Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia.

BACKGROUND: Genome variability of host genome and cancer cells play critical role in diversity of response to existing therapies and overall success in treating oncological diseases. In chronic myeloid leukemia targeted therapy with tyrosine kinase inhibitors demonstrates high efficacy in most of the patients. However about 15 % of patients demonstrate primary resistance to standard therapy. Whole exome sequencing is a good tool for unbiased search of genetic variations important for prognosis of survival and therapy efficacy in many cancers. We apply this approach to CML patients with optimal response and failure of tyrosine kinase therapy. RESULTS: We analyzed exome variations between optimal responders and failures and found 7 variants in cancer-related genes with different genotypes in two groups of patients. Five of them were found in optimal responders: rs11579366, rs1990236, rs176037, rs10653661, rs3803264 and two in failures: rs3099950, rs9471966. These variants were found in genes associated with cancers (ANKRD35, DNAH9, MAGEC1, TOX3) or participating in cancer-related signaling pathways (THSD1, MORN2, PTCRA). CONCLUSION: We found gene variants which may become early predictors of the therapy outcome and allow development of new early prognostic tests for estimation of therapy efficacy in CML patients. Normal genetic variation may influence therapy efficacy during targeted treatment of cancers.

The ability of multipotent mesenchymal stromal cells from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells.

BACKGROUND: The development of leukemia impairs normal hematopoiesis and marrow stromal microenvironment. The aim of the investigation was to study the ability of multipotent mesenchymal stromal cells (MSCs) derived from the bone marrow of patients with leukemia to maintain normal hematopoietic progenitor cells. METHODS: MSCs were obtained from the bone marrow of 14 patients with acute lymphoblastic (ALL), 25 with myeloid (AML), and 15 with chronic myeloid (CML) leukemia. As a control, MSCs from 22 healthy donors were used. The incidence of cobblestone area forming cells (CAFC 7-8 d) in the bone marrow of healthy donor cultivated on the supportive layer of patients MSCs was measured. RESULTS: The ability of MSCs from AML and ALL patients at the moment of diagnosis to maintain normal CAFC was significantly decreased when compared to donors. After chemotherapy, the restoration of ALL patients' MSCs functions was slower than that of AML. CML MSCs maintained CAFC better than donors' at the moment of diagnosis and this ability increased with treatment. CONCLUSIONS: The ability of patients' MSCs to maintain normal hematopoietic progenitor cells was shown to change in comparison with MSCs from healthy donors and depended on nosology. During treatment, the functional capacity of patients' MSCs had been partially restored.

The impact of dasatinib on pregnancy outcomes.

Prolonged survival in patients with chronic myeloid leukemia treated with BCR-ABL1-targeted tyrosine kinase inhibitors allows consideration of parenthood for patients on chronic therapy, but there are limited data about the effects of dasatinib on pregnancy. Pregnancy-related outcomes in dasatinib-treated patients or their partners reported to Bristol-Myers Squibb from clinical trials or healthcare providers through December 2013 were reviewed. Outcomes were available in 46/78 dasatinib-treated women (59%) and 33/69 partners of dasatinib-treated men (48%). Fifteen women (33%) delivered a normal infant; 18 (39%) and 8 (17%) had an elective or spontaneous abortion; and 5 (11%) had an abnormal pregnancy. There were 7 reports of fetal/infant abnormalities (encephalocele, renal tract abnormalities, and hydrops fetalis). Thirty of 33 (91%) infants fathered by dasatinib-treated men were reported normal at birth. Also, animal studies evaluated the impact of dasatinib on fertility, embryo-fetal toxicity, and development, suggesting that dasatinib may be a selective developmental toxicant. The outcomes of most pregnancies conceived by men treated with dasatinib were normal, but due to the small number of cases, further monitoring is required. Significant effects on pregnancy outcomes in women treated with dasatinib were found, supporting current recommendations that women avoid becoming pregnant during dasatinib treatment and be informed of fetal risks.

