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Atypical BCR::ABL1 transcripts are found in approximately 2% of cases of chronic myeloid leukemia. It is important to detect them since affected patients also benefit from tyrosine kinase inhibitor therapy. In the rare e8a2 atypical BCR::ABL1 transcript, two out-of-frame exons are fused, thus, interposed nucleotides are usually found at the fusion site to restore the reading frame. In approximately half of previously reported e8a2 BCR::ABL1 cases, an inserted 55 bp sequence homologous to an inverted sequence from ABL1 intron 1b was detected. The generation of this recurrent transcript variant is not obvious. This work describes the molecular analysis of such an e8a2 BCR::ABL1 translocation from a CML patient. The genomic chromosomal breakpoint is identified, and the formation of this transcript is theoretically explained. The clinical course of the patient is reported, and recommendations are provided for the molecular analysis of future e8a2 BCR::ABL1 cases. [ABSTRACT FROM AUTHOR]

Purpose: Hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) are characterized by sustained overproduction of eosinophils and organ dysfunction. CEL involves the presence of clonal genetic markers, such as a fusion of FIP1-like 1 protein and platelet-derived growth factor receptor α (FIP1L1-PDGFRα, or F/P) or PDGFRα-activating mutations. Methods: Sixteen patients with HES/CEL were enrolled in the phase 2 nilotinib registration trial (NCT00109707) and treated with nilotinib 400 mg twice daily. The median duration of treatment was 95 days (range 3–1,079). Results: Twelve patients had HES: 1 achieved a complete hematologic response (CHR), 3 achieved stable disease, 3 had progressive disease, and 5 were not evaluable for response. Four patients had CEL: 2 with the F/P fusion and 2 with PDGFRα-activating mutations. Both patients with an F/P fusion achieved a CHR; 1 also achieved a complete molecular response (CMR). Of the 2 patients with PDGFRα-activating mutations, 1 had stable disease and the other achieved CMR. At 24 months, overall survival in the HES group was 75.0 % (95 % CI 50.5–100.0) and no patients in the CEL group died. Median survival was not yet reached after a median follow-up of 32 months. The most common grade 3/4 hematologic laboratory abnormalities were lymphocytopenia (31.3 %) and neutropenia (25.0 %). The most common drug-related nonhematologic grade 3/4 adverse event was pruritus, which occurred in 2 patients (12.5 %). Conclusions: Nilotinib 400 mg twice daily was effective in some patients with HES/CEL regardless of F/P mutation status, and the safety profile was consistent with other nilotinib studies. [ABSTRACT FROM AUTHOR]

The article describes a study which examined the efficacy and safety of nilotinib in treating chronic myeloid leukemia patients who are immune to or intolerant of Imatinib. The study showed that the best responses to nilotinib were complete hematologic response (CHR) in 66% of 88 patients studied and major cytogenetic response in 43% of the study population. It concluded that patients who achieve CHR on imatinib therapy were more likely to respond positively to nilotinib and that nilotinib is safe for imatinib-resistant or intolerant patients.

The constitutively activated tyrosine kinase activity of the p210bcr-abl fusion protein, generated by a t(9;22)(q34;q11) chromosomal translocation, is pathogenetically associated with chronic myeloid leukemia (CML). However, mechanisms contributing to the expansion of a BCR-ABL positive clone are largely obscure. In the presence of an impaired immune surveillance, cells carrying any of these alterations may become phenotypically relevant. Therefore, immunosuppressed solid organ recipients represent an optimal population to investigate the frequency of mRNA products of this translocation. Blood leukocytes were studied in 201 individuals (100 organ recipients and 101 control individuals) for the presence of BCR-ABL transcripts by a nested-reverse transcriptase-polymerase chain reaction assay, routinely used in our institution. In 5/100 immunosuppressed patients, at least one out of two RT-PCR products was bcr-abl positive while all controls were negative. These findings were extended by four CML cases of organ transplant recipients (three renal and one liver transplants). Three of these cases developed CML in a total of 2088 transplantations in 9 yr, suggesting a higher incidence of CML in these patients. [ABSTRACT FROM AUTHOR]

Despite the remarkable clinical response rates to imatinib in the treatment of bcr-abl leukemic patients, pharmacokinetic data on this relatively novel substance are needed to improve our understanding of the emergence of resistance, the interindividual variations of clinical response and the clinical and biologic relevance of its main metabolite N-desmethyl-imatinib. We present here pharmacokinetic data obtained with a newly designed HPLC approach in 97 patients with chronic myeloid leukemia or acute lymphatic leukemia (ALL) under treatment with imatinib that allowed us to calculate the AUC (39.5 μg·h/ml for an oral dose of 400 mg daily), the t1/2 (18.2 h) and the peak concentration (1.92 μ/ml for an oral dose of 400 mg daily) of imatinib in plasma. In a subgroup of patients, the same parameters were analyzed for N-desmethyl-imatinib. We also provide data on the imatinib concentration in the cerebrospinal fluid (CSF) of ALL patients and demonstrate that oral administration of imatinib resulted only in a marginal flux across the blood-brain barrier. Finally, in an in vitro setting, we determined cellular concentrations of imatinib in HL-60 cells and showed an over-proportional uptake both in RPMI medium and in human plasma. Using an arithmetical approach combining all parameters obtained in imatinib-treated patients, we finally provide a conclusive approximation of basic pharmacokinetic data for both imatinib and its main metabolite N-desmethyl-imatinib. [ABSTRACT FROM AUTHOR]

Development of Janus-kinase (JAK) inhibitors has revolutionized the therapeutic landscape for patients with myeloproliferative neoplasia (MPN). Following approval of the first JAK1/2-inhibitor Ruxolitinib, symptoms of this inflammatory disease, characterized by splenomegaly, release of inflammatory cytokines and appearance of thrombosis, could be effectively reduced for the first time. However, JAK-inhibitor treatment is limited in several aspects: 1) duration of response: 3 years after initiation of therapy more than 50% of patients have discontinued JAK-inhibitor treatment due to lack of efficacy or resistance; 2) reduction of disease burden: while effective in reducing inflammation and constitutional symptoms, JAK-inhibitors fail to reduce the malignant clone in the majority of patients and therefore lack long-term efficacy. Early clinical trials for patients with myelofibrosis (MF) have tried to address these issues for patients with suboptimal response to Ruxolitinib therapy while combination therapies with Fedratinib are rare. Recent reports provided first evidence on how the JAK2-V617F mutated myeloid cells may influence T-cell responses. JAK2-V617F promoted the synthesis of PD-L1 in MPN cells leading to limited anti-neoplastic T-cell responses, metabolic changes in T-cells and eventually JAK2-V617F-driven immune-escape of MPN cells. These findings may facilitate the use of immunotherapeutic approaches for JAK-mutated clones. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. The FRACTION study is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with myelofibrosis and suboptimal or lack of response to JAK-inhibitor therapy. Over a 12 months period the trial assesses longer term outcomes, particularly the effects on clinical outcomes, such as induction of clinical remissions, quality of life and improvement of anemia. No prospective clinical trial data exist for combinations of JAK- and immune-checkpoint-inhibitors in the planned MF study population and this study will provide new findings that may contribute to advancing the treatment landscape for MF patients with suboptimal responses and limited alternatives. Trial registration: EudraCT Number 2021-004757-23. [ABSTRACT FROM AUTHOR]

