Prognosis Of Chronic Myeloid Leukemia Patients Research Articles

Real World Population- Based Data from Nationwide Registry Support the Existence of Accelerated Phase in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients Even in Tyrosine Kinase Inhibitors (TKIs) Era

Background For decades, CML has been considered to be a triphasic disease recognizing 3 distinct stages: chronic phase (CP), accelerated phase (AP), and blast crisis (BC). Since the discovery of TKIs, the prognosis of CML patients has rapidly improved and less than 10% of patients diagnosed in CP experience disease progression on the therapy. Based on low incidence of CML progression and the fact that CML biological behavior seems biphasic, the new WHO 2022 classification of CML deemed AP less relevant and suggested the omission of AP. Many experts, however, still advocate for its inclusion in CML classification (e.g. ELN 2020, ICC 2022, NCCN 2023), even though the universal definition of AP is not established and differs in between publications. Methods This retrospective, real-world study is based on the Czech nationwide CML registry INFINITY with the data of newly diagnosed CML patients who agreed and provided their written consent. Recruited subjects were adult patients diagnosed in years 2005 - 2022 with sufficient data to determine the phase of the disease at diagnosis and follow-ups to assess their overall survival (OS), disease specific survival (DSS) and progression-free survival (PFS). The phase of the disease at the time of diagnosis was determined using the classification according to ELN 2020, ICC 2022, WHO 2016, and WHO 2022. Whenever CP was established, EUTOS Long-Term Survival (ELTS) score was calculated, assigning the patient to low risk (LR), intermediate risk (IR) and high risk (HR) group. OS and PFS are defined according to published guidelines. DSS is defined as the time from diagnosis to death due to CML disease or CML treatment. Results During the studied time period, 1660 new cases of CML were reported in INIFINITY registry. Of them, 1500 patients had data sufficient to classify the phase of the disease at the time of the diagnosis according to ELN 2020 guidelines and WHO 2022 classification and 1395 patients had data to assess the phase according to WHO 2016 and ICC 2022 classifications. When using ELN 2020 guidelines, groups were assigned as follows: LR CP- 784 patients (52.3%), IR CP- 421 patients (28.1%), HR CP- 227 patients (15.1%), AP- 42 patients (2.8%), BC- 26 patients (1.7%). There were significant differences in representation by gender, age, comorbidities and performance score amongst patient groups. When comparing just HR CP and AP CML patients, there were no significant differences. Calculated estimates of 5- and 10- year OS, respectively, were 92.5% and 87.2% for LR CP, 83.5% and 65.9% for IR CP, 76.9% and 65.5% for HR CP, 59.2% and 45.9% for AP, and 32.9% for BC, p= 0.031 for HR CP versus AP (Figure 1). In the case of WHO 2016 and ICC 2022 classifications, 714 (51.2%) patients were diagnosed in LR CP, 374 (26.8%) in IR CP, 154 (11.0%) in HR CP, 125 (9.0%) in AP, and 28 (2.0%) in BC. Again, there were significant differences in representation by gender, age, comorbidities and performance score amongst patient groups. When comparing just HR CP and AP CML patients, only age at the time of diagnosis was significantly different. Calculated estimates of 5- and 10- year OS, respectively, were 93.2% and 87.5% for LR CP, 84.9% and 67.7% for IR CP, 80.0% and 69.5% for HR CP, 65.7% and 55.6% for AP, and 39.7% for BC. We also performed propensity score matching according to age for patients in HR CP and AP and calculated estimates of 5- and 10- year OS, respectively, were 85.4% and 74.4% for HR CP and 60.2%, and 52.0% for AP, p= 0.003 (Figure 2). Similar results were obtained when testing for PFS and DSS. Summary Real-world data obtained from 1500 patients diagnosed in Czechia over 17 years, in our opinion, support the need to recognize the existence of AP at the time of diagnosis, even though a singular definition of AP is not agreed upon. Patients in AP have worse survival scores (OS, DSS, PFS) compared to patients in CP and/or HR CP. Moreover, because ELTS risk score was calculated on patients in CP, it may not be suitable for patients in AP, which would be changed to CP according to the new WHO 2022 classification. In conclusion, based on the real-world data with long-term follow-up, we believe it would be reasonable to keep the AP as part of CML classification of newly diagnosed patients. This publication was supported by the grant number MUNI/A/1224/2022, Programme EXCELES, ID Project No. LX22NPO5102, and by the Ministry of Health of the Czech Republic grant number 00023736.

