"The survival rate for leukemia has improved in the past two decades, thanks to new agents designed to treat patients," said Brian J. Druker, M.D., Oregon Health and Science University, Portland, Ore. "Continued research will only strengthen our understanding of the disease and support the therapeutic potential of current and developing treatments for chronic myeloid leukemia."
CML is usually diagnosed by finding a specific chromosomal abnormality called the Philadelphia chromosome (Ph chromosome). The Ph chromosome is the result of translocation - a genetic chromosomal abnormality - between the long arms of chromosomes 9 and 22. The result is that part of the BCR (breakpoint cluster region) gene from chromosome 22 is fused with part of the ABL (abelson leukemia virus) gene on chromosome 9. The translocation takes place in a single bone marrow cell and, through the process of cell division and expansion, results in leukemia, the rapid growth of abnormal white blood cells in the bone marrow, blood, and body tissues.
The discovery of the Ph chromosome marked the first genetic abnormality consistently associated with a particular form of cancer. In addition to CML, Ph chromosome can also be found in some cases of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Imatinib, which blocks the abnormal protein driving the overproduction of abnormal white blood cells, has become a standard therapy for patients not undergoing stem cell transplantation. It is now demonstrating continued control and reduction in levels of remaining disease in chronic phase CML (CML- CP) patients. However, a number of patients have developed resistance to this treatment because their cancer cells are able to mutate and adapt.
As a result, treatment options for patients with CML continue to expand. Various studies of potential new treatments for CML yield positive results in patients whose disease is resistant to imatinib. Both dasatinib and AMN107 have been shown to be effective in treating patients with CML whose disease has progressed on imatinib.
Continuing Reduction in Level of Residual Disease After Four Years in Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase Responding to First-Line Imatinib (IM) in the IRIS Study [Abstract 163]
A recent report updated results of molecular monitoring of patients in the International Randomized Interferon vs. STI 571 (IRIS) study that prospectively compared imatinib therapy with interferon-alfa plus cytarabine. The IRIS study was initiated in June 2000, and demonstrated that after one year of imatinib treatment, an estimated 40 percent of CML-CP patients taking 400 mg per day achieved a major molecular response (MMR), defined as substantial reduction in BCR-ABL levels. This particular analysis assessed the level of BCR-ABL transcripts after approximately four years of imatinib treatment and showed continuing reduction in transcript levels.
The analysis was based on 101 patients who achieved complete cytogenetic response (CCyR) within one year, received first-line treatment for at least 24 months, and had blood collected for measuring transcript numbers at one year and four years after starting treatment. Results are expressed as a log reduction from a standardized baseline value for untreated patients. This means they are expressed as transcript copy numbers, with a one-log reduction equivalent to a fall from 100 to 10, and a two-log reduction a fall from 100 to one.
At one year, BCR-ABL transcript levels fell by at least three logs in 46 percent of the 101 patients. At the most recent measurement, at or after 44 months from start of study, 75 percent of patients demonstrated a reduction of at least three logs. Of these patients, more than half had already had a three-log reduction at year one, whereas 49 percent had not. Conversely, eight of the 47 patients with three-log reduction at one year had log reductions greater than three at four years. At the one- and four-year points, 20 percent and 36 percent of patients, respectively, achieved four-log reductions.
"The results are gratifying and show that patients in complete cytogenetic response who had an 'adequate' reduction in their BCR-ABL transcript levels at one year have a good chance at achieving a much greater reduction after four years of imatinib treatment," said John M. Goldman, D.M., National Heart,
Lung, and Blood Institute (NHLBI), Bethesda, Md. "This is an important observation because it means that imatinib continues for at least four years to reduce the quantity of residual disease and so promises to offer patients with chronic phase CML very substantial prolongation of essentially normal life, compared with previous therapies."
Control of Residual Disease in Imatinib (IM) Treated Chronic Myeloid Leukemia (CML) Patients with Peptide Vaccinations: Two Years Follow Up of CMLVAX100 Trial [Abstract 167]
In the past five years, the body of data concerning imatinib has defined its role as an effective first-line therapy for CML-CP patients. However, the persistence of disease in most patients, together with the evidence that discontinuation of imatinib inevitably results in a rapid loss of response, suggests that the cure for CML is unlikely using imatinib alone.
