Chromosome-positive ALL Research Articles

Second hematopoietic stem cell transplant using unrelated donor umbilical cord blood cures 50% of pediatric patients with leukemia relapsing after prior allogeneic transplant from a matched related sibling

Leukemic relapse after allogeneic stem cell transplant is difficult to treat and carries a poor prognosis. Cytotoxic therapy has limited efficacy and subsequent myeloablative transplants are associated with significant treatment related toxicity. We report results of 4 children who relapsed after matched related donor bone marrow transplants (BMT) and then underwent unrelated donor umbilical cord blood transplantation (UCBT) following conditioning with Fludarabine/Melphalan/ATG. Between 7/00 and 5/03 4 children who experienced leukemic relapse after 1 (n = 3) or 2 (n = 1) matched sibling transplants underwent UCBT at Duke University Medical Center. The average age at the time of UCBT was 7 1/3 years (range 5 12 to 15 12 years) old with a median weight of 26 kg (range 20–45 kg). The median time from initial BMT to UCBT was 13 months. Two children had ALL (high risk Pre-B ALL (BMT in CR2, UCBT in CR3); Philadelphia chromosome positive ALL (BMT in CR 1, DLI in CR2, UCBT in CBR3)) and two had AML (M1 AML (BMT in CR1 and CR2, UCBT in relapse); M2 AML (BMT in CR2, DLI × 4 in CR3, UCBT in relapse)). All patients had previously received TBI and were prepared for UCBT with Fludarabine 25mg/m2 qd × 5, Melphalan 45mg/m2 qd × 3 and ATG. Cyclosporine and intermediate dose steroids were given for GVHD prophylaxis. Three children received a 4/6 HLA matched UCB unit, one a 3/6 HLA matched unit, all with at least one mismatch at DRB1. The median nucleated cell dose was 9.8 × 107cells/kg (range 5.6–14.4 × 107cells/kg). All 4 demonstrated complete donor engraftment (absolute neutrophil count greater than 500/μL for three consecutive days) at a median of 24 (range 10–27) days post transplant. Platelet engraftment (untransfused platelet count >50,000/uL) occurred at a median of 55 days post transplant. One patient developed acute GVHD (grade 1 skin) and there was no chronic GVHD seen. The event free survival and overall survival are both 50%. One child died in remission of Legionella pneumonia on day +96 post transplant, and one died of relapse on day + 424 after UCBT. Two of the 4 patients are surviving disease free for a median of 775 (range 362–1189) days post transplant. UCBT after cytoreduction with fludarabine/melphalan/ATG is a viable option as a treatment for leukemic relapse after matched related allogeneic transplant, with low GVHD rate, tolerable treatment related mortality and 50% event free survival.

Isolated Central Nervous System Relapse in Lymphoid Blast Crisis Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia in Patients on Imatinib Therapy

Philadelphia chromosome positive ALL and CML have shown remarkable responses to imatinib (Gleevec, STI571) in phase I, II and III studies. However, imatinib has very poor penetration of the blood brain barrier resulting in subtherapeutic levels in the CNS. We present 2 cases of patients treated with imatinib that achieved complete cytogenetic remission within 3 months who subsequently developed CNS relapses while remaining in complete cytogenetic remission on bone marrow examination. Both patients went on to achieve CNS remission following treatment with intrathecal methotrexate and cytarabine.

The Outcome of Philadelphia Chromosome-Positive Adult ALL: Characteristics and Prognosis.

The Philadelphia (Ph) chromosome is a well- known chromosome abnormality in adults with B-lineage ALL, and is associated with a poor prognosis. This study compared the clinical manifestations and prognosis in adult Ph-positive and Ph-negative ALL patients. We retrospectively analyzed the clinical records of adult patients newly diagnosed as B-lineage ALL, between January 1995 and February 2001. Fifty five patients were included in this study. We divided the patients into Ph-positive and Ph-negative groups. Eighteen of the 55 patients (32.7%) were found to have the Ph chromosome. At initial diagnosis, the Ph-positive patients had higher circulating leukocyte counts, lower platelet counts and had a greater tendency to bleed, than the Ph-negative group. The complete remission rates were 83.3% and 83.8% for the Ph-positive and the Ph-negative groups, respectively. Four of the Ph-positive, and 13 of the Ph-negative, patients underwent allogenic bone marrow transplantation. The median follow-up for the surviving patients was 39.3 months. The three-year survival rates were 10.4% and 51.8% for the Ph-positive and the Ph-negative groups, respectively. The median disease-free survival was 7.7 months for the Ph-positive group, but did not reach the median value in the Ph-negative group. Among the Ph-positive patients, age was the only factor that had an impact on the disease outcome. In adult B-lineage ALL, the Ph-positive patients had similar complete remission rates to other patients; however, the remission was of shorter duration, with a higher relapse rate in the Ph-positive patients. More effective treatments are needed to improve the survival of the Ph-positive patients.

