Chronic Phase CML Research Articles

Efficacy and Safety Following Bosutinib Dose Reduction in Patients with Philadelphia Chromosome–Positive Chronic Myeloid Leukemia

Objectives: Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor for adult patients with Philadelphia chromosome−positive chronic myeloid leukemia (Ph+ CML), has a recommended starting dose of 500 mg/d. This analysis evaluates efficacy and safety following BOS dose reduction due to intolerance in patients with Ph+ CML.Methods: Data from 2 studies were analyzed: a phase 1/2 study (NCT00261846) that included patients with chronic phase (CP) CML following resistance/intolerance to imatinib (IM; CP2L) or to IM plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after at least IM (advanced [ADV]); and a phase 3 study (NCT00574873) in CP CML patients treated with BOS or IM as first-line therapy (CP1L).Results: Of 570 CP2L/CP3L/ADV patients receiving BOS (median treatment duration 11 months [range: 0.03−96]), 257 (45%) experienced ≥1 dose reduction (236 patients to 400 mg/d and 95 to 300 mg/d). Median time to dose reduction to 400 and 300 mg/d was 54.5 (range: 4-1875) and 146 days (8-2166), respectively; median duration of dose reduction was 3.6 (0.03-87.7) and 4.2 months (0.03-60.5), respectively. In CP1L, 248 patients received BOS (median treatment duration: 55.4 months [0.03−76]), of whom 111 (45%) experienced ≥1 dose reduction (103 to 400 mg/d and 56 to 300 mg/d). Median time to dose reduction to 400 and 300 mg/d was 64.0 (2-1714) and 139 days (20-1778), respectively; median duration of dose reduction was 2.6 (0.03-66.1) and 8.9 months (0.03-71.2), respectively. Patients achieved anew or maintained a previously achieved complete cytogenetic response following BOS dose reduction to 400 mg/d (achieved: 29% [CP2L/CP3L/ADV], 40% [CP1L]; maintained: 13% [CP2L/CP3L/ADV], 26% [CP1L]) and to 300 mg/d (achieved: 14% [CP2L/CP3L/ADV], 18% [CP1L]; maintained: 24% [CP2L/CP3L/ADV], 45% [CP1L]; Table 1). Treatment-emergent adverse events (TEAEs) were generally similar in incidence, type, and severity before vs after BOS dose reduction. However, incidences of certain gastrointestinal TEAEs were lower and of similar severity following BOS dose reduction to 400 mg/d (diarrhea: 84% vs 50% [CP2L/CP3L/ADV], 70% vs 41% [CP1L]; nausea: 45% vs 23% [CP2L/CP3L/ADV], 34% vs 21% [CP1L]; vomiting: 33% vs 21% [CP2L/CP3L/ADV], 28% vs 22% [CP1L]) or to 300 mg/d (diarrhea: 85% vs 31% [CP2L/CP3L/ADV], 75% vs 38% [CP1L]; nausea: 43% vs 14% [CP2L/CP3L/ADV], 43% vs 21% [CP1L]; vomiting: 34% vs 11% [CP2L/CP3L/ADV], 34% vs 18% [CP1L]).Conclusions: CP2L/CP3L/ADV and CP1L CML patients who required BOS dose reduction due to AEs were still able to achieve or maintain cytogenetic responses and appeared to experience fewer gastrointestinal AEs. [Display omitted] DisclosuresKota:Incyte: Membership on an entity’s Board of Directors or advisory committees; Ariad Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Brümmendorf:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Lipton:Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Kim:Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. An:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Crescenzo:Pfizer Inc: Employment. Woloj:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Equity Ownership. Khoury:Pfizer Inc: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees.

Indoleamine 2,3-Dioxygenase (IDO1) Levels and Activity Are Increased in Early Chronic Phase Chronic Myelogenous Leukemia (CML-CP) and Correlate with Molecular Response to Nilotinib Therapy

