Fast Facts: Treatment-Free Remission in Chronic Myeloid Leukemia

From concept to practice and beyond

S. Potluri

• Publisher: S. Karger
• Year: 2021
• ISBN:
  9783318068344
• Topic: Medicine
• Subtopic: Hematology

The tyrosine kinase inhibitor (TKI) imatinib was the first treatment to specifically target cancer cells, rather than the relatively indiscriminate effects of conventional chemotherapy on any rapidly dividing cells. This concept of targeted treatment in cancer is one of the important advances in modern medicine in the last 30 years. Indeed, treatment with TKIs has transformed chronic myeloid leukemia (CML) from a cancer with a poor prognosis to one in which many patients can expect a normal lifespan. Success with the TKIs has prompted the question of whether it is desirable – or feasible – for patients to remain on treatment for long periods. While the TKIs are targeted, they are associated with considerable toxicity, and long-term treatment has important economic implications for health services and patients. Thus, the concept of treatment-free remission (TFR) has emerged for patients in deep clinical remission. Clinical research over the last decade has focused on whether treatment can be stopped, how to best monitor patients while off treatment, and how to intervene before a clinical relapse. As this research progresses, the tantalizing prospect of a cure for some patients seems increasingly feasible. This new Fast Facts title outlines this trail-blazing approach to the long-term management of patients living with CML in remission. It explains the concepts of molecular and hematologic relapse, the highly sensitive technologies that allow disease monitoring, and how TFR is best managed in practice. It is a concise educational resource, ideal for any healthcare professional involved in the treatment of patients with CML who wants to understand TFR, particularly clinical nurse specialists and pharmacists who increasingly help clinicians to run CML clinics. Table of Contents: • The concept of treatment-free remission • Measurement of disease burden • Clinical practice • Future directions

2	Measurement of disease burden

To be eligible to attempt a treatment-free remission (TFR) a patient must have reached remission, defined according to the number of residual leukemic cells relative to healthy cells. The methods for defining different classes of remission, in increasing order of sensitivity, are presented in Table 2.1. Most trial data are derived from molecular testing using the polymerase chain reaction (PCR). Although next-generation sequencing (NGS) is more sensitive – BCR–ABL1 transcripts can be detected to a level of 1 chronic myeloid leukemia (CML) cell in 100 million normal cells – it is currently too expensive for routine clinical use.

TABLE 2.1 Methods for identifying remission, in order of increasing sensitivity
Method	Type of remission	Definition
Full blood count – levels of each cell type on blood film (see Figure 2.1a)	Complete hematologic remission	Platelet count < 450 × 10^9/L White cell count < 10 × 10^9/L No immature granulocytes Basophils < 5% of all white blood cells
Giemsa banding karyotyping to identify the Philadelphia chromosome; cells are treated with colchicine to arrest as many as possible in metaphase of mitosis (see Figure 2.1b)	Complete cytogenetic remission	No visible Philadelphia chromosomes
FISH: different color fluorescent probes are hybridized to BCR and ABL1 (see Figure 2.1c)	Complete cytogenetic remission	In normal cells, the two probes appear slightly separated on confocal microscopy as BCR and ABL1 are on different chromosomes In CML cells with the BCR–ABL1 transcript, the two probes appear in the same place
PCR: used to detect BCR–ABL1 transcript	Complete molecular remission	No detectable BCR–ABL1 transcripts
NGS: sensitive to 1 abnormal cell in 100 million normal cells	Complete NGS remission	No detectable BCR–ABL1 transcripts
CML, chronic myeloid leukemia; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing; PCR, polymerase chain reaction.

Several methods are used to test the disease burden in clinical practice, including the level of BCR–ABL1 transcripts. The European LeukemiaNet (ELN) guidelines¹ recommend quantification of BCR–ABL1 transcripts by quantitative reverse transcriptase PCR (RT-qPCR; see page 23), karyotyping for the Philadelphia chromosome and assessment of hematologic responses by full (complete) blood count (Figure 2.1). The response to treatment is stratified as ‘optimal’, ‘warning’ or ‘failure’ (Table 2.2).

Figure 2.1 (a) Blood film from a patient with chronic myeloid leukemia showing myeloblasts and excess myeloid cells, including myeloid progenitors. Image by Paulo Henrique Orlandi Mourao, licensed under CC BY-SA 3.0. (b) Giemsa band staining to identify the Philadelphia chromosome; arrows indicate the translocation between chromosomes 9 and 22. (c) Fluoresence in situ hybridization (FISH) probes for BCR and ABL1: co-localization of the red and green signals indicates the BCR–ABL1 transcripts. Image licensed under CC BY-SA 3.0.

TABLE 2.2 European LeukemiaNet guidelines’ stratification of responses to tyrosine kinase inhibitors^1
Time	Optimal response	Warning	Failure
Baseline		High-risk clonal chromosomal abnormalities
3 months	BCR–ABL1^IS ≤ 10% and/or Ph+ ≤ 35%	BCR–ABL1^IS > 10% and/or Ph+ 36–95%	No CHR and/or Ph+ > 95%
6 months	BCR–ABL1^IS < 1% and/or Ph+ 0%	BCR–ABL1^IS 1–10% and/or Ph+ 1–35%	BCR–ABL1^IS > 10% and/or Ph+ > 35%
12 months	BCR–ABL1^IS ≤ 0.1%	BCR–ABL1^IS > 0.1–1%	BCR–ABL1^IS > 1% and/or Ph+ > 0%
Any subsequent time	BCR–ABL1^IS ≤ 0.1%	New −7 or −7q karyotype	Any of: Loss of CHR, or cytogenetic remission on one measurement Loss of BCR–ABL1^IS ≤ 0.1% on two consecutive measurements Tyrosine kinase domain mutations New clonal chromosomal abnormalities
CHR, complete hematologic remission; ^IS, International Scale (see page 25); Ph+, Philadelphia chromosome positive.

Polymerase chain reaction

Given that most human cells contain only about 6 picograms of DNA, amplification is required to identify particular genes or transcripts. PCR can double the amount of DNA in each cycle of amplification, exponentially increasing the amount of DNA to detectable levels (Figure 2.2).²

Figure 2.2 Amplification of template DNA during the polymerase chain reaction (PCR). Multiple DNA copies are produced using DNA polymerases under controlled conditions. (D) Denaturation: the reaction is heated to 94–96^oC for 20–30 seconds, which disrupts the hydrogen bonds of the template DNA to produce single-stranded DNA. (A) Annealing: the reaction temperature is lowered to about 68^oC for 20–40 seconds, allowing DNA primers to anneal to the single-stranded DNA molecules. A good bond is formed when the prime...

Table of contents

• Cover
• Title Page
• Copyright
• Contents
• List of abbreviations
• Introduction
• The concept of treatment-free remission
• Measurement of disease burden
• Clinical practice
• Future directions
• Useful resources
• Index