Background: The leukemia cells of approximately 95% of patients with chronic myeloid leukemia and 30%-50% of adult patients with acute lymphoblastic leukemia express the Bcr/Abl oncoprotein, which is the product of a fusion gene created by a chromosomal translocation [(9:22) (q34;q11)]. This oncoprotein expresses a constitutive tyrosine kinase activity that is crucial for its cellular transforming activity. In this study, we evaluated the antineoplastic activity of CGP57148B, which is a competitive inhibitor of the Bcr/Abl tyrosine kinase.Methods: Nude mice were given an injection of the Bcr/Abl-positive human leukemia cell lines KU812 or MC3. Tumor-bearing mice were treated intraperitoneally or orally with CGP57148B according to three different schedules. In vitro drug wash-out experiments and in vivo molecular pharmacokinetic experiments were performed to optimize the in vivo treatment schedule.Results: Treatment schedules administering CGP57148B once or twice per day produced some inhibition of tumor growth, but no tumor-bearing mouse was cured. A single administration of CGP57148B caused substantial (>50%) but short-lived (2-5 hours) inhibition of Bcr/Abl kinase activity. On the basis of the results from in vitro wash-out experiments, 20-21 hours was defined as the duration of continuous exposure needed to block cell proliferation and to induce apoptosis in these two leukemia cell lines. A treatment regimen assuring the continuous block of the Bcr/Abl phosphorylating activity that was administered over an 11-day period cured 87%-100% of treated mice.Conclusion: These data indicate that the continuous block of the oncogenic tyrosine kinase of Bcr/Abl protein is needed to produce important biologic effects in vivo. [ABSTRACT FROM AUTHOR]

Background: Based on the new data from the primary analysis of the OPTIC (Optimizing Ponatinib Treatment in CP-CML) trial on dose optimization of ponatinib in patients with chronic phase (CP)-CML, the German consensus paper on ponatinib published in 2020 (Saussele S et al., Acta Haematol. 2020) has been updated in this addendum. Summary: Focus is on the update of efficacy and safety of ponatinib, reflecting the new data set, as well as the update of the benefit-risk assessment and recommendations for ponatinib starting dose in CP-CML – provided that the decision to use ponatinib has already been made. Furthermore, based on OPTIC and additional empirical data, the expert panel collaborated to develop a decision tree for ponatinib dosing, specifically for intolerant and resistant patients. The recommendations on cardiovascular management have also been updated based on the most recent 2021 guidelines of the European Society of Cardiology (ESC) on cardiovascular disease prevention in clinical practice. Key Messages: The OPTIC data confirm the high efficacy of ponatinib in patients with CP-CML and provide the basis for individualized dose adjustment during the course of treatment. [ABSTRACT FROM AUTHOR]

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently recognized systemic autoinflammatory disease caused by somatic mutations in hematopoietic progenitor cells. This case series of four patients with VEXAS syndrome and comorbid myelodysplastic syndrome (MDS) aims to describe clinical, imaging, and hematologic disease presentations as well as response to therapy. Four patients with VEXAS syndrome and MDS are described. A detailed analysis of imaging features, hemato-oncological presentation including bone marrow microscopy and clinical–rheumatological disease features and treatment outcomes is given. All patients were male; ages ranged between 64 and 81 years; all were diagnosed with MDS. CT imaging was available for three patients, all of whom exhibited pulmonary infiltrates of varying severity, resembling COVID-19 or hypersensitivity pneumonitis without traces of scarring. Bone marrow microscopy showed maturation-disordered erythropoiesis and pathognomonic vacuolation. Somatic mutation in the UBA1 codon 41 were found in all patients by next-generation sequencing. Therapy regimes included glucocorticoids, JAK1/2-inhibitors, nucleoside analogues, as well as IL-1 and IL-6 receptor antagonists. No fatalities occurred (observation period from symptom onset: 18–68 months). Given the potential underreporting of VEXAS syndrome, we highly recommend contemporary screening for UBA1 mutations in patients presenting with ambiguous signs of systemic autoinflammatory symptoms which persist over 18 months despite treatment. The emergence of cytopenia, especially macrocytic hyperchromic anemia, should prompt early testing for UBA1 mutations. Notably conspicuous, pulmonary alterations in CT imaging of patients with therapy-resistant systemic autoinflammatory symptoms should be discussed in interdisciplinary medical teams (Rheumatology, Hematology, Radiology and further specialist departments) to facilitate timely diagnosis during the clinical course of the disease. [ABSTRACT FROM AUTHOR]

A letter is presented reporting the results of a research study which investigated the incidence of severe peripheral arterial disease (PAD) and other arteriopathies including myocardial infarction in patients with chronic myeloid leukemia treated with nilotinib. Data reveals that the frequency of PAD in the cohort study appears to exceed that found in general population. The study also noted elevation of cholesterol and fasting glucose in nilotinib clinical trials.

