Cases Of Chronic Myeloid Leukemia Research Articles

Oncogenic and tumor suppressor genes expression in myeloproliferative neoplasms: The hidden side of a complex pathology.

BackgroundThe present study aimed to explore the changes in the expressions of six tumor‐related genes in myeloproliferative neoplasms (MPNs). The study population included 130 patients with MPNs (52 with chronic myeloid leukemia (CML), 49 with essential thrombocythemia (ET), 20 with polycythemia vera (PV), and 9 with primary myelofibrosis (PMF)) and 51 healthy individuals.MethodsThe expression profiling of six genes (ADAMTS18, CMTM5, CDKN2B, DCC, FHIT, and WNT5B) in the peripheral blood granulocyte cells was explored by real‐time quantitative reverse transcription polymerase chain reaction.ResultsThe patients with MPNs showed significant downregulation of CMTM5 (EFC = 0.66) and DCC (EFC = 0.65) genes in contrast to a non‐significant upregulation of ADAMTS18, CDKN2B, FHIT, and WNT5B genes. Downregulation of DCC was consistent in all subtypes of MPN (EFC range: 0.591–0.860). However, CMTM5 had a 1.22‐fold upregulation in PMF in contrast to downregulation in other MPN subtypes (EFC range: 0.599–0.775). The results revealed a significant downregulation in CMTM5 and DCC at below 60‐years of age. Furthermore, female patients showed a clear‐cut downregulation in both CMTM5 and DCC (EFC DCC: 0.436 and CMTM5: 0.570), while male patients presented a less prominent downregulation with a borderline p‐value only in DCC (EFC: 0.69; p = 0.05).ConclusionsChronic myeloid leukemia cases showed a significant upregulation of WNT5B, as a known oncogenesis gene. Two tumor suppressor genes, namely DCC and CMTM5, were downregulated in the patients with MPNs, especially in females and patients below 60 years of age.

Myeloid Sarcoma Presenting as Rectosigmoid Tumour: A Case Report

Myeloid Sarcoma (MS) or extramedullary myeloid tumor is a rare tumor affecting the skin, lymph node, and any part of the body except the bone marrow. MS may present differently depending on the site of involvement. A 61-year-old male with a known case of chronic myeloid leukemia presented to the emergency department of a district hospital with per rectal bleeding for two days. Examination revealed haematochezia with no evidence of rectal tumor. Hyperleukocytosis was noted from the blood investigation. Colonoscopy was performed, which revealed the rectosigmoid tumor. Histopathological examination confirmed the diagnosis of myeloid sarcoma. The patient was subsequently referred to a hematologist in a tertiary hospital for further care. MS may present a diagnostic challenge as it may present nonspecific symptoms depending on the site of involvement. Awareness of this condition is essential; thus, diagnosis and treatment can be initiated earlier.

STUDY OF PLATELET FUNCTION DEFECTS IN CASES OF CHRONIC MYELOID LEUKAEMIA

AIM: Chronic myeloid leukaemia (CML) is one of the chronic myeloproliferative disorders. The emerging data overwhelmingly suggests that study of platelet defects in CML would be useful for comprehensive management of CML. This study was conducted to identify the platelet function defects and to correlate the results with clinical symptoms in cases of CML. METHODS: Clinical and laboratory data of CMLpatients, diagnosed and managed at a tertiary centre from January 2018 to September 2019 were analyzed. Patient's platelet rich plasma was subjected to platelet function tests (PFT) with Chronolog Dual Channel Platelet Aggregometer using arachidonic acid, epinephrine, adenosine diphosphate (ADP) and ristocetin as agonists. RESULTS: Most cases of CML(30%) were from age range of 51 to 60 years and 83% of cases were male. Splenomegaly was seen in 97% of cases. 3 Median haemoglobin was 13 g/dl and median total WBC count was 6.315 x 10 /µL. About 64% of all cases showed the total platelet count of 201- 3 300 x 10 /µL. Median platelet distribution width (PDW) was 10.7 and median value of mean platelet volume (MPV) was 9.4. There was signicant association between platelet aggregation response with ADP and bleeding manifestations. In 98% of cases showing normal platelet aggregation responses with ADP, bleeding manifestation were absent. CONCLUSION: The present study suggests that platelet function defects are seen in CML. Platelet aggregation study can be useful especially in those patients exhibiting bleeding manifestations with normal or increased platelet counts. This would enable a comprehensive management in cases of CML.