Researchers from the University of Siena in Siena, Italy, looked at the anti-tumor effect of a vaccine (CMLVAX100) targeting the BCR-ABL genes and how it reduced remaining disease in some patients with CML who have reached a maximum response to imatinib. After a median time of 24 months of imatinib treatment, a group of 21 patients showing different degrees of persistent residual disease started vaccinations with CMLVAX100. Vaccine treatment plans included six vaccinations at two-week intervals. In patients who responded to treatment, additional boosts of vaccine were provided every four to six months.
To date, 18 of the 21 patients have completed the immunization regimen, eight of whom received four additional boosts of vaccine. After six vaccinations, six patients with persisting, progressing disease reached a complete response, with three of them achieving an undetectable level of BCR-ABL transcript. In addition, three patients starting vaccinations with persistent molecular disease further reduced their BCR-ABL level, with one reaching molecular negativity. This suggests that CMLVAX100 works effectively with imatinib in CML-CP patients with persistent minimal residual disease.
Of the eight patients who underwent four additional boosts of vaccine, one reached a complete molecular response, five maintained the response obtained after immunization, and two patients (who previously achieved an undetectable level of BCR-ABL transcript) lost the complete molecular response (CMR), but maintained CCyR. This suggests that while beneficial, a six-month interval between boosts could be too long to maintain efficient immune control on residual leukemia cells.
"Although the number of patients who participated in the trial is small, this is a very important study," said Monica Bocchia, M.D., University of Siena, Siena, Italy. "Researchers have been attempting to develop cancer vaccines for decades, and results in CML patients are a very encouraging step forward."
Dasatinib (BMS-354825) in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome- Positive Acute Lymphoblastic Leukemia (Ph + ALL) Who Are Resistant or Intolerant to Imatinib: Update of a Phase I Study [Abstract 38]
Imatinib resistance in CML and Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (Ph + ALL) is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to inhibit BCR-ABL overproduction. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor which targets BCR-ABL and SRC protein kinases. The SRC protein is a signaling protein that specializes in messages that control the growth of cells. The drug is 325-fold more potent than imatinib in cells transduced with normal BCR-ABL genes, and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants.
In an update of a phase I, dose-escalating study initiated in November 2003, researchers from the University of California, Los Angeles (UCLA) School of Medicine and The University of Texas M. D. Anderson Cancer Center looked at the use of dasatinib in imatinib-resistant or intolerant patients with CML in late chronic phase (CP), accelerated phase (AP), myeloid blast crisis (MBC), or lymphoid blast crisis (LBC)/Ph+ ALL. Data are available for 82 patients (40 CP, 10 AP, 22 MBC, 10 LBC/Ph+ ALL). A blast crisis is the progression of diseases to an acute advanced phase.
The 40 CP patients, with five years median duration of CML, were treated with 15 to 180 mg of dasatinib either once daily (QD) or twice daily (BID) for a median of 13 months. The rate of complete hematologic response (CHR) in CP patients was 93 percent, while major cytogenetic responses (MCyR) were observed in 45 percent and CCyR in 35 percent.
In advanced disease, 44 patients have been treated with dasatinib (70 to 240 mg BID) for a median of 37 months. The rate of major hematologic response (MHR) is 81 percent in AP, 61 percent in MBC, and 70 percent in LBC/Ph+ ALL. The complete response rate is 45 percent in AP, 70 percent in LBC/Ph+ ALL, and 35 percent in MBC.
The overall rates of MCyR and CCyR in advanced disease were 43 percent and 25 percent, respectively. Cytogenetic responses were seen in patients with a wide spectrum of BCR-ABL mutations, as well as in patients with minimal or no prior cytogenetic response with imatinib. Responses were durable in CP and AP patients, but relapses have occurred in the MBC and LBC/Ph+ ALL cohorts, often due to dasatinib-resistant BCR-ABL mutations.
"These data support the therapeutic potential of dasatinib in CML and Philadelphia chromosome positive acute lymphoblastic leukemia patients who are imatinib-resistant or intolerant," said Charles Sawyers, M.D., Jonsson Cancer Center, UCLA School of Medicine, Los Angeles, Calif. "We are encouraged by the results and are looking forward to seeing the results from ongoing phase II studies to confirm the effects of dasatinib in patients with all phases of the disease."
Efficacy of Dasatinib (BMS-354825) in Patients with Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia (CML) Resistant or Intolerant to Imatinib: First Results of the CA180013 'START-C' Phase II Study [Abstract 41]
After three years of imatinib therapy, hematologic relapse occurs in seven percent of newly-diagnosed CML patients and 20 percent of CML chronic phase patients after failure to respond to current standard therapy. This is mostly associated with BCR-ABL mutations and/or clonal evolution - the development of chromosomal mutations that occurs in untreated CML and leads to progression of the disease. A previous phase I, dose-escalating study provided early evidence for the safety and efficacy of dasatinib in imatinib-resistant or intolerant patients with CML-CP.
