The first step involved a team of health consultants who conducted a literature review to identify key publications on the role of quantitative PCR (BCR-ABL) in the monitoring of Chronic Myeloid Leukemia (CML).

Then, in order to increase the technical-scientific arsenal, a list with names of several specialists (physicians, managers and representatives of patient associations), who could compose a consensus panel about the impact of said test in clinical practice, was selected.

Finally, six individuals participated in the panel, namely: three hematology physicians from the main public institutions that treat patients with CML in the country (INCA and HEMORIO), a coordinator physician from the laboratory who standardized the PCR test for BCR-ABL in Brazil, located at the School of Medicine of USP-SP, a hematologist who belongs to Hospital Alemão Oswaldo Cruz (HAOC), a representative of the Brazilian society of pharmacists in Oncology (Sociedade Brasileira de Farmacêuticos em Oncologia – SOBRAFO) and a hospital unit manager (Hospital de Clínicas de Porto Alegre/UFRGS) who has specialized care for these patients, and a representative of the largest association of patients with leukemia in Brazil (ABRALE). The diversity of participants was an essential factor in the elaboration of this consensus, since all areas that comprise the global treatment of the disease (diagnosis, treatment, monitoring, resources availability and social representativeness) were contemplated in this process.

From the scientific findings, five central questions were elaborated to understand the clinical and economic impact of BCR-ABL test by quantitative PCR in CML monitoring.

The panel was held on April 3rd, 2019, in São Paulo. Each question was extensively debated through discussion rounds, and a draft was established for the answers to each question. Subsequently, the panel weighed all the information gathered in the discussion rounds and reached what was considered a complete consensus statement addressing all five pre-determined questions.

The consensual answers to the following five questions are described in the sections below, as well as the recommendations on the implementation of the test in Brazil and its importance in the monitoring of CML.

There are three important tests that must be performed by the healthcare professional to assure that the CML patient is responsive to treatment with TKIs (imatinib, nilotinib or dasatinib):

• •

  Complete blood count

  Objective: complete hematological response (CHR) at three months – which means that the number of white cells, red cells and platelets are normalized.12

• •

  Cytogenetic examination

  Objective: complete cytogenetic response (CCR) at 6 months – which means the absence of cells presenting the Philadelphia chromosome in 20 metaphases analyzed by the cytogenetic test.6

• •

  Quantitative PCR examination

  Objective: major molecular response (MMR) at 12 months – which means that the number of BCR-ABL gene transcripts decreased to less than 0.1%, according to the international scale.6

Molecular analysis is indicated to monitor molecular responses that define the percentage of BCR-ABL+ neoplastic cells present in CML patients during different treatment phases.

The monitoring at every three months that is indicated by the PCDT1 and supported by international guidelines6,13,14 can provide important prognostic data for decision making in CML patients, performing the appropriate therapeutic interventions to avoid disease progression. The progression of CML can be fatal, after disease progression, the median survival is only 10 months, and the main objective of treatment is to keep patients in the chronic phase of the disease.

Over 70% of patients may achieve complete cytogenetic remission, and 20%–40% will show suppression of BCR-ABL transcript levels, leading to the achievement of the major molecular response (<0.1% in the international scale) at the end of the first year of treatment.15

In most Brazilian institutions, it is not possible to carry out molecular monitoring (as recommended by international guidelines6,14) despite its description in the Clinical Protocol and Therapeutic Guidelines (PCDT1) of the disease, since the test does not have a code within the Management System of Procedures, Medications and OPM Table of SUS (SIGTAP).11 Currently, this molecular monitoring is carried out in private institutions or university hospitals of great complexity by initiative of the institution itself or through vouchers offered by the private initiative. Thus, the absence of molecular examination access for all patients hurts the principle of equity and integrality of SUS.