Avascular necrosis in patients with chronic myeloid leukemia: A systematic review.

Objective:Avascular necrosis (AVN)has been encountered in hematological malignancies; nonetheless, AVN is extremely uncommon in patients with chronic myeloid leukemia (CML). This review aims to describe the pathophysiology, clinical characteristics, and outcomes of AVN in CML. To our knowledge, this is the first systematic review of this topic.Methods:We searched PubMed and Google Scholar for the case reports and series of patients with CML who developed AVN from inception to July 2021.Results:We found 21 cases of AVN in CML patients,17 cases with avascular necrosis of the femoral head (AVNFH), and four cases with osteonecrosis of the jaw (ONJ). The median age was 39 years with an almost equal distribution between males and females (ratio of 1:1). AVN related to CML management has been linked to tyrosine kinase inhibitors (TKIs) and standard interferon-alpha (IFN-α) therapies. Only six (out of 17) patients who developed AVN of the femoral head eventually required a hip replacement, and one (out of 17) developed a recurrent episode of AVNFH. All the reported cases of CML with osteonecrosis of the jaw were associated with TKIs therapy.Conclusion:Clinician should consider AVN in any CML patient complaining of either hip or jaw pain. IFN-α and TKI therapies can predispose to AVN in CML patients. Further studies are required for a better understanding of this condition in CML. (www.actabiomedica.it)

Deep sequencing reveals the spectrum of BCR-ABL1 mutations upon front-line therapy resistance in chronic myeloid leukemia: An Eastern-Indian cohort study

The course of clinical management in chronic myeloid leukemia (CML) often faces a road-block in the form of front-line (imatinib) therapy resistance. Subsequently, several hotspot mutations were clinically validated in the kinase domain (KD) of BCR-ABL1, in deterring imatinib sensitivity and further, made targeted by next-generation tyrosine-kinase-inhibitor (TKI) drugs. Identifying KD mutations, occurring even at low frequencies, became pertinent here. Globally, cohorts from different origins were tested and the mutational spectra were mapped to categorize clinical management as well as related pathological features of CML. Moreover, targeted deep sequencing could reveal the mutational landscape more efficiently than the less sensitive Sanger sequencing method. However, no such efforts were reported from Eastern Indian cohorts of imatinib-resistant CML-sufferers. This study assessed a prospective study cohort of imatinib-resistant CML cases from Eastern India. Following dissecting the molecular and clinical parameters, the mutational spectrum was comparatively examined using conventional Sanger and next-generation deep sequencing method. This cohort showed a prevalence of e14a2-p210 variant of BCR-ABL1 and acquired resistance against imatinib, while the disease was mostly confined in its chronic phase. Together with a few common hotspot mutations identified in this cohort, deep sequencing revealed cases with a candidate mutation, otherwise undetermined by Sanger method. Also, cases with a second low frequency mutation were identified upon applying deep sequencing. Along with highlighting a few aspects of CML biology employing an Eastern-Indian cohort, this data could mark the immense importance of deep sequencing to contribute in the clinical management of CML upon front-line therapy resistance.

Potential to Improve Therapy of Chronic Myeloid Leukemia (CML), Especially for Patients with Older Age: Incidence, Mortality, and Survival Rates of Patients with CML in Switzerland from 1995 to 2017.

Simple SummaryIn a population-based study of chronic myeloid leukemia (CML) patients in Switzerland, we confirmed an increase in relative survival for all age groups over the last decades. This was primarily based on the stable age-adjusted rate of incidence and a substantial decrease of the age-adjusted mortality rate. Investigating data from four different study periods, before and after introduction of tyrosine kinase inhibitors and their more potent second- and third-generation compounds, we found higher increases in relative survival for older patients at later time periods compared to younger CML patients. However, for the last study period (2013–2017), the five-year relative survival (RS) in the elderly population reached only 53% compared to 89% in younger patients, implicating additional potential to improve CML therapy, especially in the elderly population.Background: Tyrosine kinase inhibitors (TKI) substantially improved chronic myeloid leukemia (CML) prognosis. We aimed to describe time period- and age-dependent outcomes by reporting real-world data of CML patients from Switzerland. Methods: Population-based incidence, mortality, and survival were assessed for four different study periods and age groups on the basis of aggregated data from Swiss Cantonal Cancer Registries. Results: A total of 1552 new CML cases were reported from 1995 to 2017. The age-standardized rate (ASR) for the incidence remained stable, while the ASR for mortality decreased by 50–80%, resulting in a five-year RS from 36% to 74% over all four age groups. Importantly, for patients <60 years (yrs), the five-year RS increased only in earlier time periods up to 92%, whereas for older patients (+80 yrs), the five-year RS continued to increase later, however, reaching only 53% until 2017. Conclusions: This is the first population-based study of CML patients in Switzerland confirming similar data compared to other population-based registries in Europe. The RS increased significantly in all age groups over the last decades after the establishment of TKI therapy. Interestingly, we found a more prominent increase in RS of patients with older age at later observation periods (45%) compared to patients at younger age (10%), implicating a greater benefit from TKI treatment for elderly occurring with delay since the establishment of TKI therapy. Our findings suggest more potential to improve CML therapy, especially for older patients.

