Philadelphia Chromosome-positive Leukemia Research Articles

Aurora A Kinase As a Promising Therapeutic Target in Philadelphia Chromosome Positive Leukemia Cells

Introduction: ABL tyrosine kinase inhibitor (TKI), imatinib and second-generation ABL TKIs, such as nilotinib and dasatinib have demonstrated the potency against chronic myeloid leukemia (CML) and Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (Ph+ALL) patients. However, resistance to ABL TKI can develop in CML patients due to BCR-ABL point mutations. Moreover, ABL TKIs do not eliminate the leukemia stem cells (LSCs). Residual CML cells are present in bone marrow microenvironment. These cells are contained within a niche in the bone marrow and are often impervious to current treatments. Aurora kinases are novel family of serine/threonine kinases that play a critical role in regulating many of the processes that are pivotal to mitosis. Aurora kinases comprises three members, designated aurora A, B, and C. Amplification of aurora kinase gene is oncogenic and has been observed in several cancers including hematologic malignancies. Therefore, new approach to the treatment for Ph-positive cells with aurora kinase inhibitors may improve the outcome of leukemia patients.Materials and methods: In this study, we investigated whether aurora kinase inhibitor could suppress Ph-positive leukemia cells including T315I mutation and primary samples.Results: One of aurora kinase A inhibitor, alisertib inhibits proliferation of leukemia cells. We found alisertib treatment inhibited the growth of Ph-positive leukemia cells in a dose dependent manner and phosphorylation of aurora kinase A was reduced. Alisertib inhibits proliferation in imatinib resistant cells including T315I mutation. In the cell cycle analysis, alisertib induces a G2/M phase arrest in Ph-positive cells. Intracellular ROS levels were also increased in a dose dependent manner. Combined treatment of Ph-positive cells with ABL tyrosine kinase inhibitors, imatinib or ponatinib and alisertib caused significantly more cytotoxicity than each drug alone. Apoptotic and Caspase 3/7 positive cells were also increased. Ph-positive cells were treated with alisertib and cellular senescence was determined by senescence- associated β-galactosidase (SA-β-gal) staining. Senescent cells were increased in a time and dose dependent manner. SA-β-gal positive cells were reduced by N-Acetyl-L-cysteine treatment. Small interfering RNA mediated knockdown of the Aurora A gene causes a proliferation defect and enhances ABL TKI activity in Ph-positive cells. We next examined tumor formation in mice model. We injected subcutaneously 1×107 T315I mutant cells in nude mice. A dose of 20 mg/kg/day p.o of ponatinib and 30 mg/kg/day p.o of alisertib inhibited tumor growth and reduced tumor volume compared with control mice. We also found that co-treatment with ponatinib and alisertib increased mouse survival. Co-treatment with ponatinib and alisertib showed reduced mouse spleen weight and size. The treatments were well tolerated with no animal health concerns observed.Conclusion: The results of our study indicate that the aurora kinase inhibitor may be a powerful strategy against ABL TKI resistant cells including T315I mutation and enhance cytotoxic effects of ABL TKI against those Ph-positive leukemia cells. DisclosuresTauchi:Otsuka pharmaceutical KK: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb KK: Honoraria, Research Funding, Speakers Bureau; Novartis pharma KK: Honoraria, Research Funding, Speakers Bureau; Phizer KK: Honoraria, Research Funding, Speakers Bureau. Ohyashiki:Bristol-Myers Squibb KK: Honoraria, Research Funding, Speakers Bureau; Phizer KK: Honoraria, Research Funding, Speakers Bureau; Novartis pharma KK: Honoraria, Research Funding, Speakers Bureau; Celegen KK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kyowa Hakko Kirin KK: Honoraria; Otsuka pharmaceutical KK: Honoraria; Jansen pharmaceutical KK: Honoraria, Research Funding; Celegen KK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Phizer KK: Honoraria, Research Funding, Speakers Bureau; Fujirebio KK: Honoraria; Dainippon Sumitomo KK: Honoraria, Research Funding, Speakers Bureau; Nippon Shinyaku: Honoraria, Research Funding, Speakers Bureau; Taiho pharmaceutical KK: Honoraria; Alexion: Honoraria; MSD KK: Honoraria; Novartis pharma KK: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb KK: Honoraria, Research Funding, Speakers Bureau; Otsuka pharmaceutical KK: Honoraria; Jansen pharmaceutical KK: Honoraria, Research Funding; Fujirebio KK: Honoraria; Nippon Shinyaku: Honoraria, Research Funding, Speakers Bureau; Chugai pharmaceutical KK: Research Funding; Dainippon Sumitomo KK: Honoraria, Research Funding, Speakers Bureau; Taiho pharmaceutical KK: Honoraria; Alexion: Honoraria; MSD KK: Honoraria; Kyowa Hakko Kirin KK: Honoraria; Chugai pharmaceutical KK: Research Funding.

