Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase [see comments]

Goldman, JM; Szydlo, Richard; Horowitz, M.; Rp, Gale; Ash, RC; Atkinson, K; Ka, Dicke; Gluckman, Éliane; Herzig, RH; Marmont, A

doi:10.1182/blood.v82.7.2235.2235

Cited by 150 publications

(22 citation statements)

References 4 publications

(4 reference statements)

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“…1,2 However, among other factors, outcome determined as capacity for unsupported hematopoietic reconstitution at day 30 following BMT is significantly influenced by progression of disease at onset and thus timing. [3][4][5] Regarding staging of chronic phase CML indicating a certain progress [4][5][6] or definition of acceler-ated or blastic phases, 7 some data have been accumulated that histopathology may offer supportive evidence. Follow-up studies on bone marrow histopathology together with clinical observations were in keeping with the finding that reduction in erythropoiesis 8 and extent of myelofibrosis [9][10][11][12] may serve as valid parameters for the assessment of disease progression.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietic reconstitution, macrophages and reticulin fibrosis in bone marrow specimens of CML patients following allogeneic transplantation

Thiele

Kvasnicka

Dw³

et al. 2000

Leukemia

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A clinicopathological study was conducted on 351 bone marrow trephine biopsies derived from 124 patients with chronic myeloid leukemia (CML) at standardized endpoints before and after allogeneic bone marrow transplantation (BMT). The purpose was to investigate quantitative changes of the nucleated erythroid precursor cell population and other associated features such as resident bone marrow macrophages and myelofibrosis and to elucidate their relevance on engraftment parameters. Monoclonal antibodies were applied for the identification of erythroid precursors and the labeling of mature macrophages; argyrophilic (reticulin-collagen) fibers were demonstrated by a silver impregnation technique. Following morphometric analysis of the pregraft bone marrow specimens statistical evaluation was in line with an adverse correlation between early to moderate reticulin fibrosis and amount of erythropoiesis. Moreover, a significant relationship was calculable between numbers of erythroid precursors and CD68+ macrophages. After myelo-ablative therapy and BMT a pronounced decrease in cellularity and in the quantity of erythropoiesis was found. Comparable with the pregraft samples, a significant association between erythroid precursors and macrophages could be determined in the regenerating donor bone marrow. A pretransplant relevant reduction of the red cell lineage and a manifest (reticulin) myelofibrosis indicating an advanced stage of disease were accompanied by a significant delay to reach transfusion independence. This result was further supported by comparable findings in trephine biopsies performed in the early post-transplant period (second month after BMT). Corresponding examinations revealed an enhancement of fiber density and a decrease in erythropoiesis in those patients who did not conform with the usually accepted criteria for successful engraftment. In conclusion, compelling evidence has been produced that a significantly reduced amount of erythroid precursors, which is usually associated with myelofibrosis in the pretransplant bone marrow, exerts an impairment to undisturbed hematopoietic reconstitution. Moreover, a close spatial and numerical relationship between the erythroid lineage and resident (mature) macrophages is observable, in particular in the state of regeneration after BMT.

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Section: Introductionmentioning

confidence: 99%

Erythropoietic reconstitution, macrophages and reticulin fibrosis in bone marrow specimens of CML patients following allogeneic transplantation

Thiele

Kvasnicka

Dw³

et al. 2000

Leukemia

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“…Allogeneic SCT is reported to produce long‐term, disease‐free survival in approximately 40–80% of patients treated in chronic phase (depending on patient age, donor source and degree of matching, and other factors). However, it is linked to an inherent risk of mortality (10–40%), as well as significant morbidities 4–6. IFN‐α therapy induces complete suppression of Ph‐positive cells (i.e., complete cytogenetic response) in 5–30% of patients and prolongs median survival to approximately 7 years 7–12.…”

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confidence: 99%

Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome‐positive chronic myelogenous leukemia in the chronic phase

