Chronic myeloid leukemia (CML) was the first human malignancy to be associated with a specific genetic lesion, the Philadelphia chromosome, harboring the BCR-ABL oncogene. Since then, it has become a paradigm for the discovery of molecular mechanisms and targeted therapeutic approaches in the field of hematologic neoplasias. The past 5 years or so have been particularly fruitful in the dissection of the signal transduction pathways abnormally activated in CML and in the translation of this knowledge to clinical practice. In this report, we discuss the biological basis for such translation and highlight the current and potential tools for the effective treatment of CML patients. The first part presents a review of the basic concepts on the biology of CML and their application to the design of targeted therapy. The mechanisms of action of the molecular-specific drugs currently used in clinical trials are discussed, with emphasis on the description of the most promising new compounds that are enhancing the potential for effective alternative or combination chemotherapy in CML. In the following section, we explain how molecular monitoring of response to imatinib mesylate in patients with CML can be used as a guide to clinical management. In particular, we discuss the relative value of regular quantitative RT/PCR and cytogenetic analyses, how responding patients should be monitored and managed, and how to investigate patients who are refractory or become resistant to imatinib treatment. In the last part of this report, a discussion on the possibility of managing CML with patient-specific strategies is presented. We review the current treatment options, highlight the factors impacting on decision making, discuss the range of possibilities for future therapeutic strategies and propose a systematic approach for individualizing treatment for patients in different disease categories.

Chronic myeloid leukemia.

Haematopoietic stem cell transplantation (HSCT) has been proposed for refractory autoimmune diseases, including systemic sclerosis (SSc) A sequential Bayesian phase I-II clinical trial was conducted in SSc patients to assess the feasibility, the tolerance and the efficacy of autologous HSCT Peripheral blood stem cells (PBSC) were collected using cyclophosphamide (4 g/m2) and recombinant human granulocyte colony-stimulating factor (5 micro g/kg/d) and reinfused after positive CD34+ selection Conditioning used cyclophosphamide (200 mg/kg) or melphalan (140 mg/m2) according to cardiac function The main end-point was the failure of the procedure, defined by failure of either PBSC mobilization, CD34+ selection or intensification procedure, or by procedure-related death Among the 12 enrolled patients, three failures occurred: one PBSC mobilization, one CD34+ selection and one CD34+ intensification Probability of graft failure was estimated at 0286 (95% confidence interval: 0095-054) Autologous PBSC (n = 10) or bone marrow (n = 1) transplantation was actually performed in 11 patients with one procedure-related death Median time to neutrophil (> 05 x 10(9)/l) and platelet (> 25 x 10(9)/l) haematopoietic reconstitution was 12 and 10 d respectively After 18 months (range 1-26), eight out of 11 patients have shown major or partial response Non-myeloablative conditioning, followed by a T cell-depleted autologous PBSC or bone marrow transplantation, appears feasible with low toxicity in severe SSc with short-term clinical benefits

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2141.2002.03895.x

Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I-II study.

Souza et al, Blood 66 1985 102(a). Sevier et al, Clin Chem 27/u, 1981, pp. 1797-1806. Kipps et al., Handbook of Experimental Immunol, ed Weir et al., 1986, pp. 108.1-108.9 Nature, vol. 319, Jan. 30, 1986, by S. Nagata, "Molecu lar Cloning and Expression of cDNA for Human Gran ulocyte Colony Stimulating Factor" pp. 415-418. Science, vol. 232, No. 4746 Apr. 4, 1986, by Souza et al, "Recombinant Human Granulocyte Colony-Stimulat ing Factor: Effects on Normal and Leukemic Myeloid Cells", pp. 61-65. Primary Examiner-Garnette D. Draper

Recombinant human granulocyte-colony stimulating factor의 토끼에 피부 및 안점막 자극 평가

Purpose: Primitive quiescent chronic myeloid leukemia (CML) cells are biologically resistant to imatinib mesylate, an inhibitor of the p210 BCR-ABL kinase. The present study was designed to investigate whether either continuous or intermittent exposure of these cells to granulocyte-colony stimulating factor (G-CSF) in vitro can overcome this limitation to the effectiveness of imatinib mesylate therapy. Experimental Design: CD34 + leukemic cells were isolated from six newly diagnosed chronic phase CML patients and cultured for 12 days in serum-free medium with or without G-CSF and/or imatinib mesylate present either continuously or intermittently (three cycles of G-CSF for 0, 1, or 4 days ± imatinib mesylate for 0, 3, or 4 days). Every 4 days, the number of residual undivided viable cells and the total number of viable cells present were measured. Results: Intermittent but not continuous exposure to G-CSF significantly accelerated the disappearance in vitro of initially quiescent CD34 + CML cells. This resulted in 3- and 5-fold fewer of these cells remaining after 8 and 12 days, respectively, relative to continuous imatinib mesylate alone ( P Conclusion: Intermittent exposure to G-CSF can enhance the effect of imatinib mesylate on CML cells by specifically targeting the primitive quiescent leukemic elements. A protocol for treating chronic-phase CML patients with imatinib mesylate that incorporates intermittent G-CSF exposure may offer a novel strategy for obtaining improved responses in vivo .

https://clincancerres.aacrjournals.org/content/clincanres/12/2/626.full.pdf

Intermittent exposure of primitive quiescent chronic myeloid leukemia cells to granulocyte-colony stimulating factor in vitro promotes their elimination by imatinib mesylate.

