Discontinuation of Tyrosine Kinase Inhibitor Therapy and Treatment Free Remission (TFR) in Chronic Myeloid Leukemia: Successful Achievement of TFR in More Than Two-Third of Patients in a Real-World Practice.

BACKGROUND: Discontinuation of TKI therapy and treatment-free remission (TFR) have become new goals for chronic-phase chronic myeloid leukemia (CP-CML). The aim of this study was to estimate the TFR post discontinuation of TKI therapy at 3 tertiary-care centers. PATIENTS AND METHODS: CP-CML patients aged ≥16 years who had an attempt to discontinue TKI therapy till June 2022, were eligible. The collected data included patients' demographics, prognostic score, type and duration of TKI therapy, response dates, relapse dates, response to re-initiation of TKI therapy, and risk factors for relapse. RESULTS: Fifty-five patients (35, 63.6% females) with a median age of 40 (range 16-74) years at diagnosis discontinued therapy. Forty-eight (87.3%) patients received imatinib as first line therapy. Twenty-nine (52.7%) patients were receiving imatinib at the time of TKI-discontinuation. Median time from diagnosis to TKI discontinuation was 86 months (IQR 60;132) and median duration of TKI therapy after achieving DMR was 66 months (IQR 47;114). After a median follow up of 34 (IQR 12;68) months, 15 (27.3%) patients relapsed. Median time to relapse was 5 months (range 2-38). Most of the relapses occurred during the first 6 months except 3 (20%) patients. All the relapsed patients achieved MMR after a median of 3 (range 2-6) months after restarting TKI therapy. None of the patients progressed to advanced-phase. CONCLUSION: Our experience confirms that discontinuation of TKI therapy in CP-CML patients is feasible and safe in routine clinical practice, and can achieve TFR in more than two-third of carefully selected patients.

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case-Control Study.

Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients' blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials.

Bleeding Diathesis as the Initial Presentation of Chronic Myeloid Leukemia: A Case Series.

Chronic myelogenous leukemia, or CML, is another name for chronic myeloid leukemia (CML), a cancer type that starts in certain bone marrow blood-forming cells. The primary initiator of granulocytic proliferation in CML, a myeloproliferative malignancy, is the BCR-ABL1 fusion protein or Philadelphia chromosome. CML is classified into three stages: chronic, accelerated, and blast. It has been widely recognized that the likelihood of developing CML varies by gender, geography, and age. In the chronic phase of CML (CML-CP), bleeding is a rare sign since the thrombocyte and coagulation functions are still adequate. Uncertainties exist regarding the CML bleeding mechanism. We report four cases of CML-CP in adult patients. The majority of these patients had CML and had idiopathic spontaneous bleeding in multiple locations.

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Eltrombopag for tyrosine kinase inhibitors-associated thrombocytopenia in chronic myeloid leukemia.

Patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML) can develop cytopenias secondary to bone marrow hypoplasia after starting tyrosine kinase inhibitor (TKI) therapy. These adverse effects are usually transient, but cytopenias can persist in some patients. TKI-associated thrombocytopenia can develop in a significant proportion of CML patients and may require TKI dose reduction or dose interruptions. The thrombopoietin receptor agonist eltrombopag may improve thrombocytopenia in these patients, but the supporting literature for this approach is limited. Herein, we describe the case of a 56-year-old woman who developed persistent TKI-associated thrombocytopenia and intracranial hemorrhage. She could not tolerate full doses of imatinib and she failed to achieve a major molecular response (MMR). She responded to eltrombopag and platelet count improved, which allowed commencement and continuation of dasatinib as second-line TKI therapy, resulting in achievement of MMR. TKI-associated thrombocytopenia can cause serious bleeding and may also interfere with the management of CML by necessitating TKI dose interruption or reduction. Use of eltrombopag can help maintain adequate platelet counts and uninterrupted delivery of TKI therapy.

Response to Lisinopril in Patients with Sickle Cell Anemia and Proteinuria.

