Profile of Pediatric Chronic Myeloid Leukemia in the Era of Imatinib - a Study from a Developing Country

Abstract INTRODUCTION Chronic myeloid leukemia (CML) is very rare in children constituting 3% of pediatric leukemias and 10% of all CML cases. There is a lack of uniform guidelines, though the leukemic biology and clinicohematological features are the same as adults. Since the advent of imatinib, treatment modalities have evolved. However the effect of long term treatment on the child and family are areas to be studied, especially in developing countries. AIM To study the clinicohematologic profile, diagnostic and therapeutic methods, follow up measures, impact of the disease on the patient's education and the psychosocioeconomic compromise of the parents. MATERIALS AND METHODS Institutional ethics committee approval and informed consent from parents was obtained. All cases of pediatric CML were included. The patients and parents were interviewed and their medical records reviewed. The demography, clinical and hematological features at presentation, treatment, compliance, toxicity and follow up details were collected. The parents were provided with a validated questionnaire to assess the psychosocioeconomic impact. RESULTS In 2011 - 2014, 7 patients below 18 years of age were diagnosed to have CML. Incidence: 5.6 % of pediatric leukemias and 9 % of CML in our centre. 1 patient opted out of treatment; 6 are undergoing treatment and follow up. 3 (50%) were above 14 years of age, 2 (33%) between 10 and 14 years, 1 (17%) below 10 years. Male to female ratio is 2:1. The predominant presenting symptoms were abdominal pain, fever, weight loss and weakness. 4 patients (67%) complained of bone pain, pallor and throat pain. 4 patients (67%) had splenomegaly. All patients presented at the chronic phase of CML. 50% had WBC count less than 20,000/µl and 1 patient (17%) had hyperleukocytosis. FISH and karyotyping detected t(9;22) in all patients. RT-PCR for bcr-abl was done. All patients were started on upfront therapy with standard dose of T.Imatinib. None needed escalated therapy. Toxic symptoms noted were gastrointestinal intolerance, skin rashes, hyperpigmentation, bone pain, myalgia and cramps which were tolerable in 5 (83%) patients. 1 (17%) had to be hospitalized. The dosage was reduced and then gradually increased. 5 patients (83%) were compliant. RESPONSE TO TREATMENT AND FOLLOWUP 3 (50%) patients obtained full treatment response attaining complete molecular response (CMR) at 12-18 months, maintaining CMR at about 4 years of follow up. 2 (33%) patients are also responding well with major molecular response at 1 year (follow up 14 months) and complete cytogenetic response at 6 months (follow up 9 months). 1 patient showed treatment failure due to default follow up and loss of compliance. PSYCHOSOCIOECONOMIC EFFECT: 4 (66%) patients absented from school for more than 6 months and lost an academic year.2 patients who were above 14 years of age absented for a few months which did not affect their studies. 5 (83%) patients belonged to upper middle socioeconomic class; they travelled to the hospital by bus and met medical expenses by insurance and support from funding agencies and friends. 1 (17%) belonged to upper class who met expenses by himself. Of the parents of patients evaluated, 33% responded to feeling guilty. 16% felt guilt related to self, 33% felt guilt with regards to interpersonal relationships. 50% were depressed with 33% admitting to feeling gloomy, 33% feeling easily upset and 33% worried about the future. 50% showed difficulty in coping, 50% felt burdened, 50% felt their activities were affected. However, nobody turned to drugs or alcohol. 33% had problems in their interpersonal relationships; 17% had issues with family, 33% did not want to mingle with others. 17% felt stigmatized; 17% felt neglected, 17% felt their social life was disturbed. 33% felt economical constraints; 33% worried about making ends meet, 17% were required to sell/ mortgage assets. DISCUSSION AND CONCLUSION: In correlation with literature, pediatric CML is rare in our centre. Patients responded well with minimum toxicity to Imatinib when compliance was good. Schooling was affected by the disease. Parents showed signs of depression and difficulty in coping. The government should initiate strategies to provide psychosocioeconomic support to CML patients and family members so they may cope with the disease. Disclosures No relevant conflicts of interest to declare.

