Presentation Of Chronic Myeloid Leukemia Research Articles

Single Center Experience with Philadelphia Chromosome-Positive Acute Myeloid Leukemia.

Background: Rare instances of Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) have been reported, constituting <1% of de novo cases. However, differentiating these cases from chronic myeloid leukemia presenting in blast phase (CML-BP) has proven difficult. Several clinical and pathologic criteria have been proposed to distinguish Ph+ AML from CML-BP, including absence of an antecedent hematologic disorder, lack of evidence of a chronic or accelerated phase of CML after induction therapy, infrequent splenomegaly and peripheral eosinophilia or basophilia, and bone marrow characteristics such as lower cellularity, basophilia, and myeloid:erythroid ratio.Methods: We searched the M.D. Anderson Cancer Center leukemia database to identify all pts that had been diagnosed with Ph+ AML by cytogenetic analysis, between 1980 and 2006. Clinical, laboratory, and hematopathologic data were reviewed in order to separate them into the following groups: Ph+ AML, CML-BP, acute biphenotypic leukemia, and indeterminate. The following scoring system was employed: 1 point (splenomegaly), 1 point (peripheral eosinophilia and/or basophilia), 1 point (bone marrow basophilia or additional copy of Ph+ chromosome or trisomy 8 or isochromosome17). Zero points was classified as Ph+ AML, 1 point as indeterminate, and 2–3 points as CML-BP. If there was evidence of an antecedent or post-remission chronic or accelerated phase, these cases were identified as CML-BP.Results: 31 patients (pts) were identified: 7 (23%) acute biphenotypic leukemia, 11 (35%) CML-BP, 9 (29%) Ph+ AML, and 4 (13%) indeterminate. Among the 9 pts with Ph+ AML the median age at diagnosis was 50 years (range, 35–76), initial white blood cell count 50 (range, 4–210), peripheral blast 64% (range, 0–96), and bone marrow blast 78% (range, 34–98). 7/9 (78%) pts had additional cytogenetic abnormalities apart from t(9;22)(q34;q11), most commonly deletion 7 (n=3). A variety of induction chemotherapy regimens were employed, including cytarabine based (n=6), gemtuzumab ozogamicin-based (n=2), anthracycline based (n=1), and with the addition of imatinib (n=1). 5/9 (56%) pts classified as Ph+ AML achieved a CR or CRp, 3 (33%) died during induction, and 1 (11%) was refractory. 3/5 pts that achieved remission relapsed, with a median CR duration of 35 weeks (range, 20–42) and median OS 58 weeks (range, 55–61). Stem cell transplant was employed in 2 pts, one refractory to induction therapy who died 34 weeks later and one transplanted in CR and alive at 56 weeks; this is also the only pt to be treated with imatinib, as part of induction therapy. The median overall survival for pts classified as Ph+ AML was 34 weeks (range, 2–64) and similar to that of pts reclassified as CML-BP, which was 64 weeks (range, 11–271) (p=0.15).Conclusion: Ph+ AML represents a rare entity that may be mistaken for de novo CML-BP. Herein, we propose a system to help with this differentiation. Clinical outcome is poor with conventional chemotherapy and combinations based on tyrosine kinase inhibitor-based therapy should be investigated.

Rituximab associated to imatinib for coexisting therapy-related chronic myeloid leukaemia and relapsed non-Hodgkin lymphoma

Philadelphia positive (Ph+) chronic myeloid leukaemia (CML) presenting synchronously or following non-Hodgkin lymphoma (NHL) has only rarely been reported. Herein, we refer on a case of Ph+ CML occurring after a breast cancer and a NHL with multiple relapses. After obtaining complete cytogenetic remission with imatinib, the patient presented a new NHL relapse, that was treated with rituximab concomitantly to imatinib. Therapy was well tolerated and the patient is presently alive in complete remission of either NHL and CML. We also reviewed the literature relating the uncommon association of these two unrelated diseases.

Megakaryocytic blast crisis as first presentation of chronic myeloid leukemia

We describe an extremely rare case of megakaryocytic blast crisis as first presentation of chronic myeloid leukemia. The patient had a very high platelet count and developed an ischemic stroke with seizures. She was treated with hydroxyurea, platelet apheresis, ARA-C, and idarubicin in order to obtain a prompt reduction of thrombocytosis and then with imatinib 600 mg/die PO. The therapy induced a complete hematological remission with a resolution of neurological signs within 4 weeks.

