The choice of first-line chronic myelogenous leukemia treatment.

Imatinib has represented a revolution in the treatment of chronic myeloid leukemia (CML), inducing an overall survival never seen with previous therapies. However, with the commonly used dosage of 400 mg, one third of the treated patients does not reach the criteria associated with an optimal outcome and could potentially benefit from a different treatment strategy. Several trials exploring modified imatinib-based treatments or second-generation tyrosine-kinase as front-line therapy have been performed. In some studies, high-dose (800 mg per day) or dose-adapted imatinib or imatinib plus interferon was reported to be able to induce better cytogenetic and molecular responses compared with standard-dose imatinib, although no improvements in progression-free survival (PFS) or overall survival (OS) have been so far reported. At the moment, these approaches are still considered investigational. On the other side, on the basis of their capacity to induce very fast and deep molecular responses, including major molecular responses (MMRs) and the newly defined very deep molecular responses MR4 and MR(4.5), and to prevent at least part of the early progressions to AP/BC that still occur during the first 2-3 years from diagnosis, dasatinib and nilotinib have been approved and registered by FDA and EMA as the first-line therapy for CML patients, opening the possibility to use different therapeutic strategies for newly diagnosed CML patients and a consequent intense debate among hematologists.

Management of chronic myeloid leukemia in blast crisis.

Due to the high efficacy of BCR-ABL tyrosine kinase inhibition (TKI) in chronic phase (CP) chronic myeloid leukemia (CML), the frequency of blast crisis (BC) is greatly reduced compared to the pre-TKI era. However, TKI treatment of BC has only marginally improved the number of favorable responses, including remissions, which for the most part have only been transitory. Occasionally, they provide a therapeutic window to perform an allogeneic stem cell transplantation (allo-SCT). The challenge remains to improve management of BC with the limited options available. We review and summarize articles pertaining to the treatment of BC CML published after 2002. Additionally, we will discuss whether there is a need for a new definition of BC and/or treatment failure.

Current treatment concepts of CML.

The elucidation of the triggering molecular mechanism of chronic myeloid leukemia gave rise to the development of imatinib, a tyrosine kinase inhibitor and a prototype of target-oriented drugs. Imatinib led to impressing response and survival rates and now represents the standard therapy of CML. However, a significant proportion of patients do not tolerate or fail to respond to imatinib treatment. Alternative therapies can be offered to those patients. The particular challenge of CML patient management is to recognize an impending imatinib failure by adequate surveillance and to know about therapeutic options to prevent progression of the disease to accelerated phase or blast crisis since these are more difficult to control. Targeted therapy with second-generation tyrosine kinase inhibitors should be used in synopsis with mutational analysis and the patients' history. In this review we present current knowledge of diagnosis, monitoring and therapy strategies of patients with CML.

Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia.

BACKGROUND: Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase. METHODS: In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome-positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. RESULTS: At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P=0.01 and P=0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups. CONCLUSIONS: Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML. (ClinicalTrials.gov number, NCT00471497.)

Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.

BACKGROUND: Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML. METHODS: In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons. RESULTS: After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P=0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P=0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar. CONCLUSIONS: Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.)

The Biology of CML blast crisis.

The natural history of chronic myeloid leukemia (CML) progresses from a relatively benign chronic phase into a fatal blast crisis, which resembles acute leukemia, but is incurable by chemotherapy. Fortunately, the progression can usually be blocked by tyrosine kinase therapy or allogeneic transplantation. The seemingly stereotypical march of progression involves changes in genetic instability and DNA repair, proliferation, differentiation, and apoptosis, and thus may serve as a unique model of cancer evolution and progression. Given that all treatments work much better in chronic-phase than advanced-phase disease, the clinical dilemma is predicting and detecting patients bound to evolve into advanced disease. This is especially important in the age of tyrosine kinase inhibition (TKI) therapy. The purpose of this review is to address the biology of blast crisis in the age of tyrosine kinase therapy, with an emphasis on what genes or pathways may be future targets of predictive assays or treatments of progression.

A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia.

This phase 2 study evaluated the efficacy and safety of the oral farnesyltransferase inhibitor tipifarnib in adults with refractory or relapsed acute myeloid leukemia (AML). Patients (n=252) received tipifarnib 600 mg twice a day for 21 days in 28-day cycles. Median age was 62 years; 99 (39%) patients were 65 years or older. Eleven (4%) of 252 patients achieved complete remission (CR) or complete remission with incomplete platelet recovery (CRp; 9 CR and 2 CRp). Nineteen patients (8%), including those who achieved CR/CRp, achieved a reduction in bone marrow blasts to less than 5% blasts. Bone marrow blasts were reduced more than 50% in an additional 8 patients (total = 27; 11%). Median survival was 369 days for patients who achieved CR/CRp. Myelosuppression was the most common adverse event. The most common nonhematologic toxicities were fever, nausea, and hypokalemia. Single-agent treatment with tipifarnib induced durable CR/CRp, which was associated with prolonged survival, in some patients with refractory or relapsed AML. The response rate observed in this heavily pretreated group of patients suggests the requirement to enhance the response rate either by combining tipifarnib with other active agents or determining factors that are predictive of response.

Atiprimod blocks phosphorylation of JAK-STAT and inhibits proliferation of acute myeloid leukemia (AML) cells.