Migration in the Management of Philadelphia Positive ALL: Towards a Lower Risk of VTE

Background:Patients (pts) with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) have been reported Vu k et al Cancer Medicine. 2015;4(1):27-35. doi:10.1002/cam4.332.to have a higher incidence of venous thromboembolism (VTE). It has been suggested that the incidence of VTE in ALL pts is affected by the use of L-Asparaginase (ASNase) which is an integral part of many chemotherapy regimens. Consistent with this we previously reported a high VTE rate (22%) in pts with Philadelphia chromosome negative (Ph - ALL) that were treated with a modified Dana Farber Cancer Institute (DFCI) chemotherapy regimen containing high dose ASNase as part of the intensification phase. In 2001 imatinib was added to our modified DFCI chemotherapy regimen for Ph+ ALL which included 30 weeks of high dose of ASNase during intensification. However, due to a relative intolerance to the combination of ASNase and imatinib, the ASNase was omitted from the protocol in 2008. In this abstract we compare the incidence of VTE in Ph+ALL pts pre and post 2008 and Ph-ALL patients.Methods:We conducted a retrospective chart review of 130 adult pts with Ph + ALL treated at Princess Margaret Cancer Center between 2001-2015. All Ph+ pts were treated first line with imatinib mesylate in addition to our modified version of the DFCI chemotherapy protocol. As noted, before Feb 1, 2008 the intensification phase included ASNase, while after that date ASNase was omitted. In addition to the Ph+ patients we assessed the incidence of VTE in Ph- ALL patients. From July-2001 to May-2009 no VTE prophylaxis (prx) was given. For the Ph- cases, enoxaparin 0.62 mg/kg was given during intensification from June2009 to Dec2014; following that the dose was increased to 0.90 mg/kg of enoxaparin. VTE was diagnosed by ultrasound or CT pulmonary embolism study. VTEs were further classified as line related or unrelated.ResultsTwenty eight thrombotic events were detected in 25/130 (19.2%) pts with Ph + ALL. VTE with pts received minim one dose ASNase Pre Feb 1, 2008: 8/47 17% post Feb 1, 2008 without ASNase: 17/83 :20.4% One third (7/25)of the VTE were associated with a venous access device. Documented pulmonary embolism occurred in five patients. Almost all events occurred while on therapy with the largest proportion (9/25:36%) occurring while on the intensification phase; 3/19 events and 5/44 during the intensification phase. Three pts developed VTE after receiving and allogeneic SCT (allo SCT). There was no association with age, gender, weight, and allo SCT and the development of VTE.For the Ph- ALL group receiving prophylaxis the incidence of VTE during intensification was 18.9% (low dose) vs 13.3% (high dose).Discussion:We have previously identified an incidence of 21.7% VTE in Ph - ALL patients treated with a modified DFCI chemotherapy that occurred during intensification. The current series describes a similar rate (19.2%) of VTE in Ph + ALL patients despite over 2/3rd of these patients never receiving ASNase. This rate is similar to that reported in other series regardless of whether or not ASNase was given. When we compare the Ph+ ALL group that never received VTE prophylaxis to the Ph- ALL patients who received prophylaxis after 2009 there was no significant difference in the incidence of VTE.Conclusions:This information indicates that the pathogenesis of VTE in Ph + ALL patients may be more complex than previously thought and it is not related to the use of ASNase as the incidence of VTE was the same before and after the use of ASNase in the imatinib treated group. Further evaluation of Ph + ALL and its treatment as an inherently prothrombotic state, using proteomic and advanced genomic analysis, may identify risk factors that can be addressed so as to ameliorate the morbidity caused by VTE events. [Display omitted] DisclosuresGupta:Incyte: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schuh:Amgen: Consultancy, Honoraria. Yee:Astex: Research Funding; Novartis Canada: Honoraria; Karyopharm: Research Funding; Oncoethix: Research Funding; Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Targeting of Glutamine Pathways Restores Sensitivity in Venetoclax Resistant Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Targeting of Glutamine Pathways Restores Sensitivity in Venetoclax Resistant Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Long-Term Follow-up on Adult Patients with Philadelphia-Chromosome Positive Acute Myeloid Leukemia Who Were Treated with Interim Imatinib Followed By Allogeneic Hematopoietic Cell Transplantation

