Late mortality after bone marrow transplant for chronic myelogenous leukemia in the context of prior tyrosine kinase inhibitor exposure: A Blood or Marrow Transplant Survivor Study (BMTSS) report

Cancer ◽  
2019 ◽  
Vol 125 (22) ◽  
pp. 4033-4042
Author(s):  
Jessica Wu ◽  
Yanjun Chen ◽  
Lindsey Hageman ◽  
Liton Francisco ◽  
Emily C. Ness ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Bone Marrow Transplant ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Marrow Transplant ◽  
Myelogenous Leukemia ◽  
Late Mortality

Treatment of chronic myelogenous leukemia with the tyrosine kinase inhibitor STI571 results in marked regression of bone marrow fibrosis

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 381-383 ◽  
Author(s):  
Christine Beham-Schmid ◽  
Ute Apfelbeck ◽  
Heinz Sill ◽  
Oleksiy Tsybrovsky ◽  
Gerald Höfler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Bone Marrow Fibrosis ◽  
Bone Marrow Trephine Biopsy ◽  
Significant Regression ◽  
Marrow Fibrosis

Morphologic bone marrow changes in patients with BCR-ABL–positive chronic myelogenous leukemia (CML) were investigated during treatment with the tyrosine kinase inhibitor STI571. Bone marrow trephine biopsy specimens from 23 pretreated patients with CML were examined morphologically and by morphometry before and 6 weeks and 3 months after the initiation of STI571 therapy (Glivec, Novartis, Basel, Switzerland). Bone marrow changes during treatment showed a quantitative normalization of erythropoiesis, a marked reduction of granulopoiesis, and a significant decrease in megakaryocytes with the reappearance of normal-sized forms. Furthermore, a significant regression of bone marrow fibrosis was observed in patients with initial fibrosis (P < .000 000 001). These results may expand the profile of STI571 and may offer novel therapeutic possibilities in diseases with bone marrow fibrosis.

Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2808-2816 ◽  
Author(s):  
Nicholas C. Wolff ◽  
Robert L. Ilaria
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Murine Model ◽  
High Efficiency ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Leukemic Cells

Abstract The murine bone marrow retroviral transduction and transplantation model of chronic myelogenous leukemia (CML) imperfectly mimics human CML because the murine CML-like disease causes death of all animals from an overwhelming granulocytosis within 3 to 4 weeks. In this report, mice reconstituted with P210BCR/ABL-transduced bone marrow cells received posttransplantation therapy with either the tyrosine kinase inhibitor STI571 or placebo. Compared with the rapidly fatal leukemia of placebo-treated animals, 80% of the STI571-treated mice were alive on day 74, with marked improvement in peripheral white blood counts and splenomegaly. There was decreased tyrosine phosphorylation of STAT5, Shc, and Crk-L in leukemic cells from STI571-treated animals, consistent with STI571-mediated inhibition of the Bcr/Abl tyrosine kinase in vivo. In some STI571-treated animals Bcr/Abl messenger RNA and protein expression were markedly increased. In contrast to the polyclonal leukemia of placebo-treated mice, STI571-treated murine CML was generally oligoclonal, suggesting that STI571 eliminated or severely suppressed certain leukemic clones. None of the STI571-treated mice were cured of the CML-like myeloproliferative disorder, however, and STI571-treated murine CML was transplanted to secondary recipients with high efficiency. These results demonstrate the utility of this murine model of CML in the evaluation of novel therapeutic agents against Bcr/Abl-induced leukemias. This improved murine chronic-phase CML model may be a useful tool for the study of STI571 resistance, CML progression, and the anti-CML immune response.

scholarly journals The Bone Phenotype and Pain Response to Pamidronate in Tyrosine Kinase Inhibitor–Treated Chronic Myelogenous Leukemia

