Chronic myeloid leukaemia: Biology and therapy.

Chronic myeloid leukaemia (CML) is caused by BCR::ABL1. Tyrosine kinase-inhibitors (TKIs) are the initial therapy. Several organizations have reported milestones to evaluate response to initial TKI-therapy and suggest when a change of TKI should be considered. Achieving treatment-free remission (TFR) is increasingly recognized as the optimal therapy goal. Which TKI is the best initial therapy for which persons and what depth and duration of molecular remission is needed to achieve TFR are controversial. In this review we discuss these issues and suggest future research directions.

Chronic Myeloid Leukemia following Exposure to Radioactive Iodine (I131): A Systematic Review.

BACKGROUND: Therapy-related leukemia is a term that describes the occurrence of leukemia following exposure to hematotoxins and radiation to emphasize the difference from leukemia that arises de novo. Many agents and host factors contribute to this entity of leukemias. Therapy-related acute myeloid leukemia has an extensive literature review in contrast to therapy-related chronic myeloid leukemia (t-CML). Radioactive iodine (RAI), an established agent in the management of differentiated thyroid carcinomas, has raised concern due to its possible carcinogenic effects. SUMMARY: In this article, we reviewed all the reports from the 1960s to date related to t-CML following RAI on Google Scholar and PubMed. We have identified 14 reports and found that most reports were for men under the age of 60 years with primary papillary thyroid carcinoma and mixed follicular-papillary thyroid carcinoma who developed t-CML mainly between 4 and 7 years after exposure to varying doses of I131. However, the mean dose was 287.78 millicuries (mCi). It was reported that a statistically significant increase in leukemia following RAI therapy (relative risk of 2.5 for I131 vs. no I131). Also, there was a linear relationship between the cumulative dose of I131 and the risk of leukemia. Doses higher than 100 mCi were associated with a greater risk of developing secondary leukemia, and most of the leukemias developed within the initial 10 years of exposure. The precise mechanism through which RAI provokes leukemia is largely unclear. A few mechanisms have been proposed. KEY MESSAGES: Although the risk for t-CML appears to be low based on current reports and does not represent a contraindication to RAI therapy, it should not be disregarded. We suggest including it in the risk-benefit discussion before initiating this therapy. Long-term follow-up for patients is advisable for those who received doses over 100 mCi with a complete blood count, possibly yearly, for the first 10 years. The new onset of significant leukocytosis post RAI exposure should raise the suspicion for t-CML. Further studies are needed to establish or refute a causal relationship.

Total marrow lymphoid irradiation and cyclophosphamide is associated with low toxicity and good outcomes in patients undergoing hematopoietic stem cell transplantation for acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crises - A phase I study.

INTRODUCTION: Total marrow lymphoid irradiation (TMLI) can deliver higher doses of irradiation without increasing toxicity compared to Total body irradiation (TBI). METHODS: Twenty adult patients undergoing hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia with lymphoid blast crises (CML-LBC) received TMLI and cyclophosphamide for conditioning. Ten patients each received 13.5 or 15 Gy of TMLI. The graft source was peripheral blood stem cells in all, and donors included matched related (n = 15), haplo-identical (n = 3) or matched unrelated donors (n = 2). RESULTS: The median cell dose infused was 9 × 106 CD34/kg (range 4.8-12.4). Engraftment occurred in all (100%) at a median of 15 days (range: 14-17). Toxicity was low with hemorrhagic cystitis seen in two but no sinusoidal obstruction syndrome. Acute GVHD occurred in 40% while chronic GVHD was seen in 70.5%. Viral infections were seen in 55% while blood stream bacterial infections occurred in 20% and invasive fungal disease (IFD) in 10%. The Day 100 non-relapse mortality (NRM) was 10%. At a median follow up of 25 months (range 2-48), two patients have relapsed. Overall survival at 2 years is 80% while the disease-free survival is 75%. CONCLUSIONS: The combination of TMLI and cyclophosphamide for myeloablative conditioning is associated with low toxicity and favorable early outcomes in patients undergoing HSCT for ALL and CML-LBC.

