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PubMed1996

An assessment of the clinicohematological criteria for the accelerated phase of chronic myeloid leukemia.

In order to assess the relative importance of the clinicohematological features most commonly associated with the accelerated phase (AP) of chronic myeloid leukemia (CML) in 175 consecutive patients, 12 variables generally considered as indicating AP were analyzed for their predictive value for blast crisis (BC) appearance in less than 1 yr. At the time of analysis, 118 patients had died and 104 had developed BC. At univariate study, 6 features were associated with a significantly higher BC-probability: poor performance status (ECOG score > or = 2), unexplained fever/sweats, severe bone pain, progressive splenomegaly despite adequate therapy, blood basophils (> or = 20%) and peripheral blasts (6-12%). At logistic regression, only bone pain and blood blasts (6-12%) retained their prognostic importance; the relative risk of unexplained fever/sweats and progressive splenomegaly was also clinically relevant. One-year BC-probability from the appearance of 1 or more of the above features was 77.3% (95% CI: 66-86.6) and 100% since all 4 were observed. Finally, at least 1 of the 4 features was present prior to death in 6 of 7 patients dying from CML-related causes while not in BC. AP can be defined by the appearance along CML evolution of 1 or more of the 4 above-mentioned clinicohematological features.

Adolescent↗
PubMed1998

Relapsed chronic myeloid leukemia in accelerated phase 10 years after allogeneic bone marrow transplantation: full chimera reconversion with donor peripheral blood stem cells infusion.

We report the case of a 44-year-old male who relapsed in accelerated phase chronic myeloid leukemia 10 years after a successful bone marrow transplantation from his HLA-identical brother, and 3 years after 12 months treatment with interferon-alpha (IFN-alpha) for chronic active hepatitis C (CAH). The patient was infused with G-CSF-primed peripheral blood cells (PBSC) from the original bone marrow donor and a full donor reconstitution, with no detectable molecular disease, was obtained within 4 months without clinical aplasia or GVHD, nor help from other forms of chemotherapy or use of biological response modifiers. We speculate that IFN-alpha for CAH delayed the onset of a clinical recurrence of chronic myeloid leukemia and that in advanced disease PBSCs can provide an advantageous alternative to donor lymphocyte infusion (DLI).

Adult↗
PubMed1992

Prolonged remission of accelerated phase Philadelphia chromosome negative chronic myeloid leukemia following autologous recovery of normal hematopoietic elements after busulfan/cyclophosphamide and allogeneic marrow transplantation.

We describe here a patient with accelerated phase Philadelphia chromosome (Ph1) negative chronic myelogenous leukemia without BCR gene rearrangement, who received an allogeneic bone marrow transplant following a conditioning regimen consisting of busulfan (BU) and cyclophosphamide (CY). Hematopoiesis was restored following splenectomy performed 1 month post-transplant. There were no distinguishing cytogenetic differences between donor and host. Five years post-transplant the patient relapsed with the original disease. Restriction fragment length polymorphism (RFLP) studies performed at that time exhibited host specific DNA markers suggesting recurrent leukemia of host origin. RFLP analysis of the cells cryopreserved immediately post-transplant also revealed all cells to be of host origin. This patient experienced 5 years of remission with autologous hematopoietic recovery from an aggressive myeloproliferative disorder after high dose BU and CY without engraftment of donor hematopoietic cells.

Adult↗
PubMed1998

Chronic myeloid leukemia in accelerated phase: treatment results with conventional chemotherapy and allogeneic bone marrow transplantation in 96 patients.

The treatment results of 96 patients with Philadelphia-positive chronic myeloid leukemia (CML) in accelerated phase (AP) were reviewed retrospectively. Treatment of AP consisted of allogeneic bone marrow transplantation in 20 (14 related and 6 unrelated donors) or conventional chemotherapy (CC) in 76 patients. Three main treatment strategies were followed in the CC group: continuation (group A) or dose escalation (group B) of chronic phase therapy or change of chronic phase therapy to hydroxyurea (group C). Median survival was 7.0 months in group A (range 1.8-110), in group B 8.3 months (range 0.9-40) and in group C 9.6 months (range 1.5-47.6), p=0.89. Survival in CC was dependent on response to therapy as the achievement of a second chronic phase was significantly associated (p<0.001) with a longer median survival (21 months) compared with stable accelerated phase disease (11 months) or treatment failure (5 months). Median survival in the BMT group was 16.7 months (range 5-77), the 5-yr probability of relapse was 25% and the 5-yr disease-free survival was 36%. For patients <55 yr median survival after BMT was significantly prolonged compared with median survival after CC (n=45, 8.3 months, p=0.008). After developing criteria of AP, median survival in our analysis has been less than 1 yr. The results of conventional chemotherapy in the treatment of accelerated phase CML are disappointing. If a suitable donor is available allogeneic BMT should be performed without delay in patients with AP.