Proteinuria is a manifestation of sickle cell anemia (SCA)-related renal disease and is a risk factor of renal impairment. Angiotensin-converting enzyme (ACE) inhibitors have benefits, but their role in SCA remains undefined. This study aimed to assess the role of lisinopril, an ACE inhibitor, in reducing proteinuria in SCA patients. Thirty-five patients older than 15 years with known SCA (HbSS or HbS-ß0) and a 24-h urinary protein level of 150 mg or more participated in this study. Urine was collected over 24 h to quantify proteinuria. The patients had a mean age of 28.5 ± 6.98 years. The median 24-h urinary protein before treatment was 0.3006 g and that after treatment was 0.150 g (P = 0.01). After a median follow-up of 38 months, 24-h urinary protein decreased in 27 (77%) patients and normalized in 18 (52%) patients. Urinary protein increased in 2 (6%) patients and remained stable (no change) in 6 (17%) patients. There was no significant difference in blood pressure (BP) before and after treatment. The average dose of lisinopril was 5 mg. Twenty patients were still on lisinopril at last follow-up. The reasons for stopping lisinopril included normalization of protein, noncompliance, adverse effects, and pregnancy. Lisinopril effectively reduced proteinuria in SCA patients, without significantly reducing BP. Only a few patients developed adverse effects, including coughing, dizziness, and diarrhea. It is unclear how long lisinopril should be continued and whether it can be stopped in patients with normalized urinary protein.

Knowledge and Behavior toward Venous Thromboembolism Event Prophylaxis and Treatment Protocols among Medical Interns in Riyadh.

Objective: This study was aimed at evaluating the knowledge and behavior toward venous thromboembolism (VTE) prophylaxis among medical interns. Methods: This is a questionnaire-based cross-sectional observational cohort study of medical interns that used a validated questionnaire. The questionnaire comprised of items that assessed behavior, knowledge, and self-assessment of VTE risk factors, diagnosis, and prophylaxis. The study was conducted in Riyadh, Saudi Arabia, from October 2020 till September 2021. Results: The respondents were 246 medical interns. The overall rate of correct responses to behavior items was 41.82%. The overall rate of correct responses to knowledge items was 47.35%. A total of 61.8% responded negatively to the use of VTE risk assessment guidelines (p < 0.0001). For the self-assessment of knowledge of VTE, more than 70% believed they did not have appropriate knowledge, were not prepared to establish the risk of VTE, and were not prepared to provide adequate prophylaxis for VTE (p < 0.0001). A high proportion of medical interns (83.3%, p < 0.0001) believed they needed further training on this topic. Conclusion: Participants in this study showed poor knowledge and negative behavior regarding the assessment of risk factors, diagnosis, and prophylaxis of VTE. The majority of participants reported they needed training on this topic. These findings underscore the need for educational programs during undergraduate training and orientation of medical interns for VTE risk assessment, diagnosis, and prophylaxis at the beginning of their internship.

Pro106Leu MPL mutation is associated with thrombocytosis and a low risk of thrombosis, splenomegaly and marrow fibrosis.

The P106L mutation in the human myeloproliferative leukemia virus oncogene (MPL) was shown to be associated with hereditary thrombocythemia in Arabs. The clinical and bone marrow (BM) features of P106L mutation are unknown. Genetic databases at two tertiary hospitals in Saudi Arabia were searched to identify patients with the MPL P106L mutation. Clinical data were collected retrospectively and the BM aspirates and biopsies were independently reviewed by two hematopathologists. In total, 115 patients were included. Median age was 33 years of which 31 patients were pediatric and 65 were female. The mutation was homozygous in 87 patients. Thrombocytosis was documented in 107 patients, with a median platelet count of 667 × 109/L. The homozygous genotype was associated with a higher platelet count. Thirty-three patients had an evaluable BM and clustering of megakaryocytes was observed in 30/33 patients. At the time of last follow-up, 114 patients were alive. The median follow-up was 7.8 years from the time of thrombocytosis. No patients developed disease progression to myelofibrosis. The P106L mutation was associated with marked thrombocytosis at a younger age and with a low risk of thrombosis, splenomegaly, and marrow fibrosis. The BM demonstrated normal or hypocellular marrow with megakaryocyte clusters.

Survival and Epidemiologic Trends of Lymphomas in Saudi Arabia: A 10-Year Report from a Tertiary Care Hospital.