Kantarjian

O’Brien

Cortes

et al. 2003

Cancer

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BACKGROUND The International Randomized study of Interferon‐alpha plus cytarabine (IFN‐α plus ara‐C) versus STI571 (imatinib mesylate) [IRIS trial] in patients with newly diagnosed Philadelphia chromosome (Ph)‐positive, chronic‐phase chronic myelogenous leukemia (CML) has not shown (to date) a survival advantage for imatinib. This was most likely because approximately 90% of patients receiving IFN‐α plus ara‐C changed to imatinib therapy after a median of 8 months into therapy. METHODS The authors analyzed the results with imatinib therapy in patients with newly diagnosed Ph‐positive CML in chronic phase and compared their outcome with patients who received IFN‐α regimens. A total of 187 patients with Ph‐positive CML in early chronic phase treated with imatinib were compared with a historic group of 650 similar patients treated with IFN‐α regimens from 1982 until 1997. RESULTS Patients who received imatinib were significantly older and had significantly more bone marrow basophilia and less leukocytosis. The complete cytogenetic response (Ph 0%) rates were better with imatinib (81% vs. 32%; P < 0.001), as were the survival rates (30‐month estimated survival rates 98% vs. 88%; P = 0.01). A multivariate analysis of the total study group of 837 patients identified imatinib therapy to be a significant independent favorable prognostic factor for survival (P = 0.01). CONCLUSIONS The current study is the first to indicate the survival advantage of imatinib compared with IFN‐α, the previous standard of care, in patients with early chronic‐phase CML. Cancer 2003;98:2636–42. © 2003 American Cancer Society.

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“…Treatment of Philadelphia chromosome (Ph)‐positive chronic myelogenous leukemia (CML) has centered around strategies that suppress the Ph‐positive cells or the Ph‐associated BCR‐ABL molecular abnormalities 1, 2. Therapeutic modalities now include allogeneic stem cell transplants (SCT), regimens containing interferon‐alpha (IFN‐α), and, more recently, the Bcr‐Abl selective tyrosine kinase inhibitor, imatinib mesylate (imatinib, Gleevec, STI571 [Novartis Pharmaceuticals, East Hanover, NJ]) 3–17. The early results with imatinib are extremely encouraging 18, 19.…”

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confidence: 99%

Results of triple therapy with interferon‐alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in early chronic phase

O’Brien

Giles

Talpaz

et al. 2003

Cancer

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BACKGROUND Before the discovery of imatinib mesylate, a Bcr‐Abl selective tyrosine kinase inhibitor, three agents, interferon‐alpha (IFN‐α), cytarabine (ara‐C), and homoharringtonine (HHT), had demonstrated activity against Philadelphia chromosome (Ph)‐positive chronic myelogenous leukemia (CML) as single agents and in couplet combinations. The goals of the current study were to evaluate the efficacy of the triple combination regimen with IFN‐α, ara‐C, and HHT in newly diagnosed Ph‐positive CML and to assess the impact of the added sequential therapy with imatinib on overall prognosis. METHODS Ninety patients with Ph‐positive CML in early chronic phase received the triple regimen. Therapy consisted of 5 million units (MU)/m2 IFN‐α subcutaneously (s.c. daily, ara‐C 10 mg s.c. daily, and HHT 2.5 mg/m2 by continuous infusion over 24 hours daily × 5 every month. After a median duration of 16.5 months of therapy, 78 patients had their therapy changed to 400 mg orally administered imatinib daily. RESULTS With the triple regimen, 85 patients (94%) achieved complete hematologic response and 67 patients (74%) had a cytogenetic response (Ph suppression to ≤ 90%) which was complete (Ph 0%) in 20 patients (22%) and major in 42 patients (46%). Myelosuppression was significant, resulting in considerable reductions in the dose schedules. After 12 months of therapy, the median IFN‐α dose was 1.6 MU/m2 daily, the median ara‐C dose was 1.85 mg daily, and the median number of HHT days was 2 every month. Only three patients developed blastic phase while receiving the triple regimen. With the change to imatinib therapy, currently 57 patients (63%) are in complete cytogenetic response and 69 patients (76%) in major cytogenetic response. With a median follow‐up time of 46 months for the total study group, the estimated 5‐year survival rate was 88%, and only 8 patients (9%) to date have developed blastic phase. CONCLUSIONS The sequence of IFN‐α, ara‐C, and HHT followed by imatinib (imposed by the discovery of the latter drug) resulted in an estimated 5‐year survival rate of 88%. This finding suggests that imatinib combination regimens may improve the prognosis in CML. Cancer 2003;98:888–93. © 2003 American Cancer Society. DOI 10.1002/cncr.11620

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Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase [see comments]

Cited by 150 publications

References 4 publications

Erythropoietic reconstitution, macrophages and reticulin fibrosis in bone marrow specimens of CML patients following allogeneic transplantation

Erythropoietic reconstitution, macrophages and reticulin fibrosis in bone marrow specimens of CML patients following allogeneic transplantation

Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome‐positive chronic myelogenous leukemia in the chronic phase

Results of triple therapy with interferon‐alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in early chronic phase

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