Introduction:Indoleamine 2,3 dioxygenase (IDO1) is the rate-limiting enzyme during metabolism of the essential amino acid tryptophan (TRP). IDO1 is up-regulated mainly by interferons during infection and inflammation and depletes tryptophan, which results in reduced T cell activation and proliferation as well as expansion of immunosuppressive regulatory T cells. Deregulation of IDO1 activity has been implicated in cancer immune evasion, but its role in chronic phase (CP) CML remains elusive so far.Methods:A large panel of circulating pro-inflammatory cytokines and components of the IDO-pathway (soluble IDO1=sIDO1 and kynurenine/tryptophan ratio=KYN/TRP as a product of IDO1 activity) as well as plasmacytoid dendritic cells (pDC) were analyzed alongside the prospective pan-european ENEST1st clinical study (NCT01061177). This substudy included 52 nilotinib-naïve chronic phase (CP)-CML patients that were subsequently treated with 300 mg BID nilotinib and analyzed at months 6 and 12. Molecular responses were quantified in central EUTOS reference laboratories.Results: Soluble IDO (sIDO1) levels and KYN/TRP ratio are significantly up-regulated in newly diagnosed CP-CML and significantly drop during nilotinib therapy. sIDO1 levels significantly correlate with increased KYN/TRP, suggesting increased IDO1 activity at diagnosis. Increased sIDO is linked to a pro-inflammatory status in CML patients, as it positively correlates to increased serum neopterin levels as well as to various other pro-inflammatory markers, such as IFN-g, IL-8, IL-10, IL-17A, sVEGF-A, sVCAM-1 and sTNFR-1. Interestingly, albeit being an IFN-regulated gene, IDO1 activity (KYN/TRP) negatively correlated with the proportion of pDC, the main producers of IFN-a. Interestingly, a higher KYN/TRP is linked to superior molecular response, as demonstrated by a significant correlation of the KYN/TRP ratio to BCR-ABL transcript levels. Patients having a high KYN/TRP ratio (> mean +2SD of post therapy levels) reach deep molecular response rates (i.e. MR4.5) significantly earlier and at higher rates.Conclusions: CML diagnosis in CP is linked to an inceased inflammatory status, as shown by increased levels of sIDO and its metabolites kynurenine leading to an increased KYN/TRP ratio. In solid cancer increased IDO expression/activity is linked to inferior outcome by favoring immune evasion. In contrast, in CML an increased KYN/TRP ratio is associated with improved molecular outcome during nilotinib 1st-line therapy. One reason could be that IDO activity may reflect endogenous IFN-α production, a known factor favoring immune-mediated CML-control. DisclosuresSopper:Novartis: Other: Travel costs reimbursement. Mustjoki:BMS, Novartis, Pfizer: Consultancy, Honoraria, Research Funding. Gastl:Novartis: Consultancy, Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Janssen:BMS: Honoraria; Pfizer: Honoraria; ARIAD: Consultancy; Novartis: Research Funding.

A Phase I Study of Ruxolitinib Plus Nilotinib in Chronic Phase CML Patients with Molecular Evidence of Disease

Background: BCR-ABL tyrosine kinase inhibitors (TKI) are the standard treatment for CP-CML. A subset of patients have profound molecular responses with BCR-ABL transcripts no longer detectable using RT-PCR (MR4.5). The ENESTnd trial compared nilotinib versus imatinib as frontline therapy in CML, and reported an increase in the cumulative incidence of MR4.5 of approximately 11% per year for the first five years in nilotinib treated patients. Discontinuation of TKIs is successful in 40-50% of patients who have a durable MR4.5. The phosphorylation of STAT3-Y705 via the JAK-STAT signaling pathway provides a protective microenvironment for the leukemic stem cells (LSC) and is a well described mechanism of resistance to TKIs. The residual LSCs likely contribute to relapse after TKI discontinuation. Data suggests that by simultaneously blocking JAK2 and TYK2, pSTAT3 is inhibited, thereby eliminating the protective environment in the bone marrow, and sensitizing the LSCs to TKIs. Ruxolitinib is a JAK2 and TYK2 inhibitor. Here we used ruxolitinib in combination with nilotinib in CP-CML patients to establish the maximal tolerated dose (MTD) of ruxolitinib, and obtain preliminary data about the impact of this combination on BCR-ABL transcript levels.Methods: This phase I, dose-escalation study used ruxolitinib plus nilotinib in CP-CML. All subjects were taking nilotinib prior to enrollment. Eligible subjects had a complete cytogenetic response (CCyR), yet had detectable BCR-ABL transcripts by RT-PCR at enrollment. We used a 3+3 design with 3 cohorts. The nilotinib dose remained unchanged, and the three doses of ruxolitinib were 5mg BID, 10mg BID and 15mg BID. Two additional subjects were treated at the MTD. Subjects remained on combination therapy for six months, at which point ruxolitinib was discontinued. RT-PCR was used to measure BCR-ABL transcript levels in the peripheral blood and/or bone marrow at baseline and every 3 months. The primary endpoint was the MTD of ruxolitinib. Secondary endpoints included toxicity assessment, incidence of MR4.5 at six months, change in fatigue severity scores and impact of ruxolitinib on pSTAT3/5 inhibition assessed with a plasma inhibitory assay (PIA) Descriptive statistics were used for baseline demographics, toxicity, MR4.5 and pSTAT3 levels. Subjects completed the fatigue severity index (FSI) questionnaire at baseline and every 3 months. A paired samples t-test was used to measure the difference in fatigue severity over time.Results: A total of 11 patients were enrolled between April 2013 and March 2016. Median age was 41 (25-63). 73% (n=8) were male. 36% (n=4) had received one TKI prior to nilotinib. The nilotinib dose was 300mg (n=8) or 400mg BID (n=3). Median time from diagnosis to enrollment was 11 months (6-135). Each cohort enrolled 3 subjects, and two additional subjects were treated at the MTD. There were no dose limiting toxicities; therefore the MTD/RP2D of ruxolitinib was 15mg PO BID. There were no grade 3/4 adverse events in any cohort, and no clinically significant cytopenias. Grade 1/2 transaminitis occurred in 1 subject in cohorts 1 and 2. No dose reductions were needed.At data cutoff, 9 subjects have completed six months on trial, and 2 remain active. Of those nine, 3 (33%) had ≥1-log reduction in BCR-ABL transcripts from baseline and 4 (44%) achieved MR4.5. One subject in cohort 1 progressed after three months and a kinase domain mutation analysis found a T315I mutation.FSI data available on seven subjects showed a non-significant decline in average fatigue severity from baseline (mean 2.78, SD 1.79) to follow-up (mean 1.86, SD 1.21), p=0.29.Results from the plasma inhibitory assay and updated results of all 11 subjects will be presented at the meeting after all subjects will have completed the trial.Conclusion: Our data suggest that ruxolitinib is safe and tolerable at 15mg PO BID when combined with nilotinib in CP-CML, and with no grade 3/4 adverse events reported, this should be considered the RP2D for future studies. The incidence of MR4.5 after six months was 44% which surpasses that of historical controls, although the sample size is small and a larger study is needed to confirm these results. The combination leads to an improvement in fatigue severity that did not reach statistical significance. This data serves as justification for future studies using ruxolitinib in combination with TKIs to determine the true impact on eradication of MRD in CP-CML. DisclosuresSweet:Karyopharm: Honoraria, Research Funding; Pfizer: Speakers Bureau; Incyte Corporation: Research Funding; Ariad: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Nodzon:Novartis: Speakers Bureau. Pinilla-Ibarz:Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Novartis: Consultancy; Abbvie: Consultancy, Speakers Bureau.

