Allogeneic stem-cell transplant (allo-Stem-cell transplantation) is the only potentially curative therapy for chronic myelogenous leukemia (chronic myelogenous leukemia). This aggressive approach is appropriate only for young (less than 55 years of age), fit patients with matched donors — a profile that accounts for less than one-third of the chronic myelogenous leukemia population.
Since its launch in 2001, the tyrosine kinase inhibitor imatinib (Novartis’s Gleevec/Glivec), alone or in combination with other agents, has been regarded as the treatment of choice for patients not destined for immediate allo-Stem-cell transplantation. Previously, the standard treatment for patients with newly diagnosed chronic-phase chronic myelogenous leukemia who were ineligible for allo-Stem-cell transplantation was interferon-alpha (interferon-a), either alone or in combination with low-dose cytarabine (LDAC) (Pfizer’s Cytosar-U, generics). interferon-a largely replaced hydroxyurea (Bristol-Myers Squibb’s Hydrea, generics) in the mid-1990s, when clinical trials demonstrated that it induces major cytogenetic responses in about one-third of patients and achieves an overall survival advantage of one to two years compared with hydroxyurea.
When disease progresses to the accelerated and blastic phases, more aggressive chemotherapeutic regimens may be employed (e.g., an anthracycline and cytarabine, high-dose cytarabine alone). In select cases, autologous transplantation is attempted. However, once chronic myelogenous leukemia starts to progress, no treatment is particularly effective. Purely palliative interventions include radiotherapy, splenectomy, and leukapheresis (the mechanical removal of white blood cells).
With the exception of the purely palliative interventions, which we do not discuss further in this report, the agents and procedures employed in the treatment of chronic myelogenous leukemia are described in the following sections. TABLE:Current Therapies Used for Chronic Myelogenous Leukemia lists brand names, marketing companies, dosage, and market availability of agents commonly used in the treatment of chronic myelogenous leukemia. TABLE:Current Therapies Used for Chronic Myelogenous Leukemia illustrates the achievements of current treatment modalities in various patient populations.
Because of the long median survival of patients in chronic-phase chronic myelogenous leukemia, primary endpoints in studies involving these patients are often hematologic and cytogenetic response rates. These response rates act as an indicator of length of survival. As novel drugs are achieving complete hematologic and complete cytogenetic responses, molecular response is becoming an increasingly popular trial end point owing to the fact that a complete molecular response indicates disease eradication. The following types of responses are generally measured:
TABLE. Current Therapies Used for Chronic Myelogenous Leukemia
|Protein tyrosine kinase inhibitors|
|Imatinib||Novartis’s Gleevec, Glivec||400 mg||US ,France, Germany,Italy, Spain, UK, Japan|
|lnterferon-alpha-2a||Roche’s Roferon-A||5x 106lU/m2||US ,France, Germany,Italy, Spain, UK, Japan|
|lnterferon-alpha-2b||Schering-Plough’s Intron-A||5x 106lU/m2||US ,France, Germany,Italy, Spain, UK, Japan|
|lnterferon-alpha-N1||Sigma -Tau’s Humoferon, GlaxoSmithKline’s Wellferon, Sumitomo’s Sumiferon||5x 106IU /m2||Italy, Spain, Japan|
|Interferon-alpha||Janssen-Cilag’s Cilferon-a, Otsuka’s Oif||5x 106IU /m2||Italy, Japan|
|Cytarabine||Pfizer’s Cytosar-U, generics||20 mg/m2||US ,France, Germany,Italy, Spain, UK, Japan|
|Hydroxyurea||Bristol-Myers Squibb’s Hydrea, generics||40-50 mg/kg||US ,France, Germany,Italy, Spain, UK, Japan|
|Busulfana||GlaxoSmithKline’s Myleran||0.1 mg/kgb||US ,France, Germany,Italy, Spain, UK, Japan|
aBusulfan is now rarely used in the treatment of chronic myelogenous leukemia but is included in the table for historical reasons. bWhen used in myeloablative regimens prior to allogeneic progenitor stem-cell transplantation, a dose of 8-16 mg/kg is given over four days.
TABLE. Achievements of Current Therapies Used for CML, 2005: Benchmarks for Evaluation of Emerging Therapies
|CHR(%)||cytogenetic response(%)||PFS After18 Months/ |
|Median Survival (months)|
|Late chronic-phase chronic myelogenous leukemia after failure with interferon-a therapy||Imatinib 400 mg dailya||95||41||89/—||—|
|Early chronic-phase chronic myelogenous leukemia||Imatinib 400 mg dailyb||—||97||76||97/90c||—|
|Early chronic-phase chronic myelogenous leukemia||interferon-a 5 MIU/m2 dailyd||—||80||26e||—||89|
|Chronic phase-chronic myelogenous leukemia||interferon-a 9 MIU/m2 dailyf||—/47g||—||10||—||104g|
|Early chronic-phase chronic myelogenous leukemia||interferon-a + LDAC (10 mg)h||70/—||92||50||—||—|
A 42-month follow-up showed PFS of 90% for patients who had achieved cytogenetic response within 12 months of beginning therapy. For patients not achieving cytogenetic response, PFS was 75%.
dKantarjian HM, 1996.
e Five-year survival for patients who achieved cytogenetic response was 90%.
fThe Italian Cooperative Study Group, 1998.
9 Data for Sokal’s low-risk patients.
hKantarjian HM, 1999.
cytogenetic response = Complete cytogenetic response.
CHR = Complete hematologic response.
CML= Chronic myelogenous leukemia.
LDAC = Low-dose cytarabine.
PFS = Progression-free survival.
• Hematologic response. A complete hematologic response (CHR) is the absence of disease-related symptoms and splenic enlargement, normalization of the white blood cell count (i.e., a count between 4,000 and 11,000 per mm3), and a normal differential white blood cell and platelet count. If only some of these criteria are met, the response may be classed as partial.
• Cytogenetic response. A complete cytogenetic response is the absence of detectable Ph-positive cells (cells expressing the Philadelphia chromosome) in metaphase. If a percentage of Ph-positive cells is detectable, the response may be classed as a major cytogenetic response (or partial cytogenetic response) (1-34% Ph-positive cells); minor cytogenetic response (35-94% Ph-positive cells); or no cytogenetic response (95-100% Ph-positive cells). Cytogenetic responses are clinically important because they are associated with better prognosis.
• Molecular response. A molecular response is the disappearance or reduction in quantities of BCR-ABL transcripts (i.e., amount of BCR-ABL oncoprotein). Monitoring the level of BCR-ABL is a way of predicting long-term patient outcomes. A thousandfold (>3 log) reduction in levels of BCR-ABL is defined as a major molecular response. The authors of a study (involving more than 1,000 chronic myelogenous leukemia patients) estimated that 100% of chronic myelogenous leukemia patients who have achieved a cytogenetic response and who achieve a major molecular response at 12 months will remain progression-free after another year. A complete molecular response is when there is no evidence of BCR-ABL transcripts, indicating disease eradication. The levels of BCR-ABL transcripts are usually measured by a quantitative real-time polymerase chain reaction (PCR) assay.