High Level of CD8+PD-1+ Cells in Patients with Chronic Myeloid Leukemia Who Experienced Loss of MMR after Imatinib Discontinuation.

Treatment-free remission (TFR) is achieved in approximately half of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The mechanisms responsible for TFR maintenance remain elusive. This study aimed to identify immune markers responsible for the control of residual CML cells early in the TFR (at 3 months), which may be the key to achieving long-term TFR and relapse-free survival (RFS) after discontinuation of imatinib. Our study included 63 CML patients after imatinib discontinuation, in whom comprehensive analysis of changes in the immune system was performed by flow cytometry, and changes in the BCR::ABL1 transcript levels were assessed by RQ-PCR and ddPCR. We demonstrated a significant increase in the percentage of CD8+PD-1+ cells in patients losing TFR. The level of CD8+PD-1+ cells is inversely related to the duration of treatment and incidence of deep molecular response (DMR) before discontinuation. Analysis of the ROC curve showed that the percentage of CD8+PD-1+ cells may be a significant factor in early molecular recurrence. Interestingly, at 3 months of TFR, patients with the e13a2 transcript had a significantly higher proportion of the PD-1-expressing immune cells compared to patients with the e14a2. Our results suggest the important involvement of CD8+PD-1+ cells in the success of TFR and may help in identifying a group of patients who could successfully discontinue imatinib.

The SNP rs460089 in the gene promoter of the drug transporter OCTN1 has prognostic value for treatment-free remission in chronic myeloid leukemia patients treated with imatinib.

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.

The Outcomes of Ponatinib Therapy in Patients With Chronic Myeloid Leukemia Resistant or Intolerant to Previous Tyrosine Kinase Inhibitors, Treated in Poland Within the Donation Program.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have greatly improved the treatment outcome for most patients with chronic myeloid leukemia (CML). Ponatinib is a new pan-inhibitor of TK active in resistant CML. This study aimed to evaluate the efficacy and safety of ponatinib in patients suffering from CML. PATIENTS AND METHODS: This multicenter, non-randomized, observational, retrospective study evaluated the efficacy and safety of ponatinib administered in adult CML patients in any disease phase, including those with a detected ABL T315I mutation, which were resistant or intolerant to previous-generation TKIs. The study comprised 43 patients benefiting from the ponatinib donation program who were treated in 16 Polish centers. RESULTS: For patients who started treatment with ponatinib in chronic phase (CP) (n = 23) and in accelerated phase (AP) (n = 3) the median time on ponatinib was 19.5 months (range: 1.0-35.4), and 31.7 months (range: 31.0-34.1), respectively. All these patients were in CP after 1 month of treatment and at the end of observation - none of them progressed to AP or blastic phase (BP) during the study, meaning that progression-free survival was 100% at the end of observation (35.4 months). The estimated 2-year survival in this group of patients was 84%. For all 43 patients, median survival was not reached (lower quartile 6.3 months), and estimated 2-year survival was 60%. CONCLUSION: Our analysis confirmed ponatinib efficacy in a significant proportion of patients heavily pre-treated with TKIs achieving durable responses in both CP and AP/BP CML groups.

Atypical chronic myeloid leukaemia: A case of an orphan disease-A multicenter report by the Polish Adult Leukemia Group.

Atypical chronic myeloid leukaemia (aCML) belongs to myelodysplastic/myeloproliferative neoplasms. Because of its rarity and changing diagnostic criteria throughout subsequent classifications, data on aCML are very scarce. Therefore, we at the Polish Adult Leukemia Group performed a nationwide survey on aCML. Eleven biggest Polish centres participated in the study. Altogether, 45 patients were reported, among whom only 18 patients (40%) fulfilled diagnostic criteria. Among misdiagnosed patients, myelodysplastic/myeloproliferative syndrome unclassifiable and chronic myelomonocytic leukaemia were the most frequent diagnoses. Thirteen patients were male, median age 64.6 years (range 40.4-80.9). The median parameters at diagnosis were as follows: white blood cell count 97 × 109 /L (23.8-342) with immature progenitors amounting at 27.5% (12-72), haemoglobin 8.6 g/dL (3.9-14.9), and platelet count 66 × 109 /L (34-833). Cytoreductive treatment was used in all patients, and 2 patients underwent allogeneic hematopoietic stem cell transplantation. The median overall survival was 14.1 months (95% CI, 7.2), with median acute myeloid leukaemia-free survival of 13.3 months (95% CI, 3.6-22.6). Cumulative incidence of acute myeloid leukaemia transformation after 1 year in aCML group was 12.5% (95% CI, 0%-29.6%). To conclude, aCML harbours a poor prognosis. Treatment options are limited, with allogeneic hematopoietic stem cell transplantation being the only curative method at present, although only a minority of patients are transplant eligible. Educational measures are needed to improve the quality of diagnoses.

Quality of Life and Adherence to Therapy in Patients With Chronic Myeloid Leukemia Treated With Nilotinib as a Second-Line Therapy: A Multicenter Prospective Observational Study.

