Treatment of Accelerated & Blastic Phase Chronic Myeloid Leukemia

by Dr. C.D. Buckner M.D. updated 6/2021

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.

Relapsed CML is characterized by any evidence of progression of disease from a stable remission. This may include the following:

• Increasing myeloid or blast cells in the peripheral blood or bone marrow.
• Cytogenetic positivity when previously cytogenetic-negative.
• FISH positivity for BCR/ABL (breakpoint cluster region/Abelson) translocation when previously FISH-negative.

Detection of the BCR/ABL translocation by RT–PCR during prolonged remissions does not constitute relapse on its own. However, exponential drops in quantitative RT–PCR measurements for 3 to 12 months correlates with the degree of cytogenetic response, just as exponential rises may be associated with quantitative RT–PCR measurements that are closely connected with clinical relapse.^1,2

Some patients, however, will be in accelerated phase at the time of initial diagnosis.

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

• Persistent presence of 10-30% 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.

Patients may progress to the accelerated phase of CML without experiencing any symptoms. The diagnosis can be made on the basis of peripheral blood or bone marrow findings only.

When CML progresses to the accelerated phase, the leukemia cells may look like either myeloid or lymphoid cells and generally respond poorly to treatment. Historically, intensive chemotherapy regimens used for the treatment of acute myeloid leukemia were used and 25-35% of patients in accelerated phase achieved a remission of relatively short duration. In 2001, the oral tyrosine kinase inhibitor, Gleevec® (imatinib) was approved for the treatment of accelerated and blastic phase CML. Since then, TKI medications have been the primary initial treatment for most patients with newly diagnosed CML in chronic phase. Thus, most of the patients who now have CML in accelerated phase have failed Gleevec treatment.

Treatment of Accelerated Phase CML in Patients Not Exposed to Gleevec

Gleevec is a commonly used treatment for the subset of patients with accelerated phase CML who have not received Gleevec in the past. Researchers affiliated with the STI571 Study Group (IRIS) have reported the results of four years of follow-up of over 1,000 CML patients with advanced disease that had previously been treated with interferon.(1) Patients were treated with Gleevec initially at a dose of 400 mg, but escalating to 600 or 800 mg per day. Survival was 82% among patients in chronic phase and 38% for patients in accelerated phase. Overall survival was more than 50% among those patients in accelerated phase who achieved a partial or complete cytogenetic response to Gleevec. Recent data suggest that Gleevec given at initial doses of 600 mg or 800 mg per day may produce optimal results.(2,3)

Certain subsets of patients in accelerated phase may have particularly good outcomes after treatment with Gleevec. According to the results of a study of 176 patients in accelerated phase, four-year survival after treatment with Gleevec was 53%.(4) Among patients who had a cytogenetic response and were not anemic, four-year survival was 88%. This suggests that long-term disease control with Gleevec is possible in a subset of CML patients in accelerated phase.

For patients who are candidates for allogeneic stem cell transplantation, Gleevec may be given to reduce the extent of disease prior to transplantation.

Treatment of CML in Accelerated Phase after Gleevec Failure

Currently the overwhelming majority of patients entering the accelerated phase of CML will have received Gleevec in the chronic phase. Patients who fail or are intolerant to Gleevec now have several alternatives to consider. These include an increased dose of Gleevec; treatment with "next generation" oral tyrosine kinase inhibitors that have been developed for the treatment of patients with CML and allogeneic stem cell transplant.

Understanding TKI Resistance

Treatment of Accelerated Phase of CML with Sprycel: Sprycel 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.

Researchers from UCLA and the M.D. Anderson Cancer Center have reported that Sprycel has significant activity in patients with Philadelphia chromosome-positive CML or ALL who have disease resistant to Gleevec.(5) In addition, researchers associated with the CA 180-005 ‘START A’ phase II study reported outcomes of patients with Gleevec-intolerant or resistant patients in the accelerated phase of CML treated with Sprycel.(6) Thirteen percent of patients had failed a stem cell transplant. Complete cytogenetic response was achieved in 34% of patients who had not received a prior transplant and 17% in patients who had received a prior transplant. The one year survival was over 80% for transplanted and non-transplanted patients.

Treatment of Accelerated Phase of CML with Tasigna: Tasigna is another drug that targets the Bcr-Abl protein. Tasigna has been approved for the treatment of Philadelphia chromosome-positive chronic phase or accelerated phase CML in adult patients who are resistant to, or intolerant of, prior treatment that includes Gleevec.

Results from a multicenter international trial suggest that Tasigna is a safe and active drug for the treatment of patients with CML or ALL who fail Gleevec.(7,8)Frequently seen side effects were different from those seen with Gleevec and included rash, liver damage and low blood cell counts.