2019 ◽  
Vol 3 (5) ◽  
pp. 857-864 ◽  
Author(s):  
Declan C T Lavoie ◽  
Marie-Eve Robinson ◽  
Donna Johnston ◽  
Marika Pagé ◽  
Victor N Konji ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Pain Response ◽  
Bone Phenotype

Imatinib Resistance Restoration with Antioxidants and Immunomodulation in Patients with Chronic Myelogenous Leukemia (CML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4818-4818
Author(s):  
Eugene McPherson ◽  
R. Shuklar ◽  
S.Y. Huang ◽  
M. Grimbel ◽  
E. Hazel
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Reductase Inhibitor ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Hmg Coa Reductase ◽  
Hmg Coa Reductase Inhibitor ◽  
Coa Reductase

Abstract Imatinib mesylate (IM) is potent BCR/abl tyrosine kinase inhibitor in patients with chronic myelogenous leukemia (CML). It has remarkable frontline clinical effects in this disease, however, the leukemic cells become resistant to IM in both chronic and blast phases. BCR/abl kinase can induce reactive oxygen species (ROS) and promote self-mutation which subsequently render IM to resistance and failure to eliminate all leukemia cells. This mechanism of resistance in IM (mutation) is caused by oxidant damage to DNA with kinase domain mutations, reduced IM binding and kinase inhibition. Antioxidants (ascorbic acid, etc.) may help overcome IM resistance and restore sensitivity to IM via suppression of transcription factor Nrf2 that regulates the gene expression gammaglutamylcysteine ((g-GCS), the rate-limiting enzyme in glutathione (GSH) biosynthesis and detoxification. P-glycoprotein (P-gp) drug efflux can also exist and complete molecular response relapse occurs. Leukemic cells that are P-gp positive, and P-gp dependent decline of intracellular IM levels are associated with retained phosphorylation pattern of BCR/abl and loss of IM effect on apoptosis and cellular proliferation. Modulation of P-gp with HMG-CoA reductase inhibitor simvastatin may help restore IM cytotoxicity. We present a case of an 80+ year old female with CML-chronic phase-II (CML-CP-II) with concommitant cormorbidities of CAD, unstable angina, hypertension, and dyslipidemia treated with aspirin, simvastatin and started on IM 400mg daily. After two months of therapy she developed grade 3 neutropenia, lower extremity edemia, nausea/vomiting and fluid retention requiring IM interruption and supportive care with growth factors. IM dose reduction to 300mg daily and simvastatin 10 mg every other day. Soluble interleukin-2 receptor (sIL-2R) levels were elevated and trending down once proinflammatory cytokines were modulated. Real-time BCR-ABL/abl-PCR ratio increased insignificantly from 0.001% to 0.003%. Betacarotene level significantly decreased to 4, ascorbic level within normal limits, VEGF remained < 31 pg/ml (normal 31–86 pg/ml), fibrinogen level 309.90 mg/dl (normal 162–431), ESR 15 mm/hr, C-reactive protein 5.55 mg/dl and sIL-2R increased to > 3,000 U/mL (normal 200– 1100 U/mL). Betacarotene and ascorbic antioxidants dosage were increased and immunomodulation of preinflammatory cytokines ROS, sIL-2R and betacarotene normalized, 512 and 44 respectively. Serial measurement of BCR-ABL/abl ratio did not exceed 0.02% on three occasions or 0.05% on two occasions, therefore no molecular relapse and persistent low levels of BCR-ABL/abl ratio with no hematologic or cytogenetic relapse. We felt that an acute coronary syndrome with perturbation of CML with some IM resistance was developed. CONCLUSION: IM, a tyrosine kinase inhibitor may develop resistance when leukemic cells are positive with P-gp and oxidative stress increase ROS along with decreases in IM intracellular levels. Modulation by HMG -CoA reductase inhibitor (simvastatin) via a mechanism of inhibition of P-gp transport and antioxidants reduction of BCR/abl mutagenesis may allow IM to efficently restore normal hematopoiesis in CML patients.

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