Real-world efficacy and safety outcomes of imatinib treatment in patients with chronic myeloid leukemia: an Australian experience

Background: Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of chronic myeloid leukaemia (CML), but patients still experience treatment-limiting toxicities or therapeutic failure. Aims: To investigate real-world use and outcomes of imatinib in patients with CML in Australia. Methods: A retrospective cohort study of patients with CML commencing imatinib (2001-2018) was conducted across two sites. Prescribing patterns, tolerability outcomes, survival and molecular response were evaluated. Results: 86 patients received 89 imatinib treatments. Dose modifications were frequently observed (12-month rate of 58%). At last follow-up, 62 patients (5-year rate of 55%) had permanently discontinued imatinib treatment, of which 44 switched to another TKI (5-year rate of 46%). Within 3 months of starting imatinib, 43% (95% CI, 32–53%) of patients experienced imatinib-related grade ≥3 adverse drug reactions (ADRs). Higher comorbidity score, lower body weight, higher imatinib starting dose, and Middle Eastern or North African ancestry were associated with a higher risk of grade ≥ 3 ADR occurrence on multivariable analysis (MVA). Estimated overall survival and event-free survival rates at 3 years were 97% (95% CI, 92–100%) and 81% (95% CI, 72–92%), respectively. Cumulative incidence of major molecular response (MMR) at 3 years was 63% (95% CI, 50–73%). On MVA, imatinib starting dose, ELTS score, BCR-ABL1 transcript type, pre-existing pulmonary disease, and potential drug-drug interactions were predictive of MMR. Conclusion: Imatinib induced deep molecular responses that translated to good survival outcomes in a real-world setting, but was associated with a higher incidence of ADRs, dose modifications and treatment discontinuations than in clinical trials.

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Dasatinib in the Treatment of CML Patients Aged > 60 Years Resistant/Intolerant to Imatinib

Blood ◽

10.1182/blood.v112.11.4253.4253 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4253-4253

Author(s):

Roberto Latagliata ◽

Massimo Breccia ◽

Fabio Stagno ◽

Silvia De Matteis ◽

Mario Annunziata ◽

...

Keyword(s):

Elderly Patients ◽

Kinase Inhibitor ◽

Standard Dose ◽

Chronic Phase ◽

Elderly Subjects ◽

Molecular Response ◽

Imatinib Treatment ◽

Starting Dose ◽

Median Period ◽

Grade 3

Abstract Dasatinib is a 2nd generation tyrosine-kinase inhibitor active in CML patients resistant or intolerant to Imatinib; at present there is no data on its toxicity and efficacy in elderly patients. To highlight this issue, 37 patients treated with Dasatinib when aged > 60 years were retrospectively evaluated. There were 21 males and 16 females, median age at Dasatinb was 69.3 years (IR 64.9–73.0), Sokal Risk at diagnosis was low in 13 patients, intermediate in 14, high in 5 and not valuable in 5. Twenty-two patients (59.4%) were primary resistant, 4 (10.8%) intolerant and 11 (29.8%) secondary resistant to Imatinib; all but 2 patients were in CP when Dasatinib was started. Median time from diagnosis to Dasatinib treatment was 99.2 months (IR 56.8–124.5); 25/37 patients (67.5%) have been pretreated with IFN ± Ara-C before Imatinib, all patients received Imatinib at standard dose (400 mg/day) followed in 20/37 (54%) by Imatinib at increased dose (600–800 mg/day) with an overall median period of Imatinib treatment of 52.8 months (IR 26.2–60.9). In addition, 7/37 patients (18.9%) received other 2nd line treatment (3 with Nilotinib, 2 with Imatinib + HU and 2 with other drugs) before Dasatinib. Starting dose of Dasatinib was 140 mg/day in 18 patients and 100 mg/day in 19 patients, respectively. After a median period of treatment of 9.4 months (IR 3.0–19.1) all patients were evaluable for toxicity; among 18 patients receiving 140 mg, grade 3–4 haematological and extra-haematological toxicities were reported in 14 (77.7%) and 6 (33.3%) patients, respectively; among 19 patients receiving 100 mg, grade 3–4 haematological and extra-haematological toxicities were reported in 4 (21.0%) and 1 (5.2%) patients, respectively. Pleuro-pericardial effusions occurred in 3 patients, all treated with 140 mg as starting dose. Overall, 3/37 patients (all treated with 140 mg) discontinued permanently Dasatinib due to early toxicity; a dose reduction was needed in 17/37 patients [16/18 (88.8%) treated with 140 mg and 1/19 (5.2%) with 100 mg]. As to response, 28 patients were considered evaluable (≥ 6 months of treatment) and 9 considered as too early; five patients (17.9%) did not have any response (including 3 patients with early Dasatinib discontinuation for toxicity) and 23 (82.1%) achieved Complete Haematological Response (CHR). Furthermore, 11/28 patients (39.2%) achieved a Cytogenetic Response (CyR) (Major CyR in 4 and Complete CyR in 7) and 4/28 patients (14.2%) achieved a molecular response. In conclusion, Dasatinib, when employed at the current recommended starting dose of 100 mg/day; seems effective and very well tolerated also in heavily pretreated elderly subjects; these results are encouraging also for a future use of this drug in early chronic phase elderly patients.