Imatinib Generics in Treatment of Chronic Myeloid Leukemia; A Prospective Observation in Large Cohort of Patients from Polish (PALG) Imatinib Generics Registry

▪Background: Generic imatinib is already available in several countries. The use of generic imatinib is expected to lower the cost of CML therapy, however the data regarding their efficacy and tolerability in larger populations of CML patients are lacking.Aim: The aim of the study was to evaluate the efficacy and tolerability of imatinib generics in patients suffering from chronic phase CML previously untreated, and in the group of patients switched from branded imatinib to imatinib generics during a one-year of observation.Methods: We report on 726 patients prospectively observed for one year within Polish Adult Leukemia Group (PALG) Imatinib Generics Registry. In 99 previously untreated patients (group A) the rate of BCR/ABL1 reduction to < 10% at 3 months and to < 1% at 6 months of therapy, the rate of optimal response, and failure according to current ELN guidelines, the rate of CCyR,MMR,MR4, and MR4,5 achieved at 12 months of therapy, and the rate of patients switched to second generation TKI have been assessed. In 627 patients switched to generic from branded imatinib (group B) the rate of sustained, improved and worsened molecular response, the rate of CCyR, MMR, MR4, and MR4,5 loss have been evaluated. To assess the tolerability of imatinib generics in both groups the rate of hematologic (3rd or 4th grade), and of non-hematologic adverse events (all grades according to CTCAE criteria) have been recorded. The one-year, "real-life" observation started on 03.APR.2014 in CML-CP patients treated in 12 Polish Hematology Centers. The registry records approximately 900 patients, in the current report we analyzed only patients who completed 12-month observation (all patients with available RQ-PCR result at 12 month), with MMR achieved before start of therapy with imatinib generics, and treated with generics for more than 12 months (group B).Results: Ninety nine patients started de novo treatment with generics: 62 with Nibix (62.6%) , 24 with Meaxin (24.2%), other generics were used to treat 13 (13.1%) patients, and 627 patients were switched from Glivec to imatinib generics: 445 to Nibix (70.9%), 146 to Meaxin (23.3%), 31 to Teva (4.3%), and to other generics in remaining 5 patients (0.8%). Early molecular response (BCR/ABL1 < 10% at 3 months) was achieved in 65.2% , the reduction of BCR/ABL1 to < 1% at 6 months in 53.3%, and an optimal response (MMR at 12 months) in 53.3% of patients in the group A. The hematologic toxicity (grade 3 or 4 according to CTCAE criteria) occurred in 3 patients (3%) (1 neutropenia, 2 thrombocytopenia). One patient (1%) was switched to 2GTKI due to recurrent thrombocytopenia. The non - hematologic toxicity was recorded in 40 patients (40.4%) . In the group A 26 patients (26.3%) have been switched from imatinib generics to 2GTKI, 12 patients (46.2%) due to intolerance (11 due to a non-hematologic toxicity), 13 patients (50%) due to resistance, and 1 patient (3.8%) due to progression to acceleration phase. In the group B the molecular response under therapy with generics was sustained, improved and worsened in 406 (64.8%) , 119 (19%), and in 94 (15%) of patients, respectively. Complete cytogenetic response, MMR and MR4,5 was lost in 2 (0.3%), 8 (1.3%) and 65 (10.3%) patients, respectively. During a one-year observation 22 patients (3.5%) were switched to 2GTKI: 15 (2.4%) due to intolerance, 4 (0.6%) due to resistance, and 2 (0.3%) patients due to progression to acceleration phase.Conclusion: This is the first report from prospective observation on imatinib generics effectiveness and tolerability in a large cohort of CML patients. Tested generics of imatinib (Meaxin, Nibix, Imatinib Teva, Imatinib Polfa, Imakrebin, and Telux ) seem to be not inferior to branded imatinib in terms of clinical efficacy and tolerability in patients with CML CP. We did not observe an increased switching rate between imatinib generics and 2GTKI during the observation period. DisclosuresSacha:Incyte: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Gora-Tybor:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria. Szarejko:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Bober:BMS: Honoraria; Novartis: Honoraria. Grzybowska-Izydorczyk:Novartis: Honoraria; BMS: Honoraria. Niesiobędzka-Krężel:BMS: Honoraria; Novartis: Honoraria. Dudziński:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Wasilewska:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Myśliwiec:Novartis: Honoraria. Gil:BMS: Honoraria; Novartis: Honoraria. Gniot:BMS: Speakers Bureau. Mędraś:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau.

