Chronic Phase CML Research Articles

Response to Ponatinib Is Not Related to the Drug Plasma Levels in Chronic Phase CML

BackgroundPonatinib is currently licensed for the treatment of patients resistant or intolerant to at least 2 tyrosine kinase inhibitors (TKI) or in patients harboring a T315I ABL mutation, in chronic, accelerated and blast phase chronic myelogenous leukemia (CML) or Ph+ ALL. Surprisingly, very little is known in terms of pharmacokinetics of this drug in CML patients and their impact on outcomes.AimsWe evaluated the impact of Ponatinib plasma concentrations determinations in chronic phase CML (CP CML) patients during treatment, and outcomes.MethodsWe enrolled after informed consent patients in CP CML in 3 cooperative centers, receiving Ponatinib at any dose and measured the plasma concentration of this compound at any time during treatment by UPLC with mass tandem detection. Data were expressed as µg/L and 24H concentrations (C24h, expressed in mg/kg/d). The C24h were estimated according to the average half-life calculated for the entire cohort. After informed consent, basic clinical data, hematologic, cytogenetic and molecular results were captured retrospectively as well as outcome. qRT-PCR results were expressed as BCR-ABL ratios in %, standardised according to the international scale, with at least 32,000 copies of ABL as control.ResultsThirty-seven CP CML patients have been involved in this study, and 50 blood samples were studied. There were 20 males and 17 females of a median age at diagnosis of 44.6 (7.6-82.5) and of 55.7 (25-86) years at ponatinib plasma measurement. Sokal score was low for 18%, intermediate for 12% and high for 70% of patients (9 patients unknown). One patient had a variant Ph, one a cryptic Ph and all the others a classical form of the Ph chromosome. All patients had a “major” BCR transcript except 1 (e19a2).The median BCR-ABL at diagnosis was 66.5 (33-110) % (IS). The median follow-up since diagnosis was 8.65 (2.5-16.7) years, 8.57 (2.48-16.7) years since first TKI initiation, and 4.32 (0.77-6.1) years since Ponatinib initiation. Two patients received Ponatinib as first-line (EPIC trial). Three patients received Ponatinib as second line, 12 as third line and 20 as fourth line therapy, all for resistance to previous lines of TKI. Fourteen patients (38%) were ABL mutated (10 T315I, 1 V379I, 1 Q252H, 1 L298V, 1 E255K). The median dose at Ponatinib initiation was 45 (30-45) mg daily and at Ponatinib plasma measurement at 30 (5-45) mg daily which represented a median C24h of 0.41 (0.05-0.94) mg/kg/day. The blood test was performed after a median of 12.25 (0.5-92.5) hours after last oral dose. Median plasma concentrations of Ponatinib were 30.75 (0-89.1) mg/l. When considering a target therapeutic concentration of 20 mg/l (= 40 nM, Cortes J. et al. NEJM 2013), 39 patients were above this level and 11 below. At plasma determination, 9 patients were in CHR, 1 in minimal CyR, 1 in minor CyR, 7 in partial CyR, 14 were in CCyR, 13 in MMR, 3 in MR4, and 2 in MR5. The median BCR-ABL at that time was 0.15 (0-47.9)% (IS). There was no significant correlation between the response observed and the plasma concentrations measured in patients and their molecular response (Figure 1.), Spearman correlation test: r= 0.134, p=0.34.There was no correlation neither with the onset of vascular events but the blood sampling was not necessarily performed when these events occurred (n=8). However and indeed, this population might be highly selected, as the majority of the patients without severe side effects and responding to treatment are maintained on Ponatinib. At latest follow-up, 4 patients died in this heavily pre-treated population of patients, 2 from post-allogeneic infectious complications, 1 form a stroke, 1 from a metastatic spinocellular carcinoma.ConclusionThe determination of TKI plasma levels is surely useful in screening patients for uncompliance (here one patient), however their relationship to the efficacy or toxicity of such a compound remains to be further assessed in a more homogeneous and larger population of patients. [Display omitted] DisclosuresNicolini:Incyte Biosciences: Honoraria, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Rea:Pfizer: Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Honoraria.

Impact of Body Mass Index on Outcome in Patients with Chronic Myeloid Leukemia in Chronic Phase Treated with Imatinib in First-Line