INTRODUCTION: The aim of this study was to evaluate quality of life (QOL) and adherence to the therapy in patients with chronic myeloid leukemia in chronic phase treated with nilotinib as second-line therapy. PATIENTS AND METHODS: A multicenter, prospective, observational trial with 6 time points was conducted; 177 patients were recruited in 23 centers in Poland who were treated with nilotinib as second-line therapy because of the ineffectiveness or intolerance of their previous therapy. QOL was evaluated with the standard European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire. Adherence to the therapy was assessed using the 4-item Morisky Medication Adherence Scale by patients and their physicians. RESULTS: The average QOL in patients who completed the study was significantly higher during the last visit (69.4 ± 17.4) than at the start of the study (59.1 ± 18.8; P < .001). At their first visit, 120 (83.2%) patients assessed themselves as highly compliant and 135 (93.4%) at the fifth visit. Low-compliance patients represented 3 (1.7% of the total) during visit 1; none of the patients self-assessed as low compliance since the fourth visit. At the first visit 151 (85.3%) patients were categorized by their physicians as highly compliant and 138 (96.0%) during the last 3 visits. Patients' and their physicians' assessments were significantly correlated. CONCLUSION: The QOL among patients receiving nilotinib administered as second-line therapy was very good and adherence to the treatment was high. The efficacy and safety of the drug were confirmed in the real-life setting.

Occurrence of secondary malignancies in chronic myeloid leukemia during therapy with imatinib mesylate-single institution experience.

INTRODUCTION: Imatinib mesylate (IM) remains the treatment of choice for chronic myeloid leukemia (CML) showing a remarkable efficacy and offers a perspective for long disease-free survival. Due to prolonged administration of IM, the questions about the possible impact on the development of secondary malignancies (SM) are raised. OBJECTIVE: To investigate the incidence and clinical outcome of secondary malignancies during IM therapy for CML. MATERIAL AND METHODS: The records of 221 CML patients treated with IM between 2003-2013 in a single institution were reviewed. The Poisson regression model was used to estimate the relative risks for SM and death in CML patients. RESULTS: Secondary malignancies developed in eight out of the 221 patients (3.6%) receiving IM for a median of 61 months (range, 10-137 months). Female/male ratio was 5/3. Two patients were diagnosed with their CML at accelerated phase whereas 6 had chronic phase. The median age at IM initiation was 58 years (range, 31-72 years). Five of these 8 SM patients received IM after other treatments failure: interferon α (n=5), hydroxyurea (n=4) and cytarabine (n=1). Three patients received IM as a frontline therapy. All patients were on IM at 400mg daily at SM occurrence. The therapy for SM included surgery (n=3), chemotherapy only (n=3), and chemotherapy followed by radiotherapy (n=1). One patient did not receive treatment due to disseminated disease. All CML patients were in hematologic and complete cytogenetic response (CCR) at the time of SM development. All of them also met the criteria for major molecular response (BCR-ABL(IS) ≤0.1%). They continued their IM while receiving treatment for SM. Among eight patients with SM, five patients are alive and remain in CCR on IM whereas three patients died due to SM. The risks for SM development as well as death due to SM in CML patients were not statistically increased if compared to age-adjusted population. CONCLUSIONS: The association between IM therapy for CML and SM development has not been found.

[A study to determine the safety and efficacy of imatinib mesylate in patients with chronic phase of chronic myeloid leukemia after interferon therapy failure. Four year follow-up]. / Ocena skutecznosci i bezpieczenistwa stosowania imatinibu mesylate u pacjentów z faza przewlekla przewleklej bialaczki szpikowej po niepowodzeniu leczenia interferonem 4 lata obserwacji.

UNLABELLED: Targeted therapy with the use of imatinib mesylate is a recognized option for patients with chronic myeloid leukemia (CML) not eligible for allogeneic hematopoietic cell transplantation. We present results of a multicenter phase II study on the use of imatinib in chronic phase after failure to interferon-alpha (IFN-alpha). Sixty patients (27 female, 33 male), median age 46 (range, 21-64), were included with hematologic relapse (n= 11), hematologic refractoriness (n=4), cytogenetic relapse/ /+65resistance (n=40) or intolerance to IFN-alpha (n=5). The median time from CML diagnosis was 39 months (range, 4-132), the median time of IFN-alpha therapy equaled 23 months (range, 1-78). Imatinib mesylate was administered at a dose of 400 mg/day for 1 year. In patients who achieved major cytogenetic response (MCR) the therapy was continued until progression. Thirty-three (55%) patients achieved MCR after one year of treatment. At 4 years the cumulative incidence of complete cytogenetic response equaled 40% (95% CI, 29-56). Among 27 patients who did not achieve MCR at 12 moths, in 12 cases the study course was discontinued prematurely because of blast crisis (n=9), prolonged neutropenia (n=l), severe transaminases elevation (n=l) or incidental death not related to the study drug or disease (n=l). The probability of OS at 4 years equaled 82% (95% CI, 72-91) and was lower for patients with the disease duration >36 months and those with Sokal index > or =0.8. Among patients who achieved MCR, the probability of progression-free survival was 78% (95% CI, 69-85). Time to progression (cytogenetic, n=6; blast crisis, n=l) varied from 3-36 months. CONCLUSIONS: Imatinib mesylate is characterized by good tolerance and allows achieving cytogenetic response in more than half of late chronic phase CML patients with failure of interferon therapy. However, the progression rate is substantial, which raises concern regarding the curative potential of monotherapy with imatinib in this group of patients.

[Severe thrombocytopenia associated with simultaneous cytomegalovirus and Epstein-barr virus infection in an immunocompetence patient]. / Ciezka izolowana maloplytkowosc w przebiegu jednoczesnej infekcji wirusem cytomegalii i Epsteina-Barr u chorej bez uposledzenia odpornosci.

A 22 year old woman, without preceeding immunological and hematological disorders was hospitalized because of severe thrombocytopenia. The results of extended workup revealed simultaneous cytomegalovirus and Epstein-Barr virus infection as the most probable causative factor. Both, thrombocytopenia and the symptoms of viral infections resolved after consequent treatment with acyclovir, corticosteroids and intravenous immunoglobulines. Based on this original case report authors suggest the need of virological tests in newly diagnosed idiopatic thrombocytopenia.