▪Background: The incidence of Philadelphia chromosome (Ph)-positivity in adult patients with acute myeloid leukemia (AML) is very low ranging from only 1 to 2%. Ph-positive AML has been included in the high-risk group presenting lower complete remission (CR) rate and early relapse after standard chemotherapy. However, the treatment outcome in a large cohort is not well elucidated due to its low incidence and variable treatment strategies including the use of tyrosine kinase inhibitors. We attempted to unveil clinical outcomes of Ph-positive AML in association with concomitant chromosomal abnormalities.Methods: We retrospectively analyzed 29 patients with Ph-positive AML (median age: 43 years old [range; 18-80]) from 2002 to 2016. Except for the 2 patients who did not get treated at all, 3 were treated repeatedly with low-dose cytarabine and 24 were treated with 3+7 standard induction chemotherapy, followed with the application of interim imatinib 400mg until the starting day of next chemotherapy or conditioning for hematopoietic cell transplantation (HCT). Among them, 17 underwent allogeneic HCT from sibling donors (n=6), unrelated donors (n=7), and haploidentical donors (n=4).Results: In total of 29 patients, 7 (24.1%) had additional inv(16). There were 3 therapy-related AML in Ph-positive AML subgroup with inv(16), while none were observed in the subgroup without inv(16). In the Ph-positive AML subgroup with inv(16), median age was younger (31 vs. 44 years old, p= 0.083) and CR rate was higher (85.7% vs. 54.5%, p= 0.214) than the opposite. Among 27 treated patients, 20 (74.1%) patients achieved CR after standard chemotherapy with interim imatinib, and 2 achieved CR after low-dose cytarabine with interim imatinib. In the entire patients group, after a median follow-up duration of 41.5 months (range: 0.2 to 156.6), 5-year overall survival (OS) was 40.1%. However, 5-year OS of 17 patients (11 in subgroup without inv(16) and 6 in subgroup with inv(16)) treated with allogeneic HCT was 69.3%, and 6 patients among them with Ph-positive AML with inv(16) were all alive after allogeneic HCT. In contrast, all 12 patients who were not treated with allogeneic HCT expired within a median of 6.3 months [range: 0.2-18].Conclusion: This study revealed that interim imatinib combined chemotherapy produced an acceptable CR rate, and allogeneic HCT as a post-remission therapy was a feasible choice for providing a long-term disease control in adult patients with Ph-positive AML. We also identified that inv(16) was related to favorable outcomes regardless of the coexisting t(9;22) and to therapy-related AML. DisclosuresKim:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Long-Term Cardiac, Vascular and Hypertensive Safety of Bosutinib in Patients with Philadelphia Chromosome-Positive (Ph+) Leukemia Resistant or Intolerant to Prior Therapy

Long-Term Cardiac, Vascular and Hypertensive Safety of Bosutinib in Patients with Philadelphia Chromosome-Positive (Ph+) Leukemia Resistant or Intolerant to Prior Therapy

What's Next in CML - a Prospective Study Evaluating Sanger Sequencing and Next Generation Sequencing (NGS) for BCR-ABL1 Kinase Domain (KD) Mutation Screening

What's Next in CML - a Prospective Study Evaluating Sanger Sequencing and Next Generation Sequencing (NGS) for BCR-ABL1 Kinase Domain (KD) Mutation Screening

Safety and Efficacy of Blinatumomab in Combination with a Tyrosine Kinase Inhibitor for the Treatment of Relapsed Philadelphia Chromosome-Positive Leukemia

Safety and Efficacy of Blinatumomab in Combination with a Tyrosine Kinase Inhibitor for the Treatment of Relapsed Philadelphia Chromosome-Positive Leukemia

Inotuzumab ozogamicin with bosutinib for relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia or lymphoid blast phase of chronic myeloid leukemia.