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Treatment with Imatinib in Very Elderly (> 75 Years) CML Patients.

Blood ◽

10.1182/blood.v112.11.1096.1096 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1096-1096

Author(s):

Roberto Latagli Ata ◽

Massimo Breccia ◽

Simona Sica ◽

Antonio Spadea ◽

Ada D’Addosio ◽

...

Keyword(s):

Late Toxicity ◽

Cytogenetic Response ◽

Imatinib Treatment ◽

Very Elderly ◽

Molecular Remission ◽

Starting Dose ◽

Daily Dose ◽

Grade 3 ◽

Early Toxicity ◽

Complete Haematological Response

Abstract Median age of patients with CML is about 65 years, according to SEER 2000–2005 data. However, the treatment with Imatinib in elderly has been seldom specifically addressed: in particular, there is a lack of data regarding very elderly CML patients. To highlight peculiar aspects of toxicity and efficacy of Imatinib in this subset which accounts for at least 10–15% of all CML cases, we revised retrospectively 28 CML patients treated with Imatinib when aged > 75 years from 4 haematological Institution in Rome; there were 12 males and 16 females, median age at Imatinib was 78.7 years (IR 75.8 – 82.9), Sokal Risk at diagnosis was intermediate in 20 patients, high in 6 and not valuable in 2. One or more concomitant diseases requiring specific treatments were present in 26/28 patients (92.8%), with 15 patients (53.5%) assuming 3 or more concomitant drugs. Nine patients (32.1%) have been pretreated ≥ 6 months with HU before starting Imatinib; on the whole, median time from diagnosis to Imatinib was 1.8 months (IR 0.7 – 25.1). Starting dose of Imatinib was 400 mg/day in 23 patients (82.1%) and 300 mg/day in 5 patients (17.9%); overall, 15 patients (53.5%) (14/23 at 400 mg starting dose and 1/5 at 300 mg starting dose) needed a dose reduction and 6 (21.4 %) discontinued Imatinib for toxicity (early toxicity in 4 and late toxicity in 2). Excluding the 4 patients who discontinued Imatinib due to early toxicity, maximum tolerated daily dose during treatment was 400 mg in 8 patients, 300 mg in 13 patients and 200 mg in 3 patients. According to CTC-AE, grade 3 – 4 haematological and extra-haematological toxicities were observed in 7 (25%) and 12 (42.8%) patients, respectively; 2 patients (7.1%) presented a pleural effusion during Imatinib treatment. All patients were fully evaluable for response to Imatinib, with a median treatment period of 30.6 months (IR 15.7 – 49.2); six patients (21.4%) failed any response, (including 4 patients who discontinued Imatinib due to early toxicity) and 22 (78.6%) achieved a complete haematological response (CHR). Among these 22 patients in CHR, 4 refused any other karyotipic or molecular evaluation (3 are still alive in CHR, 1 died in CHR from unrelated cause after 44,5 months) and 17/18 (60.7% of all 28 patients) achieved a cytogenetic response (CyR), major in 1 patient and complete in 16 patients. In addition, 7 patients (25% of all 28 patients) achieved a complete molecular remission, with an undetectable BCR/ABL hybrid gene at qualitative nested PCR. In conclusion, Imatinib at reduced daily dose of 300 mg seems a relatively safe and quite effective treatment for very elderly CML patients; from our data, no upper age limit should be given for TKinhibitors treatment but also very elderly (and with concomitant severe diseases) patients should have this chance of cure.

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Prescribing patterns for FOLFIRINOX in the real world.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.463 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 463-463

Author(s):

Chad Michael Guenther ◽

Nizar Bhulani ◽

Adam Korenke ◽

Jenny Jing Li ◽

Leticia Khosama ◽

...