The reimbursement structure of oncology therapy in SUS also influences the process of covering the test in the country. In the 1990s, the Ministry of Health gathered its internal technical bodies for a complete review of all regulations and tables of oncological procedures.16 Based on this effort, and under the basic principles of integral and integrated assistance to the Brazilian population, updating procedures and generating data for result evaluation, the Ministry of Health published several regulations to standardize procedure authorizations (APACs) in Oncology. In the specific case of Chronic Myeloid Leukemia, the current regulation presents a reimbursement value of USD 4.19 (Table 1) – which precludes the funding of molecular monitoring.

The BCR-ABL test (quantitative PCR), as already mentioned, does not have an exclusive code in SIGTAP (Management System of the Procedures, Medications and OPM Table of SUS), which promotes difficulties in its conduction quantification and valuation. In addition, specialized and properly qualified laboratories should receive the patients’ samples and perform the test quarterly – in this way, it would be possible to quantify the number of tests and patients attended, contributing to the proper follow-up of the patient during the treatment.

Experts agree that the test is an intrinsic part of the treatment for Chronic Myeloid Leukemia because it would allow the proper follow up of the patients and quantify their quarterly responses through a high sensitivity test. In the absence of molecular monitoring, it is not possible to have a truly effective treatment, exposing these patients to the risk of disease progression and death.

Therefore, the group reached the consensus that it is necessary to monitor adequately the patient to ensure the best outcome in each case. This outcome is only achieved if the patient is monitored, enabling appropriate intervention at a timely manner.

Chronic Myeloid Leukemia (CML) already has a “Clinical Protocol and Therapeutic Guideline” (PCDT)1 for guidance and patient care under SUS, as previously presented. According to this PCDT, updated in 2015, the understanding of CML pathophysiology and the improvement of diagnostic means introduced new concepts in patient monitoring – clinical response, hematological response, cytogenetic response and molecular response.

The molecular response of PCDT is defined as described in Table 2.

Also according to this PCDT,1 some tests should be performed to monitor the patient. Among them is the molecular examination, described and defined periodically as follows:

• -

  Every three months after cytogenetic response obtained and confirmed.

• -

  After obtaining and confirming major molecular response, it can be performed every six months.

• -

  Perform on peripheral blood samples.

The experts believe that the optimal number of tests that should be performed for CML patients includes:

• •

  1 qualitative PCR at the time of diagnosis;

• •

  1 quantitative PCR every 3 months (monitoring);

• •

  After achieving major molecular response (MMR), perform quantitative PCR every 6 months;

It is noted that the schemes in question are similar – however, according to the text of the current PCDT, it would only be possible to perform quantitative PCR after complete and confirmed cytogenetic examination. However, it is understood that the fulfillment of the current PCDT in relation to execution of diagnostic tests in full is crucial for CML patients, as the noncompliance of the monitoring provided in this protocol (as the test is not offered by SUS), has great impact on the treatment of these patients.

Thus, it would be important to formalize the inclusion and a proper nomenclature and code for the BCR-ABL test (with the same description of PCDT – quantification of BCR-ABL1 transcripts by RT-PCR) in SIGTAP, so that the public health system could officially fund this test in the care network.

The experts consulted found that 95% of CML patients in SUS are concentrated in large treatment centers (CACONs/UNACONs).

However, experts acknowledge that the BCR-ABL test is performed in highly complex hospitals today (mainly university and/or research hospitals), such as: Hospital das Clínicas – USP, Hospital das Clínicas de Ribeirão Preto – USP Ribeirão Preto, Hospital das Clínicas da Universidade Estadual de Campinas – UNICAMP, Hospital das Clínicas da Universidade Estadual Júlio de Mesquita – UNESP, Hospital de Clínicas de Porto Alegre/UFRGS and Hospital de Clínicas de Curitiba da Universidade Federal do Paraná. From the expert perspective, it is understood that SUS would have the technical and operational capacity to absorb the total national demand.

The experts suggested an implementation of a technical staff (supported by the society) that could be responsible for accreditation, management and quality of new laboratories, in order to increase the technical and operational capacity of the current public health system.