Dasatinib Exerts Differential Effects on Normal and BCR-ABL Positive Hematopoietic Cells in a Transgenic Mouse Model of Chronic Phase-CML

The second generation tyrosine kinase inhibitor dasatinib is a clinically approved drug for chronic myeloid leukemia (CML) as well as Ph+ acute lymphoblastic leukemia. Dasatinib is a dual-specific inhibitor of ABL and SRC family kinases but shows a broad inhibitory effect on various kinases, including Kit, EGFR, FAK and BTK. In addition to its antileukemic effects, dasatinib was shown to impact on the immune system, including alterations in B-cell development, T-cell differentiation, as well as a transient activation of quiescent hematopoietic stem cells (HSCs) in the bone marrow of wild-type mice. In CML patients treated with dasatinib, the development of pleural effusions and large granular lymphocyte (LGL) lymphocytosis during dasatinib treatment was associated with a favorable response. Non-hematologic adverse events included pulmonary artery hypertension and gastrointestinal symptoms.We investigated the influence of dasatinib (5 or 20 mg/kg p.o.) on the cellular composition of immune cells in our tetracycline-controlled transgenic BCR-ABL mice in comparison to control mice. We analyzed dasatinib-induced effects by flow cytometry in the bone marrow (BM) and spleen under steady-state conditions as well as after bone marrow transplantation. Furthermore, we conducted flow cytometry analysis of stem- and progenitor cells in the BM of BCR-ABL expressing mice treated with dasatinib or vehicle control and performed histophathology to evaluate effects on the BM, spleen, lung and intestine.Our results demonstrated that dasatinib dose-dependently increased Gr1/CD11b positive myeloid cells in the BM of normal mice, while B220 positive B cells and Ter119 positive erythrocytic cells were reduced. NK1.1 positive NK cells were decreased in BM but increased in the spleen. Interestingly, the lower dose (5 mg/kg) induced an increase of the percentage of CD41 positive megakaryocytic cells in BM and B cells in the spleen, while higher doses (20 mg/kg) decreased both percentages. The BCR-ABL-induced phenotype was strongly reversed by dasatinib in BCR-ABL expressing transgenic animals under steady-state conditions and in a transplantation setting: the oncogene-induced upregulation of granulocytes, megakaryocytes, and the reduction of erythroid cells as well as of B-lymphocytes was antagonized by dasatinib. Concurrently, a strong decrease of Linneg Sca1+ c-kit+ (LSK) HSCs and an increase of MEPs together with a reduction of GMPs were observed. Although the overall lymphocyte population was reduced in the BCR-ABL-expressing mice and replaced by granulocytes, we observed an increase of the proportion of CD3+, CD4+ and CD8+T cells among lymphocytes, and this increase was reverted by dasatinib treatment. Conversely, dasatinib did not significantly alter NK1.1 cells in these mice. Our observations in BCR-ABL-positive animals are in part contrary to the findings in wild-type animals, but this may be explained by the reversion of BCR-ABL effects in addition to the effects of dasatinib on normal hematopoietic cells. In addition to the above-mentioned changes, we observed a reduction of BCR-ABL mediated granulocyte infiltration of the small intestine indicating a beneficial effect in attenuating inflammation of the bowel. There was no significant alteration of the bronchial epithelium or bronchial arteries.Altogether, dasatinib robustly reduced the CML phenotype in vivo in our transgenic mouse model, and this effect included stem and progenitor populations and was stronger than the effects we have previously described for imatinib in this model. Thus, our transgenic CML mouse model is well suited to examine dasatinib effects on normal and malignant hematopoietic cells in vivo. Interestingly, there was a differential effect on myeloid cells in normal vs. CML mice, suggesting different targets in these cells. (CS and NC contributed equally to this study) DisclosuresBraunschweig:Bristol-Myers-Squibb: Honoraria; MSD Sharp & Dome: Honoraria. Brümmendorf:Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Koschmieder:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel funding to conferences, Research Funding.

Adverse effects of imatinib in children with chronic myelogenous leukemia.

Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor and is approved for indefinite treatment of pediatric chronic myelogenous leukemia (CML). Potential side-effects regarding growth failure and bone metabolism have been reported but data are still scarce in pediatric CML. Six chronic-phase CML children on IM treatment with a median age of 9.87 years (range, 5.33-12.67 years) were enrolled in the study. Growth, bone mineral density (BMD), bone parameters, 25(OH)-vitamin D3 (25-OHD3) and blood tests including parathyroid hormone, insulin-like growth factor-1 (IGF-1), IGF binding protein 3, thyroid function test and sex hormones were assessed. Median duration of IM treatment was 78.5 months. Height velocity was suppressed during the first 30 months of treatment and improved gradually afterwards. Two patients (33.3%) had decreased lumbar spine BMD z-scores (<1.5 SD). Patients with decreased BMD had higher mean IM exposure time than those with normal BMD. The majority of patients (n = 5) had low 25-OHD3 (<30 ng/mL), but there was no correlation between BMD and 25-OHD3 status. Other blood tests were normal. This study supports and confirms the need for monitoring the side-effects of IM treatment on growth, bone density and vitamin D status in pediatric CML. Prolonged IM treatment was associated with low BMD without disturbing bone parameters. There was high prevalence of vitamin D insufficiency. Therefore, the beneficial effect of vitamin D supplement should be explored with regard to the effects on height velocity and BMD in CML patients with vitamin D insufficiency.

Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia.

Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry-based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts. Results T cells of patients with CML at diagnosis expressed low l-selectin (CD62L) levels, which was not a result of proportional aberrations of T-cell subsets. Low numbers of CD62L-expressing CD4+ and CD8+ T cells correlated with higher Sokal score, increased spleen size, and high leukocyte and peripheral-blood blast counts. At month 6 during nilotinib therapy, CD62L expression returned to levels of healthy individuals. The level of CD62L loss on T cells directly correlated with the extent of soluble CD62L (sCD62L) elevation. In parallel, the proteolytic activity of tumor necrosis factor α-converting enzyme (TACE; ADAM17, CD156b), the metalloproteinase shedding CD62L, was increased at diagnosis and significantly decreased during nilotinib treatment. High CD62L+ expression on both CD4+ and CD8+ T cells and, vice versa, low sCD62L levels at CML diagnosis were linked to superior molecular responses. These findings were corroborated in independent validation cohorts. Conclusion We demonstrate the prognostic impact of CD62L shedding from T cells and increased sCD62L plasma levels at CML diagnosis on molecular response to tyrosine kinase inhibitor therapy in early chronic-phase CML. Functionally, decreased CD62L may be a consequence of increased TACE-mediated CD62L cleavage and potentially impairs immune-cell function. Larger prospective studies are ongoing to confirm the prognostic relevance of this finding.

The efficacy analysis of interferon combined with imatinib in chronic myelogenous leukemia patients with ABL kinase domain mutations

To retrospectively analyze the efficacy of interferon plus imatinib (IM) in patients with chronic-phase chronic myelogenous leukemia(CML-CP)and ABL kinase domain mutations. The mutation rates of ABL kinase region in patients with Sokal score low, medium and high risk CML-CP were statistically significant (6.25%, 9.42% and 47.06%, P<0.05). The response rates of interferon plus IM versus second-generation TKI in CML-CP with non-T315I ABL kinase domain mutations were comparable (61.11% vs 65.52%, P>0.05). When CML-CP patients with ABL kinase domain mutations were resistant to TKI or not accessible to second-generation TKI, interferon plus IM can be an alternative choice.

Acute Esophageal Necrosis Complicated by Severe Upper Gastroentestinal Bleeding in Association with Bosutinib Treatment for Chronic Myelogenous Leukemia

Acute Esophageal Necrosis (AEN), also known as “Black Esophagus”, is a rare life threatening condition with unknown cause. We present a case of AEN in a patient on tyrosine kinase inhibitor (TKI) for Chronic Myelogenous Leukemia (CML). TKIs have various gastrointestinal adverse effects though this is the first known case of an association with AEN. An 82 year-old male with hypertension, gastroesophageal reflux disease and chronic phase CML presented with hematemesis and melena followed by a syncope episode. Two weeks prior to presentation, bosutinib was started to manage his CML. On presentation, he was hemodynamically unstable with a reduction in his hemoglobin by a 13 g/dL from a known baseline. Esophagogastroduodenoscopy revealed pan-esophageal necrosis characterized by confluent black mucosa with a distinct transition point to normal mucosa at the gastroesophageal junction. As is often the cease with this condition, the exact etiology of AEN is unknown in our patient. Hypotension was commonly found amongst those with AEN. It has been hypothesized that acute circulatory compromise may contribute to the esophageal ischemic necrosis. However, it is difficult differentiate whether it is the cause, or effect from the bleeding. We propose a two-hit hypothesis whereby bosutinib, the first “hit”, predisposes the esophageal mucosa to ischemic compromise via an unknown mechanism. Thereafter, the second “hit”, acute hypotension, precipitates the esophageal necrosis. Given the recent start of the TKI, bosutinib, and the absence of other significant potential causes, it seemed reasonable to implicate the drug in this case of AEN.Gastrointestinal adverse effects are known to be more common in bosutinib compared to other TKIs. EGFR tyrosine kinase, the targets of bosutinib are found in gastrointestinal stromal tumors (GIST), esophageal cancers, and normal esophageal mucosal cells. Interestingly, in a mouse model of Candida esophagitis, EGFR has been implicated in mucosal defense. Another TKI, Crizotinib has been well associated with esophagitis, although this drug acts on the ALK kinase, in contrast to bosutinib, which inhibits the EGFR tyrosine kinase.To the best of our knowledge, this is the first reported case of AEN attributable to a TKI, specifically bosutinib.Figure 1

Co-expression Pattern Analysis of miR-17-92 Target Genes in Chronic Myelogenous Leukemia.