This study (START-C [CA180013]), carried out by a multinational group of 75 investigators, is a follow-up on the use of dasatinib in CP imatinib resistant or intolerant patients.
A total of 394 patients were recruited to this phase II, open-label study. To date, data from 186 patients are available for analysis. Imatinib resistance (n=127) or intolerance (n=59) was defined as a failure to respond to imatinib at maximum tolerated doses or the occurrence of BCR-ABL mutations associated with virtual insensitivity to imatinib. Dasatinib was administered to patients at 70 mg BID, based on phase I data and optimal inhibition of BCR-ABL activity from biomarker analysis. Dose escalation to 90 mg BID was permitted in patients lacking response, and dose reductions to 50 and 40 mg BID were allowed in the event of intolerance. Complete blood counts were obtained weekly for the first 12 weeks, while bone marrow was collected every three months.
Median time from diagnosis of CML was 63.8 months. Prior therapy included imatinib in 100 percent hydroxyurea or anagrelide in 86 percent, and interferon alpha in 70 percent of patients. Approximately 54 percent of patients received imatinib for more than three years.
Within the first six months, 90 percent of patients reached a complete hematologic response (87 percent resistant patients, 97 percent intolerant patients), and 45 percent achieved a major cytogenetic response (<35 percent Ph positive metaphases; 31 percent resistant patients, an, 73 percent intolerant patients), being complete in 33 percent of patients.
Interim results of Phase II dasatinib studies in advanced disease were also presented. Of the myeloid blast crisis patients resistant to imatinib (n=68), 31 percent reached a major hematologic response, and 29 percent achieved a major cytogenetic response. Of the accelerated phase patients resistant to imatinib (n=99), 59 percent achieved a major hematologic response and 31 percent a major cytogenetic response.
"Despite the short follow-up, significant improvements of hematologic and cytogenetic responses were seen in pretreated CML patients in all phases of the disease, which further supports the activity of dasatinib in BCR-ABL positive leukemia," said Andreas Hochhaus, M.D., University of Heidelberg, Mannheim, Germany. "This is very encouraging news for patients and should be viewed as a step forward in the treatment of CML."
AMN107, a Novel Aminopyrimidine Inhibitor of BCR-ABL, Has Significant Activity in Imatinib-Resistant Chronic Myeloid Leukemia (CML) or Philadelphia Chromosome-Positive Acute Lymphoid Leukemia (Ph + ALL) [Abstract 37]
AMN107 is an investigational oral compound which inhibits the activity of specific proteins, including BCR-ABL and 32 of 33 mutant forms of protein responsible for the development of CML. It is 10- to 50-fold more potent than imatinib against BCR-ABL-expressing cell lines, including most imatinib-resistant BCR-ABL mutants.
In research led by The University of Texas M.D. Anderson Cancer Center in Houston and the University of Frankfurt, Germany, 119 patients with imatinib-resistant CML in blast crisis (BC), AP, CP, or Ph+ ALL were treated with AMN107. Initial daily doses ranged from 50 mg QD to 1,200 mg QD, and 400 mg BID to 600 mg BID. Dose escalations occurred in 48 of the 69 patients in the once daily groups, and one patient in the 400 mg BID group escalated to 600 mg BID.
As of June 15, 2005, patients had been treated for a median of 120 days. AMN107 was well-tolerated, and the most common drug-related adverse events were constipation, nausea, and vomiting. Among CML patients who harbored a BCR-ABL mutation prior to treatment, 60 percent achieved a hematologic response and 41 percent achieved a cytogenetic response. In addition, 72 percent of CML patients who had no BCR-ABL mutation prior to taking AMN107 achieved a hematologic response, and 59 percent achieved a cytogenetic response. Ph+ ALL patients who harbored a mutation prior to treatment with AMN107 saw a 33 percent response rate.
"AMN107 was shown to have significant activity in patients with advanced imatinib-resistant CML and Philadelphia chromosome positive acute lymphoblastic leukemia," said Hagop M. Kantarjian, M.D., The University of Texas M. D. Anderson Cancer Center, Houston, Texas. "Current therapies, though effective, still have many limitations, and new treatment options with proven safety and efficacy can only benefit this patient population."
The American Society of Hematology (www.hematology.org) is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.