Background: Exercise therapy during cancer treatment reduces symptom burden and improves quality of life (QoL). Polycythemia vera (PV) is a myeloproliferative neoplasia associated with good overall survival (up to decades) but a significant symptom burden, including thromboembolic events and dysesthesias. There are no specific exercise recommendations for patients with PV. Thus, we aimed to determine the exercise preferences of patients with PV and to derive specific recommendations based on the most commonly reported symptoms. Methods: This multicenter survey included patients with PV ≥18 years old. Demographic, clinical, and disease burden data were collected. The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1–30 (mild), 31–70 (moderate), or 71–100 (severe). The patients' information needs about physical activity (PA) and exercise preferences were recorded depending on their motivation and analyzed with regard to demographic aspects. Results: The sample comprised 182 patients (68% female, 61 ± 12 years). The prevalence of moderate‐to‐severe symptoms was 60% for fatigue, 44% for concentration problems, and 35% for bone/muscle pain. Other commonly reported symptoms included skin reactions (49%), splenomegaly (35%), and increased bleeding tendency (28%). Overall, 67% of respondents requested more information regarding PA. Patients with PV preferred individual training (79%) located outdoors (79%) or at home (56%). Regarding the amount of training, sports‐inactive patients preferred a frequency of 1–2 times/week and session durations of 15–45 min, whereas sports‐active patients preferred 3–4 times/week and 30–60 min (p < 0.001). Higher sport‐inactiveness was observed in patients with lower educational level compared to patients with higher educational level (69% vs. 50%, p = 0.021). For beginners, combined resistance‐endurance (circuit) training two times/week, which can be performed outdoors or at home, should be recommended. In the case of splenomegaly or bleeding symptoms, exercises with a low injury risk should be chosen. Conclusion: PA is important for patients with PV; therefore, counseling should be integrated into the treatment plan. Specifically, patients with low educational level should be addressed. Prospective studies are warranted to evaluate the effects of the novel exercise recommendations. [ABSTRACT FROM AUTHOR]

Introduction: The hepatitis E virus (HEV) represents an important cause of viral hepatitis and could cause chronic infections in immunocompromised patients. However, data about immunocompromised patients other than solid organ transplant recipients are limited. Methods: We identified patients from a laboratory database and retrospectively compiled and analyzed clinical as well as laboratory data in detail. Results: Overall, 22 severely immunosuppressed patients, excluding solid organ transplant recipients, were identified. Four patients did not experience viral clearance (one without and three despite ribavirin therapy). Three patients acquired the infection after allogeneic hematopoietic stem cell transplantation (alloHSCT) and recovered spontaneously, whereas another patient, infected prior to alloHSCT, developed a chronic infection. Four patients failed to clear HEV, resulting in fatal liver failure in 2 patients. The CD4+ cell counts increased in all but 1 patient attaining a sustained virological response (SVR), as compared to patients with clinical failure. Severe immunoglobulin deficiency did not appear to obviate the control of HEV. Six of ten (60%) patients with and nine of 12 (75%) patients without ribavirin therapy achieved an SVR. Conclusions: Upfront ribavirin therapy does not appear mandatory in patients without CD4+ lymphopenia, but a prolonged HEV replication carries the risk of liver failure. Our data suggest that chronic HEV infections could cause T-cell exhaustion, which might be overruled with ribavirin therapy. [ABSTRACT FROM AUTHOR]

The article focuses on the role of imatinib for the treatment of chronic myeloid leukaemia (CML) and its limitations as well as the development of nilotinib in response for patients with advanced CML. Imatinib, however in the advanced stage of CML, it is ineffective as BCR-ABL, mutant gene that is formed when a piece of chromosome 9 attaches to the end of chromosome 22, reactivates through phosphorylation that leads to leaukaemic phenotype. Nilotinib inactivates the BCR-ABL kinase and has minor effects on proto-oncogene protein c-KIT and platelet-derived growth factor receptor (PDGF-R) kinases.

Abstract: The tyrosine kinase receptor c-Kit is critically involved in the modulation of nociceptive sensitivity in mice. Ablation of the c-Kit gene results in hyposensitivity to thermal pain, whereas activation of c-Kit produces hypersensitivity to noxious heat, without altering sensitivity to innocuous mechanical stimuli. In this study, we investigated the role of c-Kit signaling in human pain perception. We hypothesized that subjects treated with Imatinib or Nilotinib, potent inhibitors of tyrosine kinases including c-Kit but also Abl1, PDFGFRα, and PDFGFRβ, that are used to treat chronic myeloid leukemia (CML), would experience changes in thermal pain sensitivity. We examined 31 asymptomatic CML patients (14 male and 17 female) receiving Imatinib/Nilotinib treatment and compared them to 39 age- and sex-matched healthy controls (12 male and 27 female). We used cutaneous heat and cold stimulation to test normal and noxious thermal sensitivity, and a grating orientation task to assess tactile acuity. Thermal pain thresholds were significantly increased in the Imatinib/Nilotinib-treated group, whereas innocuous thermal and tactile thresholds were unchanged compared to those in the control group. In conclusion, our findings suggest that the biological effects of c-Kit inhibition are comparable in mice and humans in that c-Kit activity is required to regulate thermal pain sensitivity but does not affect innocuous thermal and mechanical sensation. The effect on experimental heat pain observed in our study is comparable to those of several common analgesics; thus modulation of the c-Kit pathway can be used to specifically modulate noxious heat and cold sensitivity in humans. [Copyright &y& Elsevier]

In patients with chronic myeloid leukemia (CML), use of the BCR-ABL1-specific tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib has greatly improved patient survival and prolonged disease remission. More than 10 years of data from imatinib clinical studies and many years of data for nilotinib and dasatinib have demonstrated that these TKIs are well tolerated in most patients with CML. However, these inhibitors are not entirely BCR-ABL1-specific, and this lack of specificity could account for the off-target effects of these drugs. Adverse events (AEs) are off-target effects that are detrimental to the patient. The underlying mechanisms that contribute to these effects are poorly understood and the long-term consequences of chronic TKI therapy remain largely unknown, particularly with the newer agents. Here, we review the preclinical and clinical data for several of the more frequent AEs associated with TKIs and discuss the therapeutic relevance of these AEs for patients with CML. [ABSTRACT FROM AUTHOR]

The systematic and standardized pretransplant risk assessment represents an important tool to predict the outcome of patients undergoing allogeneic stem cell transplantation (alloSCT). To investigate the capacity of a modified European group for blood and marrow transplantation (mEBMT) risk score to predict the outcome of patients with acute myeloid leukemia (AML) receiving allogeneic stem cell transplants, we retrospectively analyzed 214 patients transplanted at our center between 1995 and 2008. Overall survival (OS) of the whole cohort at 1, 3, and 5 yr was 62%, 48%, and 45%, whereas the cumulative incidence of relapse or non-relapse mortality (NRM) was 26%, 33%, and 33% or 19%, 21%, and 22%. In univariate analysis, a higher mEBMT risk score was associated with an inferior OS ranging from 69% for patients with a score of 0/1 to 26% for patients with a score of 5/6 at 5 yr ( P < 0.0001) and steadily increasing hazard ratios for each additional score point. Likewise, a higher mEBMT risk score was associated with an increased incidence of relapse ( P = 0.049). Importantly, the prognostic value of the mEBMT risk score in terms of OS and relapse was maintained in multivariate analysis. Taken together, this indicates that a mEBMT risk score may be used to predict the outcome of patients with AML following alloSCT. [ABSTRACT FROM AUTHOR]

