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M Keating

Publications and source records attributed to M Keating.

At least 73 records · Page 4Linked to original sources
PubMed1998

Effect of interferon-alpha therapy on bone marrow fibrosis in chronic myelogenous leukemia.

The aim of this study was to investigate the influence of interferon-alpha (IFN-alpha) on bone marrow fibrosis associated with chronic myelogenous leukemia (CML). Eighty-two bone marrow biopsies from 41 patients in chronic phase CML were stained with Snook's reticulin stain for argyrophilic fibers. Grading of reticulin fibrosis (scale of 1 to 4) was according to the quantity and pattern of distribution of reticulin. The interval between biopsies was a median of 25 months (range 12 to 40 months). Patients had been treated with IFN-alpha for at least 12 months, were still on IFN-alpha therapy during the study, and had achieved at least a complete hematological response. Before the start of IFN-alpha therapy, reticulin fibrosis was grade 1-2 in 23 patients (56%) and grade 3-4 in 18 (44%). During IFN-alpha therapy, reticulin fibrosis in bone marrow did not worsen or was reduced in 33 patients (80%) and increased by one grade in eight patients (20%). Only five patients (12%) with limited fibrosis (grade 1-2) before start of IFN-alpha therapy showed an increase towards significant fibrosis (grade 3-4), while eight of the 18 patients (44%) with grade 3-4 fibrosis achieved a decrease of fiber content in bone marrow. In summary, IFN-alpha was not associated with an enhancing effect on myelofibrosis in patients with CML and may have prevented increasing fibrosis in patients who respond to therapy.

Adult↗
PubMed1998

GM-CSF can improve the cytogenetic response obtained with interferon-alpha therapy in patients with chronic myelogenous leukemia.

Patients with chronic myelogenous leukemia (CML) who achieve a major cytogenetic remission when treated with interferon-alpha (IFN-A) have a survival advantage when compared to patients with no cytogenetic response. We investigated the effect of combining granulocyte-macrophage colony-stimulating factor (GM-CSF) with IFN-A in the cytogenetic response of patients with minor responses to IFN-A alone. CML patients were eligible if they had shown sensitivity to IFN-A as determined by achievement of a hematologic or cytogenetic response, but failed to achieve or lost a major cytogenetic response after a minimum of 12 months of therapy with IFN-A alone. Patients received GM-CSF 30 microg/m2 daily, subcutaneously and the dose was escalated to 60 microg/m2 if tolerated. IFN-A was continued at the same dose being received by the patient and escalated when possible. Fourteen evaluable patients were included, 13 in chronic phase and one in accelerated phase. The best response prior to GM-CSF was a transient major cytogenetic response in two patients (14%), minor cytogenetic response in nine (64%), and complete hematologic response in three (22%). The median time on IFN-A prior to the start of GM-CSF was 39 months (range 12-72 months). Four patients achieved a significant cytogenetic response, including two complete (14%) and two partial (14%) cytogenetic remissions during therapy. One partial cytogenetic remission converted to complete shortly after therapy was discontinued. Two other patients had a significant reduction in the percentage of Philadelphia chromosome-positive metaphases. The dose of IFN-A could be escalated in half of the patients treated. No toxicity could be attributed to the addition of GM-CSF. We conclude that the addition of GM-CSF to the treatment with IFN-A in CML patients who are sensitive to IFN-A alone but fail to achieve a major cytogenetic response may be beneficial in some patients and should be further investigated.