Relapsed/refractory (R/R) Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) and lymphoid blast phase of chronic myeloid leukemia (LBP-CML) have poor outcomes. We designed a phase 1/2 study combining inotuzumab ozogamicin with bosutinib for this patient population. Patients with T315I mutation were excluded. Bosutinib was administered daily at three dose levels (300 mg/d, 400 mg/d, 500 mg/d) in a 3 + 3 design. Inotuzumab ozogamicin was dosed weekly during cycle one, and once every 4 weeks subsequently for a total of six cycles. The primary objective was to determine the safety and the maximum tolerated dose (MTD) of bosutinib in combination with inotuzumab ozogamicin. Eighteen patients were enrolled (Ph-positive ALL, n=16; LBP-CML, n=2). The median age was 62 years (range, 19-74) and the median number of prior therapies was one (range, 1-5). Dose limiting toxicities included grade 3 skin rash and bosutinib 400 mg daily was determined as the MTD. The most frequent grade 3/4 treatment-emergent adverse events were thrombocytopenia (60%) and neutropenia (38%). A complete response (CR) / CR with incomplete count recovery (CRi) was achieved in 15/18 (83%) patients; 11/18 (61%) patients achieved negative measurable residual disease by flow cytometry. Complete molecular response was noted in 10/18 (56%) patients. The 30-day mortality was 0%. After a median follow-up of 44 months, the median duration of response and overall survival were 7.7months and 13.5months, respectively. Six patients had a subsequent allogeneic stem cell transplant. No patient developed veno-occlusive disease. Inotuzumab ozogamicin with bosutinib was well tolerated in R/R Ph-positive ALL and LBP-CML.

Clinical outcomes in patients with Philadelphia chromosome-positive leukemia treated with ponatinib in routine clinical practice\u2014data from a Belgian registry

Data on clinical use of ponatinib are limited. This prospective registry aimed to evaluate outcomes of ponatinib treatment in routine practice over 3 years (2016–2019) in Belgium (NCT03678454). Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) were treated with ponatinib per current label. Fifty patients (33 CML and 17 Ph+ ALL) were enrolled. Fifty-five percent of CML and 29% of Ph+ ALL patients had received ≥3 prior tyrosine kinase inhibitors (TKIs). Reasons for starting ponatinib were intolerance (40%), relapse or refractoriness (28%) to previous TKIs, progression (16%), or T315I mutation (16%). Median follow-up was 15 months for CML and 4.5 months for Ph+ ALL patients. Best response was a major molecular response in 58% of CML and 41% of Ph+ ALL patients. Of 20 patients who started ponatinib due to intolerance to previous TKIs, 9 (64%) CML and 4 (67%) Ph+ ALL achieved a major molecular response. Three-year estimates of overall survival were 85.3% and 85.6%, respectively, in CML and Ph+ ALL patients; estimated progression-free survival was 81.6% and 48.9%. Adverse reactions were reported in 34 patients (68%); rash (26%) and dry skin (10%) were most common. Reported cardiovascular adverse reactions included vascular stenosis (3), arterial hypertension (2), chest pain (1), palpitations (1), and vascular occlusion (1). This Belgian registry confirms results from the PACE clinical trial and supports routine ponatinib use in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or with the T315I mutation.

Patterns of surveillance for late effects of BCR-ABL tyrosine kinase inhibitors in survivors of pediatric Philadelphia chromosome positive leukemias

BackgroundTargeted anticancer therapies such as BCR-ABL tyrosine kinase inhibitors (TKIs) have improved outcomes for chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, little is known about long-term risks of TKIs in children. Exposure-based survivorship guidelines do not include TKIs, thus surveillance practices may be variable.MethodsWe retrospectively examined surveillance for cardiac and endocrine late effects in children receiving TKIs for Ph + leukemias, diagnosed at < 21 years between 2000 and 2018. Frequency of echocardiogram (ECHO), electrocardiogram (EKG), thyroid stimulating hormone (TSH), dual-energy x-ray absorptiometry (DXA), and bone age testing were abstracted. Descriptive statistics were stratified by leukemia type.Results66 patients (CML n = 44; Ph + ALL n = 22) met inclusion criteria. Among patients with CML, ≥1 evaluation was done: ECHO (50.0%), EKG (48.8%), TSH (43.9%), DXA (2.6%), bone age (7.4%). Among patients with Ph + ALL, ≥1 evaluation was done: ECHO (86.4%), EKG (68.2%), TSH (59.1%), DXA (63.6%), bone age (44.4%). Over a median 6.3 and 5.7 years of observation, respectively, 2% of patients with CML and 57% with Ph + ALL attended a survivorship clinic.ConclusionsDespite common exposure to TKIs in survivors of Ph + leukemias, patterns of surveillance for late effects differed in CML and Ph + ALL, with the latter receiving more surveillance likely due to concomitant chemotherapy exposures.Targeted therapies such as TKIs are revolutionizing cancer treatment, but surveillance for late effects and referral to survivorship clinics are variable despite the chronicity of exposure. Evidence based guidelines and longer follow-up are needed.