Background: The current trends in lymphoma cases from Saudi Arabia and their long-term survival are unknown. This study was conducted to evaluate the trends of lymphoma diagnoses and survival from a major tertiary care hospital in Saudi Arabia. Methods: This retrospective study included all new cases of lymphoma diagnosed in adults (age ≥18 years) at King Saud University Medical City, Riyadh, Saudi Arabia, from 2008 to 2018, as identified from the Saudi Cancer Registry. Data on the demographics and clinical characteristics were collected, the survival outcomes were estimated, and multivariate analysis of the overall survival was calculated. Results: A total of 422 patients were included (median age: 46 years). The number new cases of lymphoma diagnosed variably increased over the study period: From 28 (7%) cases in 2009 to 48 (11%) in 2018. The most common lymphoma was diffuse large B-cell lymphoma (175; 41%): and extranodal site was GI involvement (33.5%). In terms of survival, 79% were alive at the last follow-up. On multivariable analysis, the hazard ratio (HR) for patients aged ≥60 years was 3.44 (95% CI: 2-5.9; P = 0.0000069), adjusted for lactate dehydrogenase level (LDH) and disease stage. For advanced-stage disease and high LDH, the HR was 4.2 (95% CI: 1.5-11.8, P = 0.00637) and 0.5 (95% CI: 0.28-0.97; P = 0.04106), respectively. Conclusions: The lymphoma trend in the Saudi Arabian population showed variable increase in cases over the study period, with most patients presenting with advanced-stage disease and at a younger age. The overall survival was comparable with studies from Western countries.

Integrated Genomic Analysis Identifies ANKRD36 Gene as a Novel and Common Biomarker of Disease Progression in Chronic Myeloid Leukemia.

Background: Chronic myeloid leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(9;22) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKIs) has changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, the mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find novel biomarkers of CML progression by employing whole-exome sequencing (WES). Materials and Methods: WES of accelerated phase (AP) and blast crisis (BC) CML patients was carried out, with chronic-phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing were carried out using Illumina platforms. Statistical analysis was carried out using SAS/STAT software version 9.4, and R package was employed to find mutations shared exclusively by all AP-/BC-CML patients. Confirmation of mutations was carried out using Sanger sequencing and protein structure modeling using I-TASSER followed by mutant generation and visualization using PyMOL. Results: Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modeling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions: Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in humans. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in the biology and progression of CML.

Assessment of anti-factor Xa activity in critically ill COVID-19 patients receiving three different anticoagulation regimens.

INTRODUCTION: Critically ill COVID-19 patients are at increased risk of thrombosis with an enhanced risk of bleeding. We aimed to explore the role of anti-factor Xa levels in optimizing the high-intensity anticoagulation's safety and efficacy and finding possible associations between D-dimer levels, cytokine storm markers, and COVID-19-induced coagulopathy or thrombophilia. METHODS: Retrospective cohort study conducted on 69 critically ill COVID-19 patients who received three regimens of higher intensity anticoagulation. RESULTS: Seventeen patients (24.6%) received high-dose enoxaparin prophylaxis, 29 patients (42%) received therapeutic doses of enoxaparin, and 23 patients (33.3%) were on therapeutic unfractionated heparin infusion. Fewer than one-third of the whole cohort (n = 22; 31.8%) achieved the target range of anti-factor Xa. The patients were divided into three subgroups based on anti-factor Xa target status within each anticoagulation regimen; when compared, the only association observed among them was for interleukin-6 levels, which were significantly higher in both the "above the expected range" and "below the expected range" groups compared with the "within the expected range" group (p = 0.009). Major bleeding episodes occurred in 14 (20.3%) patients and were non-significantly more frequent in the "below the expected anti-factor Xa range group" (p = 0.415). Seven patients (10.1%) developed thrombosis. The majority of patients had anti-factor Xa levels below the expected ranges (four patients, 57.1%). CONCLUSION: Conventional anti-factor Xa ranges may not be appropriate as a predictive surrogate for bleeding in critically ill COVID-19. The clinical decision to initiate therapeutic anticoagulation preemptively may be individualized according to thrombosis and bleeding risks. Cytokine storm markers, namely, interleukin-6, may play a role in COVID-19-induced coagulopathy or thrombophilia.

Discovery and Protein Modeling Studies of Novel Compound Mutations Causing Resistance to Multiple Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia.