Tasigna may also prove to be useful in patients who are resistant to Sprycel. A study reported at the 2006 meeting of the American Society of Hematology evaluated Tasigna in patients who had failed both Gleevec and Sprycel.(9)The study included 50 patients with accelerated or blast crisis of CML. The results of the study suggest that Tasigna has significant activity in patients who have failed Gleevec and Sprycel and may overcome Sprycel resistance.

Allogeneic Stem Cell Transplantation: Prior to the use of Gleevec, selected patients in accelerated phase of CML treated with high-dose chemotherapy and allogeneic stem cell transplant (using stem cells from a related donor) had a 5-year survival of up to 45%. There has been significant recent progress in the selection of compatible unrelated stem cell donors and the use of umbilical cord blood making allogeneic stem cell transplantation a practical therapeutic choice for most patients with CML in accelerated phase. The use of reduced intensity transplant regimens has also extended the age of transplantation up to 70 years for patients who are in generally good health. While allogeneic stem cell transplants offer the possibility of a cure, the risks and benefits of the procedure will need to be considered on an individual basis.

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There are limited data concerning the outcome of allogeneic stem cell transplants among patients in the accelerated phase of CML who have failed Gleevec. Recently, researchers from the Fred Hutchinson Cancer Research Center have reported that CML patients receiving an allogeneic stem cell transplant after Gleevec treatment have similar outcomes to CML patients who received an allogeneic stem cell transplant without prior Gleevec treatment(10) Three-year survival was 45 percent in both groups of patients. These researchers suggest that pre-treatment with Gleevec did not adversely affect survival.

Blastic Phase of CML

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.

When CML progress to the blastic phase, the leukemia cells may look like either myeloid or lymphoid cells and generally responded poorly to treatment - newer precision medicines are improving outcomes. 

Lymphoid Blastic Phase

A novel chemotherapy-free regimen using the combination of Iculsig (ponatinib) and Blincyto (blinatumomab) appears safe and effective in patients in lymphoid blast crisis (CML-LBC). 

Iciulsig is a targeted tyrosine kinase inhibitor (TKI) that works by inhibiting proteins called tyrosine kinases on leukemia cells, in particular the abnormal BCR-ABL protein that causes the disease. Iculsig has an advantage over previous generations of TKIs because it is designed to overcome the T3151 mutation, the most common cause of disease relapse.

The study evaluated five CML-LBC patients and the two-year overall survival rate was 53%. The treatment was well-tolerated and the toxicity profile of both drugs was consistent with other studies, with no additional toxicity observed with the combination. The trial is ongoing and still accruing patients. The combination of Iculsig-Blincyto appears effective-whether it can be used best as a stand alone treatment or prior to stem cell transplant in patients with CML-LBC remains to be determined.²²

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.(17) 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.(18) 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.¹⁹ 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 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.^20.21 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.

References

1. 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.
2. Martinelli G, Iacobucci I, Rosti G, et al.: Prediction of response to imatinib by prospective quantitation of BCR-ABL transcript in late chronic phase chronic myeloid leukemia patients. Ann Oncol 17 (3): 495-502, 2006.
3. Aoki E, Kantarjian H, O’Brien S, et al. High-dose (HD) imatinib provides better responses in patients with untreated early chronic phase (CP) CML. Blood 2006;608a, abstract 2143.
4. Kantarjian H, Talpaz M, O’Brien S, et al. Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia—comparison with historic experience. Cancer2005;103:2099-2108.
5. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New EnglandJournal of Medicine. 2006;354:2531-2541.
6. Cortes J, Kim DW, Guilhot F, et al. Dasatinib (Sprycel®) in patients (pts) with chronic myelogenous leukemia in accelerated phase (AP-CML) that is imatinib-resistant (im-r) or –intolerant (im-i): Updated results of the CA180-005 ‘START-A’ phase II study. Blood 2006;108:613a, abstract 2160.
7. 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
8. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.The New England Journal of Medicine. 2006;354:2542-2551.
9. Jabbour E, Kantarjian H, Giles F, et al. Treatment with nilotinib for patients with chronic myeloid leukemia (CML) who failed prior therapy with imatinib and dasatinib. Blood 2006;108:616a, abstract 2171.
10. Oehler VG, Gooley T, Snyder DS, et al. The effects of imatinib mesylate treatment before allogeneic stem cell transplant for chronic myeloid leukemia.Blood 2006;October 24 [Epub ahead of print].
11. 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.
12. 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. Blood2000;95:1781-1787.
13. 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.
14. 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.
15. 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.
16. 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. Cancer2007;109:248-255.
17. 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.
18. 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.
19. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New EnglandJournal of Medicine. 2006;354:2531-2541.
20. 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.
21. 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.
22. https://meetinglibrary.asco.org/record/195835/abstract