BackgroundImatinib mesylate (IM) 400 mg daily still represents the gold standard for chronic phase chronic myelogenous leukemia (CP-CML). Currently, the initiation dose of IM is adapted to the body weight only in childhood. There are some concerns regarding the adaptation of IM prescription in overweighted patients that may respond poorly to this tyrosine kinase inhibitor (TKI). However, this has not been extensively studied in the first-line setting. In addition, it is known that IM is able to promote weight gain and further, obesity has been identified as a possible risk factor in several solid cancers and leukemias.AimsIn a retrospective observational monocentric study, we evaluated the impact of the weight and the body mass index (BMI) measured at diagnosis on CP CML patients outcomes, on IM first-line, in terms of survival, responses and kinetics.MethodsWe retrospectively enrolled in this study, newly diagnosed CP CML patients, treated with IM in first-line between 2000 and 2017. Overall survival (OS), progression-free survival (PFS), failure-free survival (FFS, defined as progression to advanced phases death, loss of CHR, CCyR, or MMR, discontinuation of IM for toxicity, primary cytogenetic resistance) were analysed since IM initiation in intention-to-treat. Responses (hematologic, cytogenetic, molecular) were analysed according to standard methods. Molecular results were standardised according to the ELN/Eutos programs since 2003, and were expressed as BCR-ABL (IS) in %. Clinical data were extracted from medical files, weight and height measured for all patients at diagnosis, and later nearly all patients being weighted at each time point. The BMI was categorized into 4 stages according to the OMS classification: underweight (BMI < 18.5), normal weight (18.5 ≤ BMI ≤ 24.9), overweight (25 ≤ BMI ≤ 29.9), and obesity (BMI ≥ 30). Serum Albumin (g/l) was regularly assessed, and the nutritional risk index (NRI) was also calculated.ResultsWe enrolled 107 patients in this study, 62 (58%) males, with a median age at diagnosis of 55.36 (17-83) years. Sokal risk and Hasford scores were low for 32% and 39%, Intermediate for 48% and 52%, and high for 20% and 9% respectively, (2 patients unknown). Eutos score was low for 95% of patients. The median BMI at diagnosis was 24.61 (17-44.3) Kg/m2. The median weight at diagnosis was 69 (48-128) Kg. We analysed the patients in 2 groups: A: low + normal BMI (<24.9) and B: overweighted + obese (>25). The median follow-up was 97.3 (3-17) months. Age at diagnosis, Sex ratio, duration on IM, Sokal, Euro, Eutos risk scores, presence of ACA at diagnosis, menopauses women, IM duration were not different between groups A & B. There was significantly more diabetic patients in group B (3 vs 11, p=0.018). The rates of CCyR at 6 months, MMR at 12 months were not different between the 2 groups (38% in group A vs 48.9% in group B, p=0.388; and 48.94% in group A vs 66.67% in group B, p=0.133). The rate of MR4 (56 [44.09-71.91]% group A vs 67.7 [52.60-80.74]% group B, p=0.817), MR4.5 (48 [33.95-62.05]% group A vs 48.9 [34.05-63.73]% group B, p=0.97) at 5 years were not significantly different.Five patients died, all in group B, from a lymphoid blast crisis in 1 patient, secondary tumours in 3 (lung, colon, prostate cancer + cholangiocarcinoma) and terminal renal insufficiency in 1. The OS rate at last follow-up was significantly better in low/normal BMI 100% months (A) versus 84.7 [71.5-100] % months (B, p=0.022) (Fig 1A), as well as the PFS 100% months versus 86.5 [75.-99.7] % months (p=0.027) (Fig 1B).The FFS rate was not different (p=0.794). Interestingly, 25 (23.4%) patients fulfilling the STIM criteria for Treatment-Free Remission, were 17 in arm A and 8 in arm B. Of note, the BMI regularly increases over time with an increase of 0.045 [0.006-0.084] Kg/m2 per month, and patients may become overweighted over time (42% at diagnosis, 45.8% at latest follow-up).ConclusionThis retrospective analysis on an homogeneous population demonstrates that being overweighted at diagnosis of CP CML, and undergoing IM treatment first-line, selectively impacts on survival. However, the rates of responses do not seem to be altered, and the majority of such patients died from CML unrelated causes, mostly from other cancers. The mechanisms responsible for that are probably complex, multifactorial, and confounding factors may interfere, and finally remain to be deciphered. [Display omitted] DisclosuresLabussiere-Wallet:Novartis: Speakers Bureau. Nicolini:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau.

Molecular Responses and Outcomes of Pediatric CML Treated with Front-Line Imatinib and a Comparison between Pediatric and Adult Cohorts

Background and PurposeChronic myeloid leukemia (CML) is a rare disease in children and constitutes 2% to 3% of pediatric leukemia. Imatinib, a potent tyrosine kinase inhibitor (TKI), is well established as a standard treatment for newly diagnosed adults with CML in chronic phase. Many pediatric oncologists have followed the treatment guidelines that originally designed for adult patients. There have been rare studies reporting the molecular responses to imatinib in children with CML. The aim of this multi-center study in Taiwan was to assess the treatment responses and outcomes of front-line imatinib therapy in pediatric CML. A comparison between pediatric and adult CML patients was also performed.Patients and MethodsBetween 2002 and 2017, there were 53 newly diagnosed children, age < 18 years old, with CML in chronic phase receiving front-line imatinib therapy with a daily dosage of 300 mg to 400 mg. b3a2, b2a2, b3a2+b2a2, and b3a3 BCR-ABL1 transcripts were detected in 32, 19, 1 and 1 patient(s) respectively. Fifty-two patients with b3a2 and or b2a2 were enrolled in this study. Peripheral blood BCR-ABL1 levels expressed as International Scale (IS) were measured by TaqMan RQ-PCR assay with the lab-specific conversion factor every 3 months in a central laboratory. The criteria of the European LeukemiaNet regarding optimal response were adopted: major cytogenetic response (MCyR, IS < 10%) at 3 months, complete cytogenetic response (CCyR, IS < 1%) at 6 months and major molecular response (MMR, IS < 0.1%) at 12 months (Blood 2013). Molecular response of a patient was censored if the patient received hematopoietic stem cell transplantation (HSCT), switched to 2nd-generation TKI, or died. An adult cohort of 685 patients who had molecular measurements in the same central laboratory, presented partly in ASH 2014 (Blood 2014. 124: 4544a), was updated for the comparison analysis.ResultsOf the 52 pediatric CML patients, 31 were males, the median age at diagnosis of 14.2 years (range, 1.4-17.9). The WBC count ranged from 24.5 to 806.5×109/L (median, 294.4). High Sokal risk group was only observed in 4% and 14.6% for score adopted for younger than 45 years old, respectively. Eight patients went on to receive HSCT, and 20 patients were shifted to 2nd-generation TKIs (14 dasatinib, 6 nilotinib), including 3 achieved optimal responses because of imatinib intolerance. Compared with the adult cohort, there was no statistical difference in the frequency of transcript subtypes. Pediatric patients classified as Sokal high-risk group were significantly lower than those in adult cohort (P < 0.0001).The molecular responses and outcomes of the pediatric cohort are summarized in Table 1. The median followed-up duration was 74.6 months (range, 3.0-182.1). Optimal responses at 3 months, 6 months and 12 months following imatinib therapy were achieved in 52.0%, 39.1% and 21.7%, respectively. MMR and MR4.5 (IS ≤ 0.0032%) were achieved in 48% and 15% of pediatric patients, respectively. The cumulative incidences (% ± SE) of CCyR by 12 months, MMR by 18 months and MMR by 24 months were 42.6 ± 7.1, 26.5 ± 6.3 and 35.2 ± 6.9, respectively. The cumulative incidence of MMR in pediatric patients was inferior to that in adult cohort (P < 0.0001) (Figure 1). Progression to accelerated phase and blast crisis occurred in 2 patients each. The 10-year progression-free survival (PFS) and overall survival (OS) (% ± SE) were not significantly different between pediatric and adult cohorts (90.4 ± 4.7 vs. 93.0 ± 1.3, P= 0.533; 90.6 ± 4.7 vs. 94.3 ± 1.6, P= 0.176).The IS levels at 3 months among three different Sokal risk groups did not differ in pediatric CML. Patients achieving MMR in Sokal low-risk group of pediatric cohort were significantly lower than those of adult patients (P= 0.002) whereas the PFS and OS by Sokal risk group in pediatric and adult CML patients did not show statistical difference.ConclusionsThe molecular responses in pediatric CML patients receiving front-line imatinib therapy were inferior to those of adult cohort, but the PFS and OS did not differ between the two cohorts. The Sokal scores did not predict outcome in pediatric CML. [Display omitted] DisclosuresShih:Novartis (Taiwan) Co., Ltd.: Research Funding.