Ph'-Positive (Ph'+) Chronic Myeloid Leukemia (CML) Presenting as Ph'+ T-Lymphoblastic Lymphoma (LL) Resistant to High-Dose Chemotherapy and Gleevec.

BACKGROUNDExtramedullary blast crisis (BC) of Ph'+ CML is infrequent and commonly affects bone, lymphoid tissue, skin and soft tissues and central or peripheral nervous system. Most of nodal lymphoid tumors occuring in the setting of CML derive from T-cell precursors and represent the evolution of CML to a lymphoid nodal BC.CASE HISTORYIn February 2004, a 52 year-old patient underwent diagnostic wide biopsy of a nasopharingeal mass that caused severe acute respiratory symptoms. At the histological examination, the nasopharyngeal mucosa exhibited a diffuse pattern of infiltration by neoplastic cells with a characteristic single-file arrangement. The cells showed typical convoluted nuclei with one or two nucleoli and abundant cytoplasm (L2, lymphoblasts). The malignant cell population expressed a preT-cell immunophenotype: cytoplasmic CD3(+), CD43 (+), TdT (+/−), CD34(+), CD4(−), CD8(−). Thus, the diagnosis of T-cell LL was formulated. Whole-body CT scan revealed nasopharingeal mass, retropharyngeal, laterocervical, axillary, inguinal enlarged nodes and splenomegaly. Laboratory tests indicated leukocytosis (58,000/μl) with a differential WBC count typical of CML in chronic phase (myeloblasts <1%). This diagnosis was confirmed by a low alkaline phosphatase value (score: 1), histological features of bone marrow (BM) biopsy, classical cytogenetics (presence of the Ph' in 100% of 25 metaphases analysed and absence of other cytogenetic abnormalities) and FISH evaluation (D-FISH bcr-abl in interphase and metaphase, Oncor probe). The nested RT-PCR (JQ Guo et al., Leukemia ; 2002, 15:2447) disclosed the presence of the hybrid protein p210 (b2,a2), but not that of p190. A laterocervical node was excised to perform cytogenetic and molecular analyses in order to determine whether the T-cell LL was an unrelated disease or the expression of an extramedullary BC. The histology confirmed the presence of a uniform population of T-lymphoblasts in which classical cytogenetic analysis disclosed the following kariotype: 49,XY,t(9;22)(q34;q11),+9,+19,+der(22)t(9;22)(q34;q11) and 50–52,XY t(9;22)(q34;q11),+6+9,+9q+,+19,+20,+22q−. The FISH analysis showed the presence of bcr-abl gene in all cells analyzed and the presence of multiple copies of this gene as well as of double Ph' chromosome. Nested RT-PCR showed the presence of both p210 and p190 transcripts. These findings indicated that the T-cell LL was an extramedullary BC of a CML simultaneously diagnosed in chronic phase in BM and peripheral blood. The patient was initially treated with vincristine, daunomicine, asparaginase and prednisone combined with Gleevec (800mg/die). Consolidation therapy, consisting of high-dose Ara-C (4g/m2 for 4 days) and mithoxantrone (10mg/m2 for 2 days), followed by a mieloablative course with mithoxantrone (60 mg/m2) and melphalan (180 mg/m2) and autologous stem cell support (ASCT) was administered after an initial clinical response. Gleevec was given during the entire treatment period. A fugacious complete clinical-hematological and a partial cytogenetic (FISH: 12% of cells bcr-abl+) and molecular (number of bcr-abl/104 ABL copies= 184, real-time quantitative RT-PCR: J Gabert et al., Leukemia ; 2003:1) remission was documented after ASCT. The patient refused further consolidation treatment with Gleevec and died, due to progressive disease, in December 2004.