Adult↗
PubMed1998

Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

PURPOSE: To investigate whether cytogenetic clonal evolution can be suppressed with interferon alfa (IFN-alpha) therapy in patients with chronic myelogenous leukemia (CML). PATIENTS AND METHODS: Ninety patients with CML and cytogenetic clonal evolution who received IFN-alpha-based regimens were analyzed. Clonal evolution was defined as the presence of karyotypic abnormalities in addition to the Philadelphia (Ph) chromosome. Patients were evaluated for the suppression of cytogenetic clonal evolution after therapy, the cytogenetic response, and survival. RESULTS: The median age of the population was 39 years (range, 15 to 70 years), median time from diagnosis to clonal evolution 14 months (range, 0 to 145 months), and median percentage of abnormal metaphases 18% (range, 4% to 100%). Fifty six patients (62%) achieved some suppression of cytogenetic clonal evolution; in 41 patients (46%), the suppression was complete. The overall median survival was 51 months, with 43% alive at 5 years. Patients who achieved a complete suppression of cytogenetic clonal evolution had a median survival of 66 months, with 51% alive at 5 years. Characteristics associated with a better response include a lower percentage of abnormal metaphases, time to cytogenetic clonal evolution of 24 months or less, and absence of other features of accelerated disease. A prognostic classification for cytogenetic clonal evolution defined three groups with complete response (CR) rates of 85%, 34%, and 0% (P < .0001) and median survival times of 58, 31, and 30 months, respectively (P=.02). CONCLUSION: Patients with cytogenetic clonal evolution can respond to IFN-alpha therapy, and this response is associated with longer survival. A previously described prognostic model separates patients into subsets with different probabilities of response to IFN-alpha and survival.

Adolescent↗
PubMed1998

Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies.

PURPOSE: To investigate the use of a nonmyeloablative fludarabine-based preparative regimen to produce sufficient immunosuppression to allow engraftment of allogeneic stem cells and induction of graft-versus-leukemia/lymphoma (GVL) as the primary treatment modality for patients with chronic lymphocytic leukemia (CLL) and lymphoma. PATIENTS AND METHODS: Fifteen patients were studied. Six patients were in advanced refractory relapse, and induction therapy had failed in two patients. Patients with CLL or low-grade lymphoma received fludarabine 90 to 150 mg/m2 and cyclophosphamide 900 to 2,000 mg/m2. Patients with intermediate-grade lymphoma or in Richter's transformation received cisplatin 25 mg/m2 daily for 4 days; fludarabine 30 mg/m2; and cytarabine 500 mg/m2 daily for 2 days. Chemotherapy was followed by allogeneic stem-cell infusion from HLA-identical siblings. Patients with residual malignant cells or mixed chimerism could receive a donor lymphocyte infusion of 0.5 to 2 x 10(8) mononuclear cells/kg 2 to 3 months posttransplantation if graft-versus-host disease (GVHD) was not present. RESULTS: Eleven patients had engraftment of donor cells, and the remaining four patients promptly recovered autologous hematopoiesis. Eight of 11 patients achieved a complete response (CR). Five of six patients (83.3%) with chemosensitive disease continue to be alive compared with two of nine patients (22.2%) who had refractory or untested disease at the time of study entry (P = .04). CONCLUSION: These findings indicate the feasibility of allogeneic hematopoietic transplantation with a nonablative preparative regimen to produce engraftment and GVL against lymphoid malignancies. The ability to induce remissions with donor lymphocyte infusion in patients with CLL, Richter's, and low-grade and intermediate-grade lymphoma is direct evidence of GVL activity against these diseases. This approach appears to be most promising in patients with chemotherapy-responsive disease and low tumor burden.

Aged↗
PubMed1998

Results of topotecan single-agent therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia.