28 patients with high-risk acute lymphoblastic (ALL) or acute myelogenous leukemia (AML) underwent nonmyeloablative stem cell transplantation (NST) from HLA-identical donors because of one or several contraindications against myeloablative conditioning. Out of 28 patients, nine (32%) had pulmonary or hepatosplenic infiltrates due to invasive fungal infections (IFI) before NST. Out of a total of 28 patients, 17 (61%) had uncontrolled leukemia before NST. Conditioning was performed with fludarabine 180 mg/m², busulfan 8mg/kg and antithymocyte globulin 40 mg/kg. After NST, fever of unknown origin, sepsis or pneumonia developed in 18/28 patients (64%) overall. IFI reactivated in 3/9 patients after NST. Out of, 28 patients, 13 (46%) had late onset of acute graft-versus-host disease (GvHD), which developed at a median of 83 days after NST. GvHD frequently developed after donor lymphocyte infusions. After a median follow-up of 8 months (2–46 months), 14/28 patients (50%) have died from relapse and 1/28 patients (4%) has died from sepsis. Among 28 patients, 13 (46%) are alive in complete remission (CR). Six of 17 patients (35%) with uncontrolled disease and 7/11 patients (63%) with CR before NST are alive in CR. Probability of overall survival at 2 years is 38%. In summary, NST offers a therapeutic alternative to patients with high-risk ALL or AML, who have contraindications against conventional high-dose conditioning. Low NRM was encountered despite high morbidity, but relapse rate was high. Therefore, controlled studies are necessary to elucidate the place of NST in the therapy of high-risk acute leukemias. [ABSTRACT FROM AUTHOR]

Background: Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL). Methods: Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days. Results: Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26–48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3–4 events; these events were generally reversible. No treatment-related deaths were reported. Conclusions: Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy. Trial registration: ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://clinicaltrials.gov/ct2/show/NCT01829711 [ABSTRACT FROM AUTHOR]

Leukemia-associated antigens (LAAs) and HLA-I epitopes published previously have shown promise in inducing leukemia-specific T cell responses. However, the clinical responses are limited, and clinical effectiveness is yet to be achieved. Limitations, among others, being the LAAs themselves, the indirect approach to HLA-I epitope identification by reverse immunology, and the use of single or few LAAs and HLA-I epitopes, which limits the spectrum of inducible tumor-specific T cells. Use of a direct approach to identify naturally processed and presented HLA-I epitopes from LAAs, and higher numbers of antigens for T cell-mediated immunotherapy for leukemia may enhance clinical responses and broaden clinical effectiveness. In a prior study we used immunoaffinity purification of HLA-I peptide complexes from the differentiated myeloid tumor cell lines MUTZ3 and THP1 coupled to high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). From this we identified in the current study seven new HLA-I epitopes and the corresponding LAAs for myeloid leukemia. In comparison, the myeloid HLA-I epitopes reported here were generally stronger HLA-binders that induce stronger T cell responses than those previously published, and their source LAAs had higher immunogenicity, higher expression levels in myeloid tumors cells compared to normal hemopoietin and other major normal tissues, and more protein interaction partners, and they are targeted by CD8 T cells in CML patients. This study analyses and compares the LAAs and HLA-I epitopes based on various immunotherapeutic targets selection criteria, and highlights new targets for T cell-mediated immunotherapy for leukemia. [ABSTRACT FROM AUTHOR]

Background: Data about haematologic malignancies from Tanzania are sparse. African studies show that chronic myeloid leukaemia (CML) is the most common leukaemia, and registry data display a lower mean age at diagnosis. Prognosis is generally good with tyrosine kinase inhibitors, but the molecular response of Imatinib treatment has never been studied in East Africa, and the outcome remains unknown. This study assessed the early molecular response (MR) as a predictor for long-term outcome and barriers to access treatment. Methods: A case series of patients with CML from Northern Tanzania documented demographics and laboratory and clinical findings at diagnosis and after 3 months. The regression analysis has been performed on early MR and clinical and demographic variables using the χ ²-test. The barriers of potential treatments have been assessed. Results: A total of 30 patients have been analysed. The mean age was 41 years. All patients had splenomegaly, whereas 16 had hepatomegaly. Complete haematologic response was achieved in 16 and early MR in 9 patients. Hepatomegaly was positively correlated with unfavourable early MR. The average kilometre from home to hospital was 282 km (5-1,158 km). Travel expenses and time investments pose an impediment to treatment. Conclusion: Patients are younger, and early MR rates are lower compared to other studies. The finding of hepatomegaly as a risk factor for unfavourable early MR was described previously in West Africa. Adherence to therapy is high in the first months of treatment. Furthermore, research is needed to understand the poor MR and the common presentation of hepatomegaly. Outreach clinics might be a solution to reduce impediments to treatment. [ABSTRACT FROM AUTHOR]

Treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia (Ph+ ALL) has been revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Most patients with CML achieve long-term survival similar to individuals without CML due to treatment with TKIs not only in frontline but also in further lines of therapy. The third-generation TKI ponatinib has demonstrated efficacy in patients with refractory CML and Ph+ ALL. Ponatinib is currently the most potent TKI in this setting demonstrating activity against T315I mutant clones. However, ponatinib's safety data revealed a dose-dependent, increased risk of serious cardiovascular (CV) events. Guidance is needed to evaluate the benefit–risk profile of TKIs, such as ponatinib, and safety measures to prevent treatment-associated CV events. An expert panel of German hematologists and cardiologists summarize current evidence regarding ponatinib's efficacy and CV safety profile. We propose CV management strategies for patients who are candidates for ponatinib. [ABSTRACT FROM AUTHOR]

Background: In the phase 3 BFORE trial (NCT02130557), treatment with bosutinib resulted in a significantly higher major molecular response rate at 12 months versus imatinib in the modified intent-to-treat (mITT) population of patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). Assessment of patient-reported outcomes (PROs) was an exploratory objective. Methods: Patients with newly diagnosed CP CML were randomized 1:1 to receive once-daily bosutinib 400 mg or imatinib 400 mg as first-line therapy. Patients completed the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EuroQoL-5 Dimensions (EQ-5D) questionnaires at baseline, every 3 months for the first 24 months of treatment, every 6 months thereafter, and at treatment completion. We report PRO results at month 12 in the mITT population (bosutinib: n = 246; imatinib: n = 241). Results: Mean FACT-Leu combined and subscale scores were similar at baseline in the bosutinib and imatinib arms; at month 12, all scores demonstrated improvement or maintenance of health-related quality of life (HRQoL) in both treatment arms. Repeated-measures mixed-effects models showed no significant difference between bosutinib and imatinib for any FACT-Leu score. Functional health status, as measured by EQ-5D, also demonstrated improvement or maintenance with bosutinib and imatinib at month 12. Conclusions: Similar improvements in PROs compared with baseline were seen after 12 months of treatment with first-line bosutinib or imatinib in the BFORE trial. Newly diagnosed patients with CP CML receiving bosutinib or imatinib can preserve or improve HRQoL during treatment, although clinical efficacy was superior with bosutinib. [ABSTRACT FROM AUTHOR]

Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome--positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n 5 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ‡90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440. [ABSTRACT FROM AUTHOR]

Purpose: ENESTfreedom is evaluating treatment-free remission (TFR) following frontline nilotinib in patients with chronic myeloid leukemia (CML) in chronic phase. Following our primary analysis at 48 weeks, we here provide an updated 96-week analysis.Methods: Attempting TFR required ≥ 3 years of nilotinib, a molecular response of MR4.5 [BCR-ABL1 ≤ 0.0032% on the International Scale (BCR-ABL1IS)], and sustained deep molecular response (DMR) during a 1-year consolidation phase. Patients restarted nilotinib following loss of major molecular response (MMR; BCR-ABL1IS ≤ 0.1%).Results: Ninety-six weeks after stopping treatment (3.6-year median prior nilotinib duration), 93 of 190 patients (48.9%) remained in TFR. Of 88 patients who restarted nilotinib following loss of MMR, 87 regained MMR and 81 regained MR4.5 by the data cut-off. Ninety-six-week TFR rates were 61.3, 50.0, and 28.6% in patients with low, intermediate, and high Sokal risk scores at diagnosis, respectively. Patients consistently in MR4.5 during consolidation had higher TFR rates (50.6%) than patients with ≥ 1 assessment without MR4.5 during consolidation (35.0%). In a landmark analysis, 96-week TFR rates for patients with MR4.5, MR4 (BCR-ABL1IS ≤ 0.01%) but not MR4.5, and MMR but not MR4 at TFR week 12 were 82.6, 23.1, and 0%, respectively. There were no reports of disease progression or death due to CML; overall adverse event frequency decreased following TFR. Within the follow-up period, TFR did not adversely affect disease outcomes.Conclusions: These results demonstrate the feasibility and durability of TFR following frontline nilotinib and emphasize the importance of sustained DMR for TFR. [ABSTRACT FROM AUTHOR]

With high survival rates for chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs), emerging consequences, such as arterial ischemic events, require consideration when evaluating treatment options. Cardiovascular ischemic event incidence in clinical trials was evaluated in 2712 dasatinib-treated patients with Philadelphia chromosome-positive (Ph+) leukemias from 11 first- and second-line trials (pooled), newly diagnosed CML patients treated with dasatinib or imatinib (DASISION), and prostate cancer patients treated with dasatinib or placebo plus docetaxel/prednisone (READY). Overall, 2-4% of dasatinib-treated patients had cardiovascular ischemic events. Most dasatinib-treated patients with an event had a history of and/or risk factor for atherosclerosis (pooled 77 with history/risk and event/96 with events; DASISION 8/10; READY 15/18). Most cardiovascular ischemic events occurred within 1 year of initiating dasatinib (pooled 69/96; DASISION 7/10; READY 16/18). Comparison of observed and expected event rates through standardized incidence ratios indicates that dasatinib does not increase risk for cardiovascular ischemic events compared with external reference populations. [ABSTRACT FROM AUTHOR]

Background: The proliferation of clonal cytotoxic T-cells or natural killer cells has been observed after dasatinib treatment in small studies of patients with chronic myeloid leukemia (CML).Methods: The incidence of lymphocytosis and its association with response, survival, and side effects were assessed in patients from 3 large clinical trials. Overall, 1402 dasatinib-treated patients with newly diagnosed CML in chronic phase (CML-CP), CML-CP refractory/intolerant to imatinib, or with CML in accelerated or myeloid-blast phase were analyzed.Results: Lymphocytosis developed in 32% to 35% of patients and persisted for >12 months. This was not observed in the patients who received treatment with imatinib. Dasatinib-treated patients in all stages of CML who developed lymphocytosis were more likely to achieve a complete cytogenetic response, and patients who had CML-CP with lymphocytosis were more likely to achieve major and deep molecular responses. Progression-free and overall survival rates were significantly longer in patients with CML-CP who were refractory to or intolerant of imatinib and had lymphocytosis. Pleural effusions developed more commonly in patients with lymphocytosis.Conclusions: Overall, lymphocytosis occurred and persisted in many dasatinib-treated patients in all phases of CML. Its presence was associated with higher response rates, significantly longer response durations, and increased overall survival, suggesting an immunomodulatory effect. Prospective studies are warranted to characterize the functional activity of these cells and to assess whether an immunologic effect against CML is detectable. Cancer 2016;122:1398-1407. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia.Methods: The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805.Findings: Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib.Interpretation: The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established.Funding: ARIAD Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Vascular safety is an emerging issue in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Whereas imatinib exhibits a well-documented and favorable long-term safety profile without obvious accumulation of vascular events, several types of vascular adverse events (VAEs) have been described in patients receiving secondor third-generation BCR/ABL1 TKIs. Such VAEs include pulmonary hypertension in patients treated with dasatinib, peripheral arterial occlusive disease and other arterial disorders in patients receiving nilo-tinib, and venous and arterial vascular occlusive events during ponatinib. Although each TKI interacts with a unique profile of molecular targets and has been associated with a unique pattern of adverse events, the mechanisms of drug- induced vasculopathy are not well understood. Here, recent data and concepts around VAEs in TKI-treated patients with CML are discussed, with special reference to potential mechanisms, event management, and strategies aimed at avoiding occurrence of such events in long-term treated patients. [ABSTRACT FROM AUTHOR]