Compromised anti-tumor-immune features of myeloid cell components in chronic myeloid leukemia patients.

Chronic myeloid leukemia (CML) is a form of myeloproliferative neoplasm caused by the oncogenic tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors have dramatically improved the prognosis of patients with CML, several problems such as resistance and recurrence still exist. Immunological control may contribute to solving these problems, and it is important to understand why CML patients fail to spontaneously develop anti-tumor immunity. Here, we show that differentiation of conventional dendritic cells (cDCs), which are vital for anti-tumor immunity, is restricted from an early stage of hematopoiesis in CML. In addition, we found that monocytes and basophils, which are increased in CML patients, express high levels of PD-L1, an immune checkpoint molecule that inhibits T cell responses. Moreover, RNA-sequencing analysis revealed that basophils express genes related to poor prognosis in CML. Our data suggest that BCR-ABL not only disrupts the "accelerator" (i.e., cDCs) but also applies the "brake" (i.e., monocytes and basophils) of anti-tumor immunity, compromising the defense against CML cells.

Serial evaluation of the pharmacokinetics of ponatinib in patients with CML and Ph + ALL.

Although tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), intolerance and resistance to TKIs have been serious problems. Due to a lack of research, the importance of the pharmacokinetics (PK) of TKIs is currently unclear. We examined the PK of the third-generation TKI ponatinib to monitor side effects and efficacy during treatments for one patient with CML-chronic phase (CP-CML) and two who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), one for CML-blastic crisis (BC-CML) and one for Ph + ALL. The patient with CP-CML was intolerant to multiple TKIs (dasatinib, nilotinib, imatinib, and bosutinib) and thus was switched to ponatinib (15 mg/day). The patients who received allo-HSCT for BC-CML and Ph + ALL received ponatinib (15 mg/day) as maintenance therapy. Notably, serial evaluation of the PK of ponatinib showed that the median trough values (ng/ml) were 17.2 (12.2-34.5), 33.1 (21.2-40.3) and 27.7 (13.6-29.9) in patients 1, 2, and 3, respectively. These values were around the target concentration (23 ng/ml). All patients are maintaining complete remission without side effects. In conclusion, serial evaluation of PK of ponatinib may yield meaningful information about its safety and efficacy.

BCR-ABL1 p210 screening for chronic myeloid leukemia in patients with peripheral blood cytoses.

INTRODUCTION: Chronic myeloid leukemia (CML) usually presents with leukocytosis with neutrophilia, left shift, and basophilia. Documentation of the BCR-ABL1 fusion is required for diagnosis, and this is often achieved via p210 BCR-ABL1 real-time polymerase chain reaction (RT-PCR). METHODS: Patients undergoing first-time testing for p210 BCR-ABL1 at our institution were retrospectively identified. The medical record was reviewed, and the patient age, sex, clinical indication for testing, and concurrent CBC with differential were identified for 518 patients. BCR-ABL1 p210 testing had been performed using a laboratory-developed quantitative RT-PCR assay. Statistical analysis of the results was performed using an unpaired t test, and P values of <.05 were considered statistically significant. RESULTS: Twenty-four patients received a new diagnosis of CML (4.6%). As compared to patients with a negative PCR, these patients were more likely to have a markedly elevated white blood cell count (WBC), neutrophilia, and a mild anemia. Ninety-two percent (22/24) of new CML patients had a WBC ≥20 × 109 /L, and the two new CML patients with WBC <20 × 109 /L had basophilia in the peripheral blood. By contrast, 92% (449/490) of non-CML patients had a WBC <20 × 109 /L. CONCLUSION: The peripheral blood parameters of total WBC ≥20 × 109 /L and absolute basophil count can help guide the need for BCR-ABL1 PCR testing, which can lead to more judicious test utilization, decreased healthcare costs, and decreased false positives, while keeping a high sensitivity for CML. This study also underscores the importance of obtaining a complete differential in patients for whom CML is suspected.

Estimating the risk of developing secondary hematologic malignancies in patients with T1/T2 prostate cancer undergoing diverse treatment modalities: A large population-based study.