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Molecular Response to Tyrosine Kinase Inhibitors (TKIs) for Chronic Myeloid Leukemia (CML), the Experience At Tawam Hospital, Abudhabi, UAE

Blood ◽

10.1182/blood.v120.21.4458.4458 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4458-4458

Author(s):

Arif Alam ◽

Sabir Hussain ◽

Amar Lal ◽

Donna Lee ◽

Jorgen Kristensen

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Molecular Technique ◽

Molecular Response ◽

Female Ratio

Abstract Abstract 4458 Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a balanced reciprocal translocation involving the long arms of chromosomes 9 and 22. The fusion gene that is created by this translocation (BCR-ABL1) encodes for a constitutively active protein tyrosine kinase that is primarily responsible for the leukemic phenotype. Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) has become the recommended first-line treatment for patients with CML. Monitoring of the CML is done with quantification of the BCR-ABL transcripts by RQ-PCR–based molecular technique. Twenty nine patients were diagnosed with CML in chronic phase between January 2009 till June 2012. The median age was 32 years (range 22–68 years). Male to female ratio was4.14:1. Three patients were lost from follow up after diagnosis and are excluded. Molecular response is available for 16 patients. Nine patients were treated with Imatinib 400 mg daily, four with Dasatinib 100 mg daily and three with Nilotinib 400 mg BID daily as upfront therapy. Twelve patients have achieved MMR/CMR (75 %) within 18months of starting therapy. Four patients have failed to achieve MMR by 24 months. All non responders were on Imatinib. Interestingly six (37.5%) patients achieved MMR/CMR within 9 months of starting TKIs. Of these only 1 was on Imatinib while the rest were on 2nd generation TKIs (Nilotinib 3 and Dasatinib 2). MMR report from Enestnd trial is 67–71% in favor of Nilotinib as compared to Imatinib 44%, while the Dasision trial reported a MMR of 44 % in favor of Dasatinib with faster rate to response. Our results mirror the results of these phase 3 randomized trial with MMR/CMR of 75 %. Until today there has been no case of progressive disease. Our data is limited but shows that the median age is much lower compared to Western countries, just reflecting differences in the age distribution of the population in the UAE with 80% being below the age of 65 years. Expatriates accounts for approximately 80% of the population in the UAE and many are temporary employed, having limited health care coverage, limited financial means as well as limited possibilities to attend regular follow-ups. This leads to compliance problems, loss from follow-up and suboptimal management and monitoring of their disease. Disclosures: Alam: BMS/Novartis: Consultancy, Honoraria. Hussain:BMS: Consultancy, Honoraria.

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Validations of Prognostic Scoring Systems in Iraqi Patients with Chronic Myeloid Leukemia in Single Center

International Journal of Pharmaceutical Quality Assurance ◽

10.25258/ijpqa.10.1.16 ◽

2019 ◽

Vol 10 (01) ◽

Author(s):

Hussein Saeed Al-Mafragy ◽

Hiyame Abdul Ridha Al-Awade

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Myeloproliferative Neoplasms ◽

