Blast crisis in chronic myeloid leukemia

Although the worst prognosis among acute forms of leukemia is persistently attributed to the blast crisis of chronic myeloid leukemia, a therapeutic nihilism seems to us to be unreasonable. Even in the developing stage of a blast crisis we consider an aggressive chemotherapy to be justified particularly in younger patients. In this connection, value and necessity of supporting of therapy are especially emphasized. Remissions can be achieved in about one third of patients during the blast crisis of CML. As in other forms of tumour therapy, the initial status, age, and secondary diseases have to be taken into account and a careful, individual therapy planning has to be made. For the future there is the hope that the increasing possibilities of differentiating blasts will allow more systematic therapeutic conclusions to be made. According to the present knowledge the greatest hopes for achieving long-term remissions or even healings can, in our opinion, be expected by bone-marrow transplantation.     

Imatinib mesylate in chronic myeloid leukemia

Chronic myeloid leukemia has become a paradigm for the discovery of target therapeutic approaches in the field of onco-hematology. Recognition of the tyrosine kinase activity of the p210Bcr-Abl oncoprotein led to the development of compounds targeting against BCR-ABL and then controlling the leukemic proliferation. Imatinib mesylate, one of the first tyrosine kinase inhibitors developed, was found effective and safe. According to five-years experience with this drug, it is recommended that the golden standard for initial treatment of newly diagnosis chronic myeloid leukemia patients should be 400 mg Imatinib daily. In this brief review, we discuss the current tools for the effective management of chronic myeloid leukemia with Imatinib, providing the updated results of IRIS and RIGHT clinical trials and then the suggestions how Imatinib-treated patients should be monitored.     

Morbidity of chronic myeloid leukemia

In 129 patients with chronic myeloid leukemia recorded in our files between 1955 and 1978, the sex ratio showed a slight decrease of the previously higher proportion of males. The morbidity rates of the two sexes are approaching. A shift of the incidence peak in males to a younger age is a striking feature, in contrast to a shift to the opposite direction in females. The incidence peak of women shifted from 35 years in the first to 65 yr in the second period, for men from 55 to 35 yr. The mean age at diagnosis was higher in women than in men. A decrease of frequency was observed during the second period 1970-1978. Whether this is a real improvement and consistent trend has to be ascertained by further studies.     

Overcoming kinase resistance in chronic myeloid leukemia

Imatinib is a small-molecule inhibitor of BCR-ABL tyrosine kinase activity, with proven efficacy and tolerability. Despite imatinib's activity, the development of resistance, whether BCR-ABL dependent or independent, is a concern. BCR-ABL-dependent resistance is commonly a result of mutations in the BCR-ABL gene, which can induce a structural predisposition towards the active conformation of the protein, resulting in a shift in the equilibrium of BCR-ABL from inactive, which imatinib binds, to active, which imatinib is unable to bind. BCR-ABL gene amplification may play a role in the development of imatinib resistance in patients with CML. There are a number of BCR-ABL-independent mechanisms of imatinib resistance, including the efflux protein multidrug resistance protein-1, of which imatinib is a substrate. Another mechanism may be the development of alternative pathways of disease progression, leading to less reliance on BCR-ABL; indeed, the SRC family tyrosine kinases LYN and HCK have been frequently implicated in treatment resistance and progression of CML. Clearly, imatinib resistance requires the development of other treatment options. Dasatinib, with increased binding potency (325-fold greater potency than imatinib for wild-type BCR-ABL), inhibition of both the active and inactive formation of BCR-ABL, and targeting of SRC family kinases, is the only agent approved for the treatment of patients with imatinib-resistant or -intolerant CML and Ph+ ALL. Dasatinib is highly active in all phases of these diseases, and is active in the majority of imatinib-resistant mutations, with the exception of T315I. The development of agents that effectively inhibit T315I mutations suggests that future treatment options will include combination therapy.     

Variant Philadelphia translocations in chronic myeloid leukemia

Up to the beginning of 1986, some 327 variant Philadelphia translocations were reported in chronic myeloid leukemia. The present study represents an attempt to determine which factors (sex, age, geographic localization, etc.) influence the occurrence and chromosome involvement of these variant Philadelphia (Ph1) translocations. Clinical data indicated that band 9q34 was always rearranged in the variant Ph1 translocations and no difference existed between the hematologic and prognostic features among patients with the standard and the variant translocations. An uneven geographic distribution of the variant Ph1 translocations was found. Whether this was due to populations with different ethnic backgrounds or to environmental factors could not be determined. Twenty-eight bands were shown to be rearranged more frequently than expected (P less than 0.05); 27 of them are known to contain a fragile site and/or an oncogene and/or are rearranged more frequently than expected in other malignancies. The chromosomes involved in these variant Ph1 translocations were found to show a very particular geographic distribution, which cannot be explained at present.     

