Chronic myeloid leukemia among patients with a history of prior malignancies: A tale of dual survivorship

Abstract Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinib-associated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%). VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years. Multivariate analysis identified age (P = .022) and dyslipidemia (P = .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued (P = .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.

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Natural History of Southeast Asian Chronic Myeloid Leukemia Patients with Different BCR-ABL Gene Variants

Acta Haematologica ◽

10.1159/000093641 ◽

2006 ◽

Vol 116 (2) ◽

pp. 114-119 ◽

Cited By ~ 4

Author(s):

C.U. Auewarakul ◽

S. Huang ◽

M. Yimyam ◽

S. Boonmoh

Keyword(s):

Chronic Myeloid Leukemia ◽

Natural History ◽

Myeloid Leukemia ◽

Southeast Asian ◽

Gene Variants ◽

History Of

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A fertile XY/XX chimeric male with chronic myeloid leukemia in a minor 46,XX cell line and a history of polycythemia vera and trisomy 9 in the major 46,XY cell line

Leukemia & Lymphoma ◽

10.1080/10428190903047761 ◽

2009 ◽

Vol 50 (8) ◽

pp. 1375-1380 ◽

Cited By ~ 1

Author(s):

Kavita S. Reddy ◽

Gary Edward Schwartz ◽

Mehdi Jamedhor

Keyword(s):

Chronic Myeloid Leukemia ◽

Polycythemia Vera ◽

Cell Line ◽

Myeloid Leukemia ◽

Trisomy 9 ◽

History Of ◽

A Minor

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Two Cases of Possible Familial Chronic Myeloid Leukemia in a Family with Extensive History of Cancer

Acta Haematologica ◽

10.1159/000513925 ◽

2021 ◽

pp. 1-6

Author(s):

Marisa J.L. Aitken ◽

Christopher B. Benton ◽

Ghayas C. Issa ◽

Koji Sasaki ◽

Musa Yilmaz ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Drug Development ◽

Fusion Protein ◽

Reciprocal Translocation ◽

Genetic Variants ◽

Myeloid Leukemia ◽

Familial Occurrence ◽

Familial Association ◽

History Of ◽

History Of Cancer

CML is defined by the presence of an oncogenic fusion protein caused by a reciprocal translocation between chromosomes 9q and 22q. While our molecular understanding of CML pathogenesis has revolutionized drug development for this disease, we have yet to identify many predisposing factors for CML. Familial occurrence of CML has been rarely reported. Here, we describe 2 cases of CML in a 24-year-old woman and in her 73-year-old maternal great aunt. We describe genetic variants in these patients and report on their environmental exposures that may have contributed to CML pathogenesis. The possible familial association of these 2 cases of CML warrants further investigation into more definitive etiologies of this disease.

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The First Results of Asciminib Therapy in Highly Pretreated Chronic Myeloid Leukemia Patients Under the Managed Access Program (MAP) in Russian Federation

Blood ◽

10.1182/blood-2021-145712 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1483-1483

Author(s):

Anna G. Turkina ◽

Oleg A. Shukhov ◽

Elza Lomaia ◽

Elena V. Morozova ◽

Anna Petrova ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Treatment Plan ◽