A Rare Case of Synchronous us Carcinoma Breast with Chronic Myeloid Leukemia

Chronic myeloid leukemia is an insidiously progressive condition and comparatively rare type of blood cell malignancy that begins in the bone marrow. Chronic myeloid leukemia typically affects adult population and is documented to be caused by chromosomal mutation that usually occurs spontaneously.&#x0D; Chronic myeloid leukemia is more common in males than in females (male: female ratio of 1.4:1) and appears more commonly in the elderly with a median age at diagnosis of 65 years [1] Exposure to ionising radiation is one of the risk factors, based on a 50 fold higher incidence of CML in Hiroshima and Nagasaki nuclear bombing survivors [1] The rate of CML in these individuals seems to reach at its peak about 10 years after the exposure [1].&#x0D; Carcinoma breast on the other hand is one of the most common causes of death in middle aged women in western countries. There are numerous factors contributing as its etiological factors such as age, gender, diet, endocrinal factors, previous radiation exposure, genetic factors and geographical factors.&#x0D; We present a case report of a 44 old female who came to Acharya Vinoba Bhave Rural Hospital (Datta Meghe Institute of Medical Sciences and Research), with presenting complaint of lump in the left breast since 2 days and abdominal mass for 1 month. On investigations, patient was diagnosed with a rare case of chronic myeloid leukemia on the complete blood count and peripheral smear and the lump in the left breast also revealed invasive ductal carcinoma of the left breast.

Simvastatin potentiates the cell-killing activity of imatinib in imatinib-resistant chronic myeloid leukemia cells mainly through PI3K/AKT pathway attenuation and Myc downregulation

Constitutively activated BCR-ABL kinase is considered the driver event responsible in the initiation and development of chronic myeloid leukemia (CML). The advent of the first BCR-ABL inhibitor imatinib has significantly improved the clinical outcome of CML cases. However, resistance to imatinib occurs in 25–30% of CML patients. Due to the lack of effective therapeutic strategies, novel treatment approaches are urgently required for imatinib-resistant CML. Simvastatin, a well-known HMG-CoA reductase inhibitor that confers tremendous clinical benefits in cardiovascular diseases, has attracted mounting attentions for its potent antitumor effects on multiple tumor types. In this study, we demonstrated that simvastatin monotherapy was effective in diminishing cell viability in both imatinib-sensitive and imatinib-resistant CML cells, including T351I mutated cells, with the latter being less vulnerable to the simvastatin than the former. Notably, we found that simvastatin acted as a robust cytotoxic sensitizer of imatinib to kill imatinib-resistant and T315I mutated CML cells in vitro and in vivo. Mechanistically, the cooperative interaction of simvastatin and imatinib was associated with the inactivation of the PI3K/Akt signaling pathway, which was a classical downstream pro-survival cascade of the BCR-ABL kinase. In addition, this drug combination obviously decreased Myc expression through attenuation of canonical Wnt/β-catenin signaling and increased H3K27 trimethylation. Taken together, we provide attractive preclinical results for the combinatorial regimen of simvastatin and imatinib against imatinib-resistant and T315I mutated CML cells. This combined regimens warrants further clinical investigations in patients with imatinib-resistant CML.