BACKGROUND: Patients with prostate cancer (PC) are at a high risk of developing secondary hematologic malignancies (SHMs) after radiation therapy (RT), while no study has assessed the relationship of different treatment modalities with the occurrence of SHMs after PC at early stage. This study aimed to investigate the risks of developing SHMs in patients with T1/T2 PC undergoing different treatment modalities. METHODS: Patients with T1/T2 PC were identified from the Surveillance, Epidemiology, and End Results database. Competing risk regression (CRR) model was performed to evaluate the hazard ratios (HRs) of developing SHMs. As SHMs scarcely occur, the relative risk (RR) analysis was employed to compare the risks of different treatment modalities associating with the development of SHMs. RESULTS: The CRR analysis showed that undergoing RT was associated with a higher risk of developing SHMs (external beam radiation therapy [EBRT]: HR = 1.21, 95% confidence interval [CI]: 1.10-1.34; radioactive implant [RI]: HR = 1.20, 95% CI: 1.06-1.36). As for different types of SHMs, EBRT, and RI were correlated with decreased risks of developing CLL (RR = 0.67, 0.72; 95% CI: 0.53-0.85, 0.54-0.96, respectively), but with the increased risks of developing NHL (RR = 1.18, 1.23; 95% CI: 1.02-1.35, 1.05-1.44, respectively); EBRT also showed increased risks of developing acute/ chronic myeloid leukemia (AML/CML, RR = 1.54, 1.56; 95% CI: 1.16-2.03,1.05-2.33, respectively); No increased risk of developing SHMs was detected in patients who only underwent prostatectomy. CONCLUSIONS: Although RT was found to be associated with the increased risks of developing SHMs in patients with T1/T2 PC, this finding cannot be extended to diverse types of SHMs. RT was correlated with the increased risks of the development of NHL, AML, and CML, but with the decreased risk of developing CLL. Prostatectomy did not increase the risk of developing SHMs.

Appropriate Starting Dose of Dasatinib Based on Analyses of Dose-Limiting Toxicities and Molecular Responses in Asian Patients With Chronic Myeloid Leukemia.

BACKGROUND: Dasatinib is administered at a fixed starting dosage of 100 mg once daily regardless of patient-specific factors. However, such fixed dosing may not be optimal for the treatment of Asian patients with chronic myeloid leukemia in chronic phase (CP-CML). PATIENTS AND METHODS: The dose-limiting toxicities (DLTs) and molecular responses (MRs) of dasatinib therapy were evaluated using clinical data obtained from 102 patients newly diagnosed with CP-CML at 17 hospitals in South Korea. RESULTS: By 36 months after the initiation of a fixed dose regimen of dasatinib 100 mg once daily as the first-line therapy, 55.9% of patients experienced at least one type of DLT. The 3 most frequent DLTs were thrombocytopenia (45.5%), pericardial or pleural effusion (30.9%), and anemia (7.3%). Patients with higher dasatinib dose adjusted for body weight (Dose/BW) had a greater rate of DLT occurrence (logit [P] = 1.58 × [Dose/BW] - 2.27, P = .03). As median Dose/BW increased from 1.23 to 2.00 mg/kg, the rate of DLT occurrence increased from 43.5% to 66.7% (P = .03). However, Dose/BW did not affect the achievement rate of major MR (60.9% to 69.6%, P = .92). CONCLUSION: The starting dosage of dasatinib may need to be reduced (eg, 80 mg once daily or lower) for Asian patients with CP-CML, especially with lighter BW, to alleviate the risk of DLT occurrence without compromising the achievement of MR.

Novel developments in chronic myeloid leukaemia.

PURPOSE OF REVIEW: Despite unprecedented challenges during the preceding year, there have been a wide range of significant advances in the field of chronic myeloid leukaemia. In this review article we highlight papers reporting on some of the most important developments over the last year, both with regards to the clinical management of patients with chronic myeloid leukaemia, as well as studies that help to increase our understanding of the pathophysiology of the disease. We have performed a PubMed search to identify important papers and abstracts listed over the last year and have included additional papers published prior to this, where relevant, to provide context. RECENT FINDINGS: We comment on novel biomarkers for treatment free remission as well as recent results from second generation Tyrosine Kinase Inhibitor (TKI) discontinuation studies. We discuss new techniques that are being used to assess TKI resistance as well as reviewing novel and emerging approaches to the management of resistant patients, including the use of combination therapies. SUMMARY: This review highlights some of the most important research to have been reported over the last year in the field of chronic myeloid leukaemia, encompassing emerging diagnostic techniques, biomarkers and novel therapeutic options.