Univariate Analysis ◽

Hazard Ratio ◽

Phase Iii ◽

Molecular Response ◽

First Results ◽

History Of ◽

Access Program

Abstract Background: The problem of resistance and intolerance to 2nd generation tyrosine kinase inhibitors (2G TKIs) in patients (pts) with chronic myeloid leukemia (CML) currently remains relevant. Ponatinib has demonstrated a high effectiveness and may be an option in CML pts with resistance or intolerance to available TKIs but the high incidence of vascular adverse events (AEs) limits its broad use. A STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor asciminib has demonstrated a superiority over bosutinib in CML pts previously treated with 2 or more TKIs (Phase III Study). Asciminib is available in Russia under the Managed Access Program (MAP) approved by Novartis. Aim: to present the first results of the use of asciminib in clinical practice under the MAP program in Russia. Methods: In total 46 CML pts from 3 Russian clinics were enrolled into the MAP program and received asciminib from September 2019 to June 2021 (1 pt started asciminib in a cinical trial and was transferred to MAP later). We analyzed therapy results of 32 pts who received asciminib for at least 3 months. Patient recruitment, dosing regimen, response monitoring, and toxicity control were performed according to the MAP treatment plan. Complete cytogenetic response (CCyR), major molecular response (MMR) and deep molecular response (MR4) rates were assessed by cumulative incident function (CIF). Differences between the subgroups were considered significant with p value ≤ 0.05 by the Gray's test. Results: Baseline characteristics: male: 41%; Меdian (Me) age 54 years (range 26-81); Me duration of CML before asciminib was 8 years (range 2-24); 23 pts were in chronic phase (CP) CML, 7 and 2 pts had a history of accelerated phase (AP) and blast crisis (BC), respectively, but were in a second CP at baseline. Nineteen (59%) pts had BCR-ABL mutations, 10 pts (31%) had BCR-ABLt315i clones, 7 (22%) pts had at least two mutations. Eight (25%) pts had additional chromosomal abnormalities (ACAs). Twenty one (66%) pts received ≥4 TKIs, 14 (44%) pts had a history of ponatinib treatment. Me duration of asciminib treatment at the time of analysis was 7 months (range 4-24), 4 (12.5%) pts discontinued asciminib due to lack of efficacy; all pts were alive. The initial asciminib dose was 40 BID in 22 (69%) pts and 200 mg BID in 10 (31%) pts. CCyR, MMR and MR4 at the time of analysis was achieved in 32% (8/25), 34% (10/29) and 17% (5/30) pts, respectively (considering pts without this kind of response at baseline). The 6 month CIF of CCyR, MMR and MR4 was 27%, 24% and 19%, respectively. Univariate analysis was performed in 29 pts without MMR at baseline evaluating the following factors of 6 month MMR achievement: initial dose of asciminib, CML phase, presence of BCR-ABL mutations and ACAs, best molecular response on previous TKIs, molecular response at the time of asciminib starting, history of ponatinib treatment, number of TKIs and duration of TKI therapy before asciminib. The duration and number of TKIs, the history of advanced phases, BCR-ABL kinase domain mutations and ACAs did not significantly effect on MMR rate (tab.1). BCR-ABL<1% on previous TKIs (54% vs 0%, p=0.0008, hazard ratio 20.9 (2.6-170)) and BCR-ABL<10% at the time of asciminib start (44% vs 15%, p=0.035, hazard ratio 3.8 (1.05-13.6)) were found as a predictive factors for MMR at 6 month. Fourteen (44%) of 32 pts had AEs of any grade and 7 (22%) had AEs of grade 3-4 (hematological AEs -6 (19%), non-hematological AE- 1 (3%)) (tab.2). Conclusion: Asciminib has shown promising efficacy and a good toxicity profile in a cohort of highly pre-treated CML pts and should be considered as a therapeutic option for CML pts resistant or intolerant to other TKIs. Figure 1 Figure 1. Disclosures Turkina: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Chelysheva: Novartis Pharma: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau.

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the Polymorphisms on Chromosome 9p21 Play a Role in the Risk for Cardiovascular Events in Chronic Myeloid Leukemia Patients?