Profiling of miRNAs and their interfering targets in peripheral blood mononuclear cells from patients with chronic myeloid leukaemia.

MicroRNAs may be implicated in the acquisition of drug resistance in chronic myeloid leukemia as they regulate the expression of not only BCR-ABL1 but also genes associated with the activation of drug transfer proteins or essential signaling pathways. To understand the impact of specifically expressed miRNAs in chronic myeloid leukemia and their target genes, we collected peripheral blood mononuclear cells (PBMC) from patients diagnosed with chronic myeloid leukemia (CML) and healthy donors to determine whole miRNA expression by small RNA sequencing and screened out 31 differentially expressed microRNAs (DE-miRNAs) with high expression. With the utilization of miRNA set enrichment analysis tools, we present here a comprehensive analysis of the relevance of DE-miRNAs to disease and biological function. Furthermore, the literature-based miRNA-target gene database was used to analyze the overall target genes of the DE-miRNAs and to define their associated biological responses. We further integrated DE-miRNA target genes to identify CML miRNA targeted gene signature singscore (CMTGSS) and used gene-set enrichment analysis (GSEA) to analyze the correlation between CMTGSS and Hallmark gene-sets in PBMC samples from clinical CML patients. Finally, the association of CMTGSS stratification with multiple CML cell lineage gene sets was validated in PBMC samples from CML patients using GSEA. Although individual miRNAs have been reported to have varying degrees of impact on CML, overall, our results show that abnormally upregulated miRNAs are associated with apoptosis and aberrantly downregulated miRNAs are associated with cell cycle. The clinical database shows that our defined DE-miRNAs are associated with the prognosis of CML patients. CMTGSS-based stratification analysis presented a tendency for miRNAs to affect cell differentiation in the blood microenvironment. Collectively, this study defined differentially expressed miRNAs by miRNA sequencing from clinical samples and comprehensively analyzed the biological functions of the differential miRNAs in association with the target genes. The analysis of the enrichment of specific myeloid differentiated cells and immune cells also suggests the magnitude and potential targets of differentially expressed miRNAs in the clinical setting. It helps us to make links between the different results obtained from the multi-faceted studies to provide more potential research directions.

EP060: Characterizing the complex chromosomal rearrangements in a Philadelphia negative BCR/ABL1 positive case