In studies of multiple myeloma cells, atiprimod was shown to block Stat3 activation and inhibited colony-forming cell proliferation. We hypothesized that atiprimod may also inhibit activation of intracellular signaling pathways in AML cells resulting in apoptosis and growth inhibition. We demonstrate that atiprimod inhibited clonogenic growth of AML cell lines and fresh AML marrow cells whereas it did not significantly affect growth of normal hematopoietic progenitors from marrow samples of healthy controls. Atiprimod decreased phosphorylation of Stat3 and Stat5, and protein levels of Jak2, whereas gene expression of Jak2 was not affected. Atiprimod further induced apoptosis by cleavage of caspase 3 and PARP. In summary, our data suggest that atiprimod has a significant antiproliferative and proapoptotic effect on AML cells. This effect may be facilitated by inhibition of the Jak-Stat signaling pathway. Further evaluation of atiprimod in clinical trials of AML should be considered.

Long-term third chronic phase of chronic myelogenous leukemia maintained by interferon-alpha and methotrexate.

The prognosis of blast crisis (BC) of chronic myelogenous leukemia (CML) is extremely poor despite many efforts to induce remission with chemotherapy. We have recently treated a long-surviving CML patient who developed three separate episodes of BC. The administration of interferon-alpha (IFN-alpha) alone as maintenance therapy was incapable of preventing BC, which occurred twice in the first 2 years after the diagnosis of CML. Intensive chemotherapy using enocitabine, mitoxantrone, and etoposide was effective to induce hematological remission. Thereafter once per week oral administration of methotrexate (10-15 mg/week) was combined with IFN-alpha after the second BC. This treatment succeeded in obtaining a major cytogenetic response and keeping him in third chronic phase for 5 years until the last most recent third BC. We present here the rare clinical course of the patient, review the past literature, and discuss the efficacy of the combination of IFN-alpha and methotrexate in this disease.

Early lymphoid blastic crisis following major karyotypic conversion in a chronic myeloid leukemia patient treated with interferon-alpha.

A major karyotypic conversion following interferon-alpha treatment delays or prevents blastic crisis in patients with chronic myeloid leukemia. We report here a 12-year-old boy with Ph1+ chronic myeloid leukemia who, after achieving a major karyotypic conversion following 12 months interferon-alpha treatment, developed an early lymphoid blastic transformation 7 months later while still under interferon-alpha therapy. A number of possible explanations for this quite unexpected event are discussed.

Peripheral blood stem cell autografts in CML.

The treatment of patients with CML in chronic phase by high dose chemotherapy followed by transfusion of autologous haemopoietic stem cells collected and cryopreserved previously may theoretically prolong survival. This benefit could result from reducing the number of leukaemia stem cells at risk for transformation or by partial re-establishment of Ph-negative haematopoiesis. In practice some patients achieve partial Ph-negative haematopoiesis after autografting but most patients have entirely Ph-positive haematopoiesis by one year after autografting. Results may be improved if methods to favour reconstitution with Ph-negative haematopoiesis can be perfected.

Attempted prevention of blast crisis in chronic myeloid leukemia by the use of pulsed doses of cytarabine and lomustine. A Cancer and Leukemia Group B study.

An attempt to prevent the blast crisis in chronic myeloid leukemia by the use of pulsed doses of (cytarabine cytosine arabinoside) and lomustine was attempted as a cooperative group study by Cancer and Leukemia Group B. The basis for this study was to delay the development of blast crisis by pulsing dose of drugs known to be effective against emerging "blast" cells. The experimental arm which consisted of cytarabine and lomustine did not produce overall results superior to conventional treatment with busulfan. This was related to the non-hematologic effects of the combination which produced significant gastrointestinal toxicity leading to relatively early discontinuation of the combination. Nevertheless, the trial design allowed relatively prompt discontinuation of experimental arm and cross-over to conventional treatment with either hydrea or busulfan. No evidence existed that the use of new drug combinations in CML prejudiced the patient's chance to response to conventional chemotherapy. Thus, a role model for future trials in this disease was developed. With the development of the interferons and other experimental forms of therapy this conceptual development may be of significance.

Attempted prevention of blast crisis in chronic myeloid leukemia by the use of pulsed doses of cytosine arabinoside and cis-chloronitrosurea during the course of busulfan-maintained remission.

We performed this chemotherapeutic trial to try to delay the onset of the blast crisis of chronic myeloid leukemia (CML) by pulsing doses of drugs most likely to be effective against emerging "blast" cells characteristic of acute phase disease. A randomized trial in patients with CML comparing busulfan maintenance to busulfan maintenance plus pulsed doses of cytarabine and lomustine did not yield any differences in either time to blast crisis or death.

[A case of successful transplantation of allogeneic bone marrow in a patient with myelocytic leukemia]. / Sluchai uspeshnoi transplantatsii allogennogo kostnogo mozga bol'noi khronicheskim mieloleikozom.

Allogenic bone marrow transplantation was performed in a patient with chronic myelocytic leukemia (Ph+) in a stable phase. A 1,5-year recurrence-free period since the time of transplantation was observed. Transplantation features were as follows: incompatibility of the recipient and donor by ABO-antigens, the development of acute graft versus host disease and transient Ph-positivity.