Chronic myeloid leukemia diagnosed in pregnancy: management and outcome of 87 patients reported to the European LeukemiaNet international registry.

The management of chronic myeloid leukemia (CML) diagnosed during pregnancy is a rare and challenging situation. We report the treatment and outcome of 87 cases diagnosed in chronic phase from 2001-2022 derived from the largest international observational registry, supported by the European LeukemiaNet (ELN), of 400 pregnancies in 299 CML women. Normal childbirth occurred in 76% without an increased rate of birth abnormalities or life-threatening events, including in patients untreated or treated with interferon-α and/or imatinib in 2nd-3rd trimester. The low birth weight rate of 12% was comparable to that seen in the normal population. Elective and spontaneous abortions occurred in 21% and 3%, respectively. The complete hematologic response rate before labor was 95% with imatinib and 47% with interferon only. No disease progression during pregnancy was observed, 28% of the patients switched their therapy at varying times after delivery. Treatment options balance the efficacy and safety for mother and infant: interferon-α can commence in the 1st trimester and continued throughout in cases of good disease control and tolerability. Because of limited placental crossing, selected tyrosine kinase inhibitors (imatinib and nilotinib) seem to be safe and effective options in 2nd and 3rd trimester while hydroxycarbamide offers few benefits.

Clinical Outcomes in Patients With COVID-19 and Hematologic Disease.

BACKGROUND: Patients with hematologic diseases are at higher risk of the SARS-CoV-2 infection and more severe clinical outcomes of the coronavirus disease. CHRONOS19 is an observational prospective cohort study with the aim to determine the short and longer-term clinical outcomes, risk factors for disease severity and mortality, and rates of postinfectious immunity in patients with malignant and nonmalignant hematologic diseases and COVID-19. PATIENTS AND METHODS: Overall, 666 patients were enrolled in the study, of which 626 were included in the final data analysis. The primary endpoint was 30-days all-cause mortality. Secondary endpoints included COVID-19 complications, rates of ICU admission and mechanical ventilation, outcomes of a hematologic disease in SARS-CoV-2 infected patients, overall survival, and risk factors for disease severity and mortality. Data from 15 centers were collected at 30, 90, and 180 days after COVID-19 was diagnosed and were managed using a web-based e-data capture platform. All evaluations were performed in the pre-omicron period of COVID-19 pandemic. RESULTS: Thirty-days all-cause mortality was 18.9%. The predominant cause of death (in 80% of cases) were COVID-19 complications. At 180 days, the majority (70%) of additional deaths were due to hematologic disease progression. At a median follow-up of 5.7 [0.03-19.04] months, 6-months overall survival was 72% [95% CI: 0.69-0.76]. One-third of patients had severe SARS-CoV-2 disease. The rate of ICU admission was 22% with 77% of these patients requiring mechanical ventilation, with poor survival rate. A univariate analysis revealed that older age (≥ 60 years), male sex, malignant hematologic disease, myelotoxic agranulocytosis, transfusion dependence, refractory disease or relapse, diabetes among comorbidities, any complications, especially ARDS alone or in combination with CRS, admission to an ICU, and mechanical ventilation were associated with higher risks of mortality. Treatment of the hematologic disease was changed, postponed, or canceled in 63% of patients. At a longer follow-up (90 and 180 days), the status of the hematologic disease changed in 7.5% of patients. CONCLUSION: Patients with hematologic disease and COVID-19 have high mortality rates, predominantly due to COVID-19 complications. At a longer-term follow-up, no significant impact of COVID-19 on the course of a hematologic disease was revealed.

Tyrosine kinase inhibitors and pregnancy in chronic myeloid leukemia: opinion, evidence, and recommendations.