Long-term treatment effects in chronic myeloid leukemia

We propose and analyze a simplified version of a partial differential equation (PDE) model for chronic myeloid leukemia (CML) derived from an agent-based model proposed by Roeder et al. This model describes the proliferation and differentiation of leukemic stem cells in the bone marrow and the effect of the drug Imatinib on these cells. We first simplify the PDE model by noting that most of the dynamics occurs in a subspace of the original 2D state space. Then we determine the dominant eigenvalue of the corresponding linearized system that controls the long-term behavior of solutions. We mathematically show a non-monotonous dependence of the dominant eigenvalue with respect to treatment dose, with the existence of a unique minimal negative eigenvalue. In terms of CML treatment, this shows that there is a unique dose that maximizes the decay rate of the CML tumor load over long time scales. Moreover this unique dose is lower than the dose that maximizes the initial tumor load decay. Numerical simulations of the full model confirm that this phenomenon is not an artifact of the simplification. Therefore, while optimal asymptotic dosage might not be the best one at short time scales, our results raise interesting perspectives in terms of strategies for achieving and improving long-term deep response.

     

Megakaryoblastic micromegakaryocytic crisis in chronic myeloid leukemia

Atypical megakaryoblasts (MKB) or megakaryocytes (MK) are occasionally present in the peripheral blood during the terminal development of chronic myeloid leukemia (CML). We report on a 49-year-old female suffering from Ph1 chromosome-positive CML with typical megakaryoblastic transformation in the peripheral blood and in the bone marrow. The small "blasts" were at the most only slightly larger and were occasionally even smaller than lymphocytes but showed megakaryoblastic or atypical megakaryocytic differentiation. The cytoplasmic cytochemical pattern of the atypical megakaryocytic cells was identical to that of large atypical thrombocytes. Platelet peroxidase was detected upon electron-microscopic (EM) examination. Immunologic characterization disclosed the presence of MK-specific antigens. When cultured in vitro on agar, the blasts transformed spontaneously into large mature MK, exhibiting characteristic cytochemical and immunological patterns. Cytogenetic examination of peripheral blood showed severe abnormalities. The patient did not respond to therapy and died 3 months after manifestation of the blast crisis.     

Molecular genetics of chronic neutrophilic leukemia,chronic myelomonocytic leukemia and atypical chronic myeloid leukemia

According to the 2008 World Health Organization classification, chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia are rare diseases. The remarkable progress in our understanding of the molecular genetics of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms has made it clear that there are some specific genetic abnormalities in these 3 rare diseases. At the same time, there is considerable overlap among these disorders at the molecular level. The various combinations of genetic abnormalities indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. This review focuses on the current knowledge and challenges related to the molecular pathogenesis of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia and relationships between molecular findings, clinical features and prognosis.     

The allometry of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is an acquired neoplastic hematopoietic stem cell (HSC) disorder characterized by the expression of the BCR-ABL oncoprotein. This gene product is necessary and sufficient to explain the chronic phase of CML. The only known cause of CML is radiation exposure leading to a mutation of at least one HSC, although the vast majority of patients with CML do not have a history of radiation exposure. Nonetheless, in humans, significant radiation exposure (after exposure to atomic bomb fallout) leads to disease diagnosis in 3-5 years. In murine models, disease dynamics are much faster and CML is fatal over the span of a few months. Our objective is to develop a model that accounts for CML across all mammals. In the following, we combine a model of CML dynamics in humans with allometric scaling of hematopoiesis across mammals to illustrate the natural history of chronic phase CML in various mammals. We show how a single cell can lead to a fatal illness in mice and humans but a higher burden of CML stem cells is necessary to induce disease in larger mammals such as elephants. The different dynamics of the disease is rationalized in terms of mammalian mass. Our work illustrates the relevance of animal models to understand human disease and highlights the importance of considering the re-scaling of the dynamics that accrues to the same biological process when planning experiments involving different species.     

Breakpoints in variant Philadelphia translocations in chronic myeloid leukemia

To date, 327 cases of variant Philadelphia translocations found in chronic myeloid leukemia have been described. A statistical analysis using the Monte Carlo simulation was performed to determine which chromosomal bands were preferentially involved in variant Philadelphia translocations. The results showed that twenty-eight bands were significantly rearranged (P less than 0.05).