The Philadelphia chromosome (Ph), produced by the reciprocal translocation t(9;22)(q34;q11.2), is a derivative chromosome 22 with a chimeric BCR/ABL1 fusion gene encoding constitutively active tyrosine kinase protein. The Ph occurs in 95% of chronic myeloid leukemia (CML) cases and the BCR/ABL1 fusion is a diagnostic hallmark for CML. A small subset of patients (around 5-10%), displaying typical features of CML, lack a Ph by chromosome analysis, but are shown to carry BCR/ABL1 fusion either by fluorescence in situ hybridization (FISH) or molecular analysis. Two major mechanisms have been proposed to explain how BCR/ABL1 rearrangements arise in these Ph-negative BCR/ABL1 positive cases: a cryptic insertion between chromosomes 9 and 22; or via two sequential translocations where a standard t(9;22) translocation is followed by an additional reverse translocation resulting in the reconstitution of the normal morphology of the partner chromosomes. The bone marrow specimen of a 66 year old female patient, presented with persistent leukocytosis with myelocytes and metamyelocytes, along with thrombocytosis, was sent to our lab for both BCR/ABL1 RT-PCR analysis and chromosome analysis, due to suspicious myeloproliferative neoplasm. The RT-PCR analysis showed the presence of the BCR/ABL1 major (p210) breakpoint fusion transcript b2a2 (e13a2). Initial chromosome analysis did not identify a typical t(9;22)(q34;q11.2) reciprocal translocation; instead, structural abnormalities were observed on the short arm of chromosome 12 and the long arm of chromosome 22. Overall, the abnormal chromosome 22 resembles the morphology of a “Philadelphia chromosome” while both homologs of chromosome 9 show normal morphology. This leads us to hypothesize that a complex rearrangement involving chromosomes 9, 12, and 22 might be contributing to this case. Metaphase fluorescence in situ hybridization (FISH) analysis was performed to test our hypothesis using BCR/ABL1 fusion probes, where the only cryptic BCR/ABL1 fusion signal was mapped to the long arm of chromosome 9 that has normal morphology at band q34, while the long arm of the derivative chromosome 22 is absent for BCR/ABL1 fusion signals, suggesting that the Ph-like derivative chromosome 22 is not a real Philadelphia chromosome, making this case a true Ph negative case. The final ISCN for the case is designated as: 46,XX,der(9)(9pter->9q34::22q11.2->22q11.2::9q34->9qter),der(12)(22qter->22q11.2::12p13->12qter),der(22)(22pter->22q11.2::12p13->12pter), and this can be explained by an initial three way translocation between chromosomes 9, 12, and 22 followed by an additional sequential reverse translocation between the derivative chromosomes 9 and 22, leading the cryptic BCR/ABL1 fusion being inserted into the long arm of chromosome 9 and bringing chromosome 9 back to a normal morphology. Cryptic BCR/ABL1 fusion has been characterized as a variant rearrangement in CML patients lacking Ph, and up to 50% of these cases with variant BCR/ABL1 fusion exhibit a del(9q) of the derivative chromosome 9, which has been considered to be a marker for poor prognosis in CML patients. Thus, chromosomal microarray analysis (CMA) was also performed for this case, and no deletions in 9q were identified. Here, we presented a case where FISH mapping was utilized to further characterize the complex chromosomal rearrangements between chromosomes 9, 12, and 22 in a Ph negative BCR/ABL1 positive case, which reveals that the cryptic BCR/ABL1 is inserted into the long arm of chromosome 9 with normal morphology at band q34, while the Ph-like derivative chromosome 22 is not a true Ph chromosome. Our study illustrates the challenge of recognizing the complex pattern of cytogenetic aberrations in these Ph negative BCR/ABL1 positive CML cases with variant BCR/ABL1 rearrangements, and highlights the importance of utilizing comprehensive cytogenomic and molecular techniques (including metaphase FISH, RT-PCR and CMA) in characterizing these complex chromosomal abnormalities for proper diagnosis and prognosis prediction.

Association of DNA repair gene XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) polymorphisms with the risk of chronic myeloid leukemia: A case-control study in a South Indian population.

Xeroderma pigmentosum complementation group C (XPC), a DNA repair protein, plays an important role in the maintenance of genomic integrity and is essential for the nucleotide excision repair pathway. Polymorphisms in the XPC gene may alter DNA repair leading to genetic instability and oncogenesis. The present study aimed to assess the relationship between the XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) non-synonymous polymorphisms and susceptibility to chronic myeloid leukemia (CML) pathogenesis, disease progression and the response to targeted therapeutic regimen, imatinib mesylate. This case-control study included 212 cases and 212 controls, and the genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism assays. Our results showed significant association of variant CT (odds ratio = 1.92, 95% confidence interval = 1.21-3.06, p =0.003) and TT (odds ratio = 2.84, 95% confidence interval = 1.22-6.71, p =0.007) genotypes in patients with the XPC Ala499Val polymorphism and CML risk. In addition, these genotypes were associated with CML progression to advanced phases (p =0.006), splenomegaly (p =0.017) and abnormal lactate dehydrogenase levels (p =0.03). XPC Lys939Gln was found to correlate with a poor response to therapy, showing borderline significant association with minor cytogenetic response (p =0.08) and a poor molecular response (p =0.06). Significant association of the Ala499Val and Lys939Gln polymorphisms with prognosis was observed (Hasford high risk, p = 0.031 and p = 0.019, respectively). Haplotype analysis showed a strong correlation of variant TC haplotype with poor therapy responses (minor cytogenetic response, p = 0.019; poor molecular response, p < 0.0001). In conclusion, our results suggest that XPC Ala499Val is a high-penetrance CML susceptibility polymorphism. Both polymorphisms studied are considered as genetic markers with respect to assessing disease progression, therapy response and prognosis in CML patients.

Assessment of Oxidative Stress in Patients with Chronic Myeloid Leukemia Depending on Associated Comorbidities.