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.

Chronic myeloid leukemia in solid organ transplant patients: a case series.

Solid organ transplant (SOT) has transformed the survival and quality of life of patients with end-organ dysfunction. Lifelong need for immunosuppressive medications prolongs life expectancy, but results in altered immune function and is associated with a higher risk of certain malignancies, including chronic myeloid leukemia (CML). In this article, we report on six patients, aged 41-79 years, diagnosed with CML, from 3 to 132 months post-various organ transplants and treated with different tyrosine kinase inhibitors (TKI), including first generation (i.e., imatinib) and second generation (i.e., dasatinib and nilotinib). Use of second-generation TKIs has not been previously reported in this population. In these six cases, treatment with different TKIs in SOT patients was feasible, well tolerated and achieved good efficacy, which was maintained in extended follow-up, as well.

Stuttering Priapism in a Teenage Boy: Lesson to be Learnt.

Untreated priapism can lead to ischemic damage of the penis and impotence. This case report describes a 14-year-old boy who presented with a history of priapism for 2 months, which was undiagnosed, ridiculed, and ignored even by medical practitioners. The underlying etiology was later identified to be chronic myeloid leukemia. Despite the usage of multimodal treatment, it took 7 days for control of priapism. The young boy is now left with an erectile dysfunction. The case highlights that priapism in children is a medical emergency needing aggressive evaluation and treatment.

CHRONIC MYELOID LEUKEMIA COURSE IN PERSONS EXPOSED TO IONIZING RADIATION AS A RESULT OF THE CHORNOBYL ACCIDENT. / PEREBIG KhRONIChNOÏ MIIeLOÏDNOÏ LEIKEMIÏ U OSIB, IaKI ZAZNALY DIÏ IONIZUIuChOGO VYPROMINIuVANNIa VNASLIDOK ChORNOBYL'S'KOÏ AVARIÏ.

OBJECTIVE: Describe and characterize the peculiarities of the chronic myeloid leukemia (CML) course and responseto treatment in patients irradiated as a result of the Chornobyl nuclear power plant (ChNPP) accident based on theassessment of clinical-laboratory and clinical parameters. MATERIALS AND METHODS: The CML patients (n = 33) exposed to ionizing radiation as a result of the ChNPP accidentwere enrolled. The comparison group consisted of CML patients (n = 725) with no history of radiation exposure. Allpatients were in the chronic phase of the disease. Clinical, hematological and molecular genetic research methodswere applied. RESULTS: Patients exposed to ionizing radiation as a result of the ChNPP accident had no differences in CML manifestation, as well as in classical genetic markers at the onset of the disease compared with patients with no historyof radiation exposure. Reduction of tumor clone on imatinib therapy was significantly less effective in the patientsexposed to ionizing radiation than in cases of no history of radiation exposure. Cases of primary resistance were statistically significantly prevalent in the ChNPP accident consequences clean-up workers while in the residents ofradiologically contaminated areas a statistically significant increase in probability of loss of complete cytogeneticresponse (development of secondary resistance) to imatinib therapy was found. An association was found betweenthe radiation exposure and probability of loss of complete cytogenetic response to imatinib therapy in this group ofpatients. CONCLUSION: The radiation exposure in the history even many years before the onset of CML is an unfavorable exogenous factor responsible for the development of resistance to imatinib therapy.

DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells.

