Consensus exists that imatinib therapy is the standard ap- proach to the treatment of CML, and this modality will be measured in the future against all new therapies. The recent addition of the highly potent TKIs nilotinib and dasatinib has further improved the armamentarium against CML but also posed new challenges. First, the role of these new compounds in modern algorithms of CML therapy is still unknown and must be defined. Despite having shown im- pressive response rates in patients after imatinib failure or intolerance, the duration of these responses will be deter- mined with longer follow-up. Their role in frontline therapy for CML will also have to be defined. Second, as our resources for controlling CML improve, the refinement in molecular monitoring must improve in parallel. In this regard, the lack of consistency among different laboratories in BCR-ABL transcript results by current PCR technolo- gies is still an ongoing problem. Future improvements in molecular techniques and their standardization by using a laboratory-specific conversion factor will be crucial to fur- ther our understanding of the dynamics of molecular re- sponse to TKIs, providing a uniform method and definition of MMR and defining the concept of molecular relapse. Other challenges, such as defining the best treatment for
The life expectancy of a newly diagnosed patient with Philadelphia chromosome-positive (Ph+), BCR- ABL1+ chronicmyeloidleukemia (CML) in chronic phase (CP) is now very close to that of age matched individuals in the general population, at least in Western countries. 1-5 This remarkable achievement re- flects the success of a large number of prospective clinical trials, summarized in management recommen- dations previously published by the European LeukemiaNet (ELN). 6-8 Several tyrosine kinase inhibitors (TKIs) are approved for the treatment of CML and the choice of therapies for individual patients is deter- mined by considerations of efficacy, tolerability, early and late toxicity and drug costs. More recently, there has been increasing focus on quality of life and avoiding long-term organ toxicities and, in particular, the identification of strategies to maximize the possibility of stopping TKI therapy resulting in so-called “treatment free remission” (TFR). However, in resource-poor countries, the availability of effective drugs and essential monitoring may be limited, and the goal of treatment remains survival. 9
The last version of the 2013 European LeukemiaNet recom- mendations suggested to continue indefinitely TKI therapy and to appropriately discontinue only in a controlled clinical trial [35••]. Hughes and Ross reported for the first time in 2016 how to move TFR into the clinical practice, suggesting that patients who may be optimal discontinuation candidates should be non-high Sokal risk at diagnosis, with a typical transcript type, in CP with optimal past history of response with more than 8 years of treatment, in MR4.5 lasting for more than 2 years. Patients who should be excluded from a discon- tinuation proposal are patients with a prior advanced phase of the disease, in failure, with less than 3 years of treatment, not in MR4.5 and with a duration of deep molecular response of less than 1 year [36••]. A position on discontinuation was also taken by NCCN in the new version of the CML guidelines 2017: candidates to discontinuation are patients in chronic phase, on therapy with one of the available TKIs for more than 3 years, in stable MR4 for almost 2 years (documented on at least four tests performed at least 3 months apart) and no history of previous resistance. Monthly molecular monitoring for the first 6 months has been suggested in a standardized molecular laboratory with a limit of detection of MR4.5. The guidelines also suggested consulting with a CML specialty center to review the appropriateness for TKI discontinuation and potential risks and benefits. The threshold to consider for relapse is the loss of MR3 [37••]. Recently, ESMO guidelines indicates that optimal candidates to discontinuation are non- high Sokal risk patients, with typical quantifiable transcript, in chronic phase, after optimal response to therapy, who have reach MR4.5 with at least a stable MR4 for more than 2 years. Institutional requirements for safe supervision of TFR include availability of high quality internationally standardized, accu- rate and sensitive RQ-PCR laboratory, with rapid turn-around of test results (within 4 weeks) .
