Interferon gamma in chronic myeloid leukemia: dose and side effects [letter]

Abstract Chronic myeloid leukemia (CML) is rare in childhood (less than 5% of all childhood leukemias). The main characteristic is the Philadelphia chromosome (BCR-ABL1 positive) and the tyrosine kinase inhibitor imatinib mesylate (Gleevec) is the treatment of choice, with the target oral dose being 440 mg/m2/day asdetermined by the COG-P9973 and COG-ADVL0122 trials, while allogeneic stem cell transplantation is postponed until CML becomes refractory to the drug. We administer a treatment dose of 400mg/m2/day but we have observed high toxicity levels associated with prolonged treatment. We present a girl with CML, with persistent residual disease (MRD), even two years following diagnosis, and serious side effects (dry skin, significant hair loss, gastrointestinal discomfort and diarrhoea) that affected her quality of life. The patient was tested for polymorphisms in the tyrosine kinase and was found negative. Careful interviewing of the family revealed that the persistent MRD was due to poor compliance of the patient to the therapeutic regimen. The child was unhappy due to the side effects and refused to take her pills (Gleevec), hence the poor compliance. Therefore, taking into consideration the child’s wellbeing and psychological welfare, it was decided that she would receive the drug on alternate months (one on/one off). Gleevec was discontinued when the patient completed two years of being MRD negative. The patient remains in complete molecular remission four years after the discontinuation of Gleevec. To date, there are few reports on childhood CML so most data come from studies in adults. Even though Gleevec is currently implemented as the primary treatment method in children, there are still doubts as to whether it can result in a permanent cure and of the potential complications of long-term use in the growth and development of these children. No specific guidelines have been set on the dosage and duration of treatment with Gleevec, especially for childhood CML patients facing a potentially lifelong treatment, who might also be faced with a wide range of unknown side effects. Psychological factors should also be taken into account and special attention should be given in avoiding adverse effects that interfere with the quality of life and the psychological welfare of this extremely fragile population. Overall, in our case, despite the persistent MRD, intermittent dosing of Gleevec proved to be an efficient method both in keeping toxicity levels to a minimum and in achieving complete and continuous remission. Persistent MRD levels in this case were due to the interrupted treatment regime, i.e. due to poor compliance, and not due to additional cytogenetic abnormalities that were resistant to Gleevec. Future clinical trials in children should investigate whether intermittent dosing of the drug produces fewer side effects during the course of treatment and whether it may present a more favourable option when considering the normal growth development of the children treated for CML. Disclosures: No relevant conflicts of interest to declare.

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Side effects and medication adherence of tyrosine kinase inhibitors for patients with chronic myeloid leukemia in Taiwan

Medicine ◽

10.1097/md.0000000000011322 ◽

2018 ◽

Vol 97 (26) ◽

pp. e11322 ◽

Cited By ~ 2

Author(s):

Yu-Fen Tsai ◽

Wen-Chuan Huang ◽

Shih-Feng Cho ◽

Hui-Hua Hsiao ◽

Yi-Chang Liu ◽

...

Keyword(s):

Medication Adherence ◽

Side Effects ◽

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors

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PB1947 COMPARISON OF EFFICACY AND SIDE EFFECTS OF SECONDLINE DASATINIB AND NILOTINIB THERAPIES IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE RESISTANT OR INTOLERANT TO IMATINIB

HemaSphere ◽

10.1097/01.hs9.0000566284.90632.fa ◽

2019 ◽

Vol 3 (S1) ◽

pp. 885

Author(s):

I. Kaygusuz Atagunduz ◽

F. Gecgel Arikan ◽

T. Memis ◽

T. Toptas ◽

F. Yilmaz ◽

...

Keyword(s):

Side Effects ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase

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Vitreous hemorrhage: A rare ophthalmic adverse effect due to imatinib treatment

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211060730 ◽

2021 ◽

pp. 107815522110607

Author(s):

Fatma Yılmaz ◽

Murat Albayrak ◽

Pınar Tığlıoğlu ◽

Mesut Tığlıoğlu ◽

Buğra Sağlam ◽

...