The presence of a Philadelphia chromosome with a corresponding BCR-ABL1 rearrangement is the hallmark of chronic myeloid leukemia, but is considered a very rare event in de novo acute myeloid leukemia (AML). Here, we report the first case in which a dominant Philadelphia chromosome-positive subclone was detected upon relapse in a formerly Philadelphia chromosome-negative MLL-AF6+ AML. Due to refractory disease under salvage chemotherapy, the patient was started on nilotinib treatment. As a result, the Philadelphia chromosome-positive subclone was eradicated within 1 month; however, disease progressed and was again dominated by the Philadelphia chromosome-negative founding clone, demonstrating rapid clonal expansion under nilotinib-induced selection pressure. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Little data are available on the relative merits of chimerism and minimal residual disease (MRD) monitoring for relapse prediction after allogeneic hematopoietic stem cell transplantation (HCT). We performed a retrospective analysis of serial chimerism assessments in 101 adult HCT recipients with acute lymphoblastic leukemia (ALL) and of serial MRD assessments in a subgroup of 22 patients. All patients had received myeloablative conditioning. The cumulative incidence of relapse was significantly higher in the patients with increasing mixed chimerism (in-MC) compared with those with complete chimerism, low-level MC, and decreasing MC, but the sensitivity of in-MC detection with regard to relapse prediction was only modest. In contrast, MRD assessment was highly sensitive and specific. Patients with MRD positivity after HCT had the highest incidence of relapse among all prognostic groups analyzed. The median time from MRD positivity to relapse was longer than the median time from detection of in-MC, but in some cases in-MC preceded MRD positivity. We conclude that MRD assessment is a powerful prognostic tool that should be included in the routine post-transplantation monitoring of patients with ALL, but chimerism analysis may provide additional information in some cases. Integration of these tools and clinical judgment should allow optimal decision making with regard to post-transplantation therapeutic interventions. [ABSTRACT FROM AUTHOR]

Janus kinases are critical components of signaling pathways that regulate hematopoiesis. Mutations of the non-receptor tyrosine kinase JAK2 are found in many BCR-ABL-negative myeloproliferative neoplasms. Preclinical results support that JAK2 inhibitors could show efficacy in treating chronic myeloproliferative neoplasms. JAK2 has also been postulated to play a role in BCR-ABL signal transduction. Therefore, inhibitors of JAK2 kinases are turning into therapeutic strategies for treatment of chronic myelogenous leukemia (CML). In this study, the effects of two novel JAK2 inhibitors, NVP-BSK805 and NVP-BVB808, have been investigated in cell lines expressing either BCR-ABL or mutant JAK2. Possible synergies between NVP-BSK805/NVP-BVB808 and the kinase inhibitors imatinib and nilotinib were assessed. Proliferation and apoptosis tests with both substances showed response in the following cell lines: CHRF-288-11, SET-2 and UKE-1. All BCR-ABL-positive cell lines showed some reduction in proliferation, but with half-maximal growth-inhibitory values >1 µM. Combination of the JAK2 inhibitors with imatinib and nilotinib showed no significant additive or synergistic effects, although all BCR-ABL-positive cell lines responded well to both CML therapeutic agents. Interestingly, it seemed that the combination of imatinib with NVP-BSK805 had a protective effect on the cells. Combination treatment with nilotinib did not show this effect. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We present long-term follow-up of a dasatinib phase 3 study of patients with imatinibresistanf- intolerant chronic myeloid leukemia (CML). In the CA180-034 study, 670 patients with imatinib-resistant/-intolerant CML in chronic phase (CML-CP) received dasatinib 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. At 6 years, 188 (28%) of 670 patients remained on study treatment. Estimated 6-year protocol-defined progression-free survival (PFS) rates were 49%, 51%, 40%, and 47%, respectively, and estimated 6-year overall survival (OS) rates were 71%, 74%, 77%, and 70%, respectively (intent-to-treat population, including protocol-defined progression or death after discontinuation). Estimated 6-year rates of survival without transformation on study treatment were 76%, 80%, 83%, and 74%, respectively. Major molecular response was achieved in 43% (100 mg once daily) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of PFS and OS. Notably, estimated 6-year PFS rates based on S1%, >1% to 10%, and >10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively. Most adverse events occurred by 2 years. lmatinib-resistant/-intolerant patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCRABL <10% at 3 months. This study was registered at ClinicalTrials.gov: NCT00123474. [ABSTRACT FROM AUTHOR]

Abstract: Sixty patients with early chronic phase CML (ECPCML) received Nilotinib on a phase II study which included a comparison of the Xpert BCR-ABL Monitor™ PCR system with standardized (IS) BCR-ABL1 real-time quantitative PCR (RQ-PCR). 88% patients achieved MMR with 45% achieving MR4.5. At 3 months BCR-ABL1/ABL1 IS >1% and <10% was associated with a lower likelihood of subsequent MR4.5 compared to patients with lower levels (p =0.018). No significant difference was observed between methodologies in identifying MMR. Nilotinib induces high molecular response rates in ECPCML and the Xpert BCR-ABL Monitor™ system merits further investigation in this setting. [Copyright &y& Elsevier]

Chronic myeloid leukemia developing after transplantation of solid organs and concomitant immunosuppression is a rare but still significant clinical phenomenon. We here describe an additional case of a 62-year-old male patient developing CML after orthotopic heart transplantation and medication with cyclosporine A, mofetil-mycophenolate, and steroids. Initial antileukemic therapy was imatinib at a standard dose and within 15 months of therapy a complete cytogenetic response was noted. In this report we discuss the clinical implications of these rare but biologically important cases. [ABSTRACT FROM AUTHOR]

Assessing the clinical significance of JAK2 V617F mutant allele burden is complicated by a myriad of techniques reported to detect and quantify the mutation. As a consequence, the level of sensitivity and how the data is reported vary. Harmonization of well-defined molecular studies would permit evaluation of the clinical significance of measuring allele burden and rapid determination of the efficacy of novel agents for the treatment of chronic myeloproliferative neoplasia via multicenter clinical trials, at the subclinical level. Here we report a comparison between the widely available TaqMan quantitative real time polymerase chain reaction (Q-PCR) and competitive PCR (C-PCR) assays. We found that the tumor load was invariably greater when measured by C-PCR compared to that recorded by Q-PCR. Furthermore, none of the samples converted from undetectable to detectable when the enriched granulocyte (GR) fraction was tested. While a difference in the V617F allele levels was detected between GR fraction and whole blood, this was not statistically significant. [ABSTRACT FROM AUTHOR]

