Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate

Imatinib mesylate, an inhibitor of the Bcr-Abl tyrosine kinase, has modest activity in refractory/relapsed Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL). Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL was explored. There were 20 patients who received hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and imatinib mesylate followed by imatinib mesylate-based consolidation/maintenance therapy. Of these patients, 11 had de novo disease, 4 were primary failures after induction (without imatinib mesylate), and 5 were in complete remission (CR) after induction (without imatinib mesylate). All 15 patients treated for active disease achieved CR. Within a median of 3.5 months in first CR, 10 patients underwent allogeneic stem cell transplantation (SCT). One patient relapsed after matched related SCT. The other 9 patients remained alive in CR with median follow-up of 12 months after SCT (range, 1+ to 17+ months). Among 10 patients ineligible for (no donor or older age) or refusing allogeneic SCT, 1 patient relapsed after one year. There were 5 patients who remained alive in continuous CR for a median of 20 months (range, 4+ to 24+ months), with 2 older patients dying in CR at 15 and 16 months of comorbid conditions. Molecular CRs were achieved in both groups (SCT or no SCT). Outcome with hyper-CVAD and imatinib mesylate appears better than with prior regimens; continued accrual and longer follow-up of the current cohort is needed.     

Philadelphia chromosome-positive acute lymphoblastic leukemia in Taiwan

From January 1986 to December 1998, 26 (23%) of 114 acute lymphoblastic leukemia (ALL) patients older than 15 years were found to have Philadelphia (Ph) chromosome. They accounted for 28% (26 of 94) of the patients with B-lineage ALL. Compared with the other 88 ALL patients, the leukemic cells from all but one Ph-positive ALL patients were early pre-B cells with a higher rate of CD34 expression (92% vs 50%, P<0.05). At presentation, the Ph-positive adult ALL patients had higher circulating blasts (mean 21.4 vs 3.66x10(4)/microl, P<0.05) and lower initial platelet counts (mean 4.47 vs 7.34x10(4)/microl, P<0.01) and showed a trend toward higher frequency of initial central nerve system (CNS) involvement (25% vs 11%, P=0.098) than the others. Among patients with adequate chemotherapy, 16 (64%) of the 25 Ph-positive ALL patients achieved complete remission (CR), an incidence marginally lower than that of Ph-negative ALL (62 of 76, 82%, P=0.06) and significantly lower than that of Ph-negative B-lineage ALL (50 of 58, 86%, P=0.0037). However, all patients relapsed except for those who received allogeneic hemopoietic stem cell transplantation (allo-HSCT). The probabilities of 5-year continuous CR and 5-year survival for Ph-positive adult ALL patients were significantly inferior to those for Ph-negative adult ALL patients (0% vs 12%, P=0.0001, and 7% vs 19%, P=0.047, respectively), and those for Ph-negative B-lineage ALL (0% vs 14%, P<0.0001, and 7% vs 23%, P=0.002, respectively). Prognostic factors were analyzed among the Ph-positive ALL patients including the 26 adults mentioned above and an additional 11 children. No clinical or biological characteristics such as age, sex, initial circulating blast count, extramedullary involvement, or CD34 expression had an impact on the disease outcome. Allo-HSCT in first CR may improve the probability of 5-year continuous CR (100% vs. 0% for those without allo-HSCT, P=0.0091) although only three patients received it in this study. In conclusion, Ph-positive ALL patients tended to have a poor prognosis, regardless of whether other possible risk factors were present or not. Aggressive treatment, such as high-dose chemotherapy with allo-HSCT, should be considered for these patients to improve survival.     

Philadelphia chromosome-positive acute lymphoblastic leukemia preceded by acute pleuropericarditis

A 69-year-old woman was admitted with sudden chest pain and high fever. Electrocardiography showed negative T waves in the precordial leads. Subsequently, pleural and pericardial effusion developed, but the symptoms and signs subsided without specific therapy. On day 31, fever, left shoulder pain and pleural effusion reappeared. 67Ga scintigraphy showed abnormal uptake in the chest and left shoulder. Blasts were detected in the peripheral blood on day 44, and in the pleural effusion and bone marrow on day 45. The blasts were positive for Philadelphia chromosome, CD10, CD19, CD33, CD34 and IgH-chain rearrangement and negative for myeloperoxidase. The clinical picture of the preceding pleuropericarditis was that of viral or idiopathic origin, but its relationship with acute lymphoblastic leukemia was unclear. Inflammatory chemokines in the pleural space may have induced invasion of the leukemic cells.     

Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Dasatinib is a potent BCR-ABL inhibitor effective in chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia (ALL) resistant/intolerant to imatinib. In the GIMEMA LAL1205 protocol, patients with newly diagnosed Ph(+) ALL older than 18 years (with no upper age limit) received dasatinib induction therapy for 84 days combined with steroids for the first 32 days and intrathecal chemotherapy. Postremission therapy was free. Fifty-three patients were evaluable (median age, 53.6 years). All patients achieved a complete hematologic remission (CHR), 49 (92.5%) at day 22. At this time point, 10 patients achieved a BCR-ABL reduction to < 10(-3). At 20 months, the overall survival was 69.2% and disease-free survival was 51.1%. A significant difference in DFS was observed between patients who showed at day 22 a decrease in BCR-ABL levels to < 10(-3) compared with patients who never reached these levels during induction. In multivariate analysis, BCR-ABL levels of < 10(-3) at day 85 correlated with disease-free survival. No deaths or relapses occurred during induction. Twenty-three patients relapsed after completing induction. A T315I mutation was detected in 12 of 17 relapsed cases. Treatment was well tolerated; only 4 patients discontinued therapy during the last phase of the induction when already in CHR. In adult Ph(+) ALL, induction treatment with dasatinib plus steroids is associated with a CHR in virtually all patients, irrespective of age, good compliance, no deaths, and a very rapid debulking of the neoplastic clone.     

Clinical analysis of adult Philadelphia chromosome-positive acute lymphoblastic leukemia with p16 gene deletion

正Objective To investigate the clinical implications of p16 gene deletion in adult Philadelphia chromosome-positive acute lymphoblastic leukemia(Ph+ALL).Methods Retrospective analysis of clinical,immunophenotypic,cytogenetics,molecular characteristics and prognosis of80 newly diagnosed Ph+ALL patients with p16 deletion.     

Phenotypic and molecular heterogeneity in Philadelphia chromosome-positive acute leukemia

Philadelphia chromosome-positive (Ph1) acute leukemia is a heterogeneous subset of acute leukemia with a poor prognosis. We studied five patients to determine the potential for phenotypic and molecular heterogeneity. Cellular characterization studies included light myeloperoxidase (L-MPO), terminal deoxynucleotidyl transferase (TdT), ultrastructural MPO (U-MPO), and immunophenotyping by flow cytometry using T11, T3, T4, T8, Leu 1, B1, Leu 12, HLA-DR (la), CALLA (J5), OKM1, My4, My7, My8, My9, and My10. DNA was analyzed for rearrangements of the breakpoint cluster region (bcr), immunoglobulin heavy chain, joining region (JH), immunoglobulin kappa light chain constant region (C kappa), and T cell receptor (TcR beta). RNA dot blots were hybridized by using molecular probes for MPO and TdT. We found that four of five cases were acute mixed-lineage leukemia (AMLL). One patient had acute unclassifiable leukemia. Of the four patients classified as having AMLL, three showed myeloid and lymphoid features, with one patient showing myeloid, T cell, and B cell features. The last case showed T cell and B cell features only. In one patient MPO/RNA was positive in spite of insufficient L-MPO or U-MPO to diagnose acute myelogenous leukemia (AML), thereby suggesting significant MPO gene expression before the production of sufficient MPO protein to meet the French-American-British criteria for AML. Three of the five patients showed rearrangement of bcr (cases 1, 2, and 5). Studies of these five patients support the concepts of molecular and phenotypic heterogeneity in Ph1 acute leukemia, demonstrate a high incidence of AMLL in this subset of acute leukemia, and support the use of lineage-associated molecular probes to define lineage at an earlier stage than previously possible.     

Philadelphia chromosome-positive acute leukemia: morphologic and clinical correlations