Role of Signal Transducing Adaptor Protein (STAP) Family in Chronic Myelogenous Leukemia

Role of Signal Transducing Adaptor Protein (STAP) Family in Chronic Myelogenous Leukemia

Dasatinib-Induced Lymphocyte Elevation and Imbalance of T Cell Receptor V Beta Gene Expression in Chronic Phase Chronic Myelogenous Leukemia Patients

Introduction: Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasms caused by a reciprocal translocation of chromosomes 9 and 22 [t(9;22)], producing the BCR-ABL fusion gene. Imatinib (Ima), the 1st generation tyrosine kinase inhibitor (TKI), has drastically improved the prognosis of CML compared to previous therapies. Imatinib and the 2nd-generation TKIs dasatinib (Dasa) and nilotinib (Nilo) are generally used for chronic phase CML (CP-CML) as induction chemotherapy. Lymphocyte proliferation and increased large granular lymphocytes (LGLs) are sometimes observed in patients treated with Dasa. These LGLs have been reported to be mainly natural killer (NK) cells. However, there is insufficient data about T-lymphocytes, including CD8 T cells, in CML patients treated with TKIs. We analyzed lymphocyte counts and percentages in CP-CML patients treated with Dasa and other TKIs. We also examined T cell receptor (TCR) V beta gene repertoire in some patients.Methods: The patients in this study were CP-CML patients diagnosed at our hospital from August 2006 to June 2016 and treated with TKIs. The main aims were to examine (1) lymphocyte rates and (2) cytotoxic T lymphocytes (CTLs) and TCR V beta gene repertoire. These analyses were conducted using flow cytometry. All statistical analyses were performed using GraphPad Prism 6 software.Results: Table 1 summarizes data comparing patients treated with Dasa and those treated with other TKIs. Six patients were treated with Dasa only. Seven and 2 patients, respectively, were treated with Ima or Nilo only. Eleven patients were treated with multiple TKIs including Dasa, and 2 patients were treated with multiple TKIs not including Dasa. The median age at first TKI administration was 60 years in patients treated with Dasa and 72 years in patients treated with other TKIs. No significant statistical difference was observed in age at first TKI administration. The median follow-up period of patients treated with TKIs without Dasa was significantly longer than that of patients treated with TKIs including Dasa. This was due to the difference in the timing of approval of Ima (1st generation TKI) and Dasa (2nd generation TKI). There was no significant difference in the best response between the Dasa and non-Dasa groups. There was also no significant difference in overall survival between the 2 groups (Log-rank, P = 0.7283). Pleural effusion was observed in 5 patients in the Dasa group and 1 in the non-Dasa group, without statistical significance. Figure 1 shows lymphocyte elevation in the Dasa group compared to the non-Dasa group with regard to both lymphocyte counts and percentages. Figure 2 shows the time courses of lymphocyte percentages. Counts from 1, 3, 6 and 12 months from the initiation of Dasa (A) and non-Dasa TKIs (B) are indicated. The lymphocyte rates in the non-Dasa group showed no significant change (Figure 2B). However, gradual lymphocyte elevation was clearly seen with the passage of time in Dasa group patients, with statistical significance (Figure 2A). The time courses of lymphocyte counts in 2 cases are shown in Figure 3. Lymphocyte elevations were clearly observed after changing to Dasa from Nilo (Figure 3A) and Ima (Figure 3B). We also analyzed the detailed lymphocyte fraction in some patients. Representative data of a patient treated with Dasa only are shown in Table 2 and Figure 4. NK cells were found in the peripheral blood, as have been seen in previous reports, and, interestingly, CTLs were also detected at all time points (Table 2). It is notable that about 20% of the peripheral blood consisted of CTLs 35 months after the first administration, which was the same percentage as that of NK cells. TCR V beta gene repertoire in the same patient is shown in Figure 4. Oligoclonal CD8 T cell expansion was observed using V beta 13.1, V beta 7.1, and V beta 2 expression. These results suggest that not only NK cells but also CTLs may play an important role in attacking CML blasts in patients treated with Dasa.Conclusions: In CP-CML patients treated with TKIs, lymphocyte elevation was obviously observed only in patients treated with Dasa. CTL analyses and TCR V beta gene analyses suggest that CTLs can be induced along with NK cells in patients treated with Dasa. These results show that Dasa can work in a different way than other TKIs. Clarifying the tumor antigens recognized by these CTLs may bring new insights and connect to new cellular therapies for refractory CML cases. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Interim Results of the Canadian Tyrosine Kinase Inhibitor Discontinuation Trial for 2nd Attempt of Treatment Free Remission: Treatment Free Remission Accomplished By Dasatinib (TRAD)

Interim Results of the Canadian Tyrosine Kinase Inhibitor Discontinuation Trial for 2nd Attempt of Treatment Free Remission: Treatment Free Remission Accomplished By Dasatinib (TRAD)

Pilot Study of Imatinib Discontinuation in Patients with Chronic Myeloid Leukemia with Deep Molecular Response (EDI-PIO) — Evaluation of Pioglitazone in Treatment-Free Remission