Oxidative stress (OS) implies an imbalance between the amount of tissue level of prooxidant and antioxidant compounds. It is involved in the pathophysiology of multiple pathological entities (neoplasms, disorders of carbohydrate and lipid metabolism, cardiovascular and renal pathology etc.), as well as in the pharmacokinetics of specific treatments for these pathologies. Chronic myeloid leukemia (CML) is a chronic myeloproliferative disease for which current standard treatment is BCR-ABL tyrosine kinase inhibitors (TKIs). It is known that OS is involved in CML pathogenesis and response to TKIs therapy, but in reality, there are a number of additional factors (associated comorbidities, specific therapies) that modulate oxidative status, possibly affecting the evolution and prognosis of CML. In the present paper we proposed the evaluation of OS in a group of patients with CML following treatment with TKIs, depending on the presence of comorbidities and associated treatments. There were considered associated comorbidities: diabetes mellitus, dyslipidemia, arterial hypertension, heart failure, chronic kidney disease. The variability of the oxidative status was found depending on the type of associated comorbidity, but also according to the associated treatment, with the possibility of producing drug interactions between the standard treatment of CML and the associated specific therapies. Their impact on the prognosis of CML patients in treatment with TKIs is not negligible and may represent a future research topic.

A Three-Years Survival Rates of Chronic Myeloid Leukemia Patients with Targeted Therapy

Introduction: Chronic myeloid leukemia (CML) is a hematopoietic stem cell cancer driven by the BCRABL fusion protein that arises from the translocation of chromosomes 9 and 22. Since the found of the Tyrosine Kinase Inhibitor (TKI) as a targeted therapy, the relative survival rate of 5 years has significantly increased compared to the era of the use of previous agents. As a successful leukemia treatment, it can be seen based on the survival rate. Several factors have been known to influence the survival and prognosis of CML patients, including the age of the patient at diagnosis, gender, and response to therapy and treatment. This study aims to determine how many a three-year survival rates for CML patients with targeted therapy in Makassar and the factors that affect survival. Method: This study used a retrospective cohort using secondary data (medical records) of CML subjects who had been outpatient or inpatient followed in the same time period. The study was conducted in January 2015 to December 2017 at Dr. Wahidin Sudirohusodo Hospital, Makassar. The samples consisted of 108 subjects who met the inclusion criteria. Gender, age, BCR-ABL transcript, targeted therapy and status were taken from medical records. Data were analyzed with SPSS 22.0 version and survival analysis, Meier Kapplan curves, survival median, log-rank and test statistic. Results: There were 108 subjects of CML patients who received targeted therapy, 58 male (53.7%), 30-39 years old 32 subjects (29.6%), b3a2 transcript 67 subjects (73.6%), Imanitib 62 subjects (57.4%) and status for 36 months was followed during the targeted treatment of dead 19 subjects (17.6%) and alive 89 (82.4%). The survival rate of a three years CML subjects who received targeted therapy of 51%, found no significant relationship between gender, age, and targeted therapy. Conclusion: The survival rate of three years of CML patients at Wahidin Sudirohusodo Makassar Hospital is 51% and factors related to age, gender, and targeted therapy tend to influence even though statistically not significant,

Analysis of Elderly Patients with Chronic Myeloid Leukemia

AimsWe aimed to evaluate in clinical results >65 years with chronic myeloid leukemia (CML).Methods191 CML patients treated with imatinib frontline were evaluated retrospectively. 56 patients who aged >65 years were included our study. The clinical characteristics and treatment outcomes of these patients were evaluated.ResultsA total of 56 patients (24 [57.1%] men, 32 [42.9%] women) were evaluated retrospectively. The median age of the patients was 72 years (range 66-92years). Of the patients, 56 (98.2%) were in the chronic phase and one (1.8%) were in the accelerated phase when diagnosed. All of patients (100%) were receiving imatinib as the first-line therapy.Imatinib treatment induced 51 (91.8%) complete hematological responses at 3 months, 29 (51.8 %) complete cytogenetic responses at 6 months and 37 (66.6%) major molecular responses at 12months.As a result, nilotinib and dasatinib were used in 28 (50%) patients as second-line therapy because of intolerance 5 (8.9%), primary and soconder unresponsiveness 14 (25%), 9 (16.1%) respectively. Second-line Tyrosine kinase inhibitors (TKI) induced 23 complete hematological responses (82.1%) at 3 months, and 20 major molecular responses (71.4%) at 12 months. Fifty-two of 56 patients (92.9%) are still alive. The 5 year median overall survival and progression free survival rates were 92% and 85% respectively.ConclusionThe prognosis of CML patients has changed with Tyrosine kinase inhibitors (TKI). In our study, we found that the response rate and survival rates elderly patients were similar to the younger patients in the literature. DisclosuresNo relevant conflicts of interest to declare.

