Key Research Findings

Treatment of chronic-phase (CP) chronic myeloid leukemia (CML) with imatinib 400 mg/d can be unsatisfactory. Optimization of treatment is warranted. 8

Imatinib is one of the tyrosine kinase inhibitors used for the treatment of chronic myeloid leukemia (CML) patients. The exact association of imatinib with anemia in CML patients is still unclear. 18

Treatment with tyrosine kinase inhibitors (TKIs) for patients with chronic myeloid leukemia (CML) is effective but needs to continue for several years, possibly indefinitely. Although generally safe, TKI may have hitherto poorly recognized effects in the quality of life (QoL) of such patients. 16

The effect of interferon (IFN) therapy on bone marrow features in chronic myeloid leukemia (CML) has been studied on successive trephine biopsies (mean interval 13 +/- 8 months) by cytochemical and immunohistochemical methods in combination with morphometry and in comparison with a control group of patients who received monotherapy by busulfan (BU). Following IFN administration (IFN-alpha frequently in combination with IFN-gamma), there was a decrease in neutrophil granulopoiesis accompanied by a significant expansion of erythroid precursors and increased numbers of hemosiderin-laden macrophages. These changes corresponded with the hematologic response in 21 of the 25 patients investigated. Numbers of megakaryocytes and reticulin/collagen fiber density increased during treatment. Most conspicuously, in responding patients atypical micromegakaryocytes, usually characterizing CML, were partially replaced by normal-sized cells of this lineage. These features are in keeping with the assumption of a reappearance of the normal hematopoietic cell clone as the result of IFN therapy, which was not found in the BU-treated control group. On the other hand, a relevant subpopulation of micromegakaryocytes (about 30%) was still maintained. This result probably relates to the failure to improve myelofibrosis more effectively. Analysis of cell proliferation (proliferating cell nuclear antigen-PCNA) and apoptosis (in situ end labeling) revealed a reduction in PCNA labeling and increased numbers of cells undergoing programmed death. Identification of the activated subset of macrophages (alpha-D-galactosyl residues expression) by appropriate lectin histochemistry disclosed an increase in the number of GSA-I binding cells. These findings were exclusively limited to IFN administration and reflect an inhibitory effect of IFN on cell proliferation and stimulation of programmed cell death. The latter phenomenon probably results in increased phagocytosis of clonally transformed myeloid cells by GSA-I-positive (activated) macrophages. 3

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered. 10

The prognosis and life expectancy of chronic myeloid leukemia (CML) patients have improved significantly with the launch of first tyrosine kinase inhibitor (TKI), imatinib. Maintaining at least one major molecular response in CML patients without the use of TKI is known as treatment-free remission (TFR). The safety of the first TFR (TFR1) effort has been reported by numerous studies. However, some patients relapse during TFR1. A second TFR (TFR2) can be tried again in those patients. This systematic review aims to evaluate individual patient characteristics for a TFR2, factors predicting successful TFR2, monitoring, consequences of the cessation of TKI, and studies about TFR2. We identified 5 studies related TFR2. The results showed that the first failed TKI discontinuation attempt is not an indicator of a second TKI discontinuation failure. TKIs could safely and successfully be discontinued for a second time in chronic phase CML patients despite a TFR1 failure. The most important factors for estimating TFR2 success are the speed of molecular relapse and the TKI-free duration after the first TKI discontinuation attempt. New trends in the management of CML patients are reducing the side effects of treatment, lessening the financial burden, and improving the quality of life of patients as CML has developed into a manageable chronic disease rather than an aggressive cancer. Although there are many studies and guidelines on TFR1, there are few studies on TFR2 and predictive factors. More data is still needed regarding TFR2 attempt in patients with CML. 19

Standard or conventional treatment of chronic myeloid leukemia (CML) had little effect on the course and the duration of the disease. Treatment with human natural and recombinant alpha-interferon (IFN) was shown to induce hematologic responses, together with partial or complete repopulation of the marrow with Ph negative cells (karyotypic response). These findings prompted a prospective comparison of IFN and conventional treatment in CML. 1

Imatinib 400 mg/day is the standard treatment for patients with chronic phase chronic myeloid leukemia. Recent reports suggested higher and more rapid cytogenetic and molecular responses with higher doses of imatinib. 7