Introduction: Successful TKI discontinuation is feasible in approximately 40-60% of CML patients with stable and deep molecular response, but the persistence of quiescent CML stem cells (LSC) may be responsible for relapse. Pioglitazone, a PPARgamma agonist may reduce STAT5 activity and cause an erosion of CML LSC.Objectives: to evaluate safety and efficacy of pioglitazone in treatment-free remission (TFR) after imatinib discontinuation in patients with CML treated with pioglitazone for 3 months before imatinib discontinuation.Patients and methods: prospective, phase II trial. Inclusion criteria: CML in chronic phase, treated with imatinib for at least 3 years, with CCyR and stable deep molecular response (MR4.5) for at least 2 years. Patients received pioglitazone 30 mg/day, orally, for 3 months before imatinib discontinuation. BCR-ABL levels were measured by real-time quantitative PCR monthly for 12 months, every two months for 12 months, and then every 3 months during the subsequent follow-up. Imatinib was reinitiated at molecular relapse, defined as any single sample with a value of >0.1% (loss of major molecular response - MMR) or two consecutive positive samples with a value >0.01% (loss of MR4.0). Treatment-free remission (TFR) was calculated from imatinib discontinuation until molecular relapse, resumption of imatinib by any cause, progression to advanced phases or death to any cause.Results: Recruitment is ongoing. Between June 2016 and July 2017, 21 chronic phase CML patients were included. Median age was 48 years (23-65) at CML diagnosis and 56 years (29-76) at trial initiation; 52.4% male; Sokal: 62.5% low risk, 25% intermediate, 12.5% high risk; 14% treated previously with IFN. Two patients had diabetes and were using hypoglycemic drugs. The median time between diagnosis and imatinib start was 2 months (1-39); the median duration of imatinib treatment was 8.2 years (4-12). Nineteen patients received pioglitazone for 3 months and discontinued imatinib and two are still using both. There were no grade 2 or 3 adverse events related to pioglitazone; one patient did not complete the first month of pioglitazone treatment due to worsening of edema and went to discontinuation phase. The median follow-up of the 20 patients that discontinued imatinib was seven months (0-11). One patient dropped out of the trial and was censured in the analysis. Seven/18 patients (38%) presented newly or worsening musculoskeletal pain or arthralgia grades 1-2 occurring within 1-6 months after imatinib discontinuation. The two diabetic patients presented increase in glucose levels (grade 2 and 3), seven and eight months after imatinib discontinuation. There was no loss of hematological response or transformation to advanced phases. However, 4/18 (22%) patients (all male) reinitiated imatinib after molecular relapse: 1 lost MMR and CCyR response; 2 lost MMR, one had confirmed loss of MR4. Two of them recovered RM4.0 in 2 and 3 months after imatinib reintroduction. TFR was 74% (95% CI: 52-96%) in 9 months. TFR was higher in female patients (100% vs. 45%, P=0.019).Conclusion: Pioglitazone was well tolerated in the majority of the patients. The rate of withdraw syndrome was similar to the reported in other discontinuation trials. Increase in glucose levels was observed in two patients with diabetes after imatinib discontinuation. TFR was higher in female patients. A longer follow-up is necessary to evaluate the duration of TFR.This trial is registered in ClinicalTrials.gov (NCT02852486) DisclosuresPagnano:Bristol-Meirs Squibb: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy.

Clinical and Molecular Characterization of Clonal Chromosomal Abnormalities Appearing in Philadelphia-Negative Metaphases of Chronic Phase CML

▪BackgroundClonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph-) emerge as patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) are treated with tyrosine kinase inhibitors (TKI). The clinical significance of CCA/Ph- remains unclear specifically among pts treated with second generation TKI. Very little is known about the molecular abnormalities associated with them.MethodsWe conducted a retrospective analysis of pts enrolled on prospective, single-institution frontline trials for CML-CP. Of the 598 pts enrolled, 279 pts (46%) were treated with imatinib, 126 (21%) with nilotinib, 143 (23%) with dasatinib and 50 (8%) with ponatinib. CCA/Ph- were defined as abnormalities present in ≥2/20 Philadelphia-negative (Ph-) metaphases or if present in one metaphase in ≥2 cytogenetic assessments. The clinical outcomes of pts with CCA/Ph- were compared to a control group without additional chromosomal abnormalities (ACAs). We performed targeted deep sequencing (median depth 490x) on a pilot study from 10 pts with various CCA/Ph- (panel of 295 genes recurrently mutated in hematological malignancies). Single nucleotide variants (SNV) and small insertions and deletions (indels) were called against virtual normal sequence developed in-house. An automatic pipeline was used to filter and annotate raw variants, and then select non-polymorphism, protein-coding changing mutation, thus identifying high confidence driver mutations.ResultsCCA/Ph- occurred in 58 pts (10%) and the most common were - Y in 25 (43%) and trisomy 8 in 7 pts (12%). Most CCA/Ph- appeared within the first year of the start of the TKI (median 6 months, range 3-78 months). CCA/Ph- were transient and were detected in 2 or less time points in 36/58 cases (62%). The median number of Ph-negative metaphases containing CCA/Ph- per analysis was 5/20 (range 1-20). We further categorized CCA/Ph- into those where - Y was the only clonal abnormality, and all others. Pts who developed CCA/Ph- were significantly older than those without ACAs (median age 59 vs 47; P<0.001). Specifically, pts with -Y CCA/Ph- were the oldest (median age 64; P<0.001), followed by those with non-Y CCA/Ph- (median age 52; P=0.003) when compared to those without ACAs (median age 47). Four pts with ACAs in Ph+ metaphases who subsequently developed CCA/Ph- were excluded from response and survival analyses. Response to TKI therapy was similar for pts with CCA/Ph- and those without ACAs. With a median follow-up for survivors of 7.6 years (range 0.2-14.7 years), we found that pts with non -Y CCA/Ph- had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS) and overall survival (OS) compared to those without ACAs with the following 5-year rates: FFS (52% vs 70%, P = 0.02), EFS (68% vs 86%, P = 0.02), TFS (76% vs 94%, P < 0.01) and OS (79% vs 94%, P = 0.03). In a multivariate analysis, non -Y CCA/Ph- increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio (HR) of 2.81 (95% CI 1.15-6.89, P = 0.02). However, this prognostic impact was not statistically significant when achieving BCR-ABL < 10% at 3 months was included in the analysis (Table 1).A total of 46 high-confidence driver mutations in 18 genes in 10/10 (100%) pts with CCA/Ph- were identified (Figure 1). Median number of driver mutations was 2.5 (range 1-9). ASXL1 frameshift mutation was detected in all examined pts (10/10 pts) mostly at low variant allelic frequency (VAF) with a median VAF of 1.6% (range 0.7% - 4.2%). Mutations were also commonly detected in PTPN11 (7/10 pts). Mutations in PTPN11 have been reported in about 4% of pts with acute myeloid leukemia (Papaemmanuil et al. NEJM 2016). Mutations in DNMT3A (R635Q) and ABL (Y253H, associated with resistance to imatinib) were observed in the same case in addition to ASXL1. In this cohort, the observed mutation rate is higher than what is expected in CP-CML when comparing to published literature (Kim et al. Blood 2017). Sequencing of a control cohort from pts with deep molecular response without ACAs is ongoing.ConclusionIn conclusion, non -Y CCA/Ph- are associated with decreased survival when emerging in pts with chronic phase CML across various TKIs. Preliminary results from deep sequencing indicate a higher than expected rate of mutations in CP-CML pts with CCA/Ph- compared to those without ACAs, mostly detected at low VAF. [Display omitted] DisclosuresKantarjian:Pfizer: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Amgen: Research Funding; Delta-Fly Pharma: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; BMS: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Teva: Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Observational Study of CML Italian Patients Who Discontinued TKIs