Keyword(s):

Side Effects ◽

Mast Cells ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Vitreous Hemorrhage ◽

Retinal Hemorrhage ◽

Imatinib Treatment ◽

Blurred Vision ◽

Eyelid Edema ◽

Sudden Decrease

Introduction Imatinib is generally well tolerated by patients. The most common ophthalmic side effects are eyelid edema and periorbital edema. Other side effects which occur at rates of <1% include blepharitis, blurred vision, conjunctival hemorrhage, conjunctivitis, retinal hemorrhage, etc. An uncommon case is here reported of a 51-year-old male with chronic myeloid leukemia who developed vitreous hemorrhage due to imatinib after 9 months of treatment. Case report A 51-year-old male with leukocytosis detected in the blood test examination was referred to the Hematology Department. The bone marrow biopsy result was compatible with chronic myeloid leukemia. Imatinib treatment (400 mg/day) was started. In the ninth month of imatinib treatment, the patient complained of a sudden decrease in vision. Vitreous hemorrhage was detected in the left eye and the patient underwent surgery. Vitreous hemorrhage recurred 1 month after the operation. On the fourth day after the discontinuation of imatinib treatment, the patient's ophthalmic complaints improved significantly. The Naranjo algorithm was applied and a score of 9 was detected. The vitreous hemorrhage of the patient was attributed to imatinib, and so the treatment of the patient was switched to bosutinib. Discussion Imatinib is an oral signal inhibitor that targets tyrosine kinase for BCR/ABL, platelet-derived growth factor, stem cell factor, and c-kit (CD117). The conjunctiva and sclera have a large amount of c-kit positive mast cells which are inhibited by imatinib. The inhibition of c-kit positive mast cells by imatinib may be responsible for further exposure of the conjunctival mucosa to injuries.

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A Prospective Analysis of Adverse Events in a Phase 2 Trial of Imatinib in the Treatment of Polycythemia Vera.

Blood ◽

10.1182/blood.v106.11.4951.4951 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4951-4951

Author(s):

C. Michael Jones ◽

Tina M. Dickinson

Keyword(s):

Side Effects ◽

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Polycythemia Vera ◽

Myeloid Leukemia ◽

Periorbital Edema ◽

Cutaneous Manifestations ◽

Female Ratio ◽

Number Of Patients ◽

Patient Reported

Abstract Imatinib has recently been demonstrated to be an effective treatment in Polycythemia Vera. Initial response rates are high, approaching 80%. Patients enrolled in our trial, Novartis CST 1571B (US 144), were asked to complete a questionnaire identifying side effects of imatinib known from previous trials in chronic myeloid leukemia and GIST. Questionnaires were completed weekly for the first month, biweekly for the second month, and monthly for the remainder of the study. Mean time on study is now 1.1 years. Target enrollment was 20 patients. Mean age was 54 years; male to female ratio was 1.3: 1. Fourteen patients were Caucasian and 2 African American. Twelve patients were naïve to treatment and 4 patients were previously treated with hydroxyurea. Two dose escalations were allowed sequentially to 600mg and 800mg daily based on response using the Polycythemia Vera Study Group Criteria. Toxicity was graded according to the NCI Common Toxicity Criteria, version 2.0. Patient reported toxicities are expressed as the total number of events reported during the 120 week study period. Diarrhea was the most common reported toxicity at 53 events. Periorbital edema (33), pruritis (39), fatigue (29), arthralgias (20), headache (18), nausea (19), reflux (38), and dry mouth (15) were the next most commonly reported events on study. Other toxicities reported less commonly were chest pain (3), depression (4), cough (5), insomnia (6), weight gain (3), taste changes (7), and depigmentation (3). Most toxicities were mild at grade 1 and resolved spontaneously within 30 to 40 weeks from the time of treatment initiation. The exceptions to this were diarrhea, periorbital edema, and reflux esophagitis, which persisted in a number of patients throughout the study. The severity of gastrointestinal side effects was dose dependent. Previous studies of imatinib induced toxicity in patients with chronic myeloid leukemia have reported cutaneous manifestations as the most common event. Our study demonstrates the toxicities of imatinib in patients with polycythemia vera are generally mild and self limited, although resolution may take up to 35 weeks. In contrast with studies of imatinib and chronic myeloid leukemia, gastrointestinal toxicity was more common and tended to persist, but did not result in patient withdrawal from study. These differences from our findings may be the result of several factors: the use of a patient reported adverse events scale, small trial size, or differences in drug metabolism in a related myeloproliferative disorder.

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Imatinib in Chronic Myeloid Leukemia - Five Years Single Center Experience.