THE MEDICAL RESEARCH COUNCIL TRIALS IN ADULT ACUTE LYMPHOCYTIC LEUKEMIA

Overall, the MRC Adult Leukaemia Trials have been successful, in that since the 1970s they have demonstrated a stepwise improvement in outcome. Examination of the survival curves shows the DFS rate at 5 years in UKALL Trial 1 of 5% rising to 38% in UKALL Trial XII (year 2000). Unfortunately, compared with children with ALL, these results in adults must be regarded as poor, because in the UKALL children's trials the EFS rate at 5 years for a child entered in the year 2000 is expected to be above 80%. With a low proportion of all adults entered into randomized trials, one cannot be certain that improvements result from treatment rather than patient selection. Only recently have randomized trials in adults become large enough to detect plausible treatment effects. The authors believe that the main contribution of these trials so far, confirmed by other groups, is in examining prognostic features in al patients and finding that age and the presence of the Ph chromosome, independent of WBC count, gender, and cell type, is the main feature for predicting outcome. The UKALL XII trial will provide valuable information on the relative merits of transplantation and molecular studies of MRD. An in-depth study of a large number of Ph chromosome-positive ALL leukemias will also provide information on which to base future studies. Preliminary data suggest that all Ph-positive patients should undergo some sort of allograft early after CR is achieved, because these patients are not rescued by BMT after relapse. At the time of the publication of this article, preliminary studies suggest that STIs may not be as effective in Ph-positive ALL as in chronic granulocytic leukemia. The challenge for the future is to understand the biologic role of age and its impact on outcome so as to overcome "ageism" in adult ALL.

A Case Report of Philadelphia Chromosome Positive ALL Successfully Treated with a Peripheral Blood Stem Cell Transplantation from the One Locus Mismatched Mother

A Case Report of Philadelphia Chromosome Positive ALL Successfully Treated with a Peripheral Blood Stem Cell Transplantation from the One Locus Mismatched Mother

Immune response to Philadelphia chromosome-positive acute lymphoblastic leukemia induced by expression of CD80, interleukin 2, and granulocyte-macrophage colony-stimulating factor.

We examined the potential of generating an immune response against Philadelphia chromosome-positive acute lymphoblastic leukemia. The immunostimulatory molecules chosen for this study were the cytokines IL-2 and GM-CSF and the costimulatory ligand CD80 (B7.1). We used a murine model based on a BALB/c pre-B cell line, BM185wt, in which leukemia is induced by the p185 BCR-ABL oncogenic product, which reproduces Philadelphia chromosome-positive ALL. BM185wt cells were transduced with retroviral vectors and the transduced clones expressing mIL-2, mGM-CSF, or mCD80 were used for challenge. Expression of the immunomodulators by BM185 cells was correlated with delay in leukemia development in immunocompetent mice, but not in immunodeficient mice, indicating an immune response against the modified leukemia cells. Expression of CD80 caused leukemia rejection in 50% of the cohort, which was associated with the CD4+ and CD8+ T cell-dependent development of anti-leukemia cytotoxic T lymphocytes. Furthermore, mice surviving the BM185/CD80 challenge or preimmunized with irradiated BM185/CD80 cells developed an immune response against subsequent challenge with the parental leukemia. These studies provide evidence that immunotherapeutic approaches can be developed for the treatment of ALL.

General aspects of cancer chemotherapy in the aged.

Age is one of the most important prognostic factors affecting outcome in the treatment of patients with neoplastic diseases. The negative impact of age is almost uniformly encountered with any solid tumor or hematologic malignancy. Detailed analysis of the negative implications of age on therapeutic outcome uncover tumorrelated factors, host-related factors and some degree of the interaction between tumor and host-related factors. For example, it is generally accepted that histologic or cytologie subtype of Hodgkin’s Disease or the acute leukemias have an important effect on outcome. The general observation is that the prognosis for Hodgkin’s Disease is worse on older i.e. > 60 years of age compared to younger patients i.e. in the 20–30 year age group. However, it is not the diagnosis of Hodgkin’s Disease per se that has a poorer prognosis in elderly patients but rather the impact of a more aggressive variant of Hodgkin’s Disease (lymphocyte depleted) which has a higher frequency of occurrence in elderly patients compared to younger patients. Likewise, the frequency and duration of response as well as curability of ALL1 in elderly patients is much lower than that possible in children. Reasons for this lesser effect include the fact that elderly patients with ALL have not only a higher frequency of biphenotypic ALL but also a higher frequency of Philadelphia chromosome positive ALL, both of which have negative prognostic implications in any age group. Older patients with AML1 more commonly have a history of antecedent myelodysplasias or secondary leukemias, historical features that have a negative prognostic impact in any age group.KeywordsAnticancer DrugAnticancer AgentDose IntensityAntineoplastic AgentRenal Plasma FlowThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.