Chronic Myeloid Leukemia in an Adolescent with Ollier's Disease after Intensive X-Ray Exposure

We report a 19-year-old man with Ollier's disease with multiple orthopedic procedures performed for leg length discrepancy; who developed chronic myeloid leukemia presenting with intramuscular hematoma. His symptoms resolved with cytoreductive treatment by hydroxyurea. Cytogenetic and molecular investigations showed a complex Philadelphia translocation t(9;22;13) (q34;q11.2;q12), with predominance of e1a2 BCR/ABL splicing and deletion of reciprocal der(9) ABL/BCR locus, all suggesting poor prognosis. The cumulative X-ray exposure from repeated operations from the age of 7 to 12 years was estimated to be around 16 mSv, approximately the dose of 720 chest X rays. Literature review showed two other cases of leukemia occurring in patients with multiple enchondromatosis. Although the development of CML in this young patient might be related partly to genetic defects, the repeated radiation exposure, especially at young age and directly on the marrow tissue in the long bones, might also be an important pathogenetic factor.

Chronic myeloid leukemia presenting with absence of basophils and marked dyspoiesis

A 61-year old woman presented to us with fever, weakness and ecchymotic patches for one year. She had leucocytosis, anemia and thrombocytopenia. Peripheral blood smear showed 62% neutrophils, 32% myelocytes and metamyelocytes, 2% promyelocytes, 1% blasts, 2% monocytes, 1% lymphocytes but no basophils and marked dyspoiesis. Bone marrow picture was essentially the same. A diagnosis of atypical chronic myeloid leukemia was suggested. The correct diagnosis of chronic myeloid leukemia-accelerated phase was, however, made on cytogenetic analysis which showed Philadelphia chromosome (Ph) and isochromosome 17q [i(17q)]. This case describes a rare and diagnostically difficult presentation of CML arising out of a combination of prominent dyspoiesis and near absence of peripheral blood basophils.

Chronic Myeloid Leukaemia Presenting as Traumatic Haemoperitoneum and Duodenal Injury

A 13-year-old boy presented with an acute abdomen after a dubious blunt abdominal injury. Evaluation at the accident and emergency department revealed the presence of haemoperitoneum. CT scan and a subsequent duodenography confirmed an accompanying duodenal hematoma and splenomegaly, but no solid organ injury was detected. As the child remained haemodynamically stable, a conservative management was adopted. Leucocytosis and thrombocytopenia were found on further investigation, which led to a final diagnosis of Philadelphia chromosome positive chronic myeloid leukaemia. We speculate that the underlying haematological malignancy in this case might have contributed to the florid intra-abdominal signs of injury. A careful search for a systemic illness would be useful in the management of childhood abdominal trauma, especially when the account of injury is dubious or apparently trivial.

Philadelphia Negative BCR-ABL Positive Chronic Myeloid Leukemia Mimicking Juvenile Chronic Myeloid Leukemia in a 2-year-old Child

We present the case of a two-year-old child with an atypical presentation of chronic myeloid leukemia. At diagnosis, he showed clinical and biological features of juvenile chronic myeloid leukemia (CML). However, eosinophilia was observed in blood and bone marrow. The bone marrow karyotype did not demonstrate the Philadelphia chromosome but BCR-ABL rearrangement was shown to be present by reverse transcriptase polymerase chain reaction (RT-PCR) analysis and confirmed by fluorescent in situ hybridization (FISH) analysis. Discussion centres on the differentiation between juvenile CML and childhood chronic myel-ogenous Leukemia and the importance of carrying out RT PCR for all juvenile CML cases.

Alloreactive CD4+ T lymphocytes can exert cytotoxicity to chronic myeloid leukaemia cells processing and presenting exogenous antigen

Existing evidence supports that CD4+ T lymphocytes play a role in the graft-versus-leukaemia (GVL) reaction after allogeneic bone marrow transplantation (BMT) for chronic myeloid leukaemia (CML), not only as initiators of the immune response but also as effectors of GVL. In BMT between HLA-identical pairs this CD4-mediated GVL would require CML cells to process and present antigens through MHC class II molecules. To investigate whether CML cells are capable of processing and presenting antigens, and suitable targets for CD4+ T-cell-mediated cytotoxicity, we generated HLA-DR1-restricted CD4+ cytotoxic T-cell clones that specifically recognized tuberculous purified protein derivative (PPD). We have shown that CML cells and B lymphoblastoid cell line (B-LCL) cells but not PHA-blasts from patients with CML processed exogenous antigen, PPD, and induced proliferative and cytotoxic CD4+ T-cell responses. Antigen presentation was blocked by antibodies to HLA-DR but not to MHC class I and by treatment with chloroquine and brefeldin. This indicates that CML cells use a classic MHC class II antigen processing pathway to present PPD antigens to CD4+ T cells. Cytotoxicity to CML was shown by antibody blocking studies to be mediated mainly through fas antigen. These findings indicate that donor CD4+ T cells alone are sufficient to mediate GVL effects following allogeneic BMT for CML.