Abstract Background: Different studies analysed the outcome of patients (pts) who discontinued tyrosine kinase inhibitors (TKIs) reporting a median treatment-free remission (TFR) rate of 55%. On these bases it is judged safe to discontinue treatment in experimental contexts. Aims: Aim of our study was to evaluate TFR in the setting of Italian pts . Material and Methods: We designed a retrospective observational study of Italian pts with chronic phase CML who discontinued TKI treatment in deep molecular response (DMR). All Hematological Centers who are part of the GIMEMA group were invited to participate to this retrospective study and 32 centers had cases and participated to the study. Results: We collected a total of 293 pts. Median age was 59 years; 59%, 30% and 11% of pts were low, intermediate and high Sokal score respectively. 72% of pts were on treatment with imatinib, 28.% with either nilotinib (n=58), dasatinib (n=23) or bosutinib (n=1) at the time of discontinuation. 55% of pts discontinued in first line, 40% in second line, 5% in third line. Median duration of treatment with the last TKI was 77 months (mos, IQR 54;111) median time to deep molecular response (DMR, i.e. undetectable transcript or MR4/MR4.5/MR5) with the last TKI was 46 mos (IQR 30;73), median duration of DMR was 46 mos (IQR 31;74) before stop. Duration of treatment with TKIs and duration of DMR were shorter with 2nd gen TKIs than with imatinib (p Conclusion: Although our study has the limitation of a retrospective study, our experience within the Italian population confirms that discontinuation of imatinib and 2nd gen TKIs is feasible and safe in the clinical practice. Disclosures Fava: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rege-Carmbrin: BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Rosti: Pfizer: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Castagnetti: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gugliotta: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Abruzzese: Bristol Myers Squibb: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy. Orlandi: Incyte: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Pregno: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Crugnola: Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Bocchia: Celgene: Other: Travel grant; Novartis: Other: Travel grant; Roche: Other: Travel grant; Jansen: Other: Travel grant. Galimberti: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau. Iurlo: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia: TEVA: Speakers Bureau. Cavazzini: Novartis: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Bristol-Meyers Squibb: Consultancy. Giai: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Musto: BMS: Honoraria; Celgene: Honoraria; Novartis: Honoraria; janssen: Honoraria. Specchia: BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Pane: Novartis: Honoraria, Speakers Bureau. Baccarani: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Saglio: Roche: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

Pattern of Mutational Changes in Patients with Chronic Phase CML Who Are Treated with Frontline TKI and Transform to Blast Phase CML

Introduction: CML patients (pts) who transform to blast phase (CML-BP) or accelerated phase (AP) from a chronic phase (CML-CP) have a poor prognosis and exhibit a poor response to therapy with TKI. Increased usage of newer TKI's has remarkably reduced the incidence of CML-BP, however, the genetic mechanisms involved in the transformation remain unclear. In this study, using paired whole-exome sequencing, we compared the pattern of gene mutations and chromosomal allelic imbalances (CAI) between CML-CP and CML-BP in patients who received front-line TKI therapy.Methods: We analysed 13 CML patients who received front-line TKI therapy in CML-CP and eventually transformed to CML-BP. In 7 of 13 patients, sufficient DNA was available for sequencing both at the time of CP and AP/BP while in the remaining 6 patients, DNA was only available at 1 time point, either BP (n=4) or CP (n=2). Whole exome sequencing (WES) was performed using Agilent exome capture kit on Illumina HiSeq. For exome mutation analysis, read alignment was done using BWA and GATK, and variants were called using GATK's UnifiedGenotyper. CAI profiles were generated using hapLOHseq. For CAI, chromosomal arm events were called if they spanned at least 20% of the genomic region of a chromosomal arm. Somatic status was assigned to variants after filtering for potential germline variants using variants identified in the ExAC project. For assessing biological processes driving each cancer's mutation profile, mutation signatures were deconvoluted using the R package deconstructSigs into a set of previously identified, weighted set of COSMIC mutation signatures. For reporting of specific mutations, only somatic variants reported in the COSMIC database were selected.Results: The median age of the study group at the time of BP was 54 years (range, 24 to 73); 53% were male. Seven pts had e13a2 and 6 had e14a2 BCR-ABL transcripts. Eleven pts (85%) were treated with imatinib and 2 pts received nilotinib as their initial therapy. The median time to transformation to BP was 19 months (range, 3.5-63). The immunophenotype of blasts was myeloid in 9 (69%), lymphoid in 3 (23%) and mixed lineage in 1 pts (8%). The cytogenetic abnormalities detected by conventional karyotyping at the time of BP included: classic Ph alone in 5 pts, 2 pts each with variant Ph, double Ph and isochromosome 17q and one pt each had inversion 3 and another with cryptic Ph. The median OS was 16 months; 9 pts had died at the time of last follow up. Both CML-CP and CML-BP samples exhibited deficiencies in DNA-mismatch repair and DNA double-strand break repair through mutation signature analyses. The median number of mutations at the time of BP was 374. The most frequently mutated genes detected exclusively during BP included ABL1 and RUNX1 . ABL1 mutation was significantly associated with CML-BP (5/10; p=0.012). Similarly suggests that RUNX1 mutation may be associated with CML-BP (4/10) although not at statistical significance (p=0.14; odds ratio of CML-BP = 6 (95% CI: 0.46 - 359). CAI profiles show that BP samples have increased genomic instability. CAI was frequent at the time of BP. CAI was significantly associated with BP (8/10; p = 0.0019; odds ratio of BP = 30 (95% CI: 2.3 - 1911). Chromosomes 7 and 8 were the most frequently altered chromosomes (each altered in 3/10 BP samples) while 0/3 (0%) AP and 1/8 (12.5%) CP samples had CAI. Gene mutation results are shown in Figure 1.Conclusions: Bypaired exome sequencing of CML patients who received frontline TKI therapy, our analyses suggest that CML-BP is associated with (1) acquisition of additional gene mutations during BP, frequently in ABL1 and RUNX1 and (2) increased chromosomal instability. Defects in DNA mismatch repair and double-strand break repair were identified in all CML phases. This may suggest that these deficient repair processes, evident in the CP phase, are early contributors to the transition to CML-BP. This hypothesis is supported by the increased chromosomal instability observed in the BP samples that may result from these cellular defects. As such, identification of these repair deficiencies may have an early predictive potential in detecting CML patients who can potentially transform to blast phase. We are performing additional studies using targeted NGS and WES in samples that did not undergo BP transformation to substantiate these hypotheses. Further studies are needed to explore the modalities to target these alterations in CML. [Display omitted] DisclosuresKantarjian:Delta-Fly Pharma: Research Funding; Novartis: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding.