Studies related to Bcr-abl gene rearrangement is of great use in making the diagnosis of CML. The drawback in cytogenetics is that the metaphase spread which is best for analysis is that may at times not be obtained. Yet another plus point over cytogenetics is that in conditions where bonemarrow is not available the test can be carried out with a peripheral blood sample for molecular analysis. This bcr-abl gene rearrangement studies can also be used to differentiate CML blast crisis from ALL. CML blast crisis will be ph+ bcr+, whereas ALL will be ph+ bcr-. This study will be of help in monitoring the course or progress of the disease. For eg. After BMT or treatment with alpha interferon , by detecting Ph chromosome we can assess the minimal residual disease.
Data on the frequency of cytogenetic evaluations, FISH, and PCRs were provided by the Munich Leukemia Laboratory (MLL). The MLL is the largest diagnostic laboratory in the field of leukemia and lymphomas in Germany and has information on the monitoring of about 5000 patients with CML. Data were used from 2010 to 2016 too. The MLL holds data on all analyses performed there in this time frame as well as the date of diagnosis and death, allowing to esti‐ mate the monitoring frequency. It has to be stated that while the KVB data represent a complete survey of the Bavarian population within the statutory health system, the MLL data represent a sam‐ ple of patients being examined at a specific laboratory. Due to data privacy regulations, it was not possible to merge both datasets or to link them to any survival data. As, for example, patients without any examination can naturally not be part of the MLL dataset, it might be seen as a positive selection. Therefore and because of the large sam‐ ple size, no significance tests, that is, no P‐values, were calculated.
Bone marrow biopsies should be done at 6-month intervals until achievement of complete cytogenetic response, to determine disease status. Evaluation of bone marrow samples for cytogenetic abnormalities is essential to rule out clonal cytogenetic evolution during therapy, which identiﬁ es patients at high risk of relapse. Once complete cytogenetic response is achieved, monitoring can continue with quantitative RT-PCR (qPCR) from peripheral blood at 3-month intervals. Though few patients (around 5% of patients) with cytogenetic responses have developed clonal cytogenetic abnormalities in Ph-negative cells, the signiﬁ cance of this ﬁ nding is less clear. 22–24 The risk of progression to myelodysplastic syndrome
Kulcsszavak: krónikus myeloid leukaemia, BCR-ABL tirozinkináz, szakmai irányelv, Magyarország
Chronic myelogenous leukemia: diagnosis and treatmentChronic myelogenous leukemia is a clonal myeloproliferative neoplasm caused by reciprocal translocation involving chromosomes 9 and 22 resulting in the expression of a constitutively activated BCR-ABL1 tyrosine kinase that leads to the malignant transformation of the hematopoietic stem cells. The condition was previously known as a relent- lessly progressive disease, but the treatment was revolutionalized by the efficacy of tyrosine kinase inhibitors. Thera- peutic success is thus currently determined by the depth of molecular response achieved on therapy. Multiple tyrosine kinase agents are available even for the first line treatment. This guideline summarizes current focal points of the treatment of chronic myelogenous leukemia specific to Hungary and provides definitions for optimal molecular re- sponses in this condition.
Investigators at MD Anderson Cancer Center also evaluated nilotinib as frontline treatment in a single-arm Phase II study. Patients received nilotinib 400 mg twice daily, administered on an empty stomach. To be eligible for study enrollment, patients were required to have had a diagnosis of CML during the 6 months before the study, have had no treatment other than hydroxyurea or a 1-month maximum of imatinib 400 mg daily, be aged $18 years, have perfor- mance status of 0–2, and normal organ function. The primary objective of this study was to evaluate the major molecular remission rate at 12 months compared with historical controls (from the IRIS study) who had received imatinib 400–800 mg daily. Other endpoints evaluated were over- all survival, event-free survival, and transformation-free survival. 46
Although TKI therapy results in a loss of excessive bone marrow proliferation with effective induction of clinical remission and prevention of progression to advanced phase of the disease, the treatment is presumed not to be curative. Ph+ CML leukemic stem cells are not dependent on BCR- ABL1 activity for their survival as they reside quiescently in the bone marrow. Indeed, after prolonged TKI treatment and clinical disease remission, the BCR-ABL1 fusion product remains detectable in virtually all CML patients. These low levels of residual disease are routinely quantified by using Real- Time Quantitative Polymerase Chain Reaction (RT-qPCR) for BCR-ABL1 demonstrating so-called deep molecular remissions. Although continuation of therapy was initially considered essential, recent studies have shown that ∼50% of patients in sustained deep molecular remission may stop their TKI treatment without clinical relapse ( 4 , 5 ). Importantly, patients showing loss of a major molecular remission with a BCR- ABL1 rising above 0.1% on the international scale, universally