Background: Nilotinib is a selective, potent BCR-ABL inhibitor. Previous studies demonstrated the efficacy and safety of nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic phase (CML-CP) or accelerated phase who failed prior imatinib.Methods: This expanded access trial further characterized the safety of nilotinib 400 mg twice daily in patients with CML-CP (N = 1422).Results: In this large, heavily pretreated population, nilotinib demonstrated significant efficacy, with complete hematologic response and complete cytogenetic response achieved in 43% and 34% of patients, respectively. Responses were rapid, mostly occurring within 6 months, and were higher in patients with suboptimal response to imatinib, with 75% and 50% achieving major cytogenetic response and complete cytogenetic response, respectively. At 18 months, the progression-free survival rate was 80%. Most patients achieved planned dosing of 400 mg twice daily and maintained the dose >12 months. Nonhematologic adverse events (AEs) were mostly mild to moderate and included rash (28%), headache (25%), and nausea (17%). Grade 3 or 4 thrombocytopenia (22%), neutropenia (14%), and anemia (3%) were low and managed by dose reduction or brief interruption. Grade 3 or 4 elevations in serum bilirubin and lipase occurred in 4% and 7% of patients, respectively. The incidence of newly occurring AEs decreased over time. Of patients who experienced a dose reduction because of AEs and attempted a re-escalation, 87% successfully achieved re-escalation to the full dose.Conclusions: This large study confirms that nilotinib was well tolerated and that grade 3 or 4 AEs occurred infrequently and were manageable through transient dose interruptions. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nilotinib is a selective, potent BCR-ABL inhibitor. Previous studies demonstrated the efficacy and safety of nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic phase (CML-CP) or accelerated phase who failed prior imatinib. METHODS: This expanded access trial further characterized the safety of nilotinib 400 mg twice daily in patients with CML-CP (N = 1422). RESULTS: In this large, heavily pretreated population, nilotinib demonstrated significant efficacy, with complete hematologic response and complete cytogenetic response achieved in 43% and 34% of patients, respectively. Responses were rapid, mostly occurring within 6 months, and were higher in patients with suboptimal response to imatinib, with 75% and 50% achieving major cytogenetic response and complete cytogenetic response, respectively. At 18 months, the progression-free survival rate was 80%. Most patients achieved planned dosing of 400 mg twice daily and maintained the dose >12 months. Nonhematologic adverse events (AEs) were mostly mild to moderate and included rash (28%), headache (25%), and nausea (17%). Grade 3 or 4 thrombocytopenia (22%), neutropenia (14%), and anemia (3%) were low and managed by dose reduction or brief interruption. Grade 3 or 4 elevations in serum bilirubin and lipase occurred in 4% and 7% of patients, respectively. The incidence of newly occurring AEs decreased over time. Of patients who experienced a dose reduction because of AEs and attempted a re-escalation, 87% successfully achieved re-escalation to the full dose. CONCLUSIONS: This large study confirms that nilotinib was well tolerated and that grade 3 or 4 AEs occurred infrequently and were manageable through transient dose interruptions. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Imatinib slows development of chronic myeloid leukemia (CML). However, available information on morbidity and mortality is largely based on sponsored trials, whereas independent long-term field studies are lacking. Patients and Methods Consecutive CML patients who started imatinib treatment before 2005 and who were in complete cytogenetic remission (CCyR) after 2 years (±3 months) were eligible for enrollment in the independent multicenter Imatinib Long-Term (Side) Effects (ILTE) study. Incidence of the first serious and nonserious adverse events and loss of CCyR were estimated according to the Kaplan–Meier method and compared with the standard log-rank test. Attainment of negative Philadelphia chromosome hematopoiesis was assessed with cytogenetics and quantitative polymerase chain reaction. Cumulative incidence of death related or unrelated to CML progression was estimated, accounting for competing risks, according to the Kalbleisch–Prentice method. Standardized incidence ratios were calculated based on population rates specific for sex and age classes. Confidence intervals were calculated by the exact method based on the χ2 distribution. All statistical tests were two-sided. Results A total of 832 patients who were treated for a median of 5.8 years were enrolled. There were 139 recorded serious adverse events, of which 19.4% were imatinib-related. A total of 830 nonserious adverse events were observed in 53% of patients; 560 (68%) were imatinib-related. The most frequent were muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon, or ligament lesions. Nineteen patients (2.3%) discontinued imatinib because of drug-related toxic effects. Forty-five patients lost CCyR, at a rate of 1.4 per 100 person-years. Durable (>1 year) negative Philadelphia chromosome hematopoiesis was attained by 179 patients. Twenty deaths were observed, with a 4.8% mortality incidence rate (standardized incidence ratio = 0.7; 95% confidence interval = 0.40 to 1.10, P = .08), with only six (30%) associated with CML progression. Conclusions In this study, CML-related deaths were uncommon in CML patients who were in CCyR 2 years after starting imatinib, and survival was not statistically significantly different from that of the general population. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented regarding the long-term effect of stem cell mobilization under imatinib mesylate (IM) therapy for patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML).

Background: Nilotinib is active in imatinib-resistant and -intolerant chronic myeloid leukemia patients and was recently approved for these indications.Methods: Data on the efficacy and safety of nilotinib treatment were collected from 2 phase 2 expanded access clinical trials with similar designs (CAMN107AIL01 and ENACT).Results: Of 88 study patients (58 chronic, 11 accelerated, 19 blast crisis), the best responses to nilotinib were complete hematologic response (CHR) in 27%, partial cytogenetic response in 12%, complete cytogenetic response in 14%, and major molecular response in 19%. Patients achieving at least a CHR during imatinib therapy were more likely to respond to nilotinib, and failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib (P=.0021). Responses were not statistically different in subgroup analysis, including that of imatinib intolerance compared with imatinib resistance, presence of ABL kinase domain mutations compared with absence of mutations, and previous treatment with another second-generation tyrosine kinase inhibitor compared no prior treatment. The overall survival and progression-free survival rates at 1 year were 83% and 48% for the entire cohort, 93% and 66% in chronic phase, and 64% and 19% in advanced phase. Adverse hematological events included thrombocytopenia (all events, 27%; grade 3-4, 13%) and leukopenia (all events, 18%; grade 3-4, 10%). The majority of the nonhematological events were mild, the most common being rash, infection, bone pain, headache, nausea, and vomiting.Conclusions: Nilotinib treatment is an efficient and safe therapy for imatinib-resistant or -intolerant patients. Prior response to imatinib therapy is a predictor for the response to nilotinib. [ABSTRACT FROM AUTHOR]

Background: Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in the chronic phase. Methods: In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome–positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. Results: At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P=0.01 and P=0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups. Conclusions: Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome–positive CML. (ClinicalTrials.gov number, NCT00471497.) N Engl J Med 2010;362:2251-9. [ABSTRACT FROM AUTHOR]

The article focuses on a research on assessing the clinical significance of Musashi 2 (MSI2) RNA-binding protein transcripts in chronic myeloid leukemia (CML) patients. Topics discussed include controlling hematopoietic stem cell self-renewal and differentiation by MSI2, monitoring of MSI2 messenger RNA levels might identify patients at risk of transformation, and effect of leukemic stem cells with increased levels of MSI2 on progression to blast crisis.