Inotuzumab Ozogamicin in Combination with Bosutinib for Patients with Relapsed or Refractory Ph+ ALL or CML in Lymphoid Blast Phase

Inotuzumab Ozogamicin in Combination with Bosutinib for Patients with Relapsed or Refractory Ph+ ALL or CML in Lymphoid Blast Phase

Allosteric Bcr-Abl Inhibitor ABL001 Overcomes Bcr-Abl Tyrosine Kinase Inhibitor Resistance and Enhances MDM2 Inhibitor CGM097 Activity in Blast Crisis CML Cells

Despite Bcr-Abl tyrosine kinase inhibitors (TKIs) are highly effective in CML, development of TKI-resistance leading to blast crisis (BC) progression is still a challenge in CML therapy. This has motivated the generation of novel agents and combination strategies to overcome the resistance. ABL001 is a small molecule allosteric Bcr-Abl kinase inhibitor that occupies the myristoyl pocket, leading to a kinase autoinhibition conformation. ABL001 has entered phase I clinical trials to treat patients with chronic, accelerated, or blast phase CML that relapsed from TKIs (Hughes et al., ASH 2016). Its activity in BC CML and ability to enhance the traditional TKIs that target ATP binding site are under investigation. TP53, a key tumor suppressor gene plays a crucial role in mediating cell death in part through regulating the expression or activity of Bcl-2 family proteins. Although highly mutated in solid tumors, the mutation rate of TP53 is relatively low in CML. However, p53 antagonist, MDM2 can be regulated by Bcr-Abl signaling and ARF, which inhibits MDM2 is frequently deleted in BC CML suggesting therapeutic potentials of inhibition of MDM2 in BC CML. Indeed, activation of p53 by MDM2 inhibition has been shown to enhance the toxicity of TKIs in BC CML (Carter et al., Oncotarget 2015, 6(31):30487). In this study, we examined the activity of ABL001 in CML cells and investigated if ABL001 enhances the activity of TKIs and synergizes with MDM2 inhibitor CGM097 in samples from heavily treated TKI resistant BC CML patients.BaF3 cells expressing BCR-ABL with or without mutations, human CML cell lines (KBM5 and KBM5-STI-T315I), and peripheral blood mononuclear cells (PBMC) isolated from primary BC CML patient samples were treated with various doses of ABL001, CGM097 or Nilotinib alone or in combination. Apoptosis was determined by Annexin V/7-AAD staining in cell lines and CD45+ (bulk), CD34+CD38+ and CD34+CD38- cells of CML patient PBMC samples. EC50 was calculated using CompuSyn or Graphpad. Protein levels were examined by Western blotting.We found that ABL001 induced apoptosis in cell lines expressing BCR-ABL (BaF3p210 and KBM5) or mutant BCR-ABL (BaF3p210E255K and KBM5-STI-T315I) but had limited activity in BaF3p210T315I cells. Importantly, ABL001 induced apoptosis in bulk, CD34+CD38+, or/and CD34+CD38- cell populations at low nM concentrations in 5 out of 6 BC CML patient samples tested. Patient samples that responded to ABL001 had either T315I and/or E255 mutations in BCR-ABL kinase domain. ABL001 inhibited Bcr-Abl signaling as measured by the levels of p-Bcr-Abl/p-Stat5/p-Crkl in BCR-ABL positive cells with or without BCR-ABL mutations. ABL001 showed higher activity than Nilotinib in 4 out of 5 responding patient samples. Nilotinib did not significantly enhance ABL001-induced apoptosis in the tested BC CML patient samples and CML cell lines. Inhibition of MDM2 with CGM097 activated p53 and induced apoptosis in BC CML patient samples. The activity of ABL001 was enhanced by CGM097 in the majority of patient samples which did not have p53 mutations. ABL001 combined with CGM097 was more effective than the combination of nilotinib with CGM097. The combinations of TKI and CGM097 were more effective in killing leukemia cells than each agent alone even when leukemia cells were co-cultured with MSCs. Neither ABL001 or CGM097 alone, nor the combination showed toxicity on normal bone marrow stem/progenitor cells.In conclusion, our results demonstrate that the allosteric Bcr-Abl Inhibitor ABL001 overcomes TKI-resistance and enhances MDM2 inhibitor CGM097 activity in BC CML cells. The combination of ABL001 and CGM097 warrants clinical evaluation. DisclosuresCarter:novartis: Research Funding; Daiichi Sankyo: Research Funding.