regain their major molecular remission upon re-initiation of their TKI. With close molecular monitoring and timely re- initiation of TKI therapy, TKI discontinuation has been proven to be safe in carefully selected patients ( 4 , 5 ). Since the BCR- ABL1 fusion product remains detectable in many patients after TKI discontinuation, this condition is called “Treatment Free Remission” (TFR), reflecting an operational, but not true cure. Maintenance of low-levels of residual disease is supposed to occur through immune regulatory mechanisms supported by associations of successful TFR with KIR (Killer Cell Immunoglobulin-like Receptors) haplotypes, T-cell CD62L expression and CD56 cytotoxic T-cell numbers ( 4 – 8 ). Achieving TFR is now an important new treatment goal in CML for both doctors and patients ( 9 ). Successful TFR improves quality of life of patients as they become free of TKI side effects, are no longer exposed to potential late toxicity and brings substantial drug cost savings. However, only a minority of patients is eligible to try
myeloid lineage. Its diagnosis is made cytogenetically, with the presence of the Philadelphia (Ph) chromosome, a shortened chromosome 22 associated with a fusion gene that codes for an oncoprotein with deregulated protein tyrosine kinase functionality and that conveys a prolifera- tive advantage to affected leukocytes. It is a commonly diagnosed hematological malignancy in Asia but, accord- ing to available data (Table 1 ) its incidence and median age of onset appear to be lower than the respective 1.5 per 100,000 and 65 years seen in the US [ 1 ]. This review covers treatment patterns and key clinical issues facing patients and clinicians in China, Hong Kong, India, the Philippines, Singapore, South Korea, Taiwan and Thailand. As in Western countries, the disease affects men more commonly than women, but perhaps less so (Table 1 : M/F ratio in US and Thailand 1.7:1 versus between 1.3 and 1.6:1 elsewhere in Asia). Indian incidence, although based on very sparse data, is closest to that seen in the US while Chinese figures, again not comprehensive, suggest a much lower incidence (0.4–0.6 per 100,000). Most patients tend to be diagnosed in the chronic phase; in the West, where diagnosis often occurs on the basis of routine blood testing, 85% of patients are diagnosed in the chronic phase and half are asymptomatic at first presentation [ 2 ].
on 260 patients, of whom 229 had a confirmed diagnosis of CML in myeloid BP. Most of the patients had not received any specific therapy for advanced CML except for IFN and palliative therapy with hydroxyurea or low-dose cyto- sine arabinoside. When Phase I dose-escalation data dem- onstrated the safety of prolonged treatment with imatinib at higher doses, the initial daily dose was increased from 400 to 600 mg daily. Imatinib-induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including CHR in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib-induced MCyR in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Non- hematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to both the underlying condi- tion and the treatment. 34 Obviously, the development of the
ChronicMyeloidLeukemia (CML) is a hematological malignancy its diagnosis is based on the histopathologic findings in the peripheral blood, characterized by the presence of the genetic aberration known by Philadelphia (Ph1) chromosome in Bone Marrow (BM) cells [1,2]. The chromosome results from a reciprocal translocation between chromosomes 9 and 22, which forms the chimerical bcr-abl oncogene . The protein product shows an elevated tyrosine kinase activity when compared to normal c-Abl protein . Bcr/abl decreases gradually the sensitivity of malignant cells to apoptotic stimuli until apoptosis prevention providing a survival advantage facilitating the outgrowth of malignant clones as commonly shared by cancer cells [5, 6]. Dendritic cells (DC) have been shown responsible for the initiation of immune responses, able to stimulate T cells with specific activity against CML cells [7-10]. This function may be favorably affected by biologic immune response modifiers such as Interferon- α (IFN- α ) [11-13]. The role of IFN- α in differentiation and activity of monocyte-derived DC from CML patients was investigated and confirmed . Cytogenetic analysis to IFN- α therapy revealed that IFN induces DC differentiation, cell-cycle arrest (CCA), and/or apoptosis which play roles in the compromised survival of the malignant cells . In addition IFN- α has a powerful capacity to cause a sustainable elimination or suppress selectively cells bearing the Philadelphia chromosome, resulting in partial or complete restoration of the normal clone . But despite of many years of current use of IFN-
Each TKI (eg, dasatinib) is associated with a distinct safety profile that should be considered when choosing the optimal treatment for an individual with CML. While choosing a TKI treatment, comorbidities of the patient together with the pos- sible drug–drug interactions, both prior to and during the TKI therapy, should be taken into consideration. In patients with imatinib failure, BCR-ABL1 KD mutation testing should be performed while starting a second-line TKI treatment. Dur- ing the follow-up, close monitoring is essential for response evaluation, as well as to detect and manage TKI-associated AEs properly.