Dasatinib—A Generation Ahead

AbstractDasatinib is a highly potent second-generation (2G) tyrosine kinase inhibitor (TKI) used in the management of Philadelphia (Ph) chromosome-positive leukemias, chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). In CML, dasatinib produces higher rates of early and deeper molecular responses compared with imatinib. The drug has its share of toxicities, namely, cytopenias, cardiovascular, and pleural effusion. This review describes the pharmacological aspects of dasatinib, clinically relevant toxicities, and their management.

Molecular remission after combination therapy with blinatumomab and ponatinib with relapsed/refractory Philadelphia chromosome-positive acute lymphocytic leukemia: two case reports

BackgroundThe outcomes of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) can improve with allogeneic hematopoietic stem cell transplantation (HSCT) during the first complete remission after treatment with a tyrosine kinase inhibitor (TKI) combined with chemotherapy. However, frail patients who are not eligible for allogeneic HSCT or those with TKI-resistant mutations within the BCR–ABL kinase domain have a poor clinical course. Blinatumomab (BLIN) is a bispecific T-cell engager antibody construct that directs cytotoxic T cells to CD19-expressing B-ALL cells. To date, only a few studies have shown the safety and efficacy of Blinatumomab (BLIN) + TKI combination therapy for relapsed/refractory (R/R) Ph+ ALL. Here we report the case of two patients with R/R Ph+ ALL who were treated with BLIN + TKI with durable molecular response.Case presentationPatient 1: A 69-year-old Japanese male with R/R Ph+ ALL was treated with conventional chemotherapy and dasatinib in April 2016. In May 2018, he developed molecular relapse due to the acquisition of T315I during dasatinib maintenance therapy. Thereafter, he achieved molecular complete remission (mCR) after switching from dasatinib to ponatinib. However, he developed a second relapse after the emergence of triple compound mutations (G250E/D276G/T315I) in November 2018. He subsequently received a total of nine cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR without any adverse events. Patient 2: A 69-year-old Japanese female with R/R Ph+ ALL was treated with chemotherapy and imatinib in April 2008. She developed molecular relapse due to the emergence of the T315I mutation in October 2017. She achieved mCR after switching from imatinib to ponatinib. However, she developed a second relapse after acquiring ABL exon4 skipping in addition to T315I. She subsequently received a total of seven cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR.ConclusionIn our two cases, BLIN + ponatinib combination therapy was highly effective for R/R Ph+ ALL without any incidence of severe adverse events. Further studies with larger cohorts are warranted to validate the safety and efficacy of this potent combination therapy.

Philadelphia chromosome positive chronic myeloid leukemia with 5q deletion at diagnosis

BackgroundAlthough, molecular genetic analyses became more and more important to guide therapy decisions in leukemia, banding cytogenetic analysis has retained its vital role in diagnosis and monitoring of chronic myeloid leukemia (CML), by quick and easy enabling identification of pathognomonic Philadelphia chromosome (Ph).Case presentationA 45 year old female presented with characteristic hematological features of CML in chronic phase; cytogenetic studies revealed the presence of the typical Ph and a deletion of almost entire long arm of a chromosome 5.Conclusion5q deletions have rarely been reported in CML. Those seen yet were either associated with tyrosine kinase inhibitor therapy or detected post allogeneic stem cell transplantation. To our knowledge, this is the first case of Ph positive CML accompanied by a 5q deletion.