OBJECTIVE: BCR-ABL fusion oncogene is the hallmark of chronic myeloid leukemia (CML), causing genomic instability which leads to accumulation of mutations in BCR-ABL as well as other genes. BCR-ABL mutations are the cause of tyrosine kinase inhibitors (TKIs) resistance in CML. Recently, compound BCR-ABL mutations have been reported to resist all FDA approved TKIs. Therefore, finding novel compound BCR-ABL mutations can help and clinically manage CML. Therefore, our objective was to find out novel drug-resistant compound BCR-ABL mutations in CML and carry out their protein modelling studies. METHODOLOGY: Peripheral blood samples were collected from ten imatinib resistant CML patients receiving nilotinib treatment. BCR-ABL transcript mutations were investigated by employing capillary sequencing. Patient follow-up was carried out using European LeukemiaNet guidelines. Protein modeling  studies were carried out for new compound mutations using PyMol to see the effects of mutations at structural level. RESULTS: A novel compound mutation (K245N mutation along with G250W mutation) and previously known T351I utation was detected in two of the nilotinib resistance CML patients respectively while in the rest of 8 nilotinib responders, no resistant mutations were detected. Protein modelling studies indicated changes in BCR-ABL mutant protein which may have negatively impacted its binding with nilotinib leading to drug resistance. CONCLUSION: We report a novel nilotinib resistant BCR-ABL compound mutation (K245N along with G250W mutation) which impacts structural modification in BCR-ABL mutant protein leading to drug resistance. As compound mutations pose a new threat by causing resistance to all FDA approved tyrosine kinase inhibitors in BCR-ABL+ leukemias, our study opens a new direction for in vitro characterization of novel BCR-ABL compound mutations and their resistant to second  generation and third generation TKIs.

Long term outcome of chronic myeloid leukemia patients treated with imatinib: Report from a developing country.

The outcome of chronic myeloid leukemia has been greatly improved by the use of Imatinib (IM), a selective BCR/ABL kinase inhibitor. The aim of present study was to report long term follow-up & outcome of IM-treated CML patients along with their clinicopathological features, risk group stratification, adverse events and to compare it with CML patients reported from western countries. The mean follow-up of 123 CML patients was 5.5 years in present study, who were treated with frontline IM 400mg daily in a tertiary care hospital in Pakistan. Risk stratification scores, response to treatment (ELN guidelines) and survival outcomes estimated by Kaplan-Meier analysis. Mean age: 35 years (9-67 years) and M: F: 1.5:1, mean follow up time: 5.5 years (1-15 years). Overall survival (OS): at 5.5, 8, 10 and 12 years were 93%, 88%, 81% and 73%, respectively. Progressions free survival (PFS) was 95%, 83%, 83% and 78% at 5.5, 8, 10 and 12 years, respectively. OS estimate by Sokal score was significant (P-value: 0.0019). Additional chromosomal aberrations: 1.6%. Eighteen (14.6%) patients progressed to AP/BC. Adverse events were moderate and tolerable. We present findings from a long term follow up of CML patients treated with IM in a developing country. CML mean age at onset was considerably lower than the western populations. Furthermore, 5.5 years OS are comparable to western CML population. IM in our patients as frontline choice proved to be very effective. IM was found to be well tolerated, safe with manageable moderate side effects.

Consensus Statement by an Expert Panel on the Diagnosis and Management of Iron Deficiency Anemia in the Gulf Cooperation Council Countries.

BACKGROUND: Iron deficiency (ID) and ID anemia (IDA) are common in the member states of the Gulf Cooperation Council (GCC). The unique genetic and lifestyle factors of the patient population in the region have necessitated the development of recommendations to help educate health-care professionals on appropriate diagnosis and management of ID/IDA. METHODS: A panel of regional experts, including gastroenterologists and hematologists with expertise in the treatment of IDA, was convened to develop regional practice recommendations for ID/IDA. After reviewing the regional and international literature, the expert panel developed consensus recommendations for screening, diagnosis, and treatment of patients with IDA in the GCC region. RESULTS: The recommendations proposed were customized to the patient population keeping in view the increasingly recognized burden of coeliac disease, high fertility and obesity rates, high prevalence of alpha- and beta-thalassemia traits, and poor tolerance and low treatment compliance with oral iron therapy. CONCLUSIONS: This consensus statement proposes recommendations for screening, diagnosis, and treatment of IDA in the GCC region.