In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98 %; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25 years: 42.7 %, 32.0-52.4 % vs 52.9 %, 43.2-62.6 %; p = 0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60 % were alive at plus 25 years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor. 11

To compare the efficacy of nilotinib and imatinib in the treatment of chronic myeloid leukemia (CML). 17

Treatment Summary

Treatment of CML has seen major advances with the introduction of TKIs, such as imatinib. Imatinib 400 mg/day monotherapy is effective for many patients and can achieve a near-normal life expectancy. 14 Higher doses of imatinib, such as 800 mg/day, may lead to deeper cytogenetic and molecular remissions. 7 Combining imatinib with interferon-α may also be beneficial. 8 For patients who do not respond well to TKIs or who experience relapse, HSCT remains a valid treatment option, particularly for those with low transplant risk. 10 However, the decision to pursue HSCT should be made carefully, considering the potential risks associated with the procedure. 6 In the case of patients who have failed initial TKI therapy, a second TFR attempt may be considered. 19

Benefits and Risks

Benefit Summary

Treatment for CML has significantly improved with the introduction of TKIs, allowing many patients to achieve remission and a near-normal life expectancy. 14 TKIs have proven effective in treating CML, leading to long-term survival rates similar to the general population. 9 Newer TKIs can achieve deep and durable molecular responses. 12

Risk Summary

While imatinib is effective in treating CML, it can cause anemia. 18 TKIs require long-term use, which can affect a patient's quality of life. 16 HSCT can be an effective treatment for CML but carries a high risk of transplantation-related mortality, making careful patient selection crucial. 10 Some patients may experience relapse after discontinuing TKIs. 19

Comparison of Studies

Commonalities

Numerous studies have confirmed the effectiveness of TKIs in treating CML. TKIs have been shown to achieve cytogenetic and molecular remissions and extend survival. However, TKIs can have side effects and require long-term use, potentially impacting a patient's quality of life. HSCT can be a successful treatment for CML but comes with a high transplantation-related mortality rate, necessitating careful patient selection.

Differences

Studies vary in their use of different TKIs, dosages, combination therapies, patient populations, and outcome measures. This makes it challenging to directly compare study results. For instance, the effectiveness and side effects of different TKIs, dosages, and combination therapies may differ. Studies on TFR attempts are limited, requiring further research.

Consistency and Contradictions in Results

Multiple studies consistently demonstrate the effectiveness of TKIs in treating CML. However, the specific effectiveness and side effects can vary based on the type of TKI, dosage, and combination therapies used. Research on TFR attempts remains limited, requiring further investigation.

Practical Implications

Treatment for CML is individualized for each patient, necessitating careful consultation with a physician to determine the most appropriate treatment plan. While TKIs are effective, they can cause side effects, making regular monitoring essential. When considering discontinuing TKIs, the risk of relapse must be factored in.

Limitations of Current Research

Research on CML is ongoing, and many questions remain unanswered. Studies on TFR attempts are limited, requiring further investigation. Due to variations in patient populations and outcome measures, directly comparing study results can be challenging.

Future Research Directions

Research on CML continues with ongoing investigations into new types of TKIs, novel administration methods, combination therapies, and TFR attempts. Standardizing patient populations and outcome measures would facilitate easier comparison of study results.

Conclusion

Significant advances in CML treatment have been achieved with the introduction of TKIs, enabling many patients to achieve remission and a near-normal life expectancy. However, TKIs can have side effects and require long-term use, which can affect quality of life. HSCT offers a treatment option but carries a high risk of transplantation-related mortality, requiring careful patient selection. CML treatment is individualized, necessitating consultation with a physician to determine the best course of action. Regular monitoring is essential due to potential side effects of TKIs, and the risk of relapse should be considered when contemplating discontinuing TKI therapy. Research on CML continues, with further studies needed to address gaps in knowledge, particularly regarding TFR attempts. Standardizing patient populations and outcome measures would enhance the comparability of research findings.

Treatment List

Imatinib, Interferon-α, Nilotinib, Busulfan, Hydrea, Allogeneic hematopoietic stem cell transplantation