Laboratory Data ◽

Scoring Systems ◽

Myelogenous Leukemia ◽

Prognostic Scores ◽

Treatment Modalities ◽

Molecular Response ◽

Female Ratio

Chronic myeloid leukemia and known as chronic myelogenous leukemia (CML) is one of the indolent myeloproliferative neoplasms. It is characterized by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22 or BCR‑ABL1 gene. Consistency in prognostic scores used to estimate the risk group of CML patients before therapy commencement can increase clinician trust in the treatment decision and play important role in modern medicine for CML changing treatment modalities. Inconsistency in prognostic scores occurs where two different risk categories are applied to the same chronic myeloid leukemia (CML) patient. The aims of this study were to validate the effectiveness of Sokal, Euro, EUTOS and ELTS scoring systems in predicting the outcome in Iraqi CML-chronic phase (CML-CP) patients treated with Tyrosine kinase inhibitors (TKIs) in Karbala city in Iraq and evaluate characteristics of CML patients and their molecular response. Seventy‑one patients with CML were recruited in this retrospective and prospective study from April 2017 to March 2018, the Center of Oncology for Hematology of Al-Hussein Medical City in Karbala, Iraq. They were evaluated from clinical point of view and their laboratory data, and molecular responses to TKIs based on polymerase chain reaction were analyzed. The median age of participants was 43 years; the male: female ratio was 1.03:1. In low risk category were 44, 41, 64, and 46 from 71 patients of them Sokal; Euro; EUTOS; ELTS scores respectively. In intermediate risk were 15, 22, 17 of 71 patient of them Sokal; Euro; ELTS scores respectively, and in high risk were 12, 8, 7, 8 from 71 patients of them Sokal; Euro; EUTOS; ELTS scores respectively. Follow- up of 30 patients who newly diagnosis was completed treated with TKIs in 3 and 6 months, 20 (66.7%) versus 28 (93.3%) achieved complete hematological response (CHR), while 9 (30%) versus 1(3.3%) were non CHR (xCHR), and 1 (3.3%) was (CCyR or MMR). In the current study, CML patients were at a younger age of onset, scoring systems are the most reliable clinical prognostic method evaluating CML patients indicates. That Sokal, Euro, EUTOS and ELTS scoring systems are effective in predicting early treatment response.

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Imatinib Mesylate Is Safe and Effective in Maintaining Cytogenetic and Molecular Response Achieved with 1 Year Nilotinib First Line in Newly Diagnosed Chronic Myeloid Leukemia: Preliminary Results of a Prospective Clinical Trial

Blood ◽

10.1182/blood-2018-99-118893 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5445-5445

Author(s):

Nour Moukalled ◽

Radwan Massoud ◽

Rami Mahfouz ◽

Jean Elcheikh ◽

Ali Bazarbachi

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Molecular Response ◽

First Line ◽

Metabolic Complications ◽

Number Of Patients ◽

Long Term Treatment

Abstract Background: Achieving complete cytogenetic response (CCyR) at 12 months for patients with chronic phase chronic myeloid leukemia (CML) treated with imatinib as first line, is associated with significantly improved progression-free survival. Nilotinib has shown a faster and higher rate of CCyR and molecular response as compared to imatinib. However, nilotinib use is associated with diet restriction, higher financial costs, and its long-term use is incriminated in cardiovascular and metabolic complications. Methods: In this prospective single center trial, we evaluated the ability of imatinib to maintain a CCyR achieved after 12 months of first-line treatment with nilotinib. Inclusion criteria were adult patients with previously untreated Philadelphia -positive CML in chronic phase, with a WHO performance status ≤ 2. Patients received 1-year treatment with nilotinib (300mg twice daily) then were shifted to imatinib 400mg daily. Results: Eleven patients (5 females) were so far enrolled in the study, with a median age at diagnosis of 50 years (range 31-83). Patients were started on Nilotinib at a median of 29 days (range 2-32) from diagnosis. One patient had to discontinue nilotinib after 6 months and start dasatinib due to recurrent pancreatitis that resolved upon interruption of nilotinib. Eight patients completed one year of nilotinib, and were switched to Imatinib. The remaining 2 patients are currently on nilotinib as per protocol (less than 12 months since inclusion). Three patients on imatinib had to be switched back to nilotinib, because of imatinib intolerance (n=2; elevated liver transaminases and myositis) or because of loss of MMR (n=1). Therefore, at last follow up (median 64 months), 5 patients are on imatinib, 5 on nilotinib and 1 on dasatinib. All patients (100%) achieved complete hematological response (CHR) and CCyR at 3 and 18 months respectively, and maintained them thereafter. At 12 months, 6 out of 8 eligible patients achieved complete molecular response (CMR; n=3) or major molecular response (MMR; n=3). At 36 months, all eligible patients (n=7) were either in CMR (n=2) or in MMR (n=5). All patients who reached 4 years (n=6), 5 years (n=5) or 6 years (n=3) of follow up remained in either MMR or CMR. No patient developed long-term serious adverse event including cardiovascular or metabolic complications. Conclusion: These findings suggest that imatinib can maintain MMR achieved on short-term nilotinib therapy. This strategy is a potentially safe and effective long-term treatment approach, minimizing costs and cardiovascular and metabolic complications. This however, needs confirmation with a larger number of patients. Table. Table. Disclosures No relevant conflicts of interest to declare.