Blood ◽

10.1182/blood.v110.11.4558.4558 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4558-4558

Author(s):

Jaroslaw Dybko ◽

Ewa Medras ◽

Renata Bednarz ◽

Donata Urbaniak ◽

Kazimierz Kuliczkowski

Keyword(s):

Side Effects ◽

Chronic Myeloid Leukemia ◽

Nested Pcr ◽

Myeloid Leukemia ◽

Point Mutations ◽

Cytogenetic Response ◽

Molecular Response ◽

Line Treatment ◽

Median Period ◽

Conventional Cytogenetics

Abstract Background: Chronic myeloid leukemia (CML) treatment standards was completely converted in last decade. This clonal myeloproliferative disease characterized by the Philadelphia (Ph) chromosome genetic abnormality which arises from the chromosomal translocation t(9;22)(q34;q11). This translocation fuses the genes encoding BCR and ABL, resulting in expression of constitutively active protein tyrosine kinase, BCR-ABL. In the pre-Imatinib era CML therapy was focused on decreasing the myeloid line proliferation. Interpheron alpha, nowadays neglected in CML, allowed approximately 30% of patients to achieve cytogenetic remission but it was accompanied by severe side effects. The only known curative therapy in CML was allogeneic stem cell transplantation (alloSCT) but the procedure was restricted to younger patients. The first of tyrosine kinase inhibitors (TKI) introduction was a milestone in CML therapy. Today we are forced to face Imatinib resistance as an expression of point mutations in kinase domains, the second or even the third line treatment is performed, however Imatinib remains the first line, relatively safe and very effective treatment in CML. Patients: 60 patients (F/M-30/30, median age-51) with CML Ph+ BCR-ABL+ diagnosed in our center in last five years were involved in the study. All diagnoses were based on hematological findings, conventional cytogenetics and nested PCR. In all cases 100% Ph+ metaphases were find by the diagnose. The b3a2 transcript type was detected in 34 cases, b2a2 in 26. All but four patients are still receiving Imatinib in dose 400 mg per day. Due to some economic disturbances in early TKI era the median period between the diagnosis of CML and the beginning of Imatinib treatment was 154 days. Three patients were transplanted from allogeneic donor due to NCyR after 12 months of treatment. One death case was related neither to CML nor to treatment toxicity. Definitions: Complete hematologic response (CHR) was defined as white blood cell count in peripheral blood <10x109/L, platelet count <10x109/L, no immature cells in blood, basophils<5% in blood or marrow, spleen non palpable. Cytogenetic response was defined as the percentage of Ph+ metaphases in conventional cytogenetics: complete (CCyR) - no Ph+ metaphases, partial (PCyR) - 1–35%, minor (mCyR) - 36–65% and minor/none (NCyR)≥66%. As for molecular response due to our PCR tools we determined complete molecular response (CMoR) as undetectable BCR-ABL transcript also by nested PCR. Methods: All patients started Imatinib therapy in dose 400 mg per day. Cytogenetic response was determined by conventional cytogenetics and molecular response by nested polymerase chain reaction (PCR). Results: The median period of treatment is 23 months (3–60 months). All patients achieved CHR after 3 months of Imatinib therapy. In the group of 8 patients NCyR was confirmed by 12 months of treatment. In 3 cases of this group allogeneic bone marrow transplantation was performed. One patient of those eight died as was previously mentioned and four of them were included into second-line treatment trial (Nilotinib). 52 patients achieved CCyR (still sustained) after 12 months of therapy. In 13 cases of these 52 CMoR was recognized. Conclusions: The management of CML is constantly changing and developing. TKI are today a group of drugs influencing the point mutations in kinase domain, even the most resistant-T315I. The future of CML treatment seems to rely on the balance between subsequent TKI generations, alloSCT and possible side effects of both therapeutic schedules.

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IFN-γ (interferon-gamma) Genotype Predict Cytogenetic and Molecular Response to Imatinib Therapy in Chronic Myeloid Leukemia.