Other diseases, such as hepatitis C, have a protocol that addresses the specific monitoring of the disease through predetermined clinical exams. PCDT for Hepatitis C and Co-infections17 defines that the initial and routine laboratory approach of patients with chronic hepatitis C has several purposes, such as defining the moment of treatment initiation, establishing the recommended therapeutic regimen, evaluating the quality of the response obtained with the therapeutic strategy and assisting in cancer tracing. In order to facilitate clinical monitoring of patients with chronic hepatitis C and to assist in the best use of technical and financial resources, PCDT indicates a list of complementary tests (Table 3).

The clinical monitoring in the public health system is already observed as a reality – this action allows the patient to be properly followed during the course of the disease and helps the best use of technical and financial resources of the system. In addition, it is known that early intervention upon the patient's clinical worsening allows quick actions that improve the patient's quality of life.

Experts have pointed out that disease progression is costly for the public healthcare system, as it leads to recurrent hospitalizations, transplants, new treatments with other lines of medication, reduced productivity, work leave, and others.

The experts achieved consensus on the importance of monitoring being linked to the possibility of discontinuing treatment with TKIs, according to results of the studies mentioned above, which currently is a clinical practice recommended by the guidelines of ESMO and NCCN, and it would benefit not only patients but also reduce costs for the health system. The discontinuation study STIM (STopIMatinib), which has the longest follow-up to date, included 100 patients who discontinued the use of imatinib after sustaining a deep molecular response for at least 2 years, 38% of whom remained more than 8 years without use of medication, maintaining treatment-free remission. However, without access to PCR examination, it is not possible to benefit patients with the treatment discontinuation possibility.

The experts agreed by consensus that the existence of a code in SIGTAP, with adequate nomenclature, is the best strategy for financing the molecular test in SUS, as the PCDT contemplates the test in the detailed monitoring of the disease and the current APAC value precluded the proper conduction of the test in specialized laboratories and/or authorized reference centers.

From the economic point of view, the incorporation of the test could reduce costs considering the currently recommended treatment for CML, since specialists work with the premise that if molecular monitoring is done properly, the patient follow up in order to prevent disease progression and death is possible; besides electing patients with sustained deep response to treatment discontinuation.18,19 This is an argument supported by the experts regarding the negotiation of incorporation of the test in SUS, as other countries have already taken this step, according to data of said studies.

In 2018, during the congress of the American Society of Hematology (ASH), a study published by leading physicians treating CML in Brazil demonstrated that discontinuation of 1 of the 3 TKIs available in SUS could generate savings for the Brazilian health system possible of paying for PCR tests for all patients with CML in the country. Finally, it is important to educate patients and physicians on the possibility of discontinuing of treatment through explanation of all treatment steps, carrying out the adequate quarterly follow-up and planning the discontinuation at the optimum point recommended by the presented studies.18,19

• 1)

  Molecular monitoring should be part of the integral treatment of patients with CML to reduce the chances of disease progression and costs to the health system;

• 2)

  The government should put into practice what is provided in the PCDT of Chronic Myeloid Leukemia in Brazil: performing the monitoring of the molecular response via quantitative PCR;

• 3)

  The government should create a code with adequate nomenclature and reimbursement value in SIGTAP, so that the test is carried out and covered by the public healthcare network, as it is contained in the PCDT of the disease and the existing APAC does not cover the operational costs for its performance;

• 4)

  Patients with chronic phase CML should perform a quantitative PCR every 3 months and, after reaching the MMR, should perform the examination every 6 months, as recommended by international guidelines. The PCDT should be updated based on international guidelines regarding PCR monitoring frequency;

• 5)

  Patients should be monitored in reference laboratories that are standardized according to the international scale;

• 6)

  The laboratories that are within the reference public centers could absorb all the test demand in Brazil, and other centers could be qualified through an ABHH accreditation;

• 7)

  Adequate molecular monitoring may allow some patients to stop taking drugs and self-financing the molecular test for all SUS patients