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Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia

Blood Advances ◽

10.1182/bloodadvances.2019000268 ◽

2020 ◽

Vol 4 (3) ◽

pp. 530-538 ◽

Cited By ~ 9

Author(s):

Onyee Chan ◽

Chetasi Talati ◽

Leidy Isenalumhe ◽

Samantha Shams ◽

Lisa Nodzon ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Inverse Correlation ◽

Cancer Center ◽

Molecular Response ◽

Starting Dose ◽

Dose Dependent Fashion ◽

Dose Dependent

Abstract Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase–CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase–CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits.

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Imatinib Mesylate Therapy in Late Ph+ Chronic Myeloid Leukemia Patients in Stable Complete Cytogenetic Response after Interferon-Alpha Results in a Very High Complete Molecular Response Rate.

Blood ◽

10.1182/blood.v108.11.2158.2158 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2158-2158

Author(s):

Giuliana Alimena ◽

Massimo Breccia ◽

Luigia Luciano ◽

Fabrizio Quarantelli ◽

Daniela Diverio ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Imatinib Mesylate ◽

Copy Number ◽

Myeloid Leukemia ◽

Residual Disease ◽

Cytogenetic Response ◽

Molecular Response ◽

Complete Cytogenetic Response ◽

Complete Molecular Response

Abstract Imatinib mesylate was given to 26 Philadelphia positive (Ph+) chronic myeloid leukemia (CML) patients who were in late chronic phase (CP) and in stable complete cytogenetic response (CCR) after interferon-alfa (IFN-α), but showed persistent positive residual disease at PCR analysis under this treatment. At diagnosis median age was 40 years (range 21–64) and according to Sokal’s score, 18 patients were low risk and 8 were intermediate risk. Median IFN treatment was 88 mo.s (range 15–202) and median CCR duration was 73 mo.s (range 10–148). Imatinib was administered at the standard dose of 400 mg/die, after stopping IFN for 1 week. Residual disease was measured on bone marrow (BM) cells at baseline, before starting Imatinib, at 3, 6, 12, 18 mo.s and at the last follow-up (median 32 mo.s, range 21–49), by assaying BCR-ABL transcripts using quantitative PCR (RQ-PCR). The copy number (CN) of BCR/ABL and ABL transcript were derived by the interpolation of CT values to the appropriate standard curve, and the result, for each sample, was expressed as ratio of BCR/ABL mRNA copies to ABL mRNA x 100 (normalized copy number - NCN). Imatinib treatment resulted in a progressive and consistent decline of residual disease in all but one patient, from a median of 0.89 at baseline to 0.01 at the end of follow-up. Major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%) and BCR/ABL transcripts were undetectable in 13 (50%). Achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response vs 18,97 for those who did not; p<0.001), but not with other clinical/biological patient characteristics. In all patients, imatinib was well tolerated with no side effects requiring drug dose reduction or dose discontinuation. Albeit obtained from an unusual subset of selected patients with favourable prognosis, and likely particularly sensitive to imatinib, present results confirm the efficacy of combining Imatinib and IFN-α and further support investigating treatment approaches employing these two drugs.

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High and Early Rates of Cytogenetic and Molecular Response with Nilotinib 800 Mg Daily as First Line Treatment of Ph-Positive Chronic Myeloid Leukemia in Chronic Phase: Results of a Phase 2 Trial of the GIMEMA CML Working Party

Blood ◽

10.1182/blood.v112.11.181.181 ◽

2008 ◽

Vol 112 (11) ◽

pp. 181-181 ◽

Cited By ~ 14

Author(s):

Gianantonio Rosti ◽

Fausto Castagnetti ◽

Angela Poerio ◽

Massimo Breccia ◽

Luciano Levato ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Working Party ◽

