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Richard T Silver

Publications and source records attributed to Richard T Silver.

27 records · Page 2Linked to original sources
PubMed2003

The emergence of Ph-, trisomy -8+ cells in patients with chronic myeloid leukemia treated with imatinib mesylate.

OBJECTIVE: To describe clinical and laboratory features of a cohort of patients with chronic myelogenous leukemia (CML) who developed Ph(-), trisomy 8(+) metaphases while on treatment with imatinib mesylate. PATIENTS AND METHODS: Conventional cytogenetics and triple-color interphase fluorescence in situ hybridization were used to identify 5 of 310 studied patients who, on follow-up analysis, had Ph(-), trisomy 8(+) cells while on therapy. RESULTS: None of the 5 patients had cytogenetic evidence of clonal evolution at the start of treatment with imatinib. All patients developed grade 3 or 4 neutropenia and thrombocytopenia during treatment. The emergence of Ph(-), trisomy 8(+) metaphases was seen at 3, 6, 13, 16, and 18 months from the start of treatment and was present at multiple time points. The maximum number of trisomy 8 metaphases ranged from 25 to 50%. Concomitantly, all patients had a profound suppression of Ph(+) cells (ranging from 0 to 65%) as well as the appearance of normal metaphases, ranging from 6 to 55%. None of the patients has shown clinical or hematologic signs of progression to a more advanced phase of CML. CONCLUSIONS: While on treatment with imatinib mesylate a small group (less than 5%) of patients with CML developed Ph(-) trisomy 8(+) clone associated with pancytopenia. None of the patients developed clinical or hematological signs of progression to a more advanced phase of CML. These observations suggest that identification of trisomy 8 cells may represent clonal Ph(-) cells that were uncovered by treatment with a selective and potent inhibitor of Ph(+) cells.

Adult↗
PubMed2003

Chronic myeloid leukemia.

Chronic myeloid leukemia is a clonal myeloproliferative disorder of a pluripotent stem cell with a specific cytogenetic abnormality, the Philadelphia chromosome, involving myeloid, erythroid, megakaryocytic, B lymphoid, and sometimes T lymphoid cells but not marrow fibroblasts. Advances in cell biology and molecular genetics and a plethora of biochemical, cytogenetic, and molecular data of clinical relevance have yielded much new information regarding this disease. This article reviews the hematologic and clinical aspects of chronic myeloid leukemia; discusses the pertinent aspects of the advances in understanding of the cytogenetics and molecular biology of the disease; and reviews treatment programs employing busulfan, hydroxyurea, interferon, and marrow transplantation, which still are clinically important and relevant despite the development of the exciting new drug imatinib mesylate, a new paradigm for cancer chemotherapy in general.

Bone Marrow Transplantation↗
PubMed2003

Treatment of the chronic phase of chronic myeloid leukemia with an intermittent schedule of recombinant interferon alfa-2b and cytarabine: results from CALGB study 9013.

Despite nine studies reporting the results achieved when treating patients with chronic myeloid leukemia (CML) with interferon (rIFNalpha) and cytarabine (araC), the optimal doses and schedule for this combination remain to be determined. Results of imatinib mesylate (STI-571) in chronic phase CML are preliminary, thus, trials of rIFNalpha-2b/araC in CML are of continued interest. We report the results of CALGB study 9013, providing a 10-year follow-up on 88 evaluable previously untreated patients. Cycles of therapy with rIFNalpha-2b and araC sufficient to cause a decline in either the white blood cell (WBC) count to < 2000/microl or platelets to < 50,000/microl were given. The starting dose of rIFNalpha-2b was 5 million units (mu)/m2/day subcutaneously (s.c.) and of araC 10 mg/m2 twice daily s.c. Treatment was discontinued when cytopenia occurred and was restarted when both the WBC and platelet counts had recovered. Bone marrow was obtained regularly for morphologic, cytogenetic and molecular studies. Medians at entry included age 48 years, WBC = 89,900/microl and platelets = 345,000/microl. The performance status was 0 or 1 in 88%; splenomegaly was present in 46%. Fifty five (63%) patients had a complete hematologic response and 10 (11%) had a partial hematologic response for an overall response rate of 74%. Median time to best response was 5.3 months. Median survival for all patients from study entry was 81 months, the 5-year survival probability was 65%. When 28 patients were censored at the time of bone marrow transplantation the median survival was 82 months. Grade 3 anorexia, nausea, vomiting and diarrhea developed in 15, 27, 13 and 7%, respectively. Mild to moderate elevations of transaminases occurred in 42%, and were severe in 5%. Sixty-three patients had adequate follow-up cytogenetic studies: 10 had a complete cytogenetic response (CCyR), 23 partial (PCyR, 50-99% normal cells), 20 minor and 10 no response (CALGB criteria). Thus, the CCyR plus PCyR rate among these 63 patients was 52%. Assuming the 25 patients with no cytogenetic follow-up as non-responders, 38% of the 88 patients had at least a PCyR. The median time to CCyR or PCyR was 5.6 months. The median time to best response in these 33 patients was 10.0 months, and median duration of cytogenetic response was 28 months. Cytogenetic responders had significantly longer survival than non-responders (p = 0.01) using a landmark analysis at 18 months. This intermittent schedule of rIFNalpha-2b/ara-C has a high response rate in patients with CML with acceptable toxicity.