AVASCULAR NECROSIS IN CHRONIC MYELOID LEUKEMIA: A REVIEW OF PATHOPHYSIOLOGY, PATIENTS’ CHARACTERISTICS, AND CLINICAL OUTCOMES

The exact incidence of avascular necrosis (AVN) in chronic myeloid leukemia (CML) is still unknown as the number of cases is limited. AVN was reported as an initial presenting manifestation in few CML patients. On the other hand, AVN was linked to medications used in CML treatment, specifically interferon-alpha (IFN-α) therapy and tyrosine kinase inhibitors (TKI). Our review aims to describe the pathophysiology, patients’ clinical characteristics, and outcomes of AVN in CML. We searched PubMed and Google Scholar for the case reports and series of patients with CML who developed AVN from inception to July 2021. We found 21 cases of AVN in CML patients,17 cases with AVNFH, and four cases with ONJ. Articles in the grey literature and non-English language publications were excluded. Patient characteristics, hematological parameters, management, and outcomes of AVN were extracted from those articles. The median age was 39 years with an almost equal distribution between males and females. WBC counts were strikingly elevated in patients who initially presented with AVNFH (above 10,0000 in most cases). AVN related to CML management has been linked to TKIs and standard IFN-α therapies. Only 6 (out of 17) patients who developed AVNFH eventually required a hip replacement, and one (out of 17) developed a recurrent episode of AVNFH. All the reported cases of CML with ONJ were associated with TKIs Given the lack of data, we could not conclude whether AVN has an adverse prognostic effect on CML. However, the overall prognosis is comparable with AVN associated with other conditions. Clinicians should consider AVN in CML patients with either hip or jaw pain because early detection and management are essential to decrease morbidity and long-term disability in such patients. A further prospective study with a larger sample size is needed to clarify the different aspects of AVN in CML patients.

PONATINIB EXPERIENCE IN A PEDIATRIC CHRONIC MYELOID LEUKEMIA PATIENT

Chronic myeloid leukemia (CML) is rarely seen in children. The development of myelofibrosis in CML is not uncommon and is associated with a poor prognosis. In cases unresponsive to treatment, tyrosine kinase mutation should be checked for drug resistance, second generation tyrosine kinase inhibitor (TKI) drugs (dasatinib/nilotinib) should be switched to and a suitable donor for bone marrow transplantation should be sought. Third-choice TKI can be used in children who are unresponsive to treatment and do not have a suitable donor. Experience of third-choice TKI(ponatinib) in a child with CML diagnosis due to unresponsiveness to treatment. A 5.5-year-old female patient with no known disease was referred to us because of hepatosplenomegaly (liver 5 cm, spleen 10 cm). There was no laboratory disorder except for anemia (hgb 8.9 g/dL) and high LDH (1104 U/L). WBC was 11.1 × 10 3 /µL neu 6.92 × 103/ µL plt 304000/µL. Peripheral smear showed leukoerythroblastosis. Bone marrow biopsy result was evaluated as compatible with myelofibrosis and an increase in blast rate from 8% to 18% in the bone marrow. The patient was diagnosed CML accelerated phase with cytogenetic (46,XX,t(9:22)(q34;q11))and translocation (t(9:22)- p210,BCR/ABL positive) results and. Imatinib treatment was started at 400 mg/m 2 .The copy number of BCR-ABL p210 checked before treatment was 72% IS. However, the patient developed febrile neutropenia, and imatinib dose reduction (< 200 mg/m 2 ) and interruption were required in the follow-up.Under imatinib treatment, BCR-ABL copy number was 16%IS at 1 month, 11%IS at 3 months, and 95%IS at 5 months. Due to the increase in the BCR-ABL copy number, nilotinib was switched to as a second-choice TKI(230 g/m2/dose, in 2 doses).No mutation could be detected in the c-ABL gene, which was examined for tyrosine kinase resistance. HLA groups were sent from the family and compatible donors were not found. Due to severe neutropenia in the follow-up, nilotinib could be continued at 50% dose. Under nilotinib treatment, the BCR-ABL copy number was 13% IS at 1 month, 10% IS at 2 months, and 31% IS at 3 months. The patient was started on ponatinib (18 mg/m 2 /day) as a third choice TKI. However, due to the deep neutropenia of the patient, it was possible to continue with a dose of 10 mg/m 2 from the 2nd week. With this dose, the neutrophil is around 0.8-1 × 10 3 /µL. Under ponatinib treatment, BCR-ABL copy number was 6.6% IS at 1 month, 0.8% IS at 3 months, 0.09% at 5 months, and 0.05% at 6 months. No significant side effects were observed except neutropenia. There is no approved treatment in pediatric CML cases where the second choice TKI fails and there is no donor for transplantation. FDA approval for ponatinib in adult patients was obtained in December 2020. Ponatinib is a natural or mutant pan-BCR-ABL mutation inhibitor. It also inhibits VEGFR, FGFR,PDGFR,EPH and SRC kinases as well as KIT,RET,TIE2 and FLT3. The use of ponatinib should be evaluated by monitoring side effects/tolerance in pediatric cases where there is no other treatment option, and there is a need for studies on this subject.