Blood ◽

10.1182/blood.v114.22.2178.2178 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2178-2178

Author(s):

Dong Hwan Dennis Kim ◽

Jee Hyun Kong ◽

Silvia Park ◽

Chul Won Jung ◽

Lakshmi Sriharsha ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Signaling Pathway ◽

Interferon Gamma ◽

Myeloid Leukemia ◽

Imatinib Therapy ◽

Functional Study ◽

Molecular Response ◽

Interferon Signaling ◽

Action Mechanism

Abstract Abstract 2178 Poster Board II-155 Purpose: Interferon therapy had served as a standard therapy before introduction of imatinib into the treatment of chronic myeloid leukemia (CML) although its action mechanism is yet fully elucidated. After introduction of imatinib therapy, it provides significant therapeutic benefit to CML patients, however its response varies person-by-person. Some patient responds quickly and maintain long-term response without development of resistance, while others do not respond well or lose their response quickly thus developing resistance to imatinib. One of interesting observation is that the patients previously treated with interferon could maintain long-term complete molecular response (CMR) even after withdrawal of imatinib therapy, suggesting interferon signaling pathway seemed to be associated with favorable response to imatinib therapy. Variable response to imatinib therapy in CML can be explained by inter-individual variation of candidate genes involved in the biologic activity of CML cells such as apoptosis or angiogenesis as well as drug transport/metabolism of imatinib in addition to Interferon gamma signaling pathway. Methods: In the current study, we investigated 80 single nucleotide polymorphism (SNP) markers involved in the pathways of apoptosis (n=31; BCL2, BAX, BCL2L2, BCL6, BCL2L11, BIRC5, CASP1, CASP3, CASP7,CASP8, CASP9, CASP10, FAS, FASL, APAF1, TNFR2, PDCD1, GZMB), angiogenesis (n=7; VEGFA, VEGFR2), myeloid cell growth (n=13; FLT2, CSF3, CSF2, JAK3, IL1A, IL1B, IL1R), xenobiotic metabolism (n=13; ABCB1, ABCG2, CYP3A5, HOCT1), WT1 signaling (n=7), interferon signaling (n=4; IFNG, IFNGR1, IFNGR2) and others (n=5; GNB3, ULK3, ORM, PTK2). Discovery cohort includes 244 patients treated at the Princess Margaret Hospital, Toronto, ON, Canada. The DNAs from peripheral blood samples were genotyped with MALDI-TOF based technique (Sequenom). The results were validated internally using a Bootstrap procedure, and externally in an independent validation cohort of 187 Korean CML patients treated at the Samsung Medical Center, Seoul, Korea or Chonnam National University Hwasun Hospital, Hwasun, Korea. Results: In a single marker analysis, several genotypes were found to be correlated with complete cytogenetic response (CCR; IFNG “p-value, 0.01”, FAS “0.03”, FASL “0.006”, CASP8 “0.04”, CASP10 “0.04”), major molecular response (MMR; IFNG “0.04”, FAS “0.05”, JAK3 “0.03”), loss of response (IFNG “0.02”, BIRC5 “0.02”), treatment failure (IFNG “0.07”), or dose escalation of imatinib (IFNG “0.03”, ABCG2 “0.02”, APAF1 “0.04”, CASP2, “0.03”). Bootstrap methods showed a good correlation of each genotype with clinical outcomes. External validation was performed in an independent cohort with 187 Korean CML patients, the IFNG genotype (rs2069705) was validated that is able to predict CCR (HR, 0.46; p=3×10-5) or MMR (HR, 0.51; p=7×10-5) in CML patients. Conclusions: The current study suggested that the interferon gamma genotype seemed to predict the response to imatinib therapy, proposing potential involvement of interferon-gamma signaling pathway in the action mechanism of imatinib therapy in CML. Further detailed study on IFNG genotype and functional study of interferon gamma phenotype will help us to reach a clear conclusion on the role of IFNG gene in the action mechanism of imatinib therapy in CML. Disclosures: No relevant conflicts of interest to declare.

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Chronic Myeloid Leukemia in Pediatrics — First Results From Study CML-PAED II.

Blood ◽

10.1182/blood.v114.22.342.342 ◽

2009 ◽

Vol 114 (22) ◽

pp. 342-342 ◽

Cited By ~ 9

Author(s):

Meinolf Suttorp ◽

Christian Thiede ◽

Josefine T Tauer ◽

Silja Roettgers ◽

Petr Sedlacek ◽

...