lack of adherence to imatinib treatment results in signif- icantly lower response rates in patients with CP-CML. In a prospective observational study (Adherence assess- ment with Glivec: indicators and outcomes; ADAGIO), adherence to imatinib treatment was analyzed in 169 patients with CML during a 90-day period and corre- lated with overall responses to treatment. Only 14% of patients were found to be perfectly adherent based on pill counts (100% of imatinib taken), with 71% of patients taking less imatinib than prescribed and 15% taking more imatinib than prescribed. Importantly, worse adherence was associated with worse treatment responses; patients who had a suboptimal response to imatinib had significant higher mean percentage of ima- tinib not taken than those with an optimal response (23% vs 7%; P = 0.005). Similarly, patients who failed to achieve a CCyR on imatinib had a higher mean percen- tage of pills not taken than patients who achieved a CCyR (24% vs 9%; P = 0.012) . In another prospec- tive observational study performed at a single institu- tion, 87 patients with CP-CML who had achieved a CCyR on imatinib were monitored for adherence for 90 days using a microelectronic monitoring device. The adherence rate was ≤ 90% in 26% and ≤ 80% in 14%. There was a strong correlation between adherence to imatinib and probabilities of MMR and CMR; patients with ≤ 90% adherence had a lower 6-year rate of MMR than patients with > 90% adherence (14% vs 94%; P = 0.002), no patient with ≤ 90% adherence achieved a CMR, and no patient with ≤ 80% adherence achieved a MMR. Significantly worse adherence rates were found in patients with various adverse events (AEs), including asthenia, nausea, muscle cramps, and bone or joint pains, and also in patients who took imatinib indepen- dently of meals. Patients who had their imatinib dose increased had significantly worse adherence than patients who remained on imatinib 400 mg QD (86% vs 99%; P = 0.021) . In a retrospective analysis of imati- nib treatment in clinical practice using US administra- tive claims data, adherence to imatinib in 267 patients was calculated using the medication possession rate (MPR), ie, the total days supply of imatinib in a 1-year period divided by 365. Overall, the mean MPR was 78% and 31% of patients had a treatment interruption of at least 30 consecutive days. Among the study population, nonadherence was higher in patients with higher num- bers of concomitant medications, women, patients with more complex disease, and patients with a higher start- ing dose of imatinib (≥ 600 mg/d). Although the reasons for worse adherence in women were not examined, the authors suggested that women may be more concerned than men with AEs characteristic of imatinib treatment, such as rash, edema, and weight gain .
