Blastic Phase

Overview

Chronic myeloid leukemia (CML) is the abnormal growth of relatively mature myeloid (white blood) cells. Half of all patients with CML are diagnosed after the age of 67.

CML is associated with a chromosomal abnormality in which genetic material from chromosome 9 is transferred to chromosome 22. The chromosome containing the genetic switch is called the Philadelphia chromosome; this chromosome plays a role in the development of CML.

The exchange of genetic information that produces the Philadelphia chromosome  brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the ABL (Ableson leukemia virus) gene on chromosome 9.  The combination of these two genes into the single BCR-ABL gene results in the production of a protein that contributes to uncontrolled cell growth.

Initially in CML, there is a gradual increase in mature, abnormal myeloid cells in the bone marrow. These cells eventually spill into the blood and other organs, causing symptoms such as fatigue from anemia or an enlarged spleen. The increase in leukemic cell numbers occurs slowly at first and is referred to as the chronic phase, but these cells invariably begin to increase more rapidly and/or include less mature cells, resulting in the accelerated or blastic phase. In order to understand the best treatment options available for chronic myeloid leukemia, it is important to know the phase of leukemia, since all new treatment information concerning chronic myeloid leukemia is categorized and discussed by the phase of disease.

Measuring Response to Treatment

Initial response to therapy is indicated by normalization of the peripheral blood counts (white blood cells, platelets and red blood cells) and return of increased bone marrow cellularity to normal. Most patients are followed with peripheral blood tests rather than repeated bone marrow examination. Cells collected from the bone marrow or peripheral blood will contain the Philadelphia chromosome, and cytogenetic tests (tests that detect chromosomal abnormalities) are used to monitor response to therapy. Currently the majority of newly diagnosed patients with CML will achieve a complete cytogenetic remission (no evidence of Philadelphia chromosome-positive cells).  More importantly, in patients with a complete cytogenetic remission a test called polymerase chain reaction (PCR) can determine the completeness of a “molecular” remission by measuring the presence of the BCR-ABL gene. As a general rule, the greater the degree of molecular response the longer the survival of an individual patient.

Staging of Chronic Myeloid Leukemia

Chronic Phase: Patients in the chronic phase of CML have stable disease with only minor symptoms, no cancer outside the bone marrow or spleen and white blood cell and platelet blood counts that are usually greater than normal.

Overview

Chronic myeloid leukemia is the abnormal growth of relatively mature myeloid white blood cells. The disease is associated with a chromosomal abnormality (Philadelphia chromosome), where genetic material from chromosome 9 is transferred to chromosome 22. This forms the Philadelphia chromosome, which plays a role in the development of the disease. Chronic myeloid leukemia normally progresses from the chronic phase to an accelerated phase and ultimately, into a blastic or acute leukemia phase over a period of several years.

The diagnosis of blastic phase requires at least one of the following:

  • Persistent presence of greater than 30% myeloblasts in marrow or peripheral blood
  • Major increase of white blood cell count to over 50,000
  • Platelet counts that are increased or decreased
  • Red blood cell levels that are low despite treatment
  • Progressive enlargement of the spleen
  • Tumor nodules outside the bone marrow or spleen
  • Any abnormal chromosome in addition to the Philadelphia chromosome
  • Persistent unexplained fever or bone pain.

The diagnosis of the blastic phase requires greater than 30% myeloblasts in marrow or blood. Patients in blastic phase live an average of 3-6 months.

A variety of factors ultimately influence a patient's decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient's chance of cure, or prolong a patient's survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.

The following is a general overview of the treatment of chronic myeloid leukemia for patients who have progressed to the blastic phase. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.

When CML progress to the blastic phase, the leukemia cells may look like either myeloid or lymphoid cells and generally respond poorly to treatment. Historically, intensive chemotherapy regimens were used for the treatment of chronic myeloid leukemia, including high-dose cytarabine and daunorubicin. They can induce remissions in 25-35% of patients in blast phase. Patients with a lymphoid blast phase who were treated with therapy similar to that given for acute lymphoid leukemia (Oncovin® (vincristine), Adriamycin® (doxorubicin), Cytoxan® (cyclophosphamide) and dexamethasone) had a complete remission rate of 60%. However, all remissions achieved with chemotherapy in blast phase were of relatively short duration. In 2001, Gleevec® (imatinib) was approved for the treatment of CML in blast crisis.

Treatment of Blastic Phase CML with Gleevec

Most of the patients currently entering blast crisis will have received prior therapy with Gleevec. For those who have not previously been treated with Gleevec, however, Gleevec is a common initial treatment. Many such patients will be treated with Gleevec in preparation for an allogeneic stem cell transplant.

