Redefining treatment-free remission criteria in chronic myeloid leukemia in India

INTRODUCTION

Chronic myeloid leukemia (CML) is one of the most common adult leukemias in the Indian population accounting for 30–60% of all adult leukemias.^[1] There is a significant age difference in the Indian population as compared to the Western world, mean age at diagnosis being lesser by 10 years in Indians as compared to the Western world in most studies.^[2] The landscape of CML has undergone a dramatic change in India as in the Western world with the introduction of BCR-ABL tyrosine kinase inhibitors (TKIs). Now with the availability of good quality generics of first and second-generation TKIs, more and more CML patients in India are having long-term control of the disease.

TREATMENT-FREE REMISSION (TFR) AND ITS IMPLICATIONS

Over 20 years of experience in using TKIs in CML has led us to better understanding of disease control and that there is at least a subset of patients in whom TKIs can be safely stopped if the disease activity can be strictly monitored. The concept of TFR has now been generally accepted as safe and achievable, especially in patients on treatment for a long time. With close monitoring and follow-up, various studies have shown that about 40–60% of patients can be kept off treatment in the long term.^[3] Even if treatment failure occurs (loss of molecular response), studies have shown that the TKI discontinuation has no impact on clinical outcomes.^[4]

There are multiple international guidelines that have endorsed treatment-free remission with strict criteria for monitoring and restarting treatment [Table 1].

National Comprehensive Cancer Network (NCCN) guidelines for TKI discontinuation recommend that TKI may be stopped if,

• Age ≥18 years

• Chronic phase-CML. No prior history of accelerated phase-CML or blastic phase-CML

• On approved TKI therapy for at least 3 years

• Prior evidence of quantifiable BCR-ABL1 transcript

• Stable molecular response (MR4; BCR-ABL1 ≤0.01% International scale [IS]) for ≥2 years, as documented on at least 4 tests, performed at least 3 months apart

• Access to a reliable polymerase chain reaction (PCR) test with a sensitivity of detection of at least MR4.5 (BCRABL1 ≤0.0032% IS) and that provides results within 2 weeks

• Molecular monitoring every 1–2 months for the first 6 months following discontinuation, bimonthly during months 7–12, and quarterly thereafter (indefinitely) for patients who remain in major molecular response (MMR) (MR3; BCR: ABL1 ≤0.1% IS)

• Prompt resumption of TKI within 4 weeks of a loss of MMR with monthly molecular monitoring until MMR is re-established, then every 3 months thereafter is recommended indefinitely for patients who have reinitiated TKI therapy after a loss of MMR. If MMR is not achieved after 3 months of TKI resumption, BCR-ABL1 kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for another 6 months

The European Society of Medical Oncology guidelines^[5] recommend that treatment discontinuation may be considered in individual patients, if proper, high-quality, and certified monitoring can be ensured. Prerequisites for safe stopping are institutional requirements for safe supervision, identification of typical BCR-ABL1 transcripts at diagnosis, at least 5 years of TKI therapy, achievement of MR4.5 (4.5-log reduction), and a stability of deep molecular response (DMR) (at least MR4) for at least 2 years. Less stringent criteria do not exclude successful TFR, but the stability of TFR is improved with longer TKI therapy and longer DMR. Informed consent should include information on the estimated risk of recurrence of the disease and the need for frequent molecular monitoring, monthly during the first half-year, 6-weekly during the second half-year, and 3-monthly later on life long.

TKI WITHDRAWAL SYNDROME ADDED TOXICITY OF DRUG WITHDRAWAL

TKI withdrawal syndrome is defined as the onset of new musculoskeletal pain and/or an increase in pre-existing pain and/or the need to start any pain medication. It usually occurs a few weeks after TKI discontinuation and is characterized by musculoskeletal pain and occurs in around 30% patients on stopping TKIs. There may be a need for the use of paracetamol, non-steroidal anti-inflammatory drugs,and steroids in severe cases. It is not dependent on prior TKI use.^[6] The positive side of this is that the patients who have TKI withdrawal syndrome have a greater chance of TFR.^[7] Patients with older age, longer TKI use, low body mass index, and body weight also have greater chances of withdrawal syndrome.^[8] The implication of this among Indian patients is that patients who are typically leaner and on TKI for longer time, especially elderly, should be warned about the TKI withdrawal symptoms and necessary remedies for the same, as many patients in rural India may find it difficult to reach their treatment centers if they develop symptoms.

PSYCHOLOGICAL IMPLICATIONS OF TKI DISCONTINUATION

Patients may experience anxiety as a result of fluctuating BCR-ABL results during TFR. This has to be weighed against the mental fatigue and boredom of continuing TKI daily and lifelong. Hence, they should be adequately counseled and highly motivated for the same. They may have a fear of disease recurrence and progression, especially as they have been living with a well-controlled disease for a long time to be eligible for discontinuation. Hence, psychological and emotional factors from patient and physician perspectives have to be addressed in each visit in the long-term decision-making.