Analysis of the Different Therapeutic Effects in 21 Ph+ Acute Lymphoblastic Leukemia Children

To analyze the outcomes of the children suffered from philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) treated with tyrosine kinase inhibitor (TKI) plus chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). 21 cases of firstly diagnosed Ph+ALL patients aged <12 year treated with Chinese Childhood Leukemia Group ALL 2008 (CCLG-ALL 2008) protocol form January 2008 and April 2015 were retrospectively analyzed．The patients were divided into two groups, one group was TKI+ chemotherapy group, the other group was allo-HSCT group. Among 21 patients, 17 were male and 4 were female with a median age of 8 years old (range, 4-12 years), the median follow-up time was 30 moths (range, 10-133 months). All the patients were treated with chemotherapy induced by the high-risk project of CCLG-ALL 2008. Among 14 patients treated with TKI plus chemotherapy, nine patients achieved complete remission. During 3 months after treatment, patients without complete molecular response or with the second complete remission and intensity desire of transplantation were treated with allo-HSCT, among 9 patients with allo-HSCT, six patients achieved long term survival. At TKI era, TKI combined with strong chemotherapy can make Ph+ ALL children achieve 5 years event-free survival as campared those treated with allo-HSCT. However, for the patients without complete molecular response persistently and relapsed they can still benefit from allo-HSCT.

Design and stability of pediatric oral formulation of imatinib.

Imatinib is a protein-tyrosine kinase inhibitor which is currently only commercially available as a tablet dosage form in the strength of 100mg and 400mg. The elaboration of new oral liquid formulations is suitable in pediatrics and for patients who have difficulties to swallow, notably in the absence of commercial forms. This enables the adaptation of dosage and secure the administration. The formulation of an oral pediatric solution of imatinib at a concentration of 30 mg/mL and the evaluation of its stability for the treatment of pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia. The physicochemical stability parameters: appearance, pH, osmolality, and drug content of formulation were evaluated for 30 days when stored at 2-8°C. Concentration of solution was measured with a validated method using high performance liquid chromatography (HPLC) coupled with an absorbance UV detector. Equally, microbiological stability was performed. The remaining imatinib concentration was at least 95% of the initial concentration after 30 days stored in fridge temperature. No changes were observed regarding the physical properties of the formulation during the study period. The stability study showed that the imatinib oral solution at a concentration of 30 mg/mL provides an alternative option at the commercial tablet dosage forms for pediatric patients and patients who have difficulties to swallow.

Stopping tyrosine kinase inhibitors started after allogeneic HCT in patients with Philadelphia chromosome-positive leukemia.

For patients with Philadelphia chromosome (Ph)-positive leukemia, there is no consensus regarding how long tyrosine kinase inhibitors (TKI) should be given or whether TKI could be stopped if TKI is administrated after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed relapse-free survival (RFS) in 92 allo-HCT patients who received TKI for >3 months after allo-HCT, and aimed to develop a novel indicator, called as current TKI- & relapse-free (cTRFree) achievement. TKI after allo-HCT was started as planned in 39 patients, based on measurable residual disease (MRD) in 53 at a median of 152 days after allo-HCT. There was no difference in post-TKI RFS between the planned and MRD-based starting groups (P = 0.69). Second-generation TKIs were associated with superior RFS in Ph-positive acute leukemia (HR 2.71, P = 0.031). TKI was stopped before relapse in 48 patients. Stopping TKI as a time-dependent covariate was not associated with subsequent hematological relapse (HR 1.18, P = 0.72). In the TKI-stop group, TKI administration for >6 months tended to be associated with superior RFS (HR = 0.30, P = 0.08). As an indicator of transplant success, cTRFree was 35% 5 years after starting TKI. TKI could be stopped for recipients with sustained undetectable MRD. However, further prospective studies will be required to establish clinical recommendations.

A case of dasatinib-induced focal segmental glomerulosclerosis in a patient with Philadelphia chromosome positive chronic myeloid leukemia

Focal segmental glomerulosclerosis is a common glomerular histological lesion, which is usually characterised by non-nephrotic range proteinuria or nephrotic syndrome. It may be idiopathic or occurs secondarily to drugs, diabetes, obesity or HIV nephropathy and other infections. Dasatinib, a tyrosine kinase inhibitor that has been used for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia, has a few renal adverse effects. Exceptional cases with non-nephrotic range proteinuria have been reported in relation with dasatinib. In this case, we report a patient with symptoms of nephrotic syndrome and nephrotic range proteinuria, who was diagnosed as focal segmental glomerulosclerosis by kidney biopsy after treated with dasatinib.

Role of BCR-ABL1 isoforms on the prognosis of Philadelphia chromosome positive acute lymphoblastic leukemia in the tyrosine kinase inhibitor era: A meta-analysis.