Blood ◽

10.1182/blood.v128.22.5100.5100 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5100-5100

Author(s):

Federica Sora ◽

Patrizia Chiusolo ◽

Laurenti Luca ◽

Pola Roberto ◽

Sabrina Giammarco ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Cardiovascular Events ◽

Myeloid Leukemia ◽

Previous History ◽

Control Group ◽

Wild Type ◽

Chromosome 9P21 ◽

History Of ◽

Test Result

Abstract The polymorphisms on chromosome 9p21 play a role in the risk for cardiovascular events in chronic myeloid leukemia patients? Chronic myeloid leukemia (CML) is an onco-haematological disease due to the aberrant expression of an onco-protein with constitutive tyrosine kinase activity. The average age of onset is 55-60 years. The treatment with tyrosine kinase inhibitors (TKIs) drastically changed the outcome of patients affected by chronic myeloid leukemia, allowing long-term improvement in overall survival and deep molecular responses. TKI treatment is also associated to an increased risk of cardiovascular event. The etiopathogenesis of this effects is not clear possibily due to a damage to the endothelial cell, the results of the interaction of genetical predisposition, risk factors and life style habit. The 9p21 region is the strongest genomic marker for cardiovascular disease that has been identified in multiple genome-wide association study. We retrospectively studied 182 patients affected by CML and treated with different TKIs for expression of polymorphism rs1333040C>T and rs7865618A>G of chromosome 9p21 in order to define the role of genetic cardiovascular risk profile to better tailor individualized treatment strategy and identify patients who require strict monitoring of additional risk factors during treatment. Patients and methods We analysed 182 CML patients in chronic phase. All patients were treated with either first, second or third generation TKIs. Patients were compared to a control group including 171 subjects. Genomic DNA was isolated from peripheral blood and the rs1333040C>T and rs7865618A>G polymorphisms were assessed by PCR-RFLP using the BsmI and MspI restriction endonucleases, respectively. Results Ninety-three out of 181 (51%) patients presented the C/T polymorphism, 82 (46%) presented T/T polymorphism and 6 (3%) patient presented wild type polymorphism C/C for rs1333040, test result was not evaluable in 1 patient. Eighty-five out of 181 (47%) patients presented the G/A polymorphism, 73 (40%) presented A/A polymorphism and 23 (13%) patient presented wild type polymorphism G/G for rs7875618 . Test result was not evaluable in 1 patient. The distribution of polymorphism C/C for rs1333040 and G/G for rs7875618 were statistically different compared to control group (p0.0004 and p0.0136 respectively) as showed in table 1. In a sub-analysis, including only 93 patients, a significantly higher incidence of cardiovascular events according to genotypes of SNP rs 1333040 was observed. In C/T group (54 patients) we retrospectively observed 3 cardiovascular events (5.55%) : 2 were transient ischemic attack (TIA) before the diagnosis of CML occurring in 2 female patients aged 69 and 73 respectively and a peripheral arterial obstructive disease (PAOD) in a female patient ,aged 74, with a baseline CAD score of 10, receiving nilotinib 800 mg/d as third line treatment. In T/T group (39 patients) we retrospectively observed 9 (23.1%) cardiovascular events at a median age of 60 years (range 44-82) and with a median estimated cardiovascular risk of 8 (range 0-20) Six patients developed a myocardial acute infarction (AMI) during treatment with TKIs, but 5 out of six had a previous history of AMI. One patient presented a TIA after history of previous of AMI. All patients with previous history of AMI were receving antiplatelets agents. One patient developed PAOD during first line treatment wih nilotinib and one developed an distal arteriopathy associated to an erectile dysfunction. The different incidence of cardiovascular events according to genotypes (T/T vs C/T ) was statistically significant by Fisher'sTest (p=0.0248). Discussion The role of 9p21 region , in particular the genes located in proximity of a noncoding RNA sequence named ANRIL, could be a useful guide for the prophylaxis of cardiovascular events during TKI therapy. Table 1 genotypes distribution between CML patients and controls rs1333040 rs7865618 Patients 82 93 6 23 85 73 46% 51% 3% 13% 47% 40% Controls 62 84 25 8 77 86 36% 49% 15% 5% 45% 50% p=0.0004 P=0.0136 Disclosures Bacigalupo: SANOFI: Speakers Bureau; PIERRE FABRE: Speakers Bureau.