In chronic myeloid leukaemia (CML), dendritic cells (DC) and leukaemic cells share a common progeny, leading to constitutive expression of putative tumour antigens, such as bcr/abl, in DC. In this phase-I/II study, autologous DC were used as a vaccine in patients with chronic phase bcr/abl+ CML, who had not achieved an adequate cytogenetic response after treatment with α-interferon or imatinib. Ten patients were enrolled, DC were generated from peripheral blood monocytes and vaccination consisted of four subcutaneous injections of increasing numbers of DC (1–50 × 106 cells per injection) on days 1, 2, 8 and 21. Vaccination was feasible and safe. Improvement of the cytogenetic/molecular response, as detected by fluorescence in situ hybridization of peripheral blood mononuclear cells (PBMC), was possibly related to vaccination in four of 10 patients. In three of these patients, T cells recognizing leukaemia-associated antigens became detectable. The proliferative capacity of PBMC in response to autologous DC increased after vaccination in all evaluable patients. We conclude that vaccination with autologous, non-irradiated ‘leukaemic’ DC is feasible, safe and induces anti-leukaemic T-cell responses in some CML patients. DC vaccination might be useful in CML as postremission therapy, i.e. after treatment with tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

The article presents a study which investigated the role of postoperative adjuvant chemotherapy in patients with rectal cancer pretreated by preoperative radiochemotherapy (RCT) and curative surgery. Data were pooled from both arms of a phase III trial in which patients with locally advanced rectal cancer were randomized to preoperative RCT alone or combined with pelvic radiofrequency hyperthermia. 73 out of 93 patients started adjuvant chemotherapy and 19 patients did not due to perioperative complications and refusal. Improved overall survival was observed in the chemotherapy group.

Abstract: Imatinib mesylate is a small molecule inhibitor of the c-Abl, platelet-derived growth factor (PDGF) receptor and c-Kit tyrosine kinases that is approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Glioblastoma multiforme is a highly malignant primary brain tumor that is usually treated with surgery and/or radiotherapy. Previous studies implicate an autocrine loop caused by high expression of PDGF and its receptor, PDGFR, in the proliferation of some glioblastomas. Here, we demonstrate that pretreatment of a human glioblastoma cell line, RuSi RS1, with imatinib significantly enhanced the cytotoxic effect of ionizing radiation. This effect was not seen in human breast cancer (BT20) and colon cancer (WiDr) cell lines. Whereas c-Abl and c-Kit were expressed about equally in the three cell lines, RuSi RS1 cells showed significantly higher expression of PDGFR-β protein in comparison to BT20 and WiDr. Imatinib treatment of RuSi RS1 cells decreased overall levels of cellular tyrosine phosphorylation and specifically inhibited phosphorylation of PDGFR-β, while c-Abl was not prominently activated in these cells. These results suggest that imatinib may have clinical utility as a radiosensitizer in the treatment of human glioblastoma, possibly through disruption of an autocrine PDGF/PDGFR loop. [Copyright &y& Elsevier]

Therapy with imatinib mesylate is limited by cellular resistance in chronic myeloid leukaemia (CML). Further, the limited availability of matching stem cell donors or an unfavourable risk profile for allogeneic stem cell transplantation (SCT) reduces the number of therapeutic options in a number of patients. To assess the possibility of stem cell mobilization (SCM) during imatinib therapy we performed granulocyte colony-stimulating factor (filgrastim)-induced SCM and subsequent aphaeresis in 15 chronic phase and three accelerated phase CML patients. Aphaeresis was successful in 13 patients (72%) (≥2·0 × 106 CD34+ cells/kg body weight) and five (28%) harvests could be obtained, which were negative for BCR/ABL mRNA as assessed by nested-reverse transcription polymerase chain reaction (RT-PCR). All harvests, except one, were negative after first round RT-PCR, implicating a low level of CML cell contamination. There was no significant change in peripheral BCR/ABL transcript load after SCM as assessed by quantitative real-time RT-PCR. Fifteen patients remained stable in complete cytogenetic remission (CCR) during a median observation period of 9·3 months. One patient achieved a molecular remission shortly after SCM. Another patient who exhibited rising BCR/ABL mRNA levels before SCM achieved CCR after autologous SCT with the generated harvest. One patient with a Philadelphia chromosome-negative, BCR/ABL-positive CML showed a cytogenetic relapse 6 months after SCM. We conclude that filgrastim-induced CD34+ cell aphaeresis under simultaneous imatinib medication is safe and feasible in CML patients. Additionally, we found evidence that this procedure could generate stem cell harvests that exhibit non-detectable levels of BCR/ABL mRNA. [ABSTRACT FROM AUTHOR]

Abstract. Imatinib (glivec®, formerly known as STI571) effectively blocks the ATP-binding site of the bcr/abl fusion protein thereby inactivating selectively the tyrosine kinase activity of bcr/abl. Therefore, it is a promising drug in Philadelphia chromosome positive chronic myeloid leukemia showing high hematologic and cytogenetic response rates combined with a mild toxicity profile. Here we report two cases of squamous cell carcinoma of the skin, which appeared in the photoexposed areas in two elderly patients treated for advanced chronic myeloid leukemia with imatinib. The role of chemotherapy, chronic sun exposure and of possible additional risk factors such as human papillomavirus infection is discussed. [ABSTRACT FROM AUTHOR]

The Wilms' tumour gene (WT1) has been suggested as a powerful parameter for molecular monitoring of minimal residual disease (MRD) in leukaemias. However, molecular monitoring via WT1 RNA levels is far from being routinely performed, which is possibly owing to the complex and inaccurate quantitative reverse transcription polymerase chain reaction (RT-PCR) procedures. Using a newly-developed quantitative real time RT-PCR, we measured WT1 transcripts in peripheral blood leucocytes of patients with acute myeloid (AML), acute lymphoid (ALL) and chronic myeloid leukaemia (CML). While healthy blood donors did not show measurable amounts of WT1 transcripts, WT1 RNA levels were detectable in all types of leukaemia. Furthermore, intraindividual WT1 transcript kinetics were exclusively dependent on disease progression, treatment and subsequent disease outcome. Using this approach, we could distinguish between treatment response and failure within the first days of therapeutic intervention. Moreover, gradually rising WT1 levels over a period of weeks and months paralleled long-term disease progression and appeared to be a prognostic indicator for subsequent clinical relapse. A linear correlation between quantities of WT1 and bcr/abl fusion transcripts could be seen in CML. We conclude that quantitative assessment of WT1 transcripts using real-time PCR is an appropriate method for molecular monitoring of AML, ALL and CML, and can be used independently for both short- and long-term monitoring of leukaemia patients. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding the differential expression of SHP-1 in chronic myeloid leukemia.