The activity of topotecan was evaluated in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Sixty patients with a diagnosis of MDS (n = 30) or CMML (n = 30) were treated. Their median age was 66 years, with 50 patients (83%) being over 60 years of age at time of study entry. Chromosomal abnormalities were present in 50% of patients and thrombocytopenia of less than 50 x 10(9)/L in 50%. Topotecan was administered as 2 mg/m2 by continuous infusion over 24 hours daily for five days (10 mg/m2 per course) every 4 to 6 weeks for two courses, then at maximum tolerated dose level (1-2 mg/m2 by continuous infusion over 24 hours daily for five days) once every 4-8 weeks for a maximum of 12 courses. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Nineteen patients (31%) achieved a complete response (CR). A CR was achieved in 11 of 30 patients with MDS (37%) and in eight of 30 with CMML (27%). A CR was achieved in 10 of 23 patients with previously untreated MDS (43%). Eight of 11 patients who presented with cytogenetic abnormalities (five of which involved chromosome 5 and/or 7 abnormalities) and achieved CR, were evaluated cytogenetically in CR: all were cytogenetically normal in CR. Characteristics associated with a higher CR rate were lack of previous chemotherapy, absence of ras oncogene mutations, and presence of less than 10% monocytes in either peripheral blood or bone marrow. In contrast, CR rates were similar by different agent groups, by different karyotype abnormalities, and by other pre-therapy peripheral blood counts. Non-myelosuppressive side effects were mucositis in 67% of patients (severe [grade 3-4] 23%), diarrhea in 38% (severe 17%), and nausea and vomiting in 28% (severe 5%). Febrile episodes during neutropenia occurred in 85% of patients and documented infections in 47 %. Mortality in the first four weeks was 20%. With a median follow-up duration of 31 months, the 12 month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. In summary, topotecan has significant single-agent activity in MDS and CMML. Complete responses associated with topotecan therapy often involve the disappearance of abnormal, poor-prognosis karyotypes, which is particularly encouraging. Future strategies to optimize topotecan's role include combination regimens with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).

Adult↗
PubMed1998

CECA-cyclophosphamide, etoposide, carboplatin and cytosine arabinoside--a new salvage regimen for relapsed or refractory acute myelogenous leukemia.

In an effort to develop more effective therapy for patients with refractory or relapsed acute myelogenous leukemia (R-AML) we combined three drugs with proven activity in AML, that are not typically used in induction regimens, with cytosine arabinoside (ara-C). Twenty-five patients (3 primary refractory, 22 relapsed) were treated. Patients received 3 days of "CECA" therapy as follows: cyclophosphamide (CTX) 1 g/m2 i.v. over 2 hrs., etoposide (VP-16) 200 mg/m2 i.v. over 3 hr, carboplatin (CBP) 150 mg/m2 i.v. over 24 hours and ara-C 1 g/m2 over 2 hr. Peripheral circulating blasts cleared in 24 cases (96%), and marrow aplasia was achieved in 19 (76%). There were 3 complete remissions (CR), 1 patient died before day 14, 5 died aplastic 14 or more days from the start of therapy, 5 had primary resistant disease, and 10 had secondary resistance i.e., leukemia reappearing after developing aplasia and 1 was lost to follow up 6 weeks into therapy. Two of the patients achieving CR received allogeneic BMT in CR (at 18 and 22 weeks): one died of fungal infection on day 50 and the other, who had CNS involvement at relapse, is alive 24 months post transplant. Toxicity was tolerable: one patient each developed grade III diarrhea and mucositis, another had grade III cardiac toxicity, a fourth developed a grade IV bilirubin elevation. Single, 2, and 3 or more infectious episodes occurred in 10, 5 and 4 patients respectively. This regimen showed definite anti-leukemic activity: the 3 patients achieving CR were among 23 patients with a 1%, 10% or 20% expectation for second CR attainment. The CECA regimen should be investigated in better prognosis salvage groups.

Adolescent↗
PubMed1998

Erythropoietin use.

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Activities of Daily Living↗
PubMed1997

Implications of potential cure in acute myelogenous leukemia: development of subsequent cancer and return to work.

Chemotherapy produces extended remissions, and potential cures, in a small minority of patients with acute myeloid leukemia (AML). We explored whether potentially cured patients were at increased risk of subsequent invasive cancer and were able to return to work. Potentially cured patients were defined as those in first or second complete remission (CR) for at least 3 years based on hazard rates for recurrence or death in CR, which declined sharply after this time. Patients who received allogeneic marrow transplant were excluded. We used questionnaires, phone contact, and chart review to obtain information about subsequent cancer and work status. The number of patients who developed invasive cancer was compared with the number expected based on age, gender, and years of follow-up using the Connecticut Tumor Registry. A total of 215 patients met our criteria for potential cure: 203 in first CR and 12 in second CR (of 1,663 treated between 1965 and December, 1992). At a median of 9.2 years from first or second CR, 163 (76%) remain alive in CR. Fifteen patients developed 18 invasive cancers (expected number of patients, 8.8; observed/expected, 1.70; 95% CI, 0.96 to 2.84; P = . 06). Patients initially treated between 1973 to 1979, patients above the potentially cured cohort's median age of 40 years, and those who presented with abnormalities of chromosomes 5 and/or 7 were more likely to develop subsequent cancer, whereas the observed/expected ratio for younger patients was 1.05 (95% CI, 0.13 to 3.80; P = .56). Seventy-four percent of the patients who were working full-time and who were under age 50 at time of treatment for AML have been working full-time in the last 6 months. Only 17 of 56 patients who are currently not working cited physical limitation as the reason. Patients with potentially cured AML are likely to be able to return to work, and at least if younger do not, on average, have an increased risk of invasive cancer.