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Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia

Cancer ◽

10.1002/cncr.33622 ◽

2021 ◽

Author(s):

Guillermo Montalban‐Bravo ◽

Rashmi Kanagal‐Shamanna ◽

Koji Sasaki ◽

Lucia Masarova ◽

Kiran Naqvi ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Natural History ◽

Myeloid Leukemia ◽

History Of ◽

Atypical Chronic Myeloid Leukemia

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An interesting case of chronic myeloid leukemia presenting as B-cell lymphoblastic crisis

Oncolog-Hematolog ro ◽

10.26416/onhe.52.3.2020.3716 ◽

2020 ◽

Vol 3 (1) ◽

pp. 30-32

Author(s):

Andreea Neculcea ◽

Andreea Spînu ◽

Diana Cisleanu ◽

Anca Nicolescu ◽

Cristina Enache ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

B Cell ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Interesting Case ◽

Favorable Prognosis ◽

Night Sweats ◽

History Of ◽

Abdominal Quadrant

We present the case of a 46-year-old male patient who came to our emergency department in December 2019 for pain in the left abdominal quadrant. The patient had no fever, night sweats or a history of weight loss. The laboratory tests revealed important leucocytosis and the abdominal ultrasound highlighted a massive splenomegaly. He was hospitalized for further investigations. We performed all the necessary laboratory tests to establish the diagnosis of the patient. Even though the osteomedullar biopsy and the flow cytometry suggested the diagnosis of acute B-cell lymphoblastic leukemia, the fluorescence in situ hybridization exam – the translocation t(9;22) was present in 100% of the analyzed cells – and the detection of BCR-ABL1 b2a2 transcript established the diagnosis of chronic myeloid leukemia, B-cell lymphoblastic crisis. We decided to start the treatment with the GRAAPH 2005 protocol associated with imatinib, and the patient was a candidate for allogeneic transplantation. We chose to present this case because the patient was young, without significant comorbidities, with chronic myeloid leukemia – B-cell lymphoblastic crisis as the initial diagnosis, whose evolution was negative, despite his favorable prognosis.

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Results of a Single Center Survey on Vaccination Against COVID-19 in Patients with Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2021-150226 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4604-4604

Author(s):

Ekaterina Yu. Chelysheva ◽

Anna Petrova ◽

Oleg A. Shukhov ◽

Margarita Gurianova ◽

Anastasiya Bykova ◽

...

Keyword(s):

Higher Education ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Blast Crisis ◽