Gimema Registry of Conception/Pregnancy in Adult Italian Patients Diagnosed with Chronic Myeloid Leukemia (CML): Report on 166 Outcomes

Background. The availability of multiple tyrosine kinase inhibitors (TKIs) and precise molecular monitoring has dramatically changed the prognosis in CML patients. With proper medical management, the planning of a pregnancy in both male (M) and female (F) patients is now possible. Towards this goal, the GIMEMA CML working party initiated a retrospective and prospective study to describe all male conceptions/female pregnancy outcomes in the CML Italian population from January 2013.Aims. The specific aims of this study were to analyze conceptions and pregnancies in male and female patients with regard to 3 general issues: 1) Illness issues, including CML treatment prior to conception/during/after pregnancy, transcript kinetics, the recovery of a lost response after therapy cessation, and the effects of treatment modifications (e.g., resistance, switching); 2) Conception/pregnancy issues, including planned, unplanned, spontaneous and medically assisted pregnancies (MAP), spontaneous/elective abortions, pregnancy progression, delivery, and breast feeding; and , 3) Post-natal health issues from birth to walking including speaking and academic performance.Patients and methods. Patients included in the study had to meet the following criteria A) Age >18 yrs; B) Confirmed CML diagnosis; C) Conception or pregnancy; D) TKI treatment before, during and/or after pregnancy; and E) Signed, IRB-approved written informed consent form. Of the 143 enrollees, data were obtained from 135 patients (83M and 52F). A total number of 166 cases were analyzable. Male conceptions were 106, and female pregnancies 60.Results 1) At time of conception 34 patients had no treatment (TF), 8 received interferon-a (IFN), and the remaining were treated with a TKI (Table 1). Considering only female patients, all stopped TKI treatment when pregnancy was discovered at 3-6 weeks (w). After placental maturation (>20w) 13 patients were treated with IFN (10), 2 with Imatinib, and 1 with Nilotinib (N). In this latter patient N concentration was tested in maternal plasma and cord blood at delivery and showed no transfer to the baby. Kinetics of rise was calculated in a subgroup of 17 patients. Doubling time [DT = duration x log(2) /log (final ratio)-log (initial ratio)] exhibits a bimodal trend, very short for some patients (5.8 days mean, range 4.5-8.2) and much longer for others (182 days mean, range 59.2-328.4), This result does not correlate with molecular status pre TF. Furthermore 76.5% of patients will not lose Major Molecular Response during pregnancy, while in TF, that is more than expected when compared to non pregnant controls (TFR). No cases of CML progression or resistance to re-treatment were observed. CML transcript ratios during pregnancy are shown in Fig.1.2) The majority of pregnancies were planned. MAPs were reported in 5M and 3F. Two spontaneous conceptions occurred in 2M after allogeneic transplant. Eleven abortions before 12 w (2 M ,induced; 9F, 5 induced) were reported (not included in the 166 cases). Pregnancies in all cases progressed normally. In F there were 2 pre-eclampsia, 2 oligohydramnios, 1 abruption placenta. In 8M and 8 F babies were born pre term and 1M and 2F were small at birth with no further consequences. Forty-two F (70%) delivered spontaneously. Babies were born at a mean 40 w (34-44) in M, 39 w (33-42) in F. Breast feeding information was collected for 45F of which18 (29%) breast feed for at least one month (range 1-28 mo).3) Post-natal information showed normal child development and growth. One respiratory arrest was noted at birth with rapid recovery and 1 macrocephaly was described with no further consequences. Of the 56 children >3 yrs old attending school (44M,12F), 2M presented with language problems and in one case autism was diagnosed. Other reported outcomes include 1 child diagnosed as having rheumatoid arthritis at 2 yr (F), and 1 diagnosed with celiac disease (M).Conclusions TKI therapy has allowed CML patients to pursue a normal life including planning/managing a family. Males do not need to stop therapy to conceive due to the therapy's non-genotoxic nature, in contrast to females who must cease therapy due to the teratogenic nature of TKIs. Kinetics of regrowth of the CML residual disease during pregnancy in female patients is different than in TFR patients. To our knowledge this is the largest multicentric study regarding CML and reproduction. Results and practical management will be presented. [Display omitted] DisclosuresAbruzzese:Novartis: Research Funding; Pfizer: Consultancy; Ariad: Consultancy; BMS: Consultancy. Castagnetti:Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Rambaldi:Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy; Amgen Inc.: Consultancy. Gaidano:Roche: Consultancy, Honoraria; Morphosys: Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

BCR-ABL Mutations in Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors and Impact on Survival

This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.