Twenty-eight adult patients with Philadelphia chromosome positive (Ph+) acute leukemia were studied to determine if additional chromosomal changes were related to specific morphologic and clinical features. Twenty patients had chronic myeloid leukemia in blast crisis (CML-BC), three had Ph+ de novo acute nonlymphocytic leukemia (ANLL), and five had de novo acute lymphoblastic leukemia (ALL). Chromosomal abnormalities in addition to a single Ph were noted in 90% of patients with CML-BC and included a second Ph (five patients), +8 or duplication of part of 8q (five patients), dicentric isochromosome 17 (two patients), and +19 (two patients). Octaploidy with 4 Ph was seen in one patient with megakaryoblastic transformation. One of two patients with a progranulocytic blast crisis had a t(15;17) abnormality. Hypodiploidy was noted in 4 of 20 patients with CML-BC. Each of the four patients had prominent extramedullary manifestations of blast crisis. All had received intensive chemotherapy prior to the detection of hypodiploidy, and the cytogenetic findings were similar to those often seen in patients with therapy-related leukemia. An inv(3)(q21q26) was noted in two patients (one CML-BC, one de novo Ph+ ANLL), one of whom had hypolobulated micromegakaryocytes. Additional cytogenetic abnormalities in de novo Ph+ ANLL (especially +19) were similar to those in CML-BC. In contrast, the additional karyotypic changes in de novo Ph+ ALL (eg, +4, -7, -20, markers) were those commonly seen in ALL without a Ph and were generally different from those seen in CML-BC.     

Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.

Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) has a poor prognosis when treated with conventional chemotherapy. We analyzed the outcome of 67 HLA-identical sibling bone marrow transplants (BMTs) for Ph1-positive ALL reported to the International Bone Marrow Transplant Registry (IBMTR). Twenty-one of 67 (31%) transplant recipients survived in continuous complete remission more than 2 years after transplant. Two-year actuarial probabilities (95% confidence interval) of leukemia-free survival were 38% (23% to 55%) for 33 patients transplanted in first remission, 41% (23% to 61%) for 22 patients transplanted after relapse, and 25% (9% to 53%) for 12 patients failing to achieve remission with conventional chemotherapy. These data indicate that transplants are effective treatment for Ph1-positive ALL.     

Immunogenotypic and clonal culture studies in Philadelphia chromosome-positive acute leukemia

Molecular analysis and blast colony assay were performed on patients with Philadelphia chromosome-positive acute leukemia (Ph+ AL). All patients were diagnosed as ALL- L2 and 3 were My+ ALL. Nine of the 12 cases had rearranged immunoglobulin heavy chain, and 4 had rearranged TCR beta. TCR gamma rearrangement was noted in 3 patients, and TCR delta involvement was also noted in 6 patients. Clonal culture analysis revealed that leukemia cells of M-BCR rearranged Ph+ AL cases had a potential to proliferate by myelopoietic CSFs and ILs, however, M-BCR nonrearranged Ph+ AL did not. These results indicate biological and immunogenotypic heterogeneity of Ph+ AL.     

Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

We reported the results of 6 allogenic bone marrow transplantation (BMT) and 3 autologous BMT for patients with Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) by Nagoya BMT group. Two of six patients who received allogenic BMT have continued complete remission (CR) on +639 days and +1,597 days. Four of six patients relapsed on +134, +203, +216, and +267 days. Two patients with a disease-free survival for a long time had both acute and chronic GVHD. It is suggested that graft-versus-leukemia (GVL) effect might prevent the relapse. On the contrary, one patient who received with monoclonal antibodies plus complement-treated autologous bone marrow is free of leukemia on +439 days. Our results suggest the follows. 1) We do chromosomal analysis at initial diagnosis in all cases to do BMT in first CR. 2) We intensify the conditioning regimen for BMT. 3) We study on application of GVL effect to prevent the relapse. 4) We establish the best purging method to eradicate residual leukemic cells for autologous BMT. 5) We do allogenic BMT using HLA-matched unrelated donor for patients without related donor.     

Recent advances in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia

The advent of imatinib, a selective inhibitor of the ABL tyrosine kinase, has revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Combined with chemotherapy, imatinib exerts remarkable efficacy in patients with newly diagnosed disease with a complete remission (CR) rate of 95% and a survival rate of 55% at 3 years. Profound eradication of leukemia cells not only provides patients with a better chance for receiving allogeneic hematopoietic stem cell transplantation during first CR but also contributes to durable CR even without transplantation. Despite such improvement, however, relapse does occur, mainly owing to acquisition of resistance. Growing comprehension of the molecular mechanisms of resistance to imatinib has led to the development of novel BCR–ABL inhibitors that yield higher affinity for BCR–ABL and/or potent inhibitory activity against other target molecules such as SRC family kinases. The second-generation ABL kinase inhibitors, namely dasatinib and nilotinib, are already showing clinical activity in patients with imatinib-resistant Ph+ ALL, and other novel agents are undergoing preclinical and early clinical evaluation. Further improvement in treatment results will be achieved by identifying each patient’s disease profile based on information obtained before and during treatment and by optimizing subsequent treatment accordingly.