Age Factors↗
PubMed1997

Protease activation is required for glucocorticoid-induced apoptosis in chronic lymphocytic leukemic lymphocytes.

Recent work has demonstrated that glucocorticoids, nucleoside analogues, and other cancer chemotherapeutics induce apoptosis in chronic lymphocytic leukemia (CLL) cells. In this study, we investigated the involvement of protease activation in these responses using selective peptide inhibitors of the interleukin-1beta converting enzyme (ICE)/caspase family and a Ca2+-activated protease we recently implicated in thymocyte apoptosis. Apoptosis was associated with proteolytic cleavage of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) and increased caspase protease activity, and cell-permeant caspase antagonists [zVAD(OMe)fmk and Boc-D(OBzl)cmk] blocked apoptosis in response to the glucocorticoid methylprednisolone or the nucleoside analogue fludarabine, indicating that caspase activation was required for these responses. However, a peptide-based inhibitor of the Ca2+-dependent lamin protease (zAPFcmk) also completely suppressed DNA fragmentation and the cleavage of lamin B1 . Strikingly, treatment of cells with zAPFcmk alone led to characteristic PARP cleavage, depletion of the precursor forms of two ICE family proteases (CPP32 and ICH-1), and phosphatidylserine exposure, suggesting that blockade of the lamin protease led to activation of the ICE family. Our results implicate the lamin protease as a target for Ca2+ during chemotherapy-induced apoptosis in CLL lymphocytes, and they identify a novel functional interaction between the protease and members of the ICE family.

Apoptosis↗
PubMed1997

Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy.

In current medical practice, patients with refractory anemia with excess blasts in transformation (RAEB-t), and especially patients with RAEB, receive chemotherapy regimens (AML Rx) administered to patients with acute myeloid leukemia (AML) less often than do patients with AML. These entities are distinguished primarily by marrow blast percentage (5% to 19% RAEB, 20% to 29% RAEB-t, and > or = 30% AML). The poor prognosis of many RAEB or RAEB-t patients, if untreated, led us to give them AML Rx using the same plan as for AML. The purpose of this analysis was to see if diagnosis (RAEB, RAEB-t, or AML) affected outcome. We treated 372 patients with AML (acute promyelocytic leukemia [APL] excluded), 106 with RAEB-t, and 52 with RAEB. AML Rx produced a 62% complete remission (CR) rate in RAEB, essentially identical to the rates in RAEB-t and AML, but event-free survival (EFS) from CR and from start of treatment (start of Rx), as well as overall survival, were poorer in RAEB than in AML or RAEB-t, with AML and RAEB-t being identical. However, patients with RAEB or RAEB-t were more likely to have poor prognostic characteristics, in particular complex abnormalities involving chromosomes 5 and/or 7. Multivariate analyses indicated that, when considered together with cytogenetics and other patient characteristics, a diagnosis of RAEB rather than AML or RAEB-t had no effect on EFS from start of Rx, EFS from CR, survival, or achievement of CR. These analyses suggested a trend for patients with RAEB-t to have better EFS from start of Rx than patients with AML or RAEB (P = .08; relative risk, 0.80; 95% confidence interval, 0.62 to 1.03), but there were no differences with respect to the other outcomes. Our data suggest that the propriety of administering AML Rx to patients with RAEB or RAEB-t who have poor prognosis without treatment is identical to the propriety of treating AML in this fashion. Deterrents to standard AML Rx in these patients could justifiably include cytogenetics, age, etc, but not a diagnosis of RAEB or RAEB-t per se.