Gimema Registry of Conception/Pregnancy in Adult Patients Diagnosed with Chronic Myeloid Leukemia (CML) Treated with Tyrosine Kinase Inhibitors (TKIs)

Abstract The management of patients with chronic myeloid leukemia (CML) during pregnancy is a matter of continuous debate. The introduction of the tyrosin kinase inhibitors (TKIs) in clinical practice has dramatically changed the prognosis of CML patients. Patients diagnosed in chronic phase can expect an excellent disease control and a normal lifespan. Issues relating to fertility and pregnancy must be introduced at diagnosis. Different reports were published in patients conceving/getting pregnant during Imatinib treatment, while there are only sporadic data about other TKIs. The GIMEMA CML working party has started a retrospective and prospective study to describe all female pregnancies/male conception outcome in the CML population from January 2013 until 2015. Inclusion criteria were age&gt;18, CML in any phase of the disease, conception/pregnancy while diagnosed with CML, treatment with TKIs (before, during or after pregnancy), and signed written informed consent IRB approved. Sixty-three patients have been enrolled so far in the study. Male to female ratio was 43/20, mother age at pregnancy (female patients or female partners of male patients) varies from 22 to 37 years. CML was diagnosed when patients were aged between 17 and 55 years old, all patients were in chronic phase at time of conception, but one. This patient was a male patient with accelerated phase aged 31 treated with Nilotinib whose conception outcome was unremarkable. Data on 71 pregnancies have been harvested. The majority of pregnancies were spontaneous, with 3 PMA (pregnancy medically assisted). All pregnancies were carried on, 2 are ongoing, and 6 ended up in an abortion within the 3rdmonth, 2 of which non induced (miscarriages). At pregnancy/conception 8 patients were treated with Nilotinib, 4 with Dasatinib, 3 with Bosutinib, the remaining patients were treated with Imatinib or were at onset with no treatment. All carried pregnancies were unremarkable, except two placental detachment, one at 5 months and one at 12 weeks pregnancy, 1 abortion threat requiring rest, 1 gestational diabetes with intra-uterine growth retard, 1 oligohydramnios, 1 congenital hip dysplasia, and 1 speech retard in a 36 months old baby girl. Data on female patients population, regarding the status of CML at pregnancy, the CML therapy since conception and throughout pregnancy, particularly regarding the organogenesis period (between 5-12 weeks), the status of the illness during pregnancy (any MR4.5, MR4 and major molecular response, complete cytogenetic response, hematologic response losses, and progressions), the outcome of pregnancy, breast feeding, baby growth and development (walk, speech, behaviour), will be detailed. The same will be for female partners of male patients treated with TKIs other than Imatinib. Acquiring detailed information about how a pregnancy/conception is managed will increase our knowledge in order to establish a consensus on patients with CML receiving TKIs who wants to father a child or become/are pregnant. Disclosures Abruzzese: novartis, bristol myers squibb, ariad, pfizer, takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gugliotta:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Baccarani:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau.

Genome-Wide Single-Nucleotide Polymorphism-Array Based Karyotyping Detects Clonal Aberrations, and Predicts the Risk of Imatinib Failure In Chronic Myeloid Leukemia.