With survival expectation that of age-matched controls and given excellent response and worldwide access to tyrosine kinase inhibitors (TKI), family planning is increasingly important for a considerable fraction of patients with chronic myeloid leukemia (CML). The potential for therapy discontinuation ("treatment free remission") can afford the opportunity for a CML patient in deep response to plan and carry a pregnancy to full term without any therapeutic interventions. However, the reality of pregnancy desired or occurring when patients are not eligible for treatment-free remission raises the discussion of therapy choices during pregnancy. To date there are no official guidelines available to assist patients and clinicians with these decisions. This first position paper aims to analyze information published and presented surrounding this challenging area, with focus on different scenarios of disease burden and time from CML diagnosis, including CML discovered during pregnancy and pregnancy during CML treatment. An updated review, supported by data and presented together with authors' joint recommendations, is aimed to counsel the practical management of CML patients and pregnancy.

Withdrawal Syndrome After Tyrosine Kinase Inhibitor Discontinuation in Patients With Chronic Myeloid Leukemia in the Russian Prospective Study RU-SKI.

We aimed to characterize withdrawal syndrome (WS) and evaluate factors associated with its development in the prospective clinical study RU-SKI in patients with chronic myeloid leukemia with deep molecular response who discontinued tyrosine kinase inhibitor (TKI) therapy. In total, 98 adult patients with chronic myeloid leukemia chronic phase, TKI therapy ≥ 3 years, and deep molecular response (BCR-ABL ≤ 0.01%) ≥ 2 years were enrolled and observed without treatment. WS was defined as newly observed or worsening musculoskeletal pain after TKI cessation. WS symptoms were found in 41 (42%) of 98 patients with a median time of observation of 25 months (range, 12-42 months). WS grades 1 to 2 and grade 3 were observed in 39 (95%) and in 2 (5%) patients, respectively. The median duration of WS was 5 months (range, 1-25 months). WS was resolved in 37 (90%) patients. Anti-inflammatory therapy was used in 21 (51%) patients. Older age (P = .039) and longer TKI therapy (P = .001) were associated with WS. The 2-month landmark analysis found no association of WS development and the rate of molecular relapses. In total, 42% of the patients experienced WS after TKI therapy discontinuation in the RU-SKI study. Physicians should be warned about the possibility of WS development, and patients of older age and with longer TKI treatment need special attention.

Exome, transcriptome and miRNA analysis don't reveal any molecular markers of TKI efficacy in primary CML patients.

BACKGROUND: Approximately 5-20% of chronic myeloid leukemia (CML) patients demonstrate primary resistance or intolerance to imatinib. None of the existing predictive scores gives a good prognosis of TKI efficacy. Gene polymorphisms, expression and microRNAs are known to be involved in the pathogenesis of TKI resistance in CML. The aim of our study is to find new molecular markers of TKI therapy efficacy in CML patients. METHODS: Newly diagnosed patients with Ph+ CML in chronic phase were included in this study. Optimal and non-optimal responses to TKI were estimated according to ELN 2013 recommendation. We performed genotyping of selected polymorphisms in 62 blood samples of CML patients, expression profiling of 33 RNA samples extracted from blood and miRNA profiling of 800 miRNA in 12 blood samples of CML patients. RESULTS: The frequencies of genotypes at the studied loci did not differ between groups of patients with an optimal and non-optimal response to TKI therapy. Analysis of the expression of 34,681 genes revealed 26 differently expressed genes (p < 0.05) in groups of patients with different TKI responses, but differences were very small and were not confirmed by qPCR. Finally, we did not find difference in miRNA expression between the groups. CONCLUSIONS: Using modern high-throughput methods such as whole-exome sequencing, transcriptome and miRNA analysis, we could not find reliable molecular markers for early prediction of TKI efficiency in Ph+ CML patients.

Breastfeeding in Patients with Chronic Myeloid Leukaemia: Case Series with Measurements of Drug Concentrations in Maternal Milk and Literature Review.