A large, multi-center, phase II trial designed to evaluate Gleevec for the treatment of CML in myeloid blast crisis has been reported.1 Patients were treated with Gleevec in daily oral doses of 400 mg or 600 mg. Eight percent of patients experienced a complete hematologic response, seven percent experienced a complete cytogenetic response, and half the patients survived for longer than seven months. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of low blood cell counts, skin disorders, or gastrointestinal reactions. The researchers concluded that these results demonstrate that Gleevec has substantial activity and a favorable safety profile when used as a single agent in patients with CML in BC.

Researchers affiliated with the STI571 Study (IRIS) Group have reported the results of four years of follow-up of over 1,000 patients with CML with advanced disease. 2 Patients were treated with Gleevec® initially at a dose of 400 mg, but escalating to 600 or 800 mg per day. Few patients in blastic phase survived, suggesting that treatment with an allogeneic stem cell transplant should be considered in those who have a response to Gleevec.

Treatment of Blastic Phase CML with Sprycel

Sprycel® (dasatinib) is a tyrosine kinase inhibitor that appears to have much greater activity against Bcr-Abl than Gleevec. It has been approved by the U.S. FDA for the treatment of patients with CML who are resistant to or intolerant of Gleevec. The FDA cited four single-arm studies involving over 400 patients who were no longer responsive to Gleevec.

One study of Sprycel reported hematological responses in 31 of 44 patients with more advanced CML or ALL. Major cytogenetic responses were observed 35% of patients with more advanced disease.3 However, most patients with ALL or blastic phase CML had relapsed at the time of this report. The main side effect appeared to be low blood cell counts.

Treatment of Blastic Phase CML with Nilotinib

Nilotinib (AMN107) is another drug that targets the Bcr-Abl protein. Nilotinib has a higher activity than Gleevec.. This agent has not yet been approved by the FDA for use in CML but this will likely occur in the very near future.

Recent studies indicate that some patients with CML in blast crisis will respond to nilotinib, including patients who have previously been treated with Gleevec.45 Frequently seen side effects were different from those seen with Gleevec and included rash, liver damage and low blood cell counts.

Allogeneic Stem Cell Transplantation

Prior to the advent of Gleevec and other tyrosine kinase inhibitors, selected patients in blastic phase treated with high-dose chemotherapy and allogeneic stem cell transplant using stem cells from a related donor had a 5-year survival of approximately 15%. There has been significant recent progress in the selection of compatible unrelated stem cell donors and in the development of umbilical cord blood transplants giving most patients an opportunity for a stem cell transplant for CML. There has also been significant progress in the development of reduced-intensity transplant regimens allowing older patients to be transplanted. For more information go to Allogeneic Stem Cell Transplant.

Strategies to Improve Treatment

While significant progress has been made in the treatment of CML, many patients still succumb to leukemia and better treatment strategies are still needed. Future progress in the treatment of leukemia will result from continued participation in appropriate clinical studies. Currently, there are several areas of active exploration aimed at improving the treatment of leukemia.

Allogeneic Stem Cell Transplant: Strategies designed to reduce the toxicity and improve the outcome of Allogeneic Stem Cell Transplant are an active area of study.

Phase I-II Chemotherapy Trials: New chemotherapy drugs continue to be developed and evaluated in phase I-II trials for patients with recurrent cancers. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anti-cancer activity in patients. Phase II trials further evaluate new therapies that appear to have promising anti-leukemia activity.

Researchers from MD Anderson Cancer have reported that the chemotherapy drug, homoharringtonine, has significant activity in patients with CML who have failed Gleevec.6

Immunotherapy: Immunotherapy agents have been evaluated in the treatment of patients with minimal residual disease. Results from a phase II trial indicate that the investigative immunotherapy agent GVAX provides promising and durable responses, including long-term molecular remissions, among patients with CML with residual disease while on therapy with Gleevec.7 Unfortunately, the pharmaceutical company sponsoring this study has cancelled plans for further testing of this agent.

Fortunately, other researchers are also developing vaccines for the treatment of CML. Researchers at the Memorial Sloan-Kettering Cancer Center developed and are testing a vaccine which has proven safe and effective in developing an immune responses in patients with CML.8 Researchers from the MD Anderson Cancer Center have reported that patients who have an immune response to the vaccine have improved progression-free survival.9 Researchers from Italy have also developed a vaccine which has been tested in a small number of patients being treated with Gleevec or interferon.10 These researchers suggested that the vaccine produced further reductions in residual molecular disease. Finally, researchers from England have tested a vaccine in patients with CML in the chronic phase; the vaccine appears to improve control of CML in patients responding to Gleevec.11

These vaccine studies are important as they offer an alternative approach to the eradication of minimal residual disease in patients with CML responding to Gleevec or other agents. Vaccines can theoretically kill clones of cells that are drug resistant. Another advantage of vaccines is that they are relatively non-toxic with few side effects.