Detection of Exon 12 and 14 Mutations in Janus Kinase 2 Gene Including a Novel Mutant in V617F Negative Polycythemia Vera Patients from Pakistan.

The most frequently reported genetic aberration among polycythemia vera (PV) patients is a gain of function mutation V617F in exon 14 of Janus kinase 2 (JAK2) gene. However in many investigations, V617F negative PV patients have been reported to harbor mutations in JAK 2 exon 12. We investigated 24 patients with PV (diagnosed following 2016 WHO guidelines) to detect V617F mutation through allele specific PCR. The frequency of which was found to be 19/24 (79.2 %). Later on JAK2 exon 12 and 14 was amplified by conventional PCR in V617F negative patients and subjected to sequence analysis. A total of 03 mutated sites in exon 12 were detected in only two V617F-negative patients 2/5 (40%). All three substitutions were heterozygous i.e. F537F/I found in both patients and R528R/T, which is a novel mutation. In addition, one patient 1/5 (10%) manifested amino acid substitution V617A in JAK2 exon 14. Hematological parameters of individuals harboring mutations do not vary significantly than rest of the PV patients. Previous history and 2.3 years of follow-up studies reveal 15-year survival of V617F positive patients (n=19) to be 76%, while it is 94% for wild type V617 patients (n=05). Mean TLC of the patient cohort was 17.6± 9.1 x 109/L, mean platelet count was 552± 253 x 109/L, mean hemoglobin was 16.9± 3.2 g/dl, mean corpuscular volume (MCV) was 77.2± 13.0 fl and mean corpuscular hemoglobin (MCH) was 25.6± 3.9 pg. This is the very first attempt from Pakistan to screen JAK2-exon 12 mutations in PV patients. We further aim to investigate Jak2 exon 12 mutations in larger number of PV patients to assess their clinical relevance and role in disease onset, progression and transformation.

Utilizing Whole-Exome Sequencing to Characterize the Phenotypic Variability of Sickle Cell Disease.

BACKGROUND: Sickle cell disease (SCD) is a monogenic disease that has wide variety of phenotypes with both and environmental factors contributing to its severity. METHODS: We performed whole-exome sequencing (WES) in 22 Saudi SCD patients to identify variants that could explain differences in disease phenotypes. All variants, except those that were benign and likely benign, described in the ClinVar database, were considered in our analysis. Gene-based association testing using sequence kernel association optimal unified test (SKAT-O) with small sample adjustment was performed to evaluate the effect of multiple variants in genes on SCD phenotypes. RESULTS: The mean age of participants was 28 (range, 10-48 years). All patients were homozygous for the sickle cell mutation. The Benin haplotype was present in 15 patients and the Arab-Indian haplotype in 7 patients. One patient who had both SCD and CHARGE association was heterozygous for pathogenic mutation p.Arg987Ter in the CHD7 gene. One SCD individual who had a stroke was a carrier of the pathogenic variant p.Asp36Tyr in the VKORC1 gene which is, associated with warfarin resistance. Two patients with steady hemoglobin levels of 7.5 and 7.1 g/dL were carriers of the pathogenic mutation p.Gly140Ser in the RPL5 gene that is associated with Diamond-Blackfan anemia. None of the patients were transfusion dependent. A heterozygous pathogenic mutation in the LDLR gene associated with autosomal dominant familial hypercholesterolemia was present in one patient with deep venous thrombosis, although their cholesterol level was normal. One individual with stroke was a carrier for the p.Arg284Ter variant in the NLRP12 gene, which is associated with familial cold autoinflammatory syndrome 2. Another patient with stroke and a pulmonary embolism was heterozygous for the p.Pro106Leu variant of the MPL gene, which has been associated with thrombocytosis. Coding variants in the GOLGB1, ENPP1, and PON1 genes showed no association with stroke in our study. SKAT-O analysis did not explain SCD heterogeneity. CONCLUSION: WES provided limited information to explain the severity of SCD. Whole genome sequencing, epigenetic studies, and assessment of environmental factors might expand our knowledge of SCD heterogeneity.

Acute Lymphoblastic Leukemia Presenting with Liver Infiltration and Severe Lactic Acidosis.