TREATMENT-FREE REMISSION - THE INDIAN EXPERIENCE

There are few published studies on the experience of TFR from India. The studies by Sarma et al.^[9] and by Sarma et al.^[10] from Tata Memorial Hospital, Mumbai are both retrospective analyses including a total of 66 patients. They report a long-term TFR of 70–80% in these studies. The prospective study by Goni et al.^[11] included 26 patients on generic imatinib. They reported a TFR rate of 44% at 1 year among the patients included. A retrospective study on pediatric CML patients by Satishkumar et al.^[12] reports a TFR of 72% among the 18 patients included. The small number of patients and retrospective nature of most of these studies precludes deriving conclusions and data for Indian patients as a whole and points to the need for large, well-designed prospective studies among Indian patients for deriving conclusions on the effect of TFR among Indian CML patients.

THE IMPLICATIONS OF TREATMENT-FREE REMISSION AMONG INDIAN PATIENTS

Treatment-free remission is a difficult challenge to deal with in India, especially rural India due to the stringent guidelines in place for discontinuation. It requires close monitoring, highly standardized tests, and dedicated and close follow-up, with high diligence and effort from both the patient and the treating oncologist.

There is an urgent need for identifying and initiating patients on TFR protocol in India because

1. Younger age at diagnosis means that the patients will be on treatment for a longer time - hence more benefit may be derived from TFR in Indian patients

2. Younger age patients being higher in number means that higher number of patients may be of childbearing age and may require TKI discontinuation to complete their families

3. Long-term adherence of Indian patients to TKIs is poor.^[13] Most Indian studies^[14] show that up to 1/3^rd patients have poor adherence to treatment. If treatment can be discontinued safely, it may be beneficial overall

On the other hand, direct application of guidelines from the Western world to our setting has significant limitations because

1. Higher number of patients with Imatinib resistance mutations - with up to 45–50% resistance mutations identified in patients with poor response to Imatinib in some Indian studies^[15,16]

2. The cost of treatment versus cost of testing - the usual cost of testing with quantitative PCR with the specificity requirement as per guidelines will be equivalent to the cost of 2–3 months of treatment with generic Imatinib at the time of writing this article in India. Hence, in a financial sense, it might be more acceptable for economically challenged patients to just continue the drug

3. Added cost of travel and frequent visits to tertiary care cancer centers for testing, results, and increased number of consultations

4. Lack of access to standardized laboratories as per the strict guidelines - most laboratories do not offer tests at the specificity of MR4.5 levels. This means that only patients who have access to the selected laboratories will be able to stop the TKIs safely

5. Low turnaround time (as per NCCN guidelines) - considering the time taken for the transport of specimens to laboratories with high accuracy testing and number of specimens needed for economically viable testing means that the guideline for turnaround time is impractical for a country like India.

The need to redefine treatment-free remission criteria in Indian CML patients and considerations to be taken into account for Indian patients.

As discussed above, the direct application of guidelines from other countries may not be feasible in India and if we try to do so, the option of TFR may be accessible only to a very limited number of patients. However, the lack of data and standardization of laboratories and lack of motivation for TKI discontinuation among both the patients and physicians restrict us from taking action in this regard. The burden of CML treatment can be significantly reduced if treatment-free remission criteria are redefined for Indian patients and the considerations to be taken into account while designing such as criteria should be

• Uniform standardization of laboratories as per Indian laboratory standardization protocols which most Indian laboratories adhere to for accreditation

• The criteria of molecular response should be made less sensitive so that testing can be done in more laboratories and at lower cost. The current evidence points to the fact that almost all patients re-achieve molecular remission on restarting TKI, so it may be time to relax the criteria if it benefits more patients

• The turnaround time mentioned in some criteria must also be relaxed if a significant number of Indian patients are to benefit from TFR

• Strict criteria for defining TKI withdrawal syndrome and guidelines for its management should be included

• The frequency of testing should be reduced at least after the initial phase of high risk of treatment failure so that the patient is not simply exchanging the burden of taking TKI for their lifetime for the burden of a lifetime of frequent hospital visits and costly testing.

The redefinition of the treatment-free remission criteria for CML should be done at the earliest with the involvement of a regulatory body of national experts so that Indian CML patients will also get the benefit of TFR with a set of guidelines feasible for India without compromising on disease control.

CONCLUSION

The common International guidelines of stopping TKIs for CML may not be practical in India due to multiple factors. Taking the unique biological, clinical and social scenario of India into account, it may be time for India to redefine and formulate its own guidelines for TKI stoppage in Indian CML patients.