CML Treatment

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Chronic myeloid leukemia (CML) accounts for about 1.5% of all leukemia cases, about 0.5% of all new cancers, and about 0.2% of all cancer-related deaths in the US. The overall incidence rate of CML has been slightly increasing while the mortality rate of CML has been declining during the last decade.

CML more commonly affects older age individuals with highest incidences observed in individuals aged between 65 to 74 years. The incidence rate of CML is slightly higher in males than in females.

Characteristically, CML is a slow-growing disorder which is mostly diagnosed in chronic phase, which may become aggressive (progressed to accelerated or blast phase) if not treated appropriately.

Treatment of CML depending on Phase

The treatment of CML depends on many factors, including but not limited to, the phase of the disease, risk group, associated comorbidities (to choose the drugs which do not have similar side effects), and performance status of the patient.

Chronic Phase (CP) CML 

In low-risk patients, both first-generation and second-generation tyrosine kinase inhibitors (TKIs) are considered as the standard treatment; however, in case of intermediate to high-risk patients, second-generation TKIs are considered the preferred treatment.

After starting the treatment, RT-PCR is done at regular intervals to assess the response to treatment. Further decision whether to continue the same drug or change the treatment is taken depending on the response.

Accelerated Phase (AP) CML

In patients with newly diagnosed accelerated phase CML, TKI therapy is considered the preferred treatment. In case of patients with chronic phase CML who have progressed to accelerated phase, mutational analysis is done to check for resistance. Thereafter, a different TKI is used that is active against the mutation detected. Allogeneic SCT can be considered in case of mutations resistant to TKIs.

Blast Phase (BP) CML

In patients with newly diagnosed blast phase CML, induction treatment for ALL or AML is given, depending upon whether it’s lymphoid or myeloid blast crisis, respectively.

Allogeneic SCT is indicated once patient has attained CR after induction. TKI is given throughout along with chemotherapy and continued thereafter. In case of patients whose disease has progressed from CP or AP to blast phase, induction treatment for ALL or AML is given, depending upon whether it’s lymphoid or myeloid blast crisis, respectively. 

Role of Targeted Therapy

targeted-therapy Targeted drugs are designed to target a specific gene or protein characteristic of the CML cells. Most patients (>95%) with CML have a well-characterized genetic abnormality – Philadelphia (Ph) chromosome that gives rise to the BCR-ABL-1 fusion gene. The defective fusion gene encodes for a protein that has intrinsic tyrosine kinase activity responsible for the uncontrolled proliferation of the CML cells. Following is the list of various TKIs currently approved for the treatment of patients with CML:

Imatinib

imatinib It is the only first-generation tyrosine kinase inhibitor (TKI) that inhibits the abnormal activity of BCR-ABL1. It is the first targeted drug approved for the treatment of CML in first-line setting due to significantly improved clinical outcome and overall survival (OS) observed in clinical studies. Side effects of imatinib include nausea, diarrhea, muscle pain, fatigue, skin rash, and fluid build-up in different body parts.

Dasatinib

Dasatinib It is a second-generation TKI that has about 350 times more potency than imatinib for inhibition of BCR-ABL tyrosine kinase. It was found effective in some patients who were resistant to imatinib treatment. It has also been approved for the treatment of patients with CML in first-line settings owing to better response and fewer chances of disease progression observed in large clinical studies. Side effects of dasatinib include edema, low blood cell counts, nausea, diarrhea, and skin rashes.

Nilotinib

It is another second-generation TKI that is a structural analog of imatinib but is about 50 times more potent than imatinib. Similar to dasatinib, nilotinib may be effective against some cases that are resistant to imatinib. Also, compared to imatinib, it showed a better response to treatment and fewer chances of disease progression when employed in the first-line setting. It has also been approved for the first- and second-line treatment of CML patients.

Bosutinib

bosutinib It is another second-generation TKI that is a potent inhibitor of BCR-ABL1 kinase activity. Although it was initially approved to be used in the second-line setting, it has recently been approved to be used in the first-line settings for the treatment of patients with CML. Side effects include nausea, vomiting, diarrhea, abdominal pain, fever, fatigue, low blood cell counts, and liver damage.

Ponatinib

ponatinib It is the third-generation TKI that is a potent inhibitor of BCR-ABL and is the only TKI active against the T315I mutation. It is approved for the treatment of patients who are not responding to prior therapy or have T315I mutation. Side effects of the drug include abdominal pain, headache, skin problems, fatigue, high blood pressure, and other heart-related problems.

Based on the results obtained from various clinical research studies following inferences have been drawn:

First-generation TKI–Imatinib, and second-generation TKIs–bosutinib, dasatinib, and nilotinib are generally employed for the treatment of most of CML patients due to their proven effective in patients with newly diagnosed chronic phase (CP)-CML.

The second generation TKIs are preferred over imatinib in patients with high-risk disease, and in women who want to achieve quick response for fertility-related reasons. Of note, the overall survival rate with second-generation TKI remain comparable to imatinib. The selection of the most appropriate TKI drug (among the second-generation agents) also depends upon the side-effects associated with the drug.