Adolescent↗
PubMed1991

Interferon alpha treatment of accelerated-phase chronic myeloid leukemia in relapse after bone marrow transplantation: a case with complete cytogenetic and molecular remission.

We describe here a patient with Philadelphia-positive chronic myeloid leukemia who had a hematologic and cytogenetic relapse after bone marrow transplantation. A diagnosis of accelerated phase was made when an additional malignant clone was detected. This clone was probably derived from the primitive Philadelphia clone, with duplication and rearrangement of the Philadelphia chromosome. The patient was treated with interferon alpha 2a and experienced a complete cytogenetic and molecular remission, with full reconstitution of the donor marrow.

Bone Marrow Transplantation↗
PubMed2001

Hematologic and cytogenetic remission by STI571 (Glivec) in a patient relapsing with accelerated phase CML after second allogeneic stem cell transplantation.

We describe the clinical activity of the ABL kinase inhibitor STI571 in a patient with accelerated phase of chronic myeloid leukemia (CML) relapsing after a second allogeneic BMT and with minimal levels of donor chimerism. STI571 resulted in rapid elimination of leukemic cells with ensuing prolonged severe leukopenia and neutropenia complicated by neutropenic fever and colitis. Subsequent hematopoietic recovery was driven by donor derived cells and was associated with grade 3 graft-versus-host disease (GVHD). STI571 induced sustained hematological and cytogenetic remission combined with controllable GvHD, therapeutic goals not achieved by two preceding allogeneic transplants and repeated donor lymphocyte transfusions (DLT).

Antineoplastic Agents↗
PubMed2000

A successful cord blood transplant in a child with second accelerated phase chronic myeloid leukemia following lymphoid blast crisis.

We describe a 5-year-old girl with Ph(+) CML who received a cord blood transplant in a second accelerated phase after a very early lymphoid blast crisis. She was induced into CR by ALL-directed chemotherapy and then maintained with IFN-alpha2b together with weekly rotational chemotherapy. Nineteen months after diagnosis, her mother gave birth to an HLA-compatible sibling, whose cord blood was cryopreserved. The patient's second acceleration occurred 22 months after the CML diagnosis. The subsequent conditioning regimen included busulfan 16 mg/kg, Ara-C 12 g/m2 and melphalan 140 mg/m2. In order to prevent GVHD, CsA alone was administered, 3 mg/kg i.v. per day for a total of 40 days. The total number of nucleated cells infused was 0.8 x 108/kg, with CD34+ cells 1.8 x 106/kg and CFU-GM 1 x 104/kg. Engraftment occurred on day +35. Respiratory distress, severe VOD and grade II acute gastrointestinal GVHD complicated the post-transplant period. No chronic GVHD occurred. The girl is alive 23 months after transplantation with complete donor chimerism; both Ph chromosome and bcr/abl RNA are negative. Bone Marrow Transplantation (2000) 25, 213-215.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes.

Relapse of chronic myeloid leukemia (CML) in chronic phase after allogeneic stem cell transplantation (SCT) can be successfully treated by donor lymphocyte infusion (DLI). However, relapse of accelerated phase CML, blast crisis, or acute leukemia after allogeneic SCT are resistant to DLI in the majority of cases. In vitro-selected and expanded leukemia-reactive T-cell lines may be more effective in inducing an antileukemic response in vivo. To treat a patient with accelerated phase CML after allogeneic SCT, leukemia-reactive cytotoxic T-lymphocyte (CTL) lines were generated from her HLA-identical donor. Using a modification of a limiting dilution assay, T cells were isolated from the donor, selected based on their ability to inhibit the in vitro growth of CML progenitor cells, and subsequently expanded in vitro to generate CTL lines. Three CTL lines were generated that lysed the leukemic cells from the patient and inhibited the growth of leukemic progenitor cells. The CTL did not react with lymphocytes from donor or recipient and did not affect donor hematopoietic progenitor cells. The 3 leukemia-reactive CTL lines were infused at 5-week intervals at a cumulative dose of 3.2 x 10(9) CTL. Shortly after the third infusion, complete eradication of the leukemic cells was observed, as shown by cytogenetic analysis, fluorescence in situ hybridization, molecular analysis of BCR/ABL-mRNA, and chimerism studies. These results show that in vitro cultured leukemia-reactive CTL lines selected on their ability to inhibit the proliferation of leukemic progenitor cells in vitro can be successfully applied to treat accelerated phase CML after allogeneic SCT.

Adult↗
PubMed2002

Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study.