MicroRNAs (miRNAs) are post-transcriptional regulators that regulate gene expression by binding to the 3′ untranslated region of target mRNAs. Mature miRNAs transcribed from the miR-17-92 cluster have an oncogenic activity, which are overexpressed in chronic-phase chronic myelogenous leukemia (CML) patients compared with normal individuals. Besides, the tyrosine kinase activity of BCR-ABL oncoprotein from the Philadelphia chromosome in CML can affect this miRNA cluster. Genes with similar mRNA expression profiles are likely to be regulated by the same regulators. We hypothesize that target genes regulated by the same miRNA are co-expressed. In this study, we aim to explore the difference in the co-expression patterns of those genes potentially regulated by miR-17-92 cluster between the normal and the CML groups. We applied a statistical method for gene pair classification by identifying a disease-specific cutoff point that classified the co-expressed gene pairs into strong and weak co-expression classes. The method effectively identified the differences in the co-expression patterns from the overall structure. Functional annotation for co-expressed gene pairs showed that genes involved in the metabolism processes were more likely to be co-expressed in the normal group compared to the CML group. Our method can identify the co-expression pattern difference from the overall structure between two different distributions using the distribution-based statistical method. Functional annotation further provides the biological support. The co-expression pattern in the normal group is regarded as the inter-gene linkages, which represents the healthy pathological balance. Dysregulation of metabolism may be related to CML pathology. Our findings will provide useful information for investigating the novel CML mechanism and treatment.

Spontaneous chronic subdural hematoma development in chronic myeloid leukemia cases at remission phase under maintenance therapy, management strategy - a series with literature review

AbstractChronic subdural hematoma (CSDH) is common squeal of trauma and rarely associated with anticoagulant therapy, antiplatelet, chemotherapeutic drugs, arteriovenous malformation, aneurysms and post-craniotomy. However its occurrence is very unusual with systemic haematological malignancy and mostly reported with acute myeloid leukemia; however incidence of SDH occurrence in chronic myelogenous leukemia (CML) is very rare. CML is a haematological malignancy characterized by chromosomal alteration, pathologically represents increased proliferation of the granulocytic cell line without loss of capacity to differentiate. CML has three phases - remission phase, accelerated phase and blast crisis. About 85 % of patients present in remission phase of disease and carries a favorable prognosis. As intracranial, subdural hematoma usually occur in the accelerated phase or blast crisis phase or extremely uncommon during chronic remission phase, although only those affected, who are neglecting therapeutic medication or discontinued therapy or rarely as an adverse effect of medications. However, important role of neurosurgeon lies in early detection and correction of platelet count and associated hematological abnormality as quite sizeable proportion of cases may not need surgical intervention instead can be managed conservatively under regular supervision in association with oncologist colleague, but few cases may need urgent surgical intervention. So, selecting a subgroup of CML cases in the remission phase requiring surgical intervention, presenting with CSDH is not only challenging, as failure to make an informed and timely precise decision can lead to catastrophic worse outcome and even mortality. So, purpose of current article is to formulate the management therapeutic plan. Authors report three cases of CML in chronic remission phase, receiving treatment under guidance of Haemto-oncologist at our institute presented with spontaneous chronic SDH. The mean age was 36 years (range 29- 44 years), 66% were male, headache was presenting feature in all 100% (n=3), 66% cases were hemiplegic and 33% unconscious each, in 66% cases CSDH were located on right fronto-temporal region and 33% had small left sided thin CSDH. About were 66% cases (n=2) were managed surgically by burr hole placement and drainage drain placement while 33% case (n=1), who had thin CSDH was managed conservatively.Favorable outcome was observed in 100% cases (n=3) Outcome was favorable in all of our cases.