Selection of Second-line Treatment for CML

The response to first-line treatment with TKIs is one of the key prognostic indicators of the clinical outcome in CML patients. The response to treatment is usually assessed by assessing the level of BCR-ABL1 transcript in the blood or bone marrow with the help of reverse transcriptase- polymerase chain reaction (RT-PCR) technique.

The requirement for continuation of the same treatment regimen or a change in treatment regimen is then assessed based on the level of BCR-ABL1 achieved at different time points as shown in the table below:

Time of Response Assessment BCR-ABL1 Level Clinical Consideration
3 months </=10% Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.
>10% There are chances of resistance development on the current treatment regimen. Assessment of compliance to treatment and mutational analysis is recommended for these patients.
6 months </=10% Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.
>10% Disease is resistant to the current treatment regimen. Second-line treatment regimen should be selected based on results from mutational analysis and considering other factors.
12 months </=1% Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.
>1% but </=10% There are chances of resistance development on the current treatment regimen. Assessment of compliance to treatment and mutational analysis is recommended for these patients.
>10% Disease is resistant to the current treatment regimen. Second-line treatment regimen should be selected based on results from mutational analysis and considering other factors.
15 months or more </=1% Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.
>1% Disease is resistant to the current treatment regimen. Second-line treatment regimen should be selected based on results from mutational analysis and considering other factors.

Mutational Analysis in CML

CML patients who do not achieve a predefined response to the first-line TKI therapy or who progressed on the initial TKI-therapy are recommended to undergo a mutation analysis. This is performed by next-generation sequencing method or conventional sequencing method.

The mutational analysis help in detection of specific mutation(s) that may have played a role in the resistance development to the initial TKI used. In case a mutation is detected, appropriate second-line therapy with an alternate TKI agent can be started based on the detected mutation. Following table indicate the most appropriate second-line TKI agents for different mutations detected in the mutational analysis.

Mutation Treatment Recommendation
Y253HE255K/V, or F359V/C/I Dasatinib
F317L/V/I/CT315A, or V299L Nilotinib
E255K/VF317L/V/I/CF359V/C/IT315A, or Y253H Bosutinib
T315I Ponatinib, Omacetaxine

 

In case of the absence of any mutation, a second line treatment therapy is selected based on the overall health of the patient and risk score. Second generation TKIs are generally preferred over imatinib for second-line treatment due to the lower risk of disease progression, especially in patients with an intermediate- to high-risk score.

Ponatinib, a third-generation TKI, is the only active TKI against the T315I mutation. It is recommended for patients with T315I mutation. Omacetaxine, a chemotherapeutic agent, can also be employed for the treatment of patients with the T315I mutation and for patients who have progressed on 2 or more prior TKIs.

Role of Stem Cell Transplant (SCT)

allogenic stem cell transplant SCT can be considered for the preferred treatment of CML in some selected patients who are good candidates for the same (good performance status) and are not responding to TKIs therapy, or patients in blast phase post induction treatment.

Allogenic stem cell transplant is mainly used for CML. In this technique, healthy stem cells to be administered to the patient after high dose chemotherapy are obtained from another person known as the donor. It is very important that donor is a close blood relative (preferably a sibling) so that donor’s HLA type closely match with the patient’s.

The allogenic SCT is more beneficial than autologous SCT because donor’s stem cells help in removing any remaining leukemia cells (due to graft versus leukemia effect). Thus, allogeneic SCT is mostly used for the treatment of CML. However, allogeneic SCT is riskier due to the graft-versus-host disease in which the new immune cells originated from donor’s cells attack the host cells.

Response Assessment after Starting Treatment

Complete hematologic response (CHR)

A CHR means complete normalization of peripheral blood counts with leukocyte count <10 x 10^9/L; platelet count <450 x 10^9/L; no immature cells, such as myelocytes, promyelocytes, or blasts in peripheral blood; and no signs and symptoms of disease with the disappearance of palpable splenomegaly.

Complete Cytogenetic Response (CCyR)

A CCyR means an absence of Ph+ cells in the bone marrow.

Partial cytogenetic response (PCyR)

A PCyR means a presence of 1% to 35% of Ph+ cells in the bone marrow.

Major cytogenetic response (MCyR)

An MCyR (includes both complete and partial responses) means a presence of 0 to 35% of Ph+ cells in the bone marrow.

Minor cytogenetic response

A minor cytogenetic response means a presence of >35% of Ph+ cells in the bone marrow.

Complete molecular response (CMR) 

A CMR means an absence of BCR-ABL1 gene in the bone marrow when assessed using RT-PCR.

Major molecular response (MMR)

An MMR means a presence of BCR-ABL1 </=0.1% by RT-PCR or >/=3-log reduction in BCR-ABL1 mRNA from the standardized baseline if RT-PCR is not available.

Early molecular response (EMR) 

An EMR means a presence of BCR-ABL1 </=10% of the baseline at 3 and 6 months.

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