B-cell lymphoma model, Serafini and colleagues showed that the expansion of a preexisting pool of T-reg can be mediated by MDSCs (23). They described MDSCs as tolerogenic antigen presenting cells with ability in antigen uptake and presentation to tumor-specific T-reg. MDSC-mediated T-reg induction required arginase, but was TGF-β independent. Inhibition of MDSC func- tion abrogated T-reg proliferation and tumor-induced tolerance. Many authors provide evidence of an increased frequency of T- reg cells in CML patients at diagnosis in association with higher Sokal scores and higher levels of BCR-ABL transcripts, indicating that an immune response may be important in the control of CML (37, 56). In addition, T-reg number was significantly lower in patients with CP CML versus the accelerated and blast phases, and was significantly lower in patients with CMR compared to those patients without CMR (57). To understand if there is a correla- tion in CML patients between MDSCs and T-reg frequency, we investigated the levels of both circulating lymphoid and myeloid subpopulations founding a direct correlation between the per- centages of T-reg and Gr-MDSCs at diagnosis (Figure 2) (6). The percentage of T-reg cells was higher in patients at diagnosis com- pared to healthy donors and decreased to the normal levels after Imatinib treatment, confirming the correlation with the levels of Gr-MDSCs.
Next-generation sequencing (NGS) in MPN and MDS/MPN NGS technology, such as whole-exons sequencing (WES) has demonstrated its power in re-sequecing human ge- nomes to enhance our understanding of how molecular genetics affect MPN and MDS/MPN [1,15,16,21,25]. How- ever, the challenge is to provide genetic information in a timely and affordable way. Thus, the utility of detailed tar- geted resequencing by capturing technologies is currently reasonable in clinical practicality. Consequently, molecular biomarkers will soon no longer be sequenced individually. Instead, panels of biomarkers will be assessed in a mas- sively parallel way with high sensitivity and multiplexing in patients with MPN or MDS/MPN for diagnosis and indi- vidualized treatment regimens.
Hematology-oncology is a specialty that deals with patients who now can count on increased survival based on the proposed treatments – treatments that, of course, are not without risks or side effects, but are tolerable. However, few studies have been con- ducted in Brazil to determine patients’ desire to participate in treatment decisions, and there have not been any studies specifi- cally on CML patients that have assessed their access to treatment and the time required for a diagnosis to be reached. Since there may be significant differences in patients’ perceptions of the qual- ity and quantity of information received and in their participation in medical decisions among populations in different countries, it
subcutaneously twice a day on days 1–14 every 28 days for two cycles, until disease progression or unacceptable toxicity occurred. Blood and urine were collected to measure con- centrations of omacetaxine mepesuccinate and its inactive metabolites. Pharmacokinetic parameters were estimated from 21 patients with a diagnosis of relapsed or refractory CML, acute promyelocytic leukemia, acute myeloid leuke- mia, or myelodysplastic syndrome, or advanced solid tumors who had exhausted or become intolerant to all available therapies. 53 Omacetaxine mepesuccinate is rapidly absorbed
As a result of these concerns, the presentation of ‘ patient disposition ’ at a given time of follow-up is increasingly seen as mandatory complement to overall survival (OS) and event free survival (EFS) estimates. Moreover, it has become clear that the results of imatinib therapy are sig- nificantly less favorable in the community setting. A report from the Hammersmith Hospital defined imatinib failure more broadly than the IRIS study as discontinuation of drug for any reason, including toxicity. Additionally, the lack of a major cytogenetic response was considered as failure, in line with recommendations by the European Leukemia Network (ELN) . Using these criteria, EFS at 5 years was calculated at only 63% . Even more alarm- ing are results from a population-based study of CML patients in Northwestern Britain that encompassed all patients diagnosed with CML in a geographically defined area over a 3.5 year period. At 24 months, only half of the patients were in CCyR and receiving imatinib . While imatinib resistance can be caused by several mechanisms, including mutations in the kinase domain of BCR-ABL, it is likely that lack of adherence to medication is a major underlying reason for these sobering data, possibly by pro- moting the emergence of resistant clones through subopti- mal, non-lethal target inhibition [12,13]. Perhaps it should not come as a surprise that chronic oral cancer therapy is subject to the same compliance limitations as other chronic drug therapies, and this will not be different with other oral agents . Here we review three frontiers of CML therapy: improvements in first-line treatment, the therapeutic objective of disease eradication and novel agents to overcome drug resistance.