A Pediatric Case of Atypical Chronic Myeloid Leukemia with CSF3R Mutation Not Responding to Ruxolitinib, but Rescued by Allogeneic Transplantation

A Pediatric Case of Atypical Chronic Myeloid Leukemia with <i>CSF3R</i> Mutation Not Responding to Ruxolitinib, but Rescued by Allogeneic Transplantation

Challenges in Treating Cancer Patients With Unstable Psychiatric Disorder.

In this review, we first present a case of chronic myeloid leukemia with acute psychosis, and then we will discuss the incidence of cancer in patients with psychotic disorders, the manifestations of new-onset psychosis, and the prevalence of preexisting psychosis in cancer patients, coupled with their impact on the treatment, diagnosis, and prognosis of cancer. This was a case that presented with acute psychosis and was found to have an elevated white blood cell count upon admission to an inpatient psychiatric unit. He was diagnosed with chronic myeloid leukemia and successfully managed with imatinib/dasatinib therapy. Psychiatrically, he was stabilized on two long-acting injectable medications to help maintain adherence. We were able to eliminate his active psychotic symptoms and return him to normal functioning in affect and thinking, achieving sustained compliance with treatment. We identified multiple inconsistencies in screening for cancer of all types in these patients, masking of signs and symptoms that would typically clue physicians to the presence of cancers, underreporting of symptoms, and disparate access to healthcare resources in patients with mental disorders when compared to the general population. Treatment of cancer in these patients as compared to the general population has also been shown to be incongruent, which will be elaborated upon. Psychiatric interventions, as well as supportive measures, for treating patients who are facing challenges during active cancer treatment will be discussed.

Patterns of Tyrosine Kinase Inhibitor Utilization in Newly Treated Patients With Chronic Myeloid Leukemia: An Exhaustive Population-Based Study in France.

We analyzed demographic characteristics, comorbidities and patterns of treatment with tyrosine kinase inhibitors (TKIs) in a cohort of 3,633 incident cases of chronic myeloid leukemia (CML) identified across France from 1 January 2011 to 31 December 2014. Patients were identified through a specific algorithm in the French Healthcare Data System and were followed up 12 months after inclusion in the cohort. The estimated incidence rate of CML for this period in France was 1.37 per 100,000 person-years (95% Confidence Interval 1.36-1.38) and was higher in men, with a peak at age 75-79 years. At baseline, the median age of the cohort was 60 years (Inter Quartile Range 47-71), the Male/Female ratio was 1.2, and 25% presented with another comorbidity. Imatinib was the first-line TKI for 77.6% of the patients, followed by nilotinib (18.3%) and dasatinib (4.1%). Twelve months after initiation, 86% of the patients remained on the same TKI, 13% switched to another TKI and 1% received subsequently three different TKIs. During the follow-up, 23% discontinued and 52% suspended the TKI. Patients received a mean of 16.7 (Standard Deviation (SD) 9.6) medications over the first year of follow-up, and a mean of 2.7 (SD 2.3) concomitant medications on the day of first TKI prescription: 24.4% of the patients received allopurinol, 6.4% proton pump inhibitors (PPI) and 6.5% antihypertensive agents. When treatment with TKI was initiated, incident CML patients presented with comorbidities and polypharmacy, which merits attention because of the persistent use of these concomitant drugs and the potential increased risk of drug-drug interactions.