The selective tyrosine kinase inhibitor imatinib (Glivec; Novartis International, Basel, Switzerland, http://www.glivec.com/content/home.jsp) is increasingly used for the treatment of Philadelphia chromosome-positive leukemias and other malignancies. In principle, the drug is well tolerated and clinical side effects are mostly moderate. However, it was shown that imatinib can affect the function of normal, nonmalignant cells, resulting in myelosuppression in treated patients. Recently, it has been demonstrated that imatinib might affect mobilization, proliferation, and differentiation of hematopoietic progenitor cells while leaving hematopoietic stem cells unaffected. Furthermore, in several in vitro studies and animal models, it was demonstrated that imatinib can affect the function and differentiation of antigen-presenting cells and inhibit the effector functions of T lymphocytes. Moreover, the induction of specific cytotoxic T cells seems to be impaired in chronic myeloid leukemia (CML) patients treated with imatinib compared with patients receiving interferon-alpha. This is of importance because some of the therapeutic effects in the treatment of patients with CML are mediated by the induction of leukemia-specific T-cell responses. Further studies investigating the effects of imatinib on normal hematopoiesis are of interest as they might lead to a better understanding of the clinically observed side effects and also might help identify new therapeutic applications of the drug, possibly in Bcr-Abl-negative myeloproliferative disorders and potentially as an immunomodulatory agent.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2005-0069

Effects of Imatinib on Normal Hematopoiesis and Immune Activation

For 10 consecutive patients in our unit who did not show a significant rise in blood progenitor cells within 14 days following chemotherapy and G-CSF, we increased the G-CSF dose from 5 to 10 microg/kg/day (n = 9) or from 10 to 15 microg/kg/day (n = 1). As a result, there were significant increases in total yield as well as yield per apheresis of mononuclear cells, CD34+ cells and CFU-GM (P < 0.025, <0.01 and <0.005, respectively). After G-CSF dose escalation, six of the 10 patients had sufficient CD34+ cells for performing transplantation. These results demonstrate a dose-dependent response of progenitor cell mobilization by G-CSF when used in combination with chemotherapy. Moreover, increasing the dose of G-CSF as late as the third week of mobilization may still provide sufficient cell yield even with patients who did not show a significant mobilization with conventional doses of G-CSF.

Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF

Imatinib mesylate (Glivec) is a selective inhibitor of bcr-abl tyrosine kinase, the product of the Philadelphia chromosome, which is the hallmark of chronic myeloid leukaemia (CML). With imatinib, complete cytogenetic response (CCR) can be achieved in over 70% of newly diagnosed patients with CML. However, the optimal long-term management of patients who achieve CCR after imatinib is unknown. With longer follow-up, it is anticipated that some patients are likely to progress and become candidates for autologous transplantation. We studied filgrastim (r-metHuG-CSF) mobilisation of peripheral blood stem cells (PBSC) in 32 patients who have achieved CCR with imatinib. Our data demonstrate that (1) the target CD34+ cell yields of ⩾2.0 × 106/kg were attained with filgrastim 10 μg/kg/day, in 9/18 (50%) of patients during uninterrupted imatinib therapy, and in 10/14 (70%) when imatinib was temporarily withheld. The median CD34+ cell yield per aphaeresis was 0.70 × 106/kg (range 0.14–2.18) and 2.90 × 106/kg (range 0.15–8.71) in the two groups, respectively (P<0.005). (2) The cell yields did not correlate with the duration of imatinib administration. (3) There was no impact of the mobilisation procedure on the level of leukaemia as measured by serial blood bcr-abl levels using real-time quantitative PCR with either protocol. (4) bcr-abl remained detectable at low levels in the harvests in most but not all patients. In conclusion, filgrastim can safely be used to mobilise PBSC in patients who have achieved CCR with imatinib, but CD34+ cell yields are significantly improved when imatinib is temporarily withheld.

Successful peripheral blood stem cell mobilisation with filgrastim in patients with chronic myeloid leukaemia achieving complete cytogenetic response with imatinib, without increasing disease burden as measured by quantitative real-time PCR.

Selected CD34 blood cell allografts for older patients: low transplant-related mortality, graft failure and acute GvHD.

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Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF

Successful peripheral blood stem cell mobilisation with filgrastim in patients with chronic myeloid leukaemia achieving complete cytogenetic response with imatinib, without increasing disease burden as measured by quantitative real-time PCR.

Selected CD34 blood cell allografts for older patients: low transplant-related mortality, graft failure and acute GvHD.