Adult↗
PubMed2003

Direct evidence that Bcr-Abl tyrosine kinase activity disrupts normal synergistic interactions between Kit ligand and cytokines in primary primitive progenitor cells.

We previously reported that chronic myelogenous leukemia (CML) primitive granulocyte-monocyte (GM) progenitors have a greatly reduced requirement for kit ligand (KL) to achieve optimal growth with granulocyte colony-stimulating factor (G-CSF) + granulocyte-monocyte colony-stimulating factor (GM-CSF). Conversely, others have demonstrated that unlike normal, CML CD34+ progenitors can proliferate in response to KL as a sole stimulus. To address these seemingly paradoxical findings, we examined the growth responses of CML CD34+ GM progenitors to various cytokines with and without a potent inhibitor of Bcr-Abl tyrosine kinase activity, PD173955. The heightened growth responses of CML GM progenitors to KL alone and to G-CSF + GM-CSF were abrogated by 10 nM PD173955 while having no effect on normal GM progenitors. While normal GM progenitors exhibited the expected synergistic response when KL was added to G-CSF + GM-CSF, CML GM progenitors had a minimal response; however, some synergism was restored by 10 nM PD173955. Normal erythroid progenitors require the synergistic interaction between KL and a saturating amount of erythropoietin (EPO, 1 unit) for optimal growth. In contrast, CML erythroid progenitors had up to 50% of optimal growth in KL alone, and, only a subthreshold amount of EPO (0.1 unit) was needed with KL to achieve 85% of the optimal response; these heightened growth responses were largely abrogated by 10 nM PD173955. Thus, direct evidence is provided that constitutively activated Bcr-Abl kinase pathways in primitive CML progenitors cooperate with single growth factors producing a heightened growth response, and, in so doing, disrupt the normally required synergistic interactions between KL and other cytokines to achieve activation and optimal growth of primitive progenitors. Coupled with our previous findings that a larger than normal proportion of CML primitive progenitors are at a later stage of maturation, we propose that this disruption of normal synergistic responses leads to increased progenitor recruitment into a committed pool by a process of accelerated maturation.

Antigens, CD34↗
PubMed2002

A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias.

The translocation (9;22) gives rise to the p190(Bcr-Abl) and p210(Bcr-Abl) tyrosine kinase proteins, considered sufficient for leukemic transformation. Philadelphia-positive (Ph(+)) acute leukemia patients failing to respond to initial induction therapy have a poor prognosis with few effective treatment options. Imatinib is an orally administered, potent inhibitor of the Bcr-Abl tyrosine kinase. We conducted a clinical trial in 56 patients with relapsed or refractory Ph(+) acute lymphoblastic leukemia (ALL; 48 patients) or chronic myelogenous leukemia in lymphoid blast crisis (LyBC; 8 patients). Imatinib was given once daily at 400 mg or 600 mg. Imatinib induced complete hematologic responses (CHRs) and complete marrow responses (marrow-CRs) in 29% of ALL patients (CHR, 19%; marrow-CR, 10%), which were sustained for at least 4 weeks in 6% of patients. Median estimated time to progression and overall survival for ALL patients were 2.2 and 4.9 months, respectively. CHRs were reported for 3 (38%) of the patients with LyBC (one sustained CHR). Grade 3 or 4 treatment-related nonhematologic toxicity was reported for 9% of patients; none of the patients discontinued therapy because of nonhematologic adverse reactions. Grade 4 neutropenia and thrombocytopenia occurred in 54% and 27% of patients, respectively. Imatinib therapy resulted in a clinically relevant hematologic response rate in relapsed or refractory Ph(+) acute lymphoid leukemia patients, but development of resistance and subsequent disease progression were rapid. Further studies are warranted to test the effects of imatinib in combination with other agents and to define the mechanisms of resistance to imatinib.

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↗
PubMed2002

Correlation of three methods of measuring cytogenetic response in chronic myelocytic leukemia.

Change in proportion of metaphases with a Ph chromosome is often used to measure effect of treatment in chronic myelocytic leukemia, but this method requires analysis of dividing cells. Dual-color fluorescence in situ hybridization (D-FISH) analysis of bone marrow (BM) or blood (PB), can be used to establish the proportion of interphase nuclei with BCR/ABL fusion. We studied the correlation of these three measures with each other and with response classification categories. In a clinical trial to test rIFN(-) versus rIFN(-) +Ara-C (N = 65 patients), we defined for each cytogenetic and FISH parameter, the patient's "best response" over time and at any given time. The strength and nature of agreement among the three measurements were determined by regression, correlation, and kappa statistic. Correlations between cyBM versus D-FISH-BM, cyBM versus D-FISH-PB and D-FISH-BM vs. D-FISH-PB were fairly strong. Regression showed cyBM values were significantly higher than those of D-FISH-PB or D-FISH-BM. No difference between D-FISH-PB and D-FISH-BM was apparent. When numerical responses (BR%) were classified into response categories (CR, PR, MR, NR), levels of agreement were weak to moderate. We observed a trend toward disagreement between cyBM and each D-FISH method, with cyBM tending to "downgrade" response category. Whether analyzed using actual numerical values or classified into response categories, cyBM differed from D-FISH-BM or D-FISH-PB. The results indicate that mixing data of different methods to measure treatment response within or between patients may be misleading clinical index.

Bone Marrow Cells↗