Hematologic Toxicity ◽

Molecular Response ◽

Average Dose ◽

Open Label ◽

Grade Iii

Abstract Imatinib (IM) 400 mg daily is the standard treatment for chronic myeloid leukemia in early chronic phase (ECP): the results of the IRIS trial have shown a 72 months overall survival of 95%; EFS and PFS were 83% and 93%, respectively; the cumulative rate of complete cytogenetic response (CCgR) for the IM 400 mg arm was 25% at 3 months (at 6, 12, 18 and 60 months it was 51%, 69%, 76% and 87%, respectively). Nilotinib, a second generation TKI, has a higher binding affinity and selectivity for Abl with respect to IM, being 20 to 50 times more active in IM-sensitive cell lines and is highly effective in IM resistant patients, across every disease phase. To investigate the therapeutic efficacy and the safety of nilotinib 400 mg BID in untreated, ECP, Ph-pos CML patients, the italian GIMEMA CML Working Party is conducting an open-label, single stage, multicentric, phase II study trial (ClinicalTrials.gov. NCT00481052); all patients provided written informed consent. The primary endpoint is the CCgR rate at 1 year; the kinetic of molecular response is studied by Q-PCR baseline and after 1, 2, 3, 6, 9 and 12 months from treatment start. PATIENTS Seventy-three patients have been enrolled from 20 Centres between June, 2007 and February, 2008. The median age was 51 years (range 18–83), 45% low, 41% intermediate and 14% high Sokal risk. Median follow-up is currently 210 days (range 68–362). RESULTS All 73 patients and 48/73 (66%) completed 3 and 6 months on treatment, respectively. Response at 3 and 6 months (ITT): the CHR rate was 100% and 98%, the CCgR rate 78% and 96%, respectively. A MMR, defined as a BCR-ABL:ABL ratio < 0.1% according to the International Scale, was achieved by 3% of all treated patients after 1 month on treatment, but this proportion rapidly increased to 22% after 2 months, 59% after 3 months and 74% after 6 months. One patient progressed at 6 months to accelerated-blastic phase with the T315I mutation. NILOTINIB DOSE AND COMPLIANCE No dose escalation was permitted in case of resistance; the median daily average dose was close to the intended dose, 789 mg (range 261 – 800); 34/73 patients (47%) interrupted nilotinib at least once, with a median duration of dose interruption of 15 days (range 2–98). The dose of nilotinib at the last visit was 400 mg BID for 52 patients (71%), 400 mg daily for 20 patients (27%) and 200 mg daily for 1 patient (1%). ADVERSE EVENTS: AEs (grade III/IV) were manageable with appropriate dose adaptations: hematologic toxicity was recorded so far in 4 pts (5% - only 1 event grade IV neutropenia); the most frequent biochemical laboratory abnormalities (grade III) were total bilirubin increase (15%), GOT/GPT increase (11%) and lipase increase (4%). Only 1 episode of grade IV lipase increase was recorded. It is noteworthy, considering the 48 cases with at least 6 months of follow-up, that the incidence of any grade II and III nonhematologic adverse event, decreased from 50% and 8% (first 3 months) to 23% and 6% (second trimester), respectively. ECG monitoring: in 16 patients (22%), transient and not clinically relevant ECG abnormalities have been recorded; 2 more patients (3%) revealed a transient and uneventful QTc prolongation (>450 but <499 msec). CONCLUSIONS: The results that have been achieved in these unselected patients and within a multicentric trial, strongly support the notion that in ECP Ph-pos CML patients both cytogenetic and molecular responses to nilotinib are substantially faster than the responses to IM. Acknowledgments: Work supported by European LeukemiaNet, COFIN, University of Bologna and BolognAIL.

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Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽

10.1182/blood.v114.22.1128.1128 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1128-1128 ◽

Cited By ~ 2

Author(s):

Hanna Jean Khoury ◽

Michael J. Mauro ◽

Yousif Matloub ◽

Tai-Tsang Chen ◽

Erkut Bahceci ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Duration ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Phase Iii ◽

Hematologic Toxicity ◽

Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

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Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽

10.1182/blood.v114.22.3302.3302 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3302-3302

Author(s):

Massimo Breccia ◽

Fabio Stagno ◽

Roberto Latagliata ◽

Paolo Vigneri ◽

Laura Cannella ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Standard Dose ◽

Acquired Resistance ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

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Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan

Blood ◽

10.1182/blood.v122.21.1493.1493 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1493-1493

Author(s):

