed for allogeneic NK cell and autologous leukemic cell cytolytic activity. Four patients developed pathologic grade 2 cutaneous acute GVHD. Of the three patients who achieved a complete remission, two had evidence of GVHD. Post-treatment, three patients (two with GVHD) in whom adequate numbers of lymphocytes could be obtained showed NK cell cytolytic activity against allogeneic tumor cells (K562), but none had cytolytic activity against their own cryopreserved leukemic cells. These data suggest that in patients with AML treated with subablative doses of chemotherapy without autotransplant, autologous GVHD can be induced, although at an incidence lower than that reported for CsA-induced GVHD following marrow transplantation. An enhancement of T cell and NK cell activity levels similar to experiences in syngeneic models of autologous GVHD was seen, but no direct autologous leukemic cell cytotoxicity could be demonstrated.     

Blast crisis of chronic myelogenous leukemia exhibiting immunophenotypic features of a myeloid/natural killer cell precursor

We report a patient with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) which transformed into blast crisis bearing the immunophenotypic features similar to those of the myeloid/natural killer (NK) cell precursor leukemia we proposed previously. Using a CD45 blast gating method, the myeloperoxidase-negative blasts were positive for CD7, CD13, CD33, CD34, CD56, and HLA-DR, but no other lymphoid antigens. Southern blot analysis showed germ line T cell receptor beta and delta genes and immunoglobulin heavy and light chain genes. Although NK cell blastic transformation with Ph1 positive CML has been reported in a single patient, this is, to our knowledge, the first report of CML blast crisis of myeloid/NK cell precursor origin.     

Successful treatment of myeloid/natural killer cell precursor acute leukemia with allogeneic peripheral blood stem cell transplantation

We report a case of myeloid/NK cell precursor acute leukemia, which was successfully treated with allogeneic peripheral blood stem cell transplantation (allo PBSCT). A 31-year-old woman was admitted to our hospital with general fatigue, anorexia and leukocytosis. Bone marrow aspiration showed infiltration of many atypical blasts. She was diagnosed as having myeloid/NK cell precursor acute leukemia by morphological and immunohistochemical analysis. Complete remission was achieved by induction chemotherapy, but as myeloid/NK cell precursor acute leukemia is reported to have an extremely poor prognosis due to frequent relapse, the patient underwent allo PBSCT from her HLA-identical father, together with a myeloablative conditioning regimen. She suffered several transplantation-related complications including acute graft versus host disease (grade II) and ischemic enterocolitis associated with thrombotic microangiopathy, but these were overcome by supportive therapy. She was discharged on day 168 after allo PBSCT, and so far there has been no evidence of relapse during a follow-up period of 15 months.     

Acute myelocytic leukemia (M0) in an elderly patient with relapsed granulocytic sarcoma (M7) of bone during the second period of complete remission 5 years after onset]

A 75-year-old man was admitted because of right knee joint pain in December 1999. He had suffered from acute myelocytic leukemia (AML: M0) in November 1994 and achieved the first complete remission (CR) then. His AML relapsed in August 1996, but fortunately he achieved a second CR. Radiographical bone examination revealed osteolytic lesions in his right knee and bone scintigraphy showed uptake in the right knee and the middle part of the left femur. MRI also revealed a low attenuation signal in the left femur. He had no abnormal findings in peripheral blood or bone marrow. Histological examination of the biopsied bone tissue showed a diffuse proliferation of round cells with medium-sized or large nuclei. These cells were histochemistrically negative for myeloperoxidase and naphtol-ASD-chloroacetate esterase, and were also negative for lysozyme, cytokeratin 7, 9, 20, EMA, CEA, CD3, CD79a on immunohistochemistry, but were positive for CD43, CD56. In immunophenotypic analysis of these cells by flow cytometry, CD7, CD13, CD33, CD41, CD56 were revealed to be strongly positive. On the basis of these findings we diagnosed these tumors as granulocytic sarcomas (GS), extramedullary recurrence of AML M7. Although radiation (36Gy) to these tumors brought a temporary relief of the pain, he died of systemic relapse of AML in February 2001. When presented CD7+ AML M0 had been diagnosed, but GS cells were also positive for CD 56 and CD41. Although CD56 had not been examined initially, he might have been had myeloid/NK cell precursor acute leukemia and CD41 might be acquired later in the course of the disease. It is known that AML M0, M7 and myeloid/NK cell precursor acute leukemia have poor prognoses, nevertheless he survived for 6 years. It may be that intensive and repeated chemotherapy for AML can obtain excellent outcome in the elderly cases in good systemic condition and with favourable prognostic factors.     