OPTIC-2L: a Superiority Trial of Two Lower Doses of Ponatinib Versus Standard Dose Nilotinib in Second-Line Chronic Phase CML

OPTIC-2L: a Superiority Trial of Two Lower Doses of Ponatinib Versus Standard Dose Nilotinib in Second-Line Chronic Phase CML

Abstract 2040: Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in patients with chronic myeloid leukemia

Abstract Introduction: Genetic polymorphisms in the genes coding for imatinib transporters &amp; metabolizing enzymes might be responsible for marked inter-individual pharmacokinetic variability seen with imatinib &amp; might result in altered therapeutic response. Methodology: Newly diagnosed patients with chronic phase CML started on imatinib therapy were enrolled &amp; followed up for 24 months. The following single nucleotide polymorphisms (SNPs) were genotyped - C1236T, C3435T, G2677T &amp; G2677A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method &amp; validated by direct gene sequencing. Plasma trough levels of imatinib were measured using LC-MS/MS. Patients who attained complete cytogenetic response by 12 months after imatinib therapy were called responders while those who failed to do so were called non-responders. Molecular response was assessed by quantitative RTPCR using international scale. Results: A total of 173 chronic phase CML patients were included in this study, out of which 71 were responders. Mean age at diagnosis was 35.9±14.3 years. All the alleles, except those for MDR1-C1236T, followed Hardy-Weinberg equilibrium. Marked variability in trough levels of imatinib was seen in patients with different genotypes (table1). The frequency of GG genotype for CYP3A5-A6986G and TT genotype for MDR1-C1236T, C3435T &amp; G2677T/A was higher in responders; while the frequency of AA genotype for CYP3A5-A6986G, CC genotype for MDR1-C1236T &amp; C3435T and GG genotype for MDR1-G2677T/A was higher in non-responders (table1). Conclusions: Genetic polymorphisms in MDR1 &amp; CYP3A5 genes have a significant role in determining imatinib levels &amp; therapeutic response in patients with CML. Genotyping of CPY3A5 &amp; MDR1 genes may be considered in patients with CML to individualize the therapy &amp; optimize the outcomes. Table 1:Trough levels of Imatinib in patients with different genotypes and frequency of different genotypes in imatinib responders and non-respondersSNPGenotypeTrough levels (mean±SD) of Imatinib (ng/mL)P valueImatinib responseP valueResponders (n = 71)Non-responders (n = 102)CYP3A5-A6986GAA1415.1 ± 1036.30.0164 (19%)17 (81%)&amp;lt; 0.001AG1610 ± 1161.120 (28%)51 (72%)GG2229 ± 1524.647 (58%)34 (42%)MDR1-C1236TCC1559.8 ± 990.40.2014 (21%)15 (79%)0.005CT1819.6 ± 1450.242 (37%)71 (63%)TT2178.4 ± 1246.725 (61%)16 (39%)MDR1-C3435TCC1418 ± 865.90.0133 (16%)16 (84%)&amp;lt; 0.001CT1695 ± 1318.928 (32%)60 (68%)TT2249.6 ± 1470.140 (61%)26 (39%)MDR1-G2677T/AGG1570.8 ± 1181.20.2974 (22%)14 (78%)0.019GT1726.5 ± 1489.323 (31%)51 (69%)TT2133.7 ± 1338.437 (54%)32 (46%)TA1840.5 ± 754.26 (60%)4 (40%)GA1450.2 ± 743.51 (50%)1 (50%) Citation Format: Natarajan Harivenkatesh, Lalit Kumar, Sameer Bakhshi, Atul Sharma, Madhulika Kabra, Thirumurthy Velpandian, Ajay Gogia, Shivaram Shastri, Yogendra Kumar Gupta. Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in patients with chronic myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2040.

Safety of discontinuation of tyrosine kinase inhibitor therapy for patients with chronic phase CML in durable MMR: A single institution restrospective study.

e18543Background: Imatinib revolutionized the treatment of CML demonstrating improved survival and durable response to treatment. Earlier and deeper response rates were observed with dasatinib and ...

A single institution retrospective review of characteristics and outcomes of patients requiring chronic dose reduction of TKIs given as front-line therapy for chronic phase CML.

e18544Background: Dosing of TKIs is standardized and is not altered based on BSA, sex, or other patient characteristics. Long-term data on the effects of dose-reduction of TKI therapy based on toxi...

Small, abnormal B lymphoid blast populations in chronic myelogenous leukemia at diagnosis: Does this finding indicate an accelerated course?

The 2008 WHO is not specific regarding subclassification of chronic myelogenous leukemia (CML) with less than 20% abnormal B lymphoid blasts (ABLB), and suggests patients with ABLB often show rapid progression (Swerdlow, 2008). Recent studies have shown variable outcomes when small abnormal B cell populations are seen by flow cytometry (El Rassi et al., Cancer 2015; 121:872-875; Vrotsos et al., Cytometry B Clin Cytom 2015). The hematopathology database was searched (7.4-year period), and patients identified through routine clinical study, who were BCR-ABL1 positive CML and had an ABLB of less than 20%. Flow cytometric (FC) and histologic data was evaluated to determine immunophenotypic abnormalities, immunohistochemical patterns, and percentage of ABLB, hematogones, and mature B cells. Seven patients with CML and ABLB identified by FC studies were found, five of which also had available histologic material to review. ABLB by FC ranged from 0.006% to 3.4%, typically demonstrated an immunophenotype with increased CD10, increased CD19, and decreased CD38, without myeloid antigens, abnormalities similar to that reported previously (Vrotsos et al., Cytometry B Clin Cytom 2015). The ABLB population was found only in diagnostic samples and always with more numerous hematogones. By immunohistochemistry, three of five patients showed ≥10% TdT positive cells. All patients showed a response to tyrosine kinase inhibitor therapy, and no patients progressed to clinical lymphoid blast phase. Immature B cells, occasionally including a small subset with an abnormal phenotype can be observed in chronic phase CML at diagnosis. We believe an approach incorporating clinical data, cytogenetic/molecular findings, and morphologic evaluation may be helpful when determining the best management of CML patients at diagnosis if small ABLB populations are identified by FC. © 2016 Clinical Cytometry Society.