Kohei Yamaguchi ◽

Kazunori Murai ◽

Shigeki Ito ◽

Tomoaki Akagi ◽

Kazuei Ogawa ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Major Molecular Response ◽

Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with <0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

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Predictive Value Of Early Molecular Responses In Outcomes Of Patients With Chronic Myeloid Leukemia Treated With Imatinib In First-Line Therapy

Blood ◽

10.1182/blood.v122.21.4941.4941 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4941-4941

Author(s):

Katia B. Pagnano ◽

Bruna Vergilio ◽

Eliana C M Miranda ◽

Marcia Torresan Delamain ◽

Maria Helena De Almeida ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cytogenetic Response ◽

Molecular Response ◽

First Line ◽

Molecular Responses ◽

Advanced Phase ◽

Significant Difference ◽

The Impact

Abstract Several studies demonstrated the prognostic significance of an early molecular response in chronic myeloid leukemia (CML) patients (pts) treated with imatinib in first line or other tyrosine kinase inhibitors. Aims: The aim of this study was to evaluate the impact of early molecular responses, at 3 and 6 months after treatment with imatinib in CML pts and correlate these responses with CCR, MMR, overall survival (OS) and event free survival (EFS). Patients and Methods Between February 2006 and June 2012, 95 adult pts with newly diagnosed CML in chronic phase (CP) received imatinib 400mg/daily. CP was defined using WHO 2008 criteria. All pts received a short course of hydroxiurea until imatinib was available. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1% (IS). Statistical analysis: OS was measured from imatinib start until date of death or last visit. An event was defined as death from any cause. EFS was measured from imatinib start until the first event (loss of complete hematological response (CHR); complete cytogenetic response (CCR), progression to advanced phase, death or imatinib discontinuation) or last visit. OS and EFS rates were calculated using Kaplan-Meier method and log-rank test to compare its curves. The MMR probabilities according to molecular responses at 3 and 6 months were calculated by c2 method and cumulative incidence, considering as competitive event death or progression, before the event. Results 95 pts were analyzed, 57 (60%) male, with a median age of 47 years (17-79); Sokal score: high, intermediate and low was 30, 38.6 and 31.4% respectively; EUTOS scores was 81.5% low and 18.5% high. The median time from diagnosis until imatinib therapy was 1 month (0-5) and the follow-up was 39 month (3-89). Responses: 88% achieved CHR; 50% CCR and 53% MMR. One patient progressed to advanced phase during follow-up, while on imatinib treatment. 21 (22%) pts discontinued imatinib due to intolerance (47.6%); resistance (42.9%), death (4.8%) and Allo-HSCT (4.8%). At 3 months from the start of therapy, 30/64 (46.8%) achieved CCR, 15/64 (23.4%) partial cytogenetic response and 20/64 (31.2%) less than partial; by RQ-PCR, 72.3% (68/94) achieved at 3 months BCR-ABL transcripts ≤10% and 27.7% (26/94) > 10%. At 6 months 55.2% (48/87) had BCR-ABL transcripts ≤ 1% and 44.8% (39/87) >1%. The OS was 97% (95%CI: 95-99%) and EFS 63% (95%CI: 52-75%).There was no significant difference in OS and EFS in pts with RQ-PCR > 10% vs ≤ 10% at 3 months (figure 1), but pts with BCR-ABL transcripts > 10 and >1-10% at 6 months had an inferior EFS in comparison with pts with BCR-ABL transcripts ≤ 1% (41%,50%,89% respectively - p= 0.005), (figure 2). The CI showed that CCR pts at 3 months reached MMR earlier at 24 month (54% vs 18%, p=0.03), as well as CCR pts at 6 months, albeit no significance statistically (52% vs 37%, p= 0.16). For RQ-PCR at 3 months, pts with BCR-ABL transcripts 0-1% had a probability of 88% to achieve MMR, 1-10% had 52% and >10% 42%, p< 0.0001 (figure 3). In conclusion, our results show that early molecular responses are predictive of achieving MMR and BCR-ABL transcripts <1% at 6 months is predictive of EFS in CP-CML treated with imatinib. Disclosures: No relevant conflicts of interest to declare.

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