AbstractAbstract 3387 Background:The current study investigated the diagnostic and clinical role of genome-wide, single nucleotide polymorphism arrays (SNP-A) which can detect microscopic copy number changes in chronic myeloid leukemia (CML). Methods and Materials:Genome-Wide Human SNP 6.0 Array (Affymetrix, CA, USA) was used for SNP-A karyotyping analysis in 132 CML patients. All patients were treated with imatinib and treatment outcomes were compared according to the presence of clonal aberrations (CAs) detected by SNP-A or additional cytogenetic abnormalities (ACAs) detected by metaphase cytogenetics (MCs). Result:Forty four clonal aberrations were identified in addition to t(9;22) (40 losses, 2 gains, 2 loss of heterozygosity [LOH]) that were not detected by MCs. The 9q34 deletions were found in 11% of cases, while 22q11.2 deletions were observed in 14% of cases. Nine cases harbored both 5‘-ABL and 3‘-BCR deletions adjacent to the t(9;22) breakpoint (7%). Copy number gains were identified at 8p and 9p, and losses at 2q, 7q, 8q, 11q, 13q, and 16p. Two cases with variant translocation showed additional deletions on the 3rd chromosome with involvement in variant translocations, which were missed by MC. We defined 3 commonly deleted regions (CDRs) on 9q34 and 22q11.2: CDR1 on 9q34 spanned approximately 162 kb between 9q34.11 and 9q34.12; CDR2 on 22q11.23 spanned 138 kb; CDR3 on 22q11.23 encompassed 102 kb.When we compared treatment outcomes according to the combination of the presence of CAs by SNP-A and/or ACAs, the patients having both CAs and ACAs showed a higher risk of failure following imatinib therapy than those with either CAs/ACAs or none (p=0.015). Conclusion:The present study suggests that SNP-A analysis is a useful tool for detection of clonal aberrations in the CML genome, and could improve the prediction of prognosis in CML patients. In addition, our data suggest that SNP-A analysis is a useful tool to detect cryptic aberrations in CML genome, could improve the prediction of prognosis in CML patients and enables us to delineate CDRs on 9q34 and 22q11.2 which might be associated with CML leukemogenesis. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

KIR2DS1 Genotype Predicts for Cytogenetic Response, Progression-Free Survival and Overall Survival In Patients with Chronic Phase CML on Imatinib

AbstractAbstract 888Natural killer (NK) cells are expanded in patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitors (TKI) and exert cytotoxicity against CML cells. NK cytotoxicity is determined by the balance between inhibitory and activating signals from cell surface killer immunoglobulin-like receptors (KIRs). The inherited repertoire of KIR genes may therefore influence susceptibility to treatment and prognosis in CML patients treated with TKI. To determine if innate immunity is associated with CML susceptibility and response to TKI, we investigated the impact of KIR genotype on the outcome of 166 consecutive patients with Philadelphia+ CML in chronic phase (CP) who received imatinib as first line treatment in our institution. The median follow up was 36 months and 75% of the patients were followed for a minimum of 24 months. One hundred and nineteen patients (71.7%) achieved CCyR, 10 (6.0%) progressed to advanced phase disease and 7 (4.2%) died. The 2-year cumulative incidence of CCyR was 72.2% and the 2 year probability of PFS and OS were 95.7% and 97.3% respectively. The presence of 2 KIR genes, namely K2DL5A and KIR2DS1, was associated with a significantly lower 2 year probability of CCyR (78.8% vs 63.2%, p=0.04 and 82.3% and 65.6%, p=0.03) respectively, PFS (98.9% vs 91.5%, p=0.02 and 98.4% vs 91.0%, p=0.01 respectively) and OS (100% vs 93.9%, p=0.02 and 100% vs 92.6% p=0.03 respectively). On multivariate analysis, the presence of KIR2DS1 (RR=0.66, p=0.03) and Sokal risk score (low risk RR=1, intermediate risk RR= 0.65, p= 0.04 and high risk RR= 0.59, p=0.034) were the only independent predictors for the achievement of CCyR. Furthermore, on multivariate analysis, the presence of KIR2DS1 was the only independent predictor for both PFS (P=0.02) and OS (P=0.03). In order to validate our results we explored the influence of the KIR genotype on achievement of CCyR and PFS and OS in a second independent patient group: KIR genotype was determined in 174 patients with CML-CP treated with first line imatinib within the multi-center STI571 Prospective International Randomised Trial (SPIRIT). The 65 patients who were KIR2DL5A positive had a significantly lower 2 year probability of achieving CCyR, PFS and OS than the 106 patients who were negative for this gene, namely 80.4% vs 86.8 (p=0.04), 85.7% vs 98.1% (p=0.01) and 94.3% vs 100% (p=0.02) respectively. Similarly, the 66 patients who were KIR2DS1 positive had a lower probability of achieving CCyR and lower PFS and OS than the 106 patients who did not have the gene (76.9% vs 87.9%, p=0.004, 85.3% vs 98.1% p=0.01 and 94.4% vs 100%, p=0.02 respectively). On multivariate analysis of this patient cohort KIR2DS1 remained the only independent predictor for the three outcomes. When patients were categorized based on their Sokal risk score and KIR2DS1 genotype, the most significant difference in CCyR, PFS and OS was observed in the 77 patients who had a high Sokal risk score and those with an intermediate Sokal risk score who were KIR2DS1 positive compared to the 89 patients who had a low Sokal risk score and those with an intermediate Sokal risk score who were KIR2DS1 negative; namely, 82.4% vs 59.3% (p=0.002), 92.1% vs 98.8% (p=0.03) and 94.2% vs 100% (p=0.03) and respectively (Figure 1). The mechanism by which KIR2DS1 predicts for a sub-optimal response to therapy is unknown. KIR2DS1+ve NK cells have been shown to secrete transforming growth factor-beta (TGF-beta) upon interaction with their ligand. TGF-b was recently shown to inhibit Akt signalling, a suppressor of the forkhead O transcription factor, FOXO3a, in the CML leukaemia-initiating cells (LICs) and may represent an important mechanism for the CML LIC to survive imatinib. Alternatively, KIR2DS1 may be simply a surrogate marker for another neighboring gene that is directly involved in pathogenesis of CML. In conclusion, our data demonstrate that KIR immunogenetics represent a novel prognostic tool for patients with CML-CP on TKI, and that KIR2DS1 positivity may predict response to imatinib and identify patients at greater risk of treatment failure. Functional and phenotypic studies to determine the expression of KIR2DS1 on the surface of NK cells and to assess the role of the cytokine milieu and the NK phenotype on outcome are currently underway. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Are Chronic Myeloid Leukemia Patients More at Risk for Second Malignancies? A Population-based Study