Accelerated phase of chronic myeloid leukemia presenting as pericardial extramedullary hematopoiesis

Accelerated phase of chronic myeloid leukemia presenting as pericardial extramedullary hematopoiesis

Prognosis of Chronic Myeloid Leukemia: Studies from the Barcelona Group

Individual and multicenter efforts have facilitated the recognition of different parameters with prognostic value at presentation of chronic myeloid leukemia (CML). Interest is currently focused on the prognostic evaluation of features obtained from molecular analysis, and isolation of data with evolutive predictive value. The site of breakpoint within the M-BCR has been suggested as a prognostic factor in some studies. A recent analysis from our group failed to demonstrate differences in either duration of chronic phase or survival between patients with 5' and 3' breakpoints. We have confirmed in a sequential study that a decrease in the expression of some myeloid differentiation antigens of the blood granulocytes can be a prognostic indicator along CML evolution. Our more recent study, separating blast crises on immunological and molecular grounds, confirms lymphoid cases as a distinct subgroup and shows a trend for an association between megakaryoblastic blast crisis and 3' location of the breakpoint.

Atypical Ph negative chronic myeloid leukaemia presenting as sudden profound deafness.

A patient with atypical Ph negative chronic myeloid leukaemia presented with the sudden onset of profound deafness. He survived only eight months. Detailed histological investigation performed at necropsy showed loss of ganglion cells and afferent nerve fibres in the cochlea and vestibule associated with extensive fibrosis and new bone formation in the labyrinthine spaces. Both leucophoresis and high dose chemotherapy capable of rapid cytoreduction are recommended in patients with chronic myeloid leukaemia with profound hearing loss, as conventional chemotherapy is rarely followed by recovery.

Chronic myeloid leukemia presenting as a gynecological emergency

An unusual case of chronic myeloid leukemia presenting to the gynecological unit as a case of septic abortion is presented. Though history and clinical examination suggested the possibility of double pathology of septic abortion and chronic myeloid leukemia, histology of the products removed from the uterus showed it to be leukemic deposits. The diagnosis of leukemia was confirmed by marrow aspiration (trephine biopsy). Careful clinical examination and systematic investigation helped in diagnosing the pathology and to treat her appropriately.

Acute Myeloid Leukaemia with the Philadelphia Chromosome

A case report of serial chromosome studies on a 26-year-old male with acute myeloid leukaemia (AML) is presented. The classic Philadelphia chromosome (Ph1) translocation, t (9;22) was found in 77% of the metaphases at diagnosis and in 100% in relapse; during a 3-month remission period the cytogenetic picture was normal or the Ph1 was present in a minor cell population only. The clinical and morphologic features of this case indicated that it was really a case of AML and less likely chronic myeloid leukaemia (CML) presenting in blast crisis. It is suggested that the oncogen producing the 9;22-translocation and CML may also induce AML in rare instances.

Blast Crisis of Chronic Myeloid Leukaemia (CML): I. PRESENTATION SIMULATING ACUTE LYMPHOID LEUKAEMIA (ALL)

Seven patients presenting as an acute leukaemia caused difficulty in diagnosis. The lymphoid appearance of the balst cells either initially or during treatment suggested acute lymphoid leukaemia (ALL). In each case the Philadelphia chromosome was shown to be present thus suggesting that these cases were examples of chronic myeloid leukaemia (CML) presenting in blast crisis without a detectable chronic phase. The implications of these findings are discussed and the difficulty in achieving a precise diagnosis in the acute leukaemias is emphasised. Cytogenetic analysis should be carried out whenever the type of acute leukaemia present is of critical importance.