Breastfeeding in patients with chronic myeloid leukaemia (CML) during tyrosine kinase inhibitors (TKIs) therapy is not recommended but interruption of TKI treatment may cause the loss of remission. We studied the 3 cases of pregnancy and breastfeeding in women with CML and observed that stopping treatment without major molecular response may end in haematological relapse. The concentrations of nilotinib and imatinib in maternal milk were measured and nilotinib distribution in human breast milk was demonstrated for the first time. The estimated maximal doses of imatinib and nilotinib which an infant may ingest with the maternal milk were less than the therapeutical doses. However, the unknown impact of the low dose chronic exposure to these TKIs in infants imposes the limitations on their use during breastfeeding. Breastfeeding without TKI treatment may be safe with molecular monitoring, but preferably in those patients with CML who have durable deep molecular response.

Placental transfer of tyrosine kinase inhibitors used for chronic myeloid leukemia treatment.

Both favorable pregnancy outcomes and fetal abnormalities have been associated with the use of tyrosine kinase inhibitors (TKIs) during pregnancy. The placental transfer of TKIs in humans is poorly understood. We observed women with chronic myeloid leukemia who used imatinib or nilotinib during the late pregnancy stages. The newborns had no birth abnormalities. We evaluated the drug concentrations in maternal blood, umbilical cord blood, and placental samples collected during labor. We found limited placental transfer of the TKIs. The fetal/maternal concentration ratio ranged from 0.5 to 0.58 for nilotinib and from 0.05 to 0.22 for imatinib. The placental/maternal ratio was higher for imatinib than for nilotinib. Theoretical pharmacokinetic modeling of passive placental crossing was insufficient to predict the in vivo data because the calculated fetal/maternal ratio was close to 1 for both drugs. We propose that active placental transport contributes to fetal protection against TKI exposure during pregnancy.

Copy number variation analysis in cytochromes and glutathione S-transferases may predict efficacy of tyrosine kinase inhibitors in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of BCR/ABL fusion gene in leukemic cells, which promotes uncontrolled cell proliferation. Up to 20% of CML patients show primary resistance or non-optimal response to tyrosine kinase inhibitor (TKI) therapy. We investigated the association between copy number variation (CNV) in glutathione S-transferases (GST) and cytochromes (CYP) and the response rate to TKI. We enrolled 47 patients with CML: 31 with an optimal response and 16 with failure at 6 months in accordance with European LeukemiaNet 2013 recommendations. CNV detection was performed using SALSA MLPA P128-C1 Cytochrome P450 probe mix. Patients with optimal response and with failure of TKI therapy showed different frequencies of wild type and mutated CYPs and GST (p<0.0013). Validation in the group of 15 patients proved high prognostic value (p = 0.02): positive and negative predictive value 83% and 78%; sensitivity and specificity 71% and 88%. Wild type genotypes of CYP and GST associate with a worse response to TKI treatment in CML patients. This test can be recommended for further clinical trials.

Whole-exome sequencing reveals potential molecular predictors of relapse after discontinuation of the targeted therapy in chronic myeloid leukemia patients.

Chronic myeloid leukemia (CML) is a myeloproliferative disease well treated by tyrosine kinase inhibitors (TKIs). The aim was to identify genes with a predictive value for relapse-free survival after TKI cessation in CML patients. We performed whole-exome sequencing of DNA from six CML patients in long-lasting deep molecular remission. Patients were divided into two groups with relapse (n = 3) and without relapse (n = 3) after TKI discontinuation. We found variants in genes CYP1B1, ALPK2, and IRF1 in group of patients with relapse and one variant in gene PARP9 in group of patients without relapse. We verified prognostic value of the found markers in a small group of patients with TKI discontinuation and demonstrated their high sensitivity (77%), specificity (86%), positive (85%), and negative (79%) predictive values. Thus we revealed genetic variants, which are potential markers of outcome prediction in CML patients after TKI discontinuation.