Chronic myeloid leukemia is a hematological cancer driven by the oncoprotein BCR-ABL1, and lifelong treatment with tyrosine kinase inhibitors extends patient survival to nearly the life expectancy of the general population. Despite advances in the development of more potent tyrosine kinase inhibitors to induce a durable deep molecular response, more than half of patients relapse upon treatment discontinuation. This clinical finding supports the paradigm that leukemia stem cells feed the neoplasm, resist tyrosine kinase inhibition, and reactivate upon drug withdrawal depending on the fitness of the patient's immune surveillance. This concept lends support to the idea that treatment-free remission is not achieved solely with tyrosine kinase inhibitors and that new molecular targets independent of BCR-ABL1 signaling are needed in order to develop adjuvant therapy to more efficiently eradicate the leukemia stem cell population responsible for chemoresistance and relapse. Future efforts must focus on the identification of new targets to support the discovery of potent and safe small molecules able to specifically eradicate the leukemic stem cell population. In this review, we briefly discuss molecular maintenance in leukemia stem cells in chronic myeloid leukemia and provide a more in-depth discussion of the dual-specificity kinase DYRK2, which has been identified as a novel actionable checkpoint in a critical leukemic network. DYRK2 controls the activation of p53 and proteasomal degradation of c-MYC, leading to impaired survival and self-renewal of leukemia stem cells; thus, pharmacological activation of DYRK2 as an adjuvant to standard therapy has the potential to induce treatment-free remission.

Secondary chronic myeloid leukemia following acute myeloid leukemia treated with autologous hematopoietic stem cell transplantation: a case report.

OBJECTIVE: Acute myeloid leukemia (AML) is a hematopoietic stem cell malignancy and the most common type of leukemia, with the 5-year relative survival rate of 19% in Europe. Chronic myeloid leukemia (CML) is a slowly progressive clonal malignant disease, and a myeloproliferative disorder which is derived from biphasic hematopoietic stem cells but driven by progenitor cells. AML following CML is common, which can be caused by an antecedent myeloid malignancy, leukemogenic therapy, or without an identifiable prodrome or exposure to cytotoxic agents. However, the case of secondary chronic myeloid leukemia following acute myeloid leukemia treated with autologous hematopoietic stem cell transplantation is rare. METHODS: Here we report a unique case of secondary CML after AML treated by chemotherapy and autologous peripheral blood stem cell transplantation. The 34-year-old male was diagnosed with AML subtype M5b according to clinical features in 2011. The patient was treated with the MAE program (mitoxantrone, cytosine arabinoside, etoposide) for two courses, followed by the IAE program (idarubicin, cytosine arabinoside, etoposide) and cytosine arabinoside for consolidation chemotherapy. An autologous hematopoietic stem cell transplantation with prophylactic intrathecal methotrexate cytarabine and dexamethasone was initiated. RESULTS: Subsequently, the patient achieved complete remission in 2012. After 4 years, the patient presented with leukocyte elevation of more than 4 months, and then was diagnosed with secondary CML. Based on this diagnosis, and with respect to the patient's severely compromised overall condition, tyrosine kinase inhibitors (TKI) therapy was conducted in 2016. The patient achieved, and continue to be in, complete remission. CONCLUSIONS: The case expands the understanding of secondary CML and emphasizes the importance of oncological vigilance in patients with secondary CML after AML therapy.

Therapy-related chronic myeloid leukemia in a patient receiving peptide receptor radionuclide therapy for pancreatic neuroendocrine tumor.

BACKGROUND: Therapy-related leukemia is a well-recognized clinical syndrome. Peptide receptor radionuclide therapy (PRRT) is a modern therapeutic approach using radionuclide combined with somatostatin analog peptide for inoperable or metastatic neuroendocrine tumors. AIMS: Hematologic toxicities including late-onset myeloid neoplasms have been reported after PRRT; however, therapy-related chronic myeloid leukemia (TR-CML) following PRRT is a relatively rare entity. METHODS: We present a 64-year-old male who received PRRT for pancreas neuroendocrine tumor and then developed TR-CML 60 months after the initiation of PRRT. The patient responded well to imatinib therapy. RESULTS: Patients with TR-CML generally have similar tyrosine kinase inhibitor responses and outcomes when compared to de novo cases. CONCLUSIONS: The physicians should be aware of the short- and long-term hematologic toxicities of PRRT including TR-CML, and careful monitoring is mandatory in this group of patients.