BCR-ABL1 fusion gene is the driver mutation of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Although the prognostic value of BCR-ABL1 isoforms in Ph+ ALL patients has been investigated in numerous studies in the tyrosine kinase inhibitor (TKI) era, the results were still conflicting. Hence we performed herein the meta-analysis to comprehensively assess the impact of BCR-ABL1 isoforms on the clinical outcomes of Ph+ ALL patients. Systematic literature review was conducted in PubMed, Embase, and Cochrane databases with the data access date up to June 15, 2020. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Furthermore, subgroup analyses were performed to assess the robustness of the associations. Nine studies with a total number of 1582 patients were eligible for this meta-analysis. Combined HRs suggested that p210 was slightly associated with inferior event-free survival (EFS) (HR = 1.34, 95% CI 1.05–1.72). The overall survival (OS) was not significantly affected (HR = 1.15, 95% CI 0.92–1.45). In subgroup analyses, the HRs showed a trend toward adverse impact of p210 on clinical outcomes. However, the confidence intervals were not crossing the null value only in a minority of subgroups including Caucasian studies, first-generation TKI treated cohort and transplant cohort. Our findings suggested that p210 might pose a mild adverse impact on the EFS of Ph+ ALL patients. This effect might be compromised by the use of second- or third-generation TKIs. Further studies are needed to verify our conclusions.

Clinical Outcome in Pediatric Patients with Philadelphia Chromosome Positive ALL Treated with Tyrosine Kinase Inhibitors Plus Chemotherapy-The Experience of a Polish Pediatric Leukemia and Lymphoma Study Group.

Simple SummaryPhiladelphia chromosome positive acute lymphoblastic leukemia (ALL Ph+) is rare in children, but outcomes are still poor. The aim of our study was to analyze the toxicity events and results of children with ALL Ph+ treated according to the EsPhALL2010 protocol (the European intergroup study of post induction treatment of Philadelphia chromosome positive ALL) in Poland between the years 2012 and 2019. Our treatment outcomes are still disappointing compared to those in other reports. Improvements in supportive care and emphasis placed on the determination of MRD at successive time points, which will impact decisions on therapy, may be required.The treatment of children with Philadelphia chromosome positive acute lymphoblastic leukemia (ALL Ph+) is currently unsuccessful. The use of tyrosine kinase inhibitors (TKIs) combined with chemotherapy has modernized ALL Ph+ therapy and appears to improve clinical outcome. We report herein the toxicity events and results of children with ALL Ph+ treated according to the EsPhALL2010 protocol (the European intergroup study of post-induction treatment of Philadelphia chromosome positive ALL) in 15 hemato-oncological centers in Poland between the years 2012 and 2019. The study group included 31 patients, aged 1–18 years, with newly diagnosed ALL Ph+. All patients received TKIs. Imatinib was used in 30 patients, and ponatinib was applied in one child due to T315I and M244V mutation. During therapy, imatinib was replaced with dasatinib in three children. The overall survival of children with ALL Ph+ treated according to the EsPhALL2010 protocol was 74.1% and event-free survival was 54.2% after five years. The cumulative death risk of the study group at five years was estimated at 25.9%, and its cumulative relapse risk was 30%. Our treatment outcomes are still disappointing compared to other reports. Improvements in supportive care and emphasis placed on the determination of minimal residual disease at successive time points, which will impact decisions on therapy, may be required.

Identification of the motifs of beta-turns and mutated amino acids studies on BCR (Breakpoint cluster region) protein using Insilico techniques

Recent investigations have rapidly added crucial new insights into the complex functions of the normal BCR gene and of the BCR-ABL chimaera. They are yielding potential therapeutic breakthroughs in the treatment of Philadelphia (Ph) chromosome-positive leukemias. The objective of the present in silico research investigation is to find out whether the functional part (beta-turns) is present in the mutated amino acids of BCR (Breakpoint cluster region) protein. Two significant steps are involved in this study. First, we performed protein sequence modeling of BCR using automated protein modeling servers and the 3D structure was visualized using molecular visualization software and tools. In the second step, the function domains and motifs regions of BCR gene-coded protein is predicted using “PDBsum generate” tool in order to show where exactly the beta-turns lie on the clinically-proven mutated amino acids of BCR protein. The results of our investigation can be used as potential drug binding sites in the field of drug docking studies. It can act as a potential therapeutic agent for Chronic Myeloid Leukemia (CML) type of Leukemia.