Chronic Phase ◽

Molecular Response ◽

Concomitant Disease ◽

Advanced Phase ◽

History Of ◽

June July

Abstract Introduction Despite the availability of vaccination against COVID 19 for all population categories since January 2021, it is moving slowly in Russia. Patients (pts) with chronic myeloid leukemia (CML) usually lead a normal life with social interactions. In the context of the COVID 19 pandemic, we find it important to identify the factors of adherence to vaccination and clarify the concerns. Objective: To determine the proportion of CML pts willing to consider vaccination against COVID 19, adherence factors and reasons for not vaccinating. Materials and methods. A survey on the attitude to vaccination against COVID 19 was prospectively carried out among all pts with CML consulted at the outpatient department of National Research Center for Hematology (Moscow, Russia) who agreed to participate. The key questions included considerations for and against vaccination, socio-demographic and clinical characteristics, lifestyle, comorbidities and history of COVID 19. Results. Within 4 months (from March 15 to July 19, 2021), 172 CML pts completed the questionnaire. CML chronic phase, advanced phase and blast crisis were in 167 (97%), 4 (2%) and 1(1%) respectively. In total, 141 (82%) pts were on therapy with 1 st, 2 nd and >3 rd therapy line in 77 (55%), 33 (23%) and 31 (22%) pts, respectively. Thirty one (18%) had no therapy: 6 (3.5%) newly diagnozed, 25 (14.5%) in a treatment-free remission. A deep and major molecular response was in 77 (45%) and 30 (17%) pts, respectively. Presence and absence of molecular response MR2 was in 20 (12%) and 45 (26%) pts respectively. The median age of pts was 46 years (range 19-82), 75(44%) were males. Married 108 (63%), 70 (41%) lived with elderly relatives, 35 (20%) with children. A higher education was in 123 (72%) pts, 123 (72%) could not work remotely and 46 (27%) had interactions to people by work. Any comorbidity was in 89 (52%) pts, 42(24%) had >1 concomitant disease, 48 (28%) had cardiovascular diseases, 44 (26%) had an obesity. A history of COVID 19 was in 41 (24%) pts and in the close circle of 74 (43%) pts. Vaccination was supported by 94(55%) pts (with 29 (17%) already vaccinated) and not supported by 76 (44%) pts, 2 (1%) pts did not answer. Among those supporting vaccination vs not supporting there was significantly more males (52% vs 33%, p=0,012), married pts (73% vs 49%, p<0,001) and pts with higher education (88% vs 51%, p=0,006). Other factors (age, comorbidities, obesity, profession-related features, COVID 19 in pts or their environment, living with elderly relatives or children, therapy and treatment response) were not significant. Less pts were against vaccination in June-July 2021 before the 3 rd outbreak of COVID 19 compared to spring period (33% vs 50%, p=0,045). The two most common reasons to avoid vaccination were the fear of complications in 37(49%) pts and waiting for additional data in 19(25%) (Fig.1). Notably, 7 (9%) pts considered CML as a contraindication to vaccination. Among those supporting vaccination, 55(59%) preferred to choose the GamCovidVac (Sputnik V) vaccine, 20(21%) had no preference (Fig.2). Out of 32 pts who gave the rationale for the Sputnik V choice 19(59%) noted its best availability, study or popularity (Fig.3). Among 23 pts with additional questions 12 (52%) wondered about the possibility of vaccination with CML diagnosis and 6 (26%) asked help with a vaccine choice. Conclusion: Despite access to vaccines against COVID 19 with proven efficacy and safety, almost half of CML pts (44%) do not support vaccination. Socio-demographic factors such as gender, education, marriage status appeared to be significant for this decision. Considering the frequent concerns of the possibility of vaccination with CML diagnosis as well as the fear of complications, hematologists should provide a relevant clarifying information on these issues. Figure 1 Figure 1. Disclosures Chelysheva: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau. Kokhno: Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Turkina: Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

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Nilotinib-Induced Acute Interstitial Nephritis during the Treatment of Chronic Myeloid Leukemia

Kosin Medical Journal ◽

10.7180/kmj.2021.36.2.153 ◽

2021 ◽

Vol 36 (2) ◽

pp. 153-160.

Author(s):

Min Jeong Kim

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Targeted Therapy ◽

Chronic Myeloid Leukemia ◽

Interstitial Nephritis ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kidney Injury ◽

Acute Interstitial Nephritis ◽

History Of

Tyrosine kinase inhibitors (TKIs) are targeted therapy drugs that selectively inhibit protein kinases. Nephrotoxicity associated with TKIs is uncommon. We report a case of a 39-year-old man with acute kidney injury that developed after nilotinib treatment for chronic myeloid leukemia (CML). The renal function of the patient decreased during treatment with nilotinib but improved when treatment was discontinued due to neutropenia. However, the renal function of the patient deteriorated again with the reintroduction of nilotinib for treatment. A renal biopsy revealed acute interstitial nephritis (AIN). The patient had no history of comorbidities and medication causing renal injury. Finally, we diagnosed the patient with nilotinib-induced AIN. After switching to imatinib mesylate, the renal function of the patient stabilized without further deterioration. Our case indicates that nilotinib can be a potential cause of renal dysfunction by inducing AIN when renal function deteriorates in patients treated with nilotinib.

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