Acute Disease↗
PubMed1997

Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy.

The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen-mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 x 10(9)/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 x 10(9)/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were < 5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade > or = 2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed > or = 90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have > or = 80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.

Acute Disease↗
PubMed1997

Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome.

OBJECTIVES: We sought to analyze age-gender differences in the rate-corrected QT (QTc) interval in the presence of a QT-prolonging gene. BACKGROUND: Compared with men, women exhibit a longer QTc interval and an increased propensity toward torsade de pointes. In normal subjects, the QTc gender difference reflects QTc interval shortening in men during adolescence. METHODS: QTc intervals were analyzed according to age (< 16 or > or = 16 years) and gender in 460 genotyped blood relatives from families with long QT syndrome linked to chromosome 11p (KVLQT1; n = 199), 7q (HERG; n = 208) or 3p (SCN5A; n = 53). RESULTS: The mean QTc interval in genotype-negative blood relatives (n = 240) was shortest in men, but similar among women, boys and girls. For genotype-positive blood relatives, men exhibited the shortest mean QTc interval in chromosome 7q- and 11p-linked blood relatives (n = 194), but not in the smaller 3p-linked group (n = 26). Among pooled 7q- and 11p-linked blood relatives, multiple regression analysis identified both genotype (p < 0.001) and age-gender group (men vs. women/children; p < 0.001) as significant predictors of the QTc interval; and heart rate (p < 0.001), genotype (p < 0.001) and age-gender group (p = 0.01) as significant predictors of the absolute QT interval. A shorter mean QT interval in men was most evident for heart rates < 60 beats/min. CONCLUSIONS: In familial long QT syndrome linked to either chromosome 7q or 11p, men exhibit shorter mean QTc values than both women and children, for both genotype-positive and -negative blood relatives. Thus, adult gender differences in propensity toward torsade de pointes may reflect the relatively greater presence in men of a factor that blunts QT prolongation responses, especially at slow heart rates.

Adolescent↗
PubMed1997

Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases.

New treatments which may change the course of a disease, or which have potential carcinogenicity, may result in the development of new cytogenetic or clinical disorders. Three patients with Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia (CML) who developed new cytogenetic abnormalities after achieving a cytogenetic complete remission (CR) of their Ph-positive disease with interferon alpha (IFN-alpha) based therapy are described. Patient 1 developed chromosomal abnormalities involving chromosomes 5 (5q13-34) and later 7 (monosomy 7) 60 months after the start of therapy and 20 months after IFN-alpha was discontinued. A myelodysplastic syndrome was noted 83 months from the start of therapy. Patient 2 developed a myeloproliferative syndrome with 18p11 chromosomal abnormalities 90 months after the start of the therapy and 60 months after IFN-alpha was discontinued. Patient 3 developed a chromosome 11 abnormality (11q21-23) 23 months after the start of therapy, without hematological manifestations. All three patients remain in cytogenetic CR of Ph-positive disease with the hypermetaphase fluorescent in situ hybridization and polymerase chain reaction studies for BCR/ABL showing minimal residual disease. The emergence of new cytogenetic or clinical disorders in patients with CML on IFN-alpha therapy needs to be monitored. These findings may be related to changing the natural course of CML, to therapy, or to the emergence of suppressed clones in a stem cell disorder.

Aged↗
PubMed1997

Treatment of chronic myelogenous leukemia with nucleoside analogs deoxycoformycin and fludarabine.