Leukemia and lymphoma of natural killer lineage cells

Natural killer (NK) cells are lymphocytes with a large granular lymphocyte morphology, a CD3- CD56+ phenotype, a non-major histocompatibility complex-restricted cytotoxicity, and germline configuration T-cell receptor genes. NK cell lineage tumors originate from either precursor NK cells or mature NK cells. Tumors originating conceivably from precursor NK cells include myeloid/NK cell precursor acute leukemia, precursor NK cell acute lymphoblastic leukemia, and blastic NK cell lymphoma. However, because the developmental pathway of normal NK cells and the characteristics of these NK precursors are not fully understood, the definition and characterization of the tumors are only provisional. Tumors of mature NK cell origin include aggressive NK cell leukemia/lymphoma, nasal-type NK cell lymphoma, and chronic NK lymphocytosis, but the last disorder seems to be reactive in most cases. Because NK cell tumors are rare and difficult to manage, vigorous studies are required for their understanding and management.     

CD56+CD7+ stem cell leukemia/lymphoma with D2-Jdelta1 rearrangement.

OBJECT: We describe the characteristics of three patients with CD56+CD7+ stem cell leukemia/lymphoma. METHODS: These blasts were analyzed for morphologic, karyotypic, immunophenotypic, and immunogenotypic features using Southern blot and polymerase chain reaction analysis. MATERIALS: Peripheral blood, bone marrow aspirates, or biopsied mediastinal tumor specimens of three CD56+CD7+ stem cell leukemia/lymphoma patients were investigated. RESULTS: The bone marrow of all patients showed myeloperoxidase (MPO) negative blast cells with basophilic cytoplasm and distinct nucleoli with no azurophilic granules. The blasts of two patients were classified as acute lymphoblastic leukemia (L2). The liver, spleen, and lymph nodes were unaffected in all patients. All had an aggressive clinical course. The blasts were strongly positive for both CD7 and CD56 but negative for other T-lineage associated antigens, including CD1, CD2, surface membrane CD3, cytoplasmic CD3c (2/2), CD4, CD5 and CD8. The additional antigens were recognized as follows: CD19 (1/3 cases) as a B lineage, CD33 (1/3) as a myeloid marker, CD34 (2/3) as a stem cell, CD38 (1/1) and HLA-DR (2/3). When the patients relapsed, the phenotypes changed to blasts positive for CD5, CD10 and CD13 in patient 1, CD5 in patient 2, and CD33 in patient 3. MPO, however, remained negative. Cytogenetic analysis showed no common abnormal karyotype. All had a common D2-Jdelta1 induced by T-cell specific enhancer. Rearrangement of TCR beta and gamma genes occurred in patient 2, and IgH and TCR beta underwent rearrangement in patient 3. CONCLUSION: Although a more comprehensive case analysis is necessary, these data suggest the possibility that the blasts of the present cases come from a common lymphoid precursor (T, NK, and B cell) or from a NKT precursor as the fourth lymphoid lineage.     

Unrelated donor bone marrow transplantation for acute mixed lineage (myeloid and B-lymphoid lineage) leukemia in an adult with Down syndrome

This article describes a rare case of bone marrow transplantation (BMT) from an unrelated donor (URD) in an adult Japanese male with Down syndrome (DS) diagnosed as having acute mixed lineage leukemia. Examination of peripheral blood demonstrated WBC 6.2 x 10(9)/l with 45.5% blasts at admission. Leukemic blasts with positive peroxidase stain, but negative periodic acid-Schiff stain comprised 91.6% on bone marrow specimen. Surface marker analysis of these blasts showed the following: CD3(-), CD5(-), CD7(-), CD10(+), CD19(+), CD13(+), CD14(-), CD33(+), CD34(+), CD41a(-), and CD56(-). Based on these data, he was diagnosed as having acute mixed lineage (myeloid and B-lymphoid lineage) leukemia. He achieved complete remission (CR) by lymphoid-oriented chemotherapy performed after ineffective myeloid-oriented therapy. After four courses of consolidation chemotherapy for lymphoid lineage blasts, recurrence due to proliferation of myeloblasts had occurred. Thereafter, a second CR was obtained by low dose cytosine arabinoside (AraC) therapy. As this patient was considered to have a high risk of relapse, we selected allogeneic BMT from URD. Severe stomatitis due to methotrexate (MTX) occurred probably due to altered pharmacokinetics usually observed in DS patients. Though acute graft-versus-host disease (GVHD) of systemic skin (grade II) and pneumonia were observed during neutropenia due to the post-conditioning regimen, he could be discharged from our hospital on the 135th day after BMT. On day 205 post-BMT, however, bronchiolitis obliterans (BO) occurred as a chronic GVHD disorder. Despite therapy with prednisolone and FK506, he died on day 400 post-BMT because of respiratory failure due to BO. In DS patients, superfluous toxicities due to MTX and AraC treatment have been reported, and these toxicities have been considered due to altered pharmacokinetics in patients with DS. This patient could tolerate the transplant conditioning regimen commonly used in patients without DS.