Preleukemic phase of chronic myelogenous leukemia: morphologic and immunohistochemical characterization of 7 cases

Patients with chronic myelogenous leukemia (CML) present typically with an elevated white blood cell count (WBC) and cytogenetic or molecular genetic evidence of t(9;22)/BCR-ABL1 fusion gene. Rarely, CML patients may present with a normal or mildly elevated WBC and are asymptomatic, and we describe 7 patients in this study. The WBC in these patients ranged from 3.6 to 14.3 K/mm(3) with 50% to 73% granulocytes and 0% blasts. In all patients, t(9;22)(q34;q11.2) was detected by conventional cytogenetics, and BCR-ABL1 fusion was shown, supporting the diagnosis of preleukemic CML (pre-CML). We compared these patients with a group of 5 cases of CML in chronic phase (CML-CP) and 5 bone marrow specimens with a leukemoid reaction (n=5). Reticulin, CD34, and CD61 immunostains were performed on all bone marrow biopsy specimens. Peripheral blood absolute basophilia (≥200/mm(3)) was noted in only 4 of 7 pre-CML cases, whereas it was present in all CML-CP cases and absent in leukemoid reaction cases. The mean ±SD of microvascular density of pre-CML cases (10.0 ± 4.3 vessels/200× field) was twice that of leukemoid reaction cases (5.0 ± 1.0) (P=.02; Student t test) but similar to that of CML-CP cases (12.5 ± 3.6). Microvessels in pre-CML, highlighted by CD34, were tortuous with abnormal branching, although to a lesser extent than those found in CML-CP. Microvessels in leukemoid reaction were generally straight. The percentage of small, hypolobated megakaryocytes, highlighted by CD61 in pre-CML, was 40%, 3 times that found in leukemoid reaction cases (13%) but less than that of CML-CP cases (86%). We conclude that pre-CML should be suspected in patients with a normal to mildly elevated WBC and absolute basophilia. Bone marrow examination can usually distinguish pre-CML from a leukemoid reaction based on the percentage of small, hypolobated megakaryocytes; microvascular density; and morphologic features.

Update on the management of Philadelphia chromosome positive chronic myelogenous leukemia: role of nilotinib.

Chronic myelogenous leukemia (CML) is a pluripotent stem cell disease characterized by the presence of the Philadelphia chromosome and the bcr-abl gene. The discovery of tyrosine kinase inhibitors (TKIs) revolutionized therapy for CML, such that durable response, increased overall survival, and increased progression-free survival of patients in chronic phase CML is now possible. Due to resistance and intolerance to imatinib, there was need for development of second- and third-generation TKIs for the treatment of CML. This review examines the role of nilotinib, an oral second-generation TKI, in the treatment of Philadelphia positive CML. The pharmacology, efficacy, and safety of nilotinib are critically evaluated. Patient-related issues, including tolerance, drug interactions, and quality of life issues are also examined.

Treatment of chronic myelogenous leukemia.

Treatment options for chronic-phase chronic myelogenous leukemia (CML) based on medication-resistant mutations in BCR-ABL are reviewed. Imatinib, nilotinib, and dasatinib are first-line therapies for chronic-phase CML. Nilotinib or dasatinib can be used as first- or second-line treatment, with nilotinib preferred in patients with BCR-ABL F317 and V229 mutations and dasatinib in patients with Y253H, E255, and F359 mutations. All three medications are associated with neutropenia, thrombocytopenia, and anemia; the reported rates varied but ranged from 38% to 90% in Phase III studies. Although less data are available for bosutinib, the drug can be used as second-line therapy and is effective against F317L, Y253H, and F359 mutations. Mutations at position T315I are generally resistant to all of these tyrosine kinase inhibitors (TKIs) but may respond to ponatinib or omacetaxine. The choice of third-line therapy can be driven by mutational analysis or patient-specific characteristics. While ponatinib and omacetaxine have activity in patients with T351I mutations, they have not been directly compared. Differences in patient characteristics and adverse-effect profiles may also aid in the selection of appropriate therapy. Several TKIs are effective in the treatment of chronic-phase CML. Imatinib, nilotinib, or dasatinib may be used as first-line therapy, while second- and third-line treatments are determined based on previous failed therapy as well as BCR-ABL mutation status.

Isolated CNS Blast Crisis of CML in A Patient on Dasatinib Therapy

We report a case of a young male with chronic phase CML who despite achieving an excellent response to dasatinib therapy, developed isolated CNS blast crisis even though this tyrosine kinase inhibitor is the only one reported to cross the blood brain barrier.