BACKGROUND Type-B lactic acidosis is a rare complication of solid tumors and hematological malignancies. It occurs secondary to Warburg effect, when glucose metabolism in cancer cells switches from the oxidative pathway to the glycolytic pathway. Malignant lactic acidosis is a life-threatening condition if not promptly diagnosed and treated urgently. CASE REPORT We report the case of a 58-year-old male patient who presented with severe chest pain, dyspnea, systemic symptoms, leukopenia, normocytic anemia, and severe lactic acidosis. He was admitted with a possible diagnosis of acute pericarditis and lactic acidosis. Sodium bicarbonate replacement did not improve the lactic acidosis. Liver biopsy was performed because of persistently elevated alkaline phosphatase and gamma-glutamyl transferase; the biopsy showed atypical lymphoblasts and bone marrow biopsy confirmed the diagnosis of precursor B acute lymphoblastic leukemia. Lactic acidosis normalized after initiation of chemotherapy. CONCLUSIONS Cancer, particularly hematological malignancy, should be considered as an etiology and differential diagnosis of type-B lactic acidosis. Prompt recognition and urgent initiation of specific therapy to control the underlying malignancy are critical to manage this serious metabolic complication.

Impact of Day 14 Bone Marrow Biopsy on Re-Induction Decisions and Prediction of a Complete Response in Acute Myeloid Leukemia Cases

Background: With acute myeloid leukemia (AML), there are limited data about the accuracy of day 14 bone marrow (BM) biopsies for predicting complete remission as compared to day 28 BM biopsy results. We here aimed to estimate the correlation between, and the diagnostic accuracy of, both approaches. Materials and Methods: We reviewed 84 patients with AML treated with standard induction chemotherapy to evaluate the remission rate and treatment decisions based on day 14 BM biopsy from 2000-2012. Results: Sixty five patients (77%) demonstrated remission (CR) with less than 5% blasts on their day 14 BM. Thirteen patients (16%) had residual disease (RD), and 6 (7%) were classified as indeterminate response (IR) i.e., blasts 5-20%. Two patients with RD on day 14 underwent re-induction. Out of the 17 remaining cases with RD+IR, 14 (all 6 with IR and 8 out of 11 with residual disease with no re-induction) demonstrated a morphologic complete remission (CR) on day 28 BM. The percentages for complete remissions on days 28 and 14 were significantly different [94% versus 79.3%, respectively; p=0.004, (OR= 0.143, 95% CI: 0.032-0.63)]. Day 14 BM had 82% sensitivity in predicting CR on Day 28; however, it had insufficient specificity (60%) in predicting failure of CR. Conclusions: Induction treatment response assessment based on day 14 BM does not accurately predict the response rate on day 28 and the use of day 14 BM as a sole marker of response to therapy might expose patients to unnecessary interventions.

Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression.

BCR-ABL kinase domain (KD) mutations are well known for causing resistance against tyrosine kinase inhibitors (TKIs) and disease progression in chronic myeloid leukemia (CML). In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib (IM) sensitive CML patients. Therefore, we investigated presence of ABL-KD mutations in chronic phase (n = 41), late chronic phase (n = 33) and accelerated phase (n = 16) imatinib responders. Direct sequencing analysis was used for this purpose. Eleven patients (12.22%) in late-CP CML were detected having total 24 types of point mutations, out of which 8 (72.72%) harbored compound mutated sites. SH2 contact site mutations were dominant in our study cohort, with E355G (3.33%) being the most prevalent. Five patients (45%) all having compound mutated sites, progressed to advanced phases of disease during follow up studies. Two novel silent mutations G208G and E292E/E were detected in combination with other mutants, indicating limited tolerance for BCR-ABL1 kinase domain for missense mutations. However, no patient in early CP of disease manifested mutated ABL-KD. Occurrence of mutations was found associated with elevated platelet count (p = 0.037) and patients of male sex (p = 0.049). The median overall survival and event free survival of CML patients (n = 90) was 6.98 and 5.8 y respectively. The compound missense mutations in BCR-ABL kinase domain responsible to elicit disease progression, drug resistance or disease relapse in CML, can be present in yet Imatinib sensitive patients. Disease progression observed here, emphasizes the need of ABL-KD mutation screening in late chronic phase CML patients for improved clinical management of disease.