Chronic myelogenous leukemia (CML) is caused by expression of the BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Patients with CML in accelerated phase have rapidly progressive disease and are characteristically unresponsive to existing therapies. Imatinib (formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl kinase. A total of 235 CML patients were enrolled in this study, of whom 181 had a confirmed diagnosis of accelerated phase. Patients were treated with imatinib at 400 or 600 mg/d and were evaluated for hematologic and cytogenetic response, time to progression, survival, and toxicity. Imatinib induced hematologic response in 82% of patients and sustained hematologic responses lasting at least 4 weeks in 69% (complete in 34%). The rate of major cytogenetic response was 24% (complete in 17%). Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. Nonhematologic toxicity was usually mild or moderate, and hematologic toxicity was manageable. In comparison to 400 mg, imatinib doses of 600 mg/d led to more cytogenetic responses (28% compared to 16%), longer duration of response (79% compared to 57% at 12 months), time to disease progression (67% compared to 44% at 12 months), and overall survival (78% compared to 65% at 12 months), with no clinically relevant increase in toxicity. Orally administered imatinib is an effective and well-tolerated treatment for patients with CML in accelerated phase. A daily dose of 600 mg is more effective than 400 mg, with similar toxicity.

Adult↗
PubMed2004

Overexpression of cyclin D1 in accelerated-phase chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a bi- or triphasic disease. Molecular markers distinct for the phase evolution would be clinically helpful. For signaling transformation and proliferation activities in CML, Bcr-Abl is the pivotal protein. As downstream signals of Bcr-Abl , RAS, PI3-K, and Stat 5 may lead to cell cycle progression mediated by increased expression of cyclin Ds. We analyzed copy numbers of bcr-abl and cyclin D1 transcripts by reverse transcription (RT) and competitive PCR titration in bone marrow cells of 20 patients with CML, 10 in chronic phase (CP) and the other 10 in accelerated phase (AP). The level of bcr-abl transcripts in the AP was not significantly higher than that in the CP; in contrast, the level of cyclin D1 transcripts in the AP was significantly higher than that in the CP (p <0.001). Cyclin D1 RNA expression in the CP of CML was also found to have clinical relevance to time to AP transformation. The median time to AP transformation for the CP patients with cyclin D1 transcripts of 1.50 x 10(4)/microg RNA was significantly shorter than that for those with cyclin D1 transcripts < 1.50 x 10(4)/microg RNA (15 vs. 67 months, p=0.0354) although confirmation to conduct in a larger patient group is required. These results suggest that the expression level of cyclin D1 RNA in bone marrow cells is predictive of the phase evolution in CML and may be helpful in treatment decision-making.

Adult↗
PubMed2002

Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies.

We investigated the clinical activity of the farnesyl transferase inhibitor R115777 in 22 patients with chronic myelogenous leukemia (CML) in chronic, accelerated, or blastic phase and in 8 patients with myelofibrosis (MF) and 10 patients with multiple myeloma (MM). R115777 was administered at 600 mg orally twice daily for 4 weeks every 6 weeks. Seven patients with CML (6 in chronic phase, 1 in advanced phase) achieved complete or partial hematologic response. Four of them had a minor cytogenetic response. Responses were transient, with a median duration of 9 weeks (range, 3-23 weeks). Two patients discontinued therapy because of toxicity while in complete hematologic response. Two MF patients had a significant decrease in splenomegaly, one had normalization of white blood cell count and differential, and one became transfusion independent. One patient with MM had a reduction in monoclonal protein of 34%. Adverse events included nausea in 22 patients (55%; all grade 2 or lower) and fatigue in 19 (48%; grade 3 or higher in 1). Other grade 3 or 4 toxicities included skin rash (4 patients, 10%), peripheral neuropathy (2 patients, 5%), and liver toxicity (2 patients, 5%). Patients who responded to therapy had significantly higher plasma vascular endothelial growth factor (VEGF) concentrations prior to treatment than nonresponders. Plasma concentrations decreased significantly during therapy among responders. R115777 showed clinical activity in patients with CML and MF. The effect on VEGF needs to be further investigated to determine whether this might be a possible mechanism of action of R115777.

Adult↗
PubMedDate not supplied

Extramedullary blast crisis in chronic myeloid leukemia.

Among 235 patients with CML we reviewed 91 patients with BC diagnosed between 1980 and 1995; 15 of the 91 (16%) developed extramedullary disease (EMD). The sites involved were the lymph nodes (13/15), CNS (1/15) and suborbital mass (1/15). The appearance of EMD was associated with chronic phase (CP) features in the bone marrow in 3/15 cases, with accelerated phase (AP) in 3/15 and with BC in 9/15. 11/15 (73%) cases of EMD were classified as myeloid (My-EMD) and 4/15 as lymphoid-type (Ly-EMD): three B-phenotype and one T-phenotype. All Ly-EMD cases were treated with vincristine, daunorubicin and prednisone and obtained complete remission (CR). Cases of My-EMD were treated with daunorubicin and cytosine arabinoside, of which only 1/11 achieved CR. We suggest that in EMD also, the type, lymphoid or myeloid, of BC has a bearing on treatment response and prognosis: Ly-EMD is more responsive to treatment and has longer survival than My-EMD.