Importance of BCR/ABL1 Transcript Type in CML

<h3>Introduction</h3> The <i>BCR/ABL1</i> fusion exists in several different isoforms, depending on the precise position of the t(9;22)(q34;q11) genomic breakpoints in each case. In chronic myeloid leukemia (CML), the two most common isoforms are known as e13a2 and e14a2, which are shorthand for mRNA fusions of <i>BCR</i> exon 13 or <i>BCR</i> exon 14, respectively, to <i>ABL1</i> exon 2. Historically, these two fusions were referred to as b2a2 and b3a2, with b2 (<i>BCR</i> exon 13) and b3 (<i>BCR</i> exon 14) corresponding to the second and third exons within the classically-defined 5.8-kb major breakpoint cluster region (M-BCR) within <i>BCR.</i>¹ Both e13a2 and e14a2 encode a 210-kDa BCR/ABL1 protein (p210), but e14a2 encodes a chimeric protein that is 25 amino acids larger than e13a2, corresponding to the 75 bp of <i>BCR</i> exon 14. At the genomic DNA level, the chromosome 22 breakpoint typically occurs in <i>BCR</i> intron 13 for e13a2 and <i>BCR</i> intron 14 for e14a2. Collectively, e13a2 and e14a2 <i>BCR/ABL1</i> account for 98% of CML cases, with the majority of these expressing e14a2. Approximately 10% of cases express both isoforms.^1,2 A large international survey of CML cases found small but significant differences in the relative prevalence of the two fusions in relation to age and gender, with e13a2 being more frequent in males and less common in the elderly.²

Spectrum of BCR-ABL Mutations and Treatment Outcomes in Ethiopian Imatinib-Resistant Patients With Chronic Myeloid Leukemia.

PURPOSEDespite the successes achieved in chronic myeloid leukemia (CML) with tyrosine kinase inhibitor (TKI) therapy, resistance remains an obstacle. The most common mechanism of resistance is the acquisition of a point mutation in the BCR-ABL kinase domain. Few studies have reported African patients with CML in regard to such mutations. We here report the types of BCR-ABL mutations in Ethiopian imatinib-resistant patients with CML and their outcome.PATIENTS AND METHODSPatients with CML with a diagnosis of imatinib resistance who were tested for BCR-ABL mutation between 2014 and September 2019 were included.RESULTSA total of 962 cases of CML on imatinib therapy were reviewed and 164 cases of failure were found. Of these, only 31 cases (19%) had mutation analysis performed. Most cases (94%) were secondary failures. At the time of CML diagnosis, the median age was 33 years and the majority presented with features of advanced-phase disease. Of the 31 patients, 22 mutations were found (65%). The types of mutations detected were as follows: non–P-loop mutations 36% (11), P-loop mutations 13% (four), and alternatively spliced BCR-ABL variants 23% (seven). The splice variant frequently detected was BCR-ABL35INS (20%). Twenty-six of the 31 patients (84%) were switched to second-line TKIs, whereas in four patients (13%), imatinib dose escalation was done. Overall, the outcome revealed that 16 patients (52%) were alive with complete hematologic response, whereas 12 patients (39%) had died. All patients who expressed BCR-ABL135INS were treated with second-line TKIs, and two of them (33%) had died because of disease progression.CONCLUSIONIn Ethiopia, CML affects the young and point mutations were frequently detected in imatinib-resistant patients. BCR-ABL1 35INS was also prevalent and associated with disease progression.

Long-Term Outcome of Philadelphia Chromosome Positive Leukemia From Eastern Indian Subcontinent: An Experience in the Era of Tyrosine Kinase Inhibitor (TKI) Therapy

IntroductionPhiladelphia chromosome (Ph) marks a group of leukemia with almost all cases of chronic myeloid leukemia (CML), a subset of acute lymphoid leukemia (ALL) and rare cases of acute myeloid leukemia (AML). In the era of precision medicine, such cases are successfully managed with tyrosine kinase inhibitor (TKI) drugs. This study examined the features and long-term outcome of Ph+ve cases from a tertiary cancer care center from Eastern Indian subcontinent. Materials and MethodsReviewing retrospective case-records registered between 2005 and 2015, cases of CML and ALL were documented under Ph+ve category; while no instance of Ph+ve AML was found. ResultsIn CML cohort, adult and juvenile incidences were 95.2% and 4.8% respectively; in ALL cohort, the same was found for 66.67% and 33.33% cases. Among the CML cases, 10-year overall survival (OS) and progression-free survival (PFS) were significantly affected upon the phase of disease at time of detection. Furthermore, both OS and PFS significantly dropped whenever non-TKI-based treatment was applied prior to TKI-commencement. Long-term (10-year) sensitivity to 1st generation TKI, imatinib, was noted 88.51% and 83.33% for adult and juvenile CML cohorts, respectively. For Ph+ ALL cohort, the OS was benefitted upon combinatorial TKI and chemotherapy. However, large fractions of affected individual from CML as well as ALL cohorts were found to discontinue follow-up. ConclusionTogether with differences in outcome on the basis of drug-use from onset, age (juvenile versus adult) and stage at diagnosis, our analyses bring forward the real-world scenario of Ph+ve leukemia managed with precision medicine.