Incidence of Low Level Mutations in Newly Diagnosed CML Patients: A Substudy of the German Tiger Trial

Background:The presence of BCR-ABL kinase domain mutations below the detection limit of Sanger sequencing (low level mutations, LLM) predicts the outcome of subsequent therapy in patients (pts) with imatinib resistance (Parker et al. JCO 2011, Blood 2012). The incidence of LLM in the ENEST1st trial, in which newly diagnosed chronic phase CML pts were treated with nilotinib, was 51%. Presence of LLM could not be correlated with clinical endpoints (Franke et al.; ASH 2014), but only 41 pts samples were available for analysis. We therefore investigated the importance of LLM in a much larger cohort of pts within the German CML V (TIGER) trial, in which newly diagnosed CP CML pts were treated with nilotinib or nilotinib plus interferon. Study endpoints are rates of MMR at 18 months of treatment and after TKI discontinuation. We report here on the incidence and type of LLM in this cohort of pts.Methods:467 TIGER study pts provided 10ml of peripheral blood or 2ml bone marrow after written informed consent. CD34+ selection was carried out by MACS® (Miltenyi Biotec) and the CD34+purity was determined by fluorescent activated cell sorting (FACS). Aliquots of 105 CD34+ were used for RNA extraction, cDNA synthesis and BCR-ABL amplification followed by Ligation PCR (L-PCR) for mutations T315I, Y253H, E255K/V, and F359V. This method has previously been shown to achieve a dynamic detection range of 100% to <0.1% mutant allele (3-3.5 log). For 343 of 467 pts (75%) >= 105 CD34+ cells with a purity of >50% were available for BCR-ABL amplification.Results:Mean CD34+ purity was 86% and the rate of successfully amplified samples was 70% (328/467 samples). A total of 1640 L-PCR assays of CD34+ cells identified 75 (4.6%) mutations in 60/328 pts (18.3%). The most frequently detected LLM was E255K (n=45), followed by Y253H (n=22). The T315I mutation was detected in 6 pts and E225V in 2 pts. No pt was positive for F359V. Forty-seven pts had only one LLM, 11 had two LLM and 2 pts had 3 LLM. The median quantitative level of mutant alleles in CD34+ cells was 0.085 (range 0.02-4.96) BCR-ABL mutant/ BCR-ABL unmutated.Conclusion:LLM potentially causing resistance to nilotinib and other tyrosine kinase inhibitors can be detected in newly diagnosed CML pts. Nearly twenty percent harbor one or more LLM at diagnosis, with 1.7% displaying the T315I mutation. The significance of this observation will be evaluated in regards to the study endpoints of the TIGER trial. DisclosuresFranke:Takeda: Consultancy; Pfizer: Honoraria; Novartis: Honoraria, Research Funding. Hochhaus:BMS: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; MSD: Research Funding. Lange:Novartis: Honoraria, Research Funding.

Altered Expression of Pdgfrα and Its Downstream Signalling Components May be Causal in the Development of Imatinib Induced Thrombocytopenia in CML Patients Receiving Imatinib Treatment

Background:The main regulators of most of the cellular signalling pathways are protein kinases. Among these the receptor tyrosine kinases (RTKs) play important roles in cellular growth and proliferation by transmitting extracellular messages to intracellular signalling circuits. An important component of the intracellular circuits is the (PDGFR/PI3K/Akt/mTOR) pathway. Aberrant functioning of this pathway is known to occur in a number of diseases through various mechanisms. We report here that expression of PDGFRα gene and its downstream signalling components viz. PI3K and AKT is down regulated after imatinib treatment in some CML patients on imatinib therapy and may be a causal in the development of imatinib induced thrombocytopenia in these patients.Methods:A cohort of 100 chronic phase CML patients admitted to the Lok Nayak Hospital, New Delhi, India were included in this study. After initiation of imatinib treatment, haematological response of CML patients was monitored regularly for two years, in which development of thrombocytopenia was the primary end point.Total RNA, from blood samples of CML patients, was extracted using Trizol method. RNA concentration was determined by measuring absorbance at 260 nm. A cDNA synthesis kit (ThermoFisher Scientific, USA) was used for cDNA synthesis according to the manufacturer's instructions. The mRNA expression of all the genes was evaluated by quantitative SYBR Green based real time polymerase chain reaction (qRT-PCR) and results were expressed as fold change (2-∆∆ct). Results:Expression of PDGFRα, PI3K and AKT1 genes was significantly downregulated after imatinib treatment with a fold change (Mean + SD) of (2.12 + 0.41, 2.38 + 0.53 and 4.78 + 0.38 respectively) in CML patients receiving imatinib therapy (p < 0.0001). Further, we analysed the expression of PDGFRα, PI3K and AKT1 genes in two groups of CML patients- one that developed thrombocytopenia after imatinib treatment and the other that did not. We observed that there was a differential expression of PDGFRα and AKT1genes in thrombocytopenic and nonthrombocytopenic CML patients. Thrombocytopenic CML patients had a lower expression of PDGFRα and AKT1 genes in comparison to non-thrombocytopenic CML patients and this difference reached a statistical significance with a p-value of 0.02 and 0.04 respectively. Moreover, the expression of PI3K gene was also slightly downregulated in thrombocytopenic CML patients (fold change = 2.21+ 0.47 ) compared to nonthrombocytopenic ones (fold change = -2.55 + 0.57) but this difference did not reach a statistical significance (p=0.14). DisclosuresNo relevant conflicts of interest to declare.

Issue Highlights — May 2021

Issue Highlights — May 2021

Kronik Myeloid Lösemi Tanılı Hastaların Klinik Özellikleri ve Tedaviye Yanıtlarının Değerlendirilmesi: Tek Merkez Deneyimi

Background: Chronic myeloid leukemia is a clonal hematopoietic stem cell disorder that leads to an increase in myeloid cells, erythroid series, and platelets in peripheral blood and causes pronounced myeloid hyperplasia in the bone marrow. The treatment and follow-up criteria in patients with CML have changed significantly in the recent years. In the pre-imatinib period, CML has been treated with hydroxyurea, interferon therapy, chemotherapy, and most effectively, allogenic stem cell transplantation. The addition of imatinib mesylate, a tyrosine kinase inhibitor, to the treatment regime provided a superior overall survival rate compared to previous standard treatments. In this study, our aim is to demonstrate the demographic characteristics, clinical features, treatment and follow-up strategies, response status, and general survival rates of CML patients treated in our clinic. Materials and Methods: 110 patients who were diagnosed with chronic phase CML during 2003–2019 were included in this study. The demographic characteristics and clinical findings including laboratory values, ultrasound findings, and bone marrow pathology results were evaluated retrospectively from their medical records Results: Among the 110 patients included, 59 (53.6%) were male, and 51 (46.4%) were female, and the median age was 49.5 (18–82). At the time of diagnosis, only 32 (29.0%) patients were symptomatic, 71 (64.5%) had splenomegaly, and 51 (46.4%) had hepatomegaly. All patients were given 400 mg of imatinib as first-line therapy. With imatinib treatment, the rates of complete hematologic response (CHR), complete cytogenetic response (CyCR), and major molecular response (MMR) were 100.0%, 72.5% and 69.6%, respectively. In the follow-up, 3 (2.7%) patients were observed to progress to the blastic phase. The overall survival rate was 86.4%. Conclusions: Imatinib has proven to be a tolerable, effective and safe agent in the first-line treatment of CML patients. Treatment choice after imatinib should take into consideration the patients' comorbidities.