In vitro studies suggest that nucleoside analogs have an antileukemic effect against chronic myelogenous leukemia (CML). We investigated the antileukemia effect of deoxycoformycin (DCF) and fludarabine in patients with CML. Four patients with Philadelphia chromosome (Ph)-positive CML were treated with DCF at 4 mg/m2 every week for 4 weeks, then every other week for four doses, and then every month as maintenance. Two patients were in late chronic phase and two in accelerated phase. All had previously failed therapy with interferon-alpha (IFN-A). Nine patients were treated with fludarabine 30 mg/m2/day for 5 days every 28 days. Three had Ph-positive CML, and six Ph-negative disease. Five patients were in accelerated phase and four in late chronic phase. Three patients treated with DCF had normalization of WBC counts while on the weekly schedule but progressed when changed to every other week. The fourth patient had no objective response. There were no cytogenetic responses. DCF was well tolerated with only mild nausea and vomiting in all patients. Patients treated with fludarabine received a median of two courses (range 1-4). In two patients (both Ph-positive), disease progressed to blastic phase upon recovery. Two other patients died of hemorrhagic complications secondary to thrombocytopenia. In all other cases fludarabine produced a transient reduction of WBC counts, but counts recovered to levels equal to or greater than the pre-treatment values. There were no cytogenetic responses. These results, together with previous experience with 2-CDA producing only hematologic responses, suggest that nucleoside analogs may not have a significant role in the management of CML.

Adult↗
PubMed1997

A pilot study of all-trans retinoic acid in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

Retinoids have significant antiproliferative effect against chronic myelogenous leukemia (CML) cells in vitro. We conducted a pilot study to investigate the clinical effect of all-trans retinoic acid (ATRA) in patients with CML. Thirteen patients with Philadelphia chromosome (Ph)-positive CML in late chronic phase (n=7), accelerated phase (n=5), or blastic phase (n=1) were treated. All had been previously treated and 12 (92%) had disease refractory to interferon-alpha therapy. They received ATRA 175 mg/m2 orally in two divided doses daily until disease progression. The median duration of therapy was 56 days (range 11 to 190). Only one patient in late chronic phase had a transient decrease in WBC counts; all other patients in late chronic phase showed no response to therapy. Four of the five patients in accelerated phase showed evidence of antileukemia effect manifested by a decrease in bone marrow and/or peripheral blood blasts, promyelocyte and/or basophil percentages. In all cases the response was transient. The patient in blastic phase had no evidence of antileukemic effect. The treatment was well tolerated with the major side-effects being headache, nausea, dry skin, and dry mucosal membranes. One patient required dose reductions due to toxicity. We conclude that in this population of patients with extensively treated, advanced stage, Ph-positive CML, ATRA alone is ineffective for long-term therapy. The antileukemia effect seen in some patients warrants further investigation of retinoids in other schedules and in combinations in patients with CML.

Adolescent↗
PubMed1997

Analysis of the BCR-ABL protein in Philadelphia chromosome-positive adult acute lymphocytic leukemia.

Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL) constitutes 15-35% of all ALL in adults. Its detection is prognostically significant. The Ph abnormality is usually detected through standard cytogenetic analysis but 20-30% of patients have insufficient metaphases (IM) with such analysis. To detect the BCR-ABL oncoprotein in peripheral blood specimen of patients with ALL at the time of diagnosis and at follow-up, a new sensitive technique of enhanced chemiluminescence Western blot (ECL-WB) analysis was investigated. Among 41 patients with newly diagnosed ALL, nine were Ph positive by cytogenetic studies; they were also BCR-ABL positive according to ECL-WB. Eight had p190 disease, and one had p210 disease. Among the 16 patients with IM, none demonstrated the oncoprotein through ECL-WB or through simultaneous Southern blot (SB) for p210 rearrangement. Follow-up studies were available for seven patients: four had detectable protein and three of them relapsed 4-20 weeks later; three had undetectable protein and one of them (who had low level protein at the time of diagnosis) relapsed 11 weeks later. Although none of the patients with IM at diagnosis had detectable protein according to ECL-WB, this was probably due to the small number of patients studied. One patient with IM studied at follow-up demonstrated the protein by ECL-WB. In summary, we describe a technique that is useful in the detection of p190/p210 ALL at diagnosis. It is less time consuming, and more cost effective than standard chromosome banding techniques. It may also detect the oncoprotein in cases with IM. Although a larger number of patients should be studied to prove its clinical usefulness, this technique may also be of value for monitoring residual disease at follow-up.

Blotting, Western↗