Alterations in Sialylation Patterns are Significantly Associated with Imatinib Mesylate Resistance in Chronic Myeloid Leukemia

The study examined sialylation changes for their potential predictive value in assessment of imatinib mesylate (IM) resistance, alone and/or with BCR-ABL1 transcript variants among chronic myeloid leukemia (CML) cases. A total of 98 CML cases (un-treated cases, IM non-responders and IM responders) were enrolled in the study. Total sialic acid (TSA) and total protein (TP) levels were estimated spectrophotometrically, the expression profiles of BCR-ABL1, ST3GAL1 and ST3GAL2 were evaluated using qRT-PCR assays and BCR-ABL1 transcript variants were identified through subjecting PCR products to agarose gel electrophoresis. The results manifested increase in e14a2 transcript and decrease in co-expression of both transcripts (e13a2 and e14a2) in IM non-responders than un-treated CML cases. Notably, TSA/TP ratio was higher, whereas ST3GAL1 and ST3GAL2 expressions were lower in un-treated CML cases and IM non-responders as against IM responders. Further, ST3GAL2 expression was lower in un-treated CML cases than IM non-responders. Receiver operating characteristic curves also proved their discriminatory efficiencies. Decisively, the rise in TSA levels and the fall in ST3GAL1 and ST3GAL2 levels were evidently related to CML progression and clinical indicators of treatment failure (high BCR-ABL1 ratio, high WBC count, high platelet count and low Hb levels). The alterations in TSA, ST3GAL1 and ST3GAL2 levels were remarkably associated with each other. The altered levels of TSA, ST3GAL1 and ST3GAL2 are, to a significant extent, associated with IM resistance in CML, which have clinical relevance in treatment monitoring and IM resistance treatment.

Chronic Myeloid Leukemia with Pancytopenia in a 30-year Old Male: Challenges in Care

We report a case of chronic myeloid leukemia (CML) of a 30-year-old man who presented to a University Teaching Hospital with a history of spontaneous epistaxis associated with generalized body weakness and on and off right-sided chest pains, palpitations, fatigue, hyperhidrosis, and loss of weight. He is a known patient who had been on treatment for a period of 7 months with 400mg of imatinib. He presented with a nasal pack, pallor of grade 2, and splenomegaly. His labs showed pancytopenia, with severe thrombocytopenia and had a working diagnosis established through examination of a bone marrow aspirate. A more definitive diagnosis could not be attained though due to the unavailability of molecular techniques such as reverse transcription PCR (RT-PCR) for the demonstration of the BCR-ABL gene. The case also presented a management dilemma in terms of its progression and the deterioration of the patient despite being fairly compliant and receiving appropriate treatment.

Epidemiological, therapeutic, cytogenetic, and molecular profile of chronic myeloid leukemia at the national reference university hospital of N’Djamena from 2010-2020, Chad

The aim is to determine the epidemiological and cytogenetic profile (Philadelphia chromosome: Ph1) and the bcr-abl gene in patients with chronic myeloid leukemia (CML) and to assess the therapeutic response of patients to hydroxy-urea and Imatinib treatment. From January 1, 2010 to December 30, 2020, an observational study for diagnostic and analytical purposes was carried out in 54 cases of CML at the National Reference University Hospital (CHU-RN) of N’Djamena. All selected patients presented with splenomegaly on physical examination. Significant differences were observed between the proportion of housewives (31.48%) and civil servants (3.70%), emaciated patients (27.84%) and those with fever (3.70%) with the probabilities of 0.001 and 0.001 respectively. Hyperleukocytosis ranged from 100,000-149,000 GB / mm3 (42.30%) and the platelet count ranged from 20,000 / mm3 to 611,000 / mm3. Polymorphic and massive myeloma was 30-80% of cases, a medullary karyotype with 33.33% Ph1 + chromosome and 66.66% Ph1-, 33.33% bcr-abl transcript and 33.33% transcribed b3 a2 respectively. The treatment regimens were: Hydroxy-Urea (HU) + prednisolone (60%), and Imatinib + prednisolone (40%). Partial hematological remission was obtained in 40% of cases. CML is a condition that occurs at all ages and especially in men in our region. The continuation of this study at the national level will allow the public authorities to achieve national prevalence and to organize effective prevention and early management.