The authors used cancer registry data to assess the incidence rate of second primary cancers among chronic myeloid leukemia (CML) patients and the long-term survival of CML patients before the introduction of tyrosine kinase inhibitors. In the Swedish Cancer Registry, the authors identified 2,753 adult CML patients diagnosed between 1970 and 1995 who were followed through December 2007. Standardized incidence ratios (SIRs) and relative survival ratios were computed. With a total of 145 subsequent primary malignancies, an increased incidence rate of second malignancy was found for stomach cancer (SIR = 2.76, 95% confidence interval (CI): 1.33, 5.08), skin cancer (SIR = 5.36, 95% CI: 3.18, 8.47), urogenital tract cancer (SIR = 1.61, 95% CI: 1.15, 2.21), and lymphoid leukemia (SIR = 5.53, 95% CI: 1.79, 12.89). Long-term relative survival figures showed that CML was related, in the era prior to the introduction of imatinib, to a very steep decline in survival (2 years from diagnosis, relative survival = 51%, 95% CI: 49, 53). This was in spite of a marginal improvement after 1985, possibly related to the introduction of interferon-α for treatment. These estimates constitute a relevant reference for future studies and a benchmark for comparisons with prognosis in CML patients after chronic use of tyrosine kinase inhibitors.

Prognostic relevance of 9q34 deletion and the suppressor of cytokine signalling-1 in CML patients

Chronic myeloid leukemia (CML) is characterized by formation of the BCR/ABL fusion gene. The response to therapy may vary because of development of secondary cytogenetic changes or resistance. In addition, suppressor of cytokine signalling (SOCS) proteins is also hypothesized as a cause of resistance and poor prognosis when aberrantly overexpressed. This study aims to determine the incidence and prognostic value of the 9q34 deletion using fluorescence in situ hybridization and SOCS-1 mRNA aberrant expression by PCR in 43 CML patients at different phases of the disease and in 10 normal controls and correlate the data to interferon response. All patients were Philadelphia-positive, deletions of 9q34 were observed in 20.9% of all patients (13.3% chronic phase, 10% accelerated phase and 33.3% in blast crisis). SOCS expressions were positive in 53.4% of all patients (40% chronic phase, 50% AP and 66.67% in blast crisis). Analysing outcome based on 9q34 deletion and SOCS expression status showed a statistically significant difference in overall survival and progression-free survival between those with deletions and those without (P<0.001) and between those with abnormal SOCS expression and those without (P<0.001). Deletion of 9q34 and aberrant expression of SOCS-1 are associated with poor prognosis in CML patients with different phases of the disease under interferon therapy.