Adult↗
PubMed1991

[Causes of death in chronic myeloid leukemia. Analysis of 109 patients].

The cause of death was revised in 109 cases of Ph'-positive chronic myelogenous leukaemia (CML) who died in a 15-year period. The median survival of the series, which included eight patients with initial criteria of blastic crisis, was 33.7 months (ranging between 2 and 192). Eight patients (7.3%) died during the chronic phase of the disease, 7 (6.4%) in the accelerated phase, and 94 (86.3%) in the blastic crisis. The cause of death in the chronic phase was frequently unrelated to CML (a second malignancy, cirrhosis of the liver, suicide, in four cases as opposed to infection, haemorrhage of hyperuricaemic renal failure in four others), but this was not so in the deaths occurred in the accelerated phase or blastic crisis. Thus, most of the deaths appearing in the accelerated phase were due to infection or haemorrhage, whereas in the blastic crisis they were mainly due to infection (54 of the 94 cases), followed by haemorrhage and leucostasis. All in all, these three complications were responsible for 94% of the deaths occurring in that evolutive phase of CML.

Adolescent↗
PubMed1995

Specific antisense oligomer anti Bcr-abl junctions in chronic myeloid leukemia: a cell cycle analysis and CFU-GM study.

Antisense oligonucleotides were used to determine the role of the BCR-ABL gene in the proliferation of chronic myeloid leukaemia (CML) clonogenic cells. Peripheral blood Philadelphia chromosome positive cells were obtained from eight CML patients at diagnosis (chronic phase = 7; accelerated phase = 1). Mononuclear cells were incubated with synthetic antisense 18-mer oligonucleotides complementary to the two different junctions b2a2 or b3a2. The type of junction (b2a2 or b3a2) was previously determined by RT-PCR techniques. Cells incubated for 12 to 14 hours with or without sense oligonucleotides served as controls. After incubation with oligonucleotides, the cell DNA synthesis was analysed by flow cytometry using the BrdUrd/DNA method and the cell plating efficiency in methylcellulose was determined. In six of the seven patients in chronic phase, there was a significant inhibition of CFU-GM production which was only 68.4 +/- 19%; (p < .01) of that found in controls. The S phase index, which depends upon the percentage of S phase cells as well as the fluorescence intensity, was 48 +/- 29% (p < .01) of the control values for the seven patients in chronic phase. Interestingly, for the only CML patient in accelerated phase, antisense oligomers had no inhibitory effect on either the production of CFU-GM or the number of S phase cells. In improving the specificity of oligomers, it might be useful for gene-targeted anti-leukemic therapy and/or bone marrow purging.

Base Sequence↗
PubMed1997

[The methylation of CT gene in chronic myeloid leukemia].

To investigate the relationship between the abnormal methylation of the calcitonin (CT) gene and the karyotypic abnormality in predicting the disease progress in chronic myeloid leukemia (CML), we studied the abnormal methylation of the CT gene in 47 CML patients by using a sensitive PCR method. At the same time, cytogenetic study was made in the same group of patients. The abnormal methylation of CT gene was found in only 4 of 24 patients in chronic phase, but in 6 of 9 patients in accelerated phase, and in 12 of 14 patients in blast crisis. Sequential studies in one patient also showed that the gene is normally methylated during the chronic phase but turns hypermethylated as the disease progresses. Our findings indicate that abnormal methylation of the 5' region of the CT gene is regularly a marker of disease progression in CML.

Adolescent↗
PubMed1994

Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia.

The records were reviewed of 58 patients receiving transplants in Seattle with unmanipulated marrow from HLA-identical siblings during the accelerated phase (AP) of chronic myeloid leukemia. Variables examined for association with survival and relapse included the interval from diagnosis to transplant, the reasons for categorization as AP, age, regimen, and cytomegalovirus serology. Four patients relapsed. The 4-year probabilities of survival, relapse-free survival, nonrelapse mortality, and relapse were 0.49, 0.43, 0.51, and 0.12, respectively. After completion of the stepwise multivariate analysis, age less than 38 years and categorization as AP solely on the basis of chromosomal abnormalities emerged as being independently significantly associated with improved survival. The 4-year probability of survival for the 16 patients categorized as AP because of chromosomal abnormalities and receiving transplant less than 1 year from diagnosis was 0.74. The low probability of relapse in these patients suggests that more aggressive preparative regimens are not indicated for patients receiving transplants in AP because of the increased risk of transplant-related mortality.

Acute Disease↗