Atherosclerotic Arterial Disease-Related Mortality in Chronic Myeloid Patients Treated with Tyrosine Kinase Inhibitors

Introduction:Vascular events is an emerging issue in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). As these patients achieve near-normal life expectancies on TKIs, there is clinical concern that TKI-associated vascular events may adversely affect survival. Cardiovascular disease-related mortality (CVDRM), including heart disease and stroke, is the leading cause of death in the US and disproportionately affects African-Americans (AA) whose age-adjusted CVDRM rates are 33% higher than the US population. Whether use of TKIs in AA patients with CML further increases the risk of CVDRM is not known. In this population level study, we compared the risk of CVDRM in CML patients between pre-TKI and TKI treatment eras and between ethnicities.Methods: All 18 Surveillance Epidemiology and End Results (SEER) registries were queried for CML cases, information on ethnicity, survival and cause of death using the custom-built SEERaBomb program. Treatment periods were defined based on the year of introduction of imatinib (2001). Pre-TKI and TKI treatment eras therefore included CML cases diagnosed before and after 2002, respectively. Pharmacotherapy (PhT) receipt in SEER includes both chemotherapy and targeted anti-cancer agents and is recorded only if the initial treatment was initiated within the first 3 months of diagnosis. For this study, we assumed PhT in the TKI era to be predominantly TKIs. CVDRM included mortality from cardiac and cerebrovascular diseases. Absolute CVDRM risks were calculated based on observed deaths and number of patients at risk for years 2-10 after cancer diagnosis, because mortality in the first year is likely to be influenced by predisposing conditions. Hazard ratios (HR) for CVDRM were calculated in multivariate Cox regression analyses with backwards selection procedures. Relative risks (RR) for CVDRM, adjusted for age, sex and year, were calculated by comparing CVDRM rates in CML cohort to the general population using US background population data from the Centers of Disease Control's Wonder dataset.Results: Of 21,997 CML cases, 10,326 were diagnosed in the pre-TKI era and 11,671 in the TKI era. 17,697 patients where white and 2,380 were of AA ethnicity. In the TKI era, 74% and 78% of white and AA CML patients received PhT, respectively. When compared to the referent background US population rates, CVDRM rates were higher in the pre-TKI era than in the TKI era (Fig 1). In the pre-TKI era, there were no differences in CVDRM risks (heart disease or cerebrovascular disease) based on receipt of PhT (Fig 1a+c). In contrast, in the TKI era, receipt of PhT was associated with significantly lower risks of CVDRM compared to no PhT in years 2-10 after diagnosis (RR for PhT vs. no PhT: 0.69 [95% CI 0.55-0.88] P= 0.002; Fig 1b+d). Absolute risk for CVDRM in years 2-10 after CML diagnosis was higher in the pre-TKI era than in the TKI era (8.1% vs. 3.8%). In the TKI era, absolute risk for CVDRM in years 2-10 was lower in those who received PhT compared to untreated patients (2.9% vs. 7.0%). In multivariable regression analyses, receipt of PhT was significantly associated with lower hazard of CVDRM, while AA ethnicity was associated with significantly higher CVDRM hazards in the TKI era but not in the pre-TKI era (Table 1). While CVDRM risks remained stable in Caucasian CML patients and was not influenced by PhT, in AA CML patients on PhT (compared to no PhT) the CVDRM risks continue to show a steady upward trend even a decade out from diagnosis (Fig 2).Conclusion: This study is the first to shed light on differences in CVDRM risks in CML patients by ethnicity and receipt of PhT. A worrisome finding was the observed increased risk of CVDRM in AA CML treated with PhT, suggesting that these patients are particularly vulnerable to TKI-associated fatal atherosclerotic complications. This data argues for aggressive management of CVD risk factors in AA CML patients on PhT. The reason for why risks of CVDRM in CML patients treated with PhT is lower than those untreated in the TKI era is not clear. One plausible explanation is that although PhT (TKIs) increase risks of CVD (as shown in randomized clinical trials), majority of these atherosclerotic events may not be necessarily fatal. Future research should be directed towards understanding the biology behind ethnic differences in risk of CVDRM with TKI use and its potential interaction with other atherosclerotic risk factors. [Display omitted] DisclosuresAdvani:Pfizer: Consultancy; Takeda/ Millenium: Research Funding. Gerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Apellis Pharmaceuticals: Consultancy; Ra Pharma: Consultancy. Majhail:Sanofi: Honoraria; Anthem, Inc.: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.