Development of New Kinase Inhibitors: There are now two agents for treating Gleevec failures: Sprycel and nilotinib. Researchers are continuing to develop new kinase inhibitors with greater activity than those used currently.

Supportive Care: Supportive care refers to treatments designed to prevent and control the side effects of cancer and its treatment. Side effects not only cause patients discomfort, but also may prevent the optimal delivery of therapy at its planned dose and schedule. In order to achieve optimal outcomes from treatment and improve quality of life, it is imperative that side effects resulting from cancer and its treatment are appropriately managed. Side effects of the tyrosine kinase inhibitors; Gleevec, Sprycel and nilotinib are predominantly low white blood cell counts and anemia. Neupogen® (filgrastim) and Neulasta® (pegfilgrastim) can be used to prevent or treat low white blood cell counts12 and Procrit® (epoetin alfa) or Aranesp® (darbepoetin alfa) can be used to prevent or correct anemia.1314For more information, go to Managing Side Effects.

References:


1 Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002:99:3530-3539.

2 Silver, RT, Talpaz M, Sawyers CL, et al. Four years of follow-up of 1027 patients with late chronic phase (L-CP), accelerated phase (AP), or blast crisis (BC) chronic myeloid leukemia (CML) treated with imatinib in three large phase II trials. Proceedings of the American Society of Hematology. Blood. 2004;104:11a, abstract number 23.

3 Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New England Journal of Medicine. 2006;354:2531-2541.

4 Ottmann O, Kantarjian H, Larson R, et al. A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL). Blood 2006;108,528a, abstract 1862.

5 Giles F, Ottmann O, Bhalla K, et al. Update on AMN107 in Leukemia. Proceedings from the 23rd annual Chemotherapy Symposium. New York, NY. November 2005. Abstract #19.

6 Quintas-Cardana, Kantarjian H, Garcia-Manero G, et al. Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer 2007;109:248-255.

7 Smith B, Kasamon Y, Miller C, et al. K562/GM-CSF Vaccination Reduces Tumor Burden, Including Achieving Molecular Remissions, in Chronic Myeloid Leukemia (CML) in Patients (Pts) with Residual Disease on Imatinib Mesylate (IM). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 6509.

8 Pinilla-Ibarz J, Cathcart K, Korontsvit T, et al. Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Blood 2000;95:1781-1787.

9 Qazilbash MH, Wieder E, Rios R et al. Vaccination with the PRI leukemia-associated antigen can induce complete remission in patients with myeloid leukemia. Blood 2004;104:77a, abstract 259.

10 Bocchia M, Gentili S, Abruzzese E, et al. Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. The Lancet 2005;365:657-662.

11 Rojas JM, Knight K, Wang L-H, et al. Clinical BCR-ABL peptide vaccination in chronic myeloid leukaemia: Results of the EPIC study. 2005. Blood 2006;108:623a, abstract 2197.

12 Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Granulocyte-Colony Stimulating Factor (Filgrastim) May Overcome Imatinib-Induced Neutropenia in Patients with Chronic-Phase Chronic Myelogenous Leukemia. Cancer 2004;100:2592-2597.

13 Cortes J, O’Brien S, Quintas A, et al. Erythropoietin is Effective in Improving the Anemia Induced by Imatinib Mesylate Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase. Cancer 2004;100:2396-2402.

14 Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Granulocyte-Colony Stimulating Factor (Filgrastim) May Overcome Imatinib-Induced Neutropenia in Patients with Chronic-Phase Chronic Myelogenous Leukemia. Cancer 2004;100:2592-2597

Accelerated Phase: When chronic myeloid leukemia is difficult to control with Gleevec® (imatinib) or other therapies, the white blood count begins to increase. New symptoms may appear and old symptoms may worsen. The spleen may enlarge and/or new abnormal chromosomes can be detected in the bone marrow cells. Eventually, the leukemia becomes completely resistant to treatment and the bone marrow becomes overburdened with large numbers of immature white blood cells known as "blasts". A diagnosis of accelerated phase requires at least one of the following:

  • The persistent presence of 10-30% myeloblasts in the bone marrow or peripheral blood.
  • A major increase of the white blood cell count to over 50,000, platelet counts that are increased or decreased and red blood cell levels that are low despite treatment.
  • Progressive enlargement of the spleen.
  • Growth of leukemia outside the bone marrow or spleen.
  • The presence of any cytogenetic abnormality in addition to a Philadelphia chromosome.
  • Persistent unexplained fever or bone pain.

Blastic Phase: Greater than 30% myeloblasts in marrow or blood