Keyword(s):

Side Effects ◽

Chronic Myeloid Leukemia ◽

Bone Metabolism ◽

Treatment Response ◽

Muscle Pain ◽

Myeloid Leukemia ◽

Research Funding ◽

Response Rates ◽

Longitudinal Growth ◽

Molecular Response

Abstract Abstract 342 Background: Chronic myeloid leukemia (CML) is a rare malignancy in pediatrics. In this decade -like in adults- imatinib meyslate (IMA) has been established also as first line treatment for children with CML while allogeneic stem cell transplantation (SCT) as treatment option is postponed for those cases becoming intolerant or refractory to tyrosine kinase inhibitor (TKI) treatment. However, results from controlled trials in children are lacking so far. We here report an analysis of pediatric data from patients (pts) with newly diagnosed Philadelphia-chromosome positive (Ph+) CML on up-front treatment with IMA. Pts and Methods: According to protocol CML-PAED II pediatric pts with confirmed diagnosis of Ph+ CML were treated in CP with IMA 300 mg/sqm once daily, while in accelerated phase (AP) or in blastic phase (BC) the dose was increased to 400 mg/sqm and 500 mg/sqm (bis daily), respectively. Initial and long-term clinical and laboratory data, treatment response and side effects were reported to the study center on standardized forms by the treating physician. Specimen from peripheral blood (pB) and bone marrow (BM) were assessed by cytogenetics and by quantitative RT-PCR for BCR-ABL transcript rates in central laboratories for standardized monitoring in three months intervals. Results: From 1. Jan 2004 until 31. Mrch 2009 a total of 51 pts (21 female, 30 male; median age: 10.6 yrs [range:1-20 yrs]) were registered: 10 pts with ongoing IMA treatment were recruited and analyzed retrospectively while 41 pts were enrolled prospectively from centers in Austria (n=1), Czech Rep. (n=6), Germany (n=40), Italy (n=1), Netherlands (n=1), Slovak Rep. (n=2). Stages of disease were: CP n=47; AP n=1; BC n=3 (two myeloid). Those four pts diagnosed in AP and BC underwent early SCT. Observed side effects in the whole group included: nausea (n=9), muscle pain (n=7), edema (n=3), rhabdomyolysis (n=1, short interruption of IMA), reduced blood cell count (n=2, short interruption of IMA in one pt), biochemical alterations in bone metabolism [for details see: N Engl J Med 2006;354:2006] (n = 8), impaired longitudinal growth (n=1, [Haematologica 2009;94:1177]). Two pts experienced intolerance (muscle pain) or toxicity (hepatic), respectively, therefore stopped IMA and were put on dasatinib after 4 and 10 months, respectively. Having achieved complete cytogenetic response (CyR) and 2 log-fold reduction of BCR-ABL transcript rate, one pt opted for SCT from her HLA-identical brother after 15 mo of treatment. Response rates in advanced stages of CML were as follows: in BC (n=3) two pts became hematological responders (HR), one pt exhibited partial HR. The only one pt diagnosed in AC exhibited partial CyR but complete HR. A landmark analysis in pts entering CML-paed II in CP exhibited that 2/42 pts (5%) had no complete HR at month 3; 2/28 (7%) had no complete CyR at month 12, and 2/19 (15%) pts achieved no major molecular response (MMR, defined as >0.1% BCR-ABL [Blood 2006;108:28–37]) at month 18 after start of IMA. Each two of those four patients with incomplete response (one pt with no CyR at month 12, one pt with no MMR at month 18) underwent SCT from a sibling donor and the other two pts stopped IMA and were put on dasatinib. With a median follow-up of 19 months (range: 0-63 months) all 47 pts diagnosed in CP are alive. Of note none of the six pts (median age at diagnosis: 5 yrs; range 1–13 years) treated by imatinib meanwhile for >36 months have opted for SCT. Conclusion: Keeping in mind that the number of pediatric pts is still small, IMA treatment for children and adolescents with CML in CP is associated -like in adults- with high treatment response rates. Refractoriness to IMA is uncommon and side effects seem tolerable, as only 10% of the total cohort stopped imatinib and were put on 2nd generation TKI. However, disturbances of bone metabolism and longitudinal growth impairment may be of special concern in this not yet outgrown cohort [N Engl J Med 2006;354:2006, Blood 2008;111:2538; Haematologica 2008;93:1101; Lancet 2008;372:111; Int J Hematol; 2009;89:251; Haematologica 2009;94:1177]. Only 3/47 pts not diagnosed in advanced phases of CML so far underwent SCT thus underlining that also in pediatrics SCT has been shifted to a second-line strategy for high-risk patients and those who failed therapy with IMA. Disclosures: Suttorp: Novartis : Research Funding. Thiede:Novartis: Research Funding.

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