Efficacy of allogeneic hematopoietic cell transplantation in patients with chronic phase CML resistant or intolerant to tyrosine kinase inhibitors

Approximately 15–20% of chronic myeloid leukemia (CML) patients fail tyrosine kinase inhibitor (TKI) therapy secondary to resistance or intolerance. In the pre-TKI era, front-line allogeneic hematopoietic cell transplantation (allo-HCT) represented the standard approach for patients with chronic phase-CML (CP-CML) who were deemed fit to tolerate the procedure and had a human leukocyte antigen compatible donor available. Currently, CP-CML patients are eligible for allo-HCT only if they fail more than one TKI and/or are intolerant to the drug. We performed a systematic review/meta-analysis of the available literature to assess the evidence regarding allo-HCT efficacy in CP-CML patients. Data from eligible studies were extracted in relation to benefits (overall survival [OS], progression-free survival, disease-free survival [DFS], complete remission [CR], and molecular response [MR]) and harms (nonrelapse mortality [NRM], relapse, and acute and chronic graft-versus-host disease), and stratified by age into adult and pediatric groups. For adult allo-HCT recipients, the pooled OS, DFS, CR and, MR were 84% [95% confidence interval (CI) 59–99%], 66% (95% CI 59–73%), 56% (95% CI 30–80%), and 88% (95% CI 62–98%), respectively. Pooled NRM and relapse were 20% (95% CI 15–26%) and 19% (95% CI 10–28%), respectively. For the pediatric group, the OS rate was reported in one study and was 91% (95% CI 72–99%). Our results suggest that allo-HCT is an effective treatment for TKI-resistant or TKI-intolerant CP-CML. Post-transplant strategies are still needed to further mitigate the risk of relapse.

Efficacy and safety of Bosutinib in Patient with Chronic myeloid leukemia who was intolerant to DASTANIB,NILOTUNIB -Case report

Treatment for Chronic myeloid leukemia has been revolutionized because of availability of different tyrosine kinase inhibitors. Each TKI come with its on toxicity profile as this needs to be taken in account before starting therapy with particular agent in a patient. Most of the adverse effects related to TKI are mild and can be managed by either symptomatic treatment or either by dose reduction. But some patients can become intolerant and to switch to other TKI remains the only option. Bosutinib is currently approved for treatment of chronic phase CML in patients who are either resistant or intolerant to previous TKI. We present a case of 59 year old male patient with CML who was intolerant to Dastanib and Nilotinib but showed excellent hematological and major molecular response to bosutinib

Effect of short-term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukemia: an analysis from the International Bone Marrow Transplant Registry

Allogeneic bone marrow transplantation (BMT) is the only curative therapy for chronic myelogenous leukemia (CML), though several studies indicate that prolonged survival can result from interferon-alpha (IFN-alpha) treatment. IFN-alpha is now often used as initial therapy for CML, before donor availability is known. Because identifying potential donors can take several weeks to months, it is important to know whether IFN-alpha adversely affects outcome of a subsequent BMT. If it does, initiation of IFN-alpha therapy might be delayed until donor availability is determined and avoided in patients for whom BMT is planned. We studied 873 patients who received HLA-identical sibling BMT for chronic-phase CML in 153 centers participating in the International Bone Marrow Transplant Registry. The object was to compare outcome in the 664 who received only hydroxyurea before BMT with outcome in the 209 who received IFN-alpha with or without hydroxyurea. The median duration of IFN-alpha therapy was 2 months (range, 1 to 39 months). Cox proportional hazards analysis was used to compare engraftment, graft-versus-host disease (GVHD), nonrelapse mortality, relapse, survival, and leukemia-free survival after adjustment for other prognostic variables. We found a higher risk of nonengraftment among patients given IFN-alpha than among those given hydroxyurea alone (2% versus 0.2%; P = 0.01). Patients who received IFN-alpha had a lower risk of relapse (relative risk, 0.17; 95% confidence interval, 0.04-0.70). Probabilities of GVHD, nonrelapse mortality, survival, and leukemia-free survival were similar in the two treatment groups. These results suggest that a short course of IFN-alpha does not adversely affect survival after a subsequent HLA-identical sibling BMT for chronic-phase CML. (Blood. 2000;95:410-415)

Plasma imatinib levels and ABCB1 polymorphism influences early molecular response and failure-free survival in newly diagnosed chronic phase CML patients

Achieving early molecular response (EMR) has been shown to be associated with better event free survival in patients with chronic phase chronic myeloid leukemia (CP-CML) on Imatinib therapy. We prospectively evaluated the factors influencing the 2-year failure free survival (FFS) and EMR to imatinib therapy in these patients including day29 plasma Imatinib levels, genetic variants and the gene expression of target genes in imatinib transport and biotransformation. Patients with low and intermediate Sokal score had better 2-year FFS compared to those with high Sokal Score (p = 0.02). Patients carrying ABCB1-C1236T variants had high day29 plasma imatinib levels (P = 0.005), increased EMR at 3 months (P = 0.044) and a better 2 year FFS (P = 0.003) when compared to those with wild type genotype. This translates to patients with lower ABCB1 mRNA expression having a significantly higher intracellular imatinib levels (P = 0.029). Higher day29 plasma imatinib levels was found to be strongly associated with patients achieving EMR at 3 months (P = 0.022), MMR at 12 months (P = 0.041) which essentially resulted in better 2-year FFS (p = 0.05). Also, patients who achieved EMR at 3 months, 6 months and MMR at 12 months had better FFS when compared to those who did not. This study suggests the incorporation of these variables in to the imatinib dosing algorithm as predictive biomarkers of response to Imatinib therapy.