Keyword(s):

Real World ◽

Prescribing Patterns ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Bivariate Analysis ◽

Treatment Delays ◽

The Real ◽

Significant Difference ◽

Ed Visits ◽

Dose Modifications

463 Background: FOLFIRINOX therapy is associated with improved outcome in patients with gastrointestinal cancers. The regimen can be associated with significant toxicity and empiric dose modifications are often used. We analyzed 1) real-world prescribing patterns of FOLFIRINOX and 2) toxicity of therapy. Methods: Patients undergoing FOLFIRINOX chemotherapy at an academic, NCI-Designated Comprehensive Cancer Center were identified and electronic medical records reviewed. Patients who received at least one dose of FOLFIRINOX were included. Chemotherapy dose, growth factor use and toxicity data was abstracted for the first 8 weeks. ‘Standard FOLFIRNOX’ was defined as the regimen utilized by Conroy et al (NEJM 2011). Any empiric reduction/withholding of drug dose for cycle 1 was classified as ‘modified FOLFIRINOX’. Bivariate analysis was performed on the data. Results: There were 111 patients seen between 5/2011-3/2017 and 94% had pancreatic cancer. Age range was 29-87 years and 52% were female. 59% received ‘modified FOLFIRINOX’ and 20% received empiric growth factors. Line of therapy for standard vs modified respectively was 71.1% vs 45.5% for 1st, 17.8% vs 36.4% for 2nd, and 11.1% vs 18.2% for beyond 2nd (p = 0.03). Patients with ‘modified FOLFIRINOX’ were more likely to have metastatic disease (p = 0.01), have received second line or beyond, and higher ECOG score (p = 0.03). Patients with ‘modified FOLFIRINOX’ had a trend toward fewer treatment-related ED visits or hospitalization vs ‘standard FOLFIRINOX’ (27.2% vs 42.2% p = 0.10) and fewer treatment delays (25.8% vs 42.2% p = 0.07). Conclusions: In the real world setting, a majority of patients on FOLFIRINOX receive empiric dose modifications. Although modified dose did not translate to a significant difference in ED visits, hospitalizations or treatment delays, there was a trend toward fewer events.

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A Phase 1/2 Study Of Bosutinib (SKI-606) In Japanese Adults With Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia (CML)

Blood ◽

10.1182/blood.v122.21.2736.2736 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2736-2736

Author(s):

Naoto Takahashi ◽

Kenichi Ishizawa ◽

Chiaki Nakaseko ◽

Yukio Kobayashi ◽

Kazuteru Ohashi ◽

...

Keyword(s):

Research Funding ◽

Phase 1 ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Clinical Activity ◽

Molecular Response ◽

Multiple Doses ◽

Starting Dose ◽

Daily Dose ◽

Grade 3

Abstract Background Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor, has demonstrated efficacy and acceptable safety in patients (pts) with chronic phase (CP)-CML resistant/intolerant to imatinib (IM). This ongoing open-label, 2-part, phase 1/2 study evaluated the safety, pharmacokinetics (PK), and efficacy of BOS in Japanese pts with Ph+ CML. Methods In this study, Part 1 was designed to confirm the safety of BOS up to 600 mg/d (or establish a maximum tolerated dose <600 mg/d) and evaluate PK parameters in IM-resistant/intolerant CP-CML pts. In Part 1, BOS (400 mg, 500 mg, and 600 mg) was administered to successive cohorts of pts aged ≥20 to <75 y as a single daily dose on d 1 and as a continuous once-daily dose from d 3, with each cohort (3-6 pts) evaluated for 28 d before enrolling the next dosing cohort. Part 2 evaluated the efficacy and safety of BOS in CP-CML or advanced (ADV) CML pts after resistance/intolerance to IM (second-line [2L]) or to IM plus dasatinib or nilotinib (third-line [3L]; exploratory cohort). In Part 2, BOS (starting dose: 500 mg/d) was administered to pts aged ≥20 y, with dose escalation to 600 mg/d allowed for lack of efficacy. The primary efficacy endpoint was the cumulative major cytogenetic response (MCyR) rate by wk 24 in CP-CML 2L pts (primary cohort). Results In Part 1, 17 pts received BOS (400 mg, n=7, 500 mg, n=7; 600 mg, n=3); 1 pt each in the 400 mg and 500 mg dose groups was not evaluable for dose limiting toxicities (DLTs) due to early study discontinuation (disease progression and pt request, respectively). DLTs during the first 28 d of treatment occurred in 1/6 pt receiving BOS 400 mg (grade 3 liver injury) and 1/6 pt receiving BOS 500 mg (grade 4 abnormal hepatic function); no DLTs occurred in the 3 BOS 600-mg pts. BOS 500 mg was chosen as starting dose for Part 2 based on DLTs and previous results (Cortes et al. Blood. 2011;118:4567-76). PK analyses indicated relatively slow absorption, with a median Tmax of ∼4 h after single or multiple doses of BOS 400–600 mg. BOS exposure (Cmax and AUC) generally increased with increasing dose after single and multiple doses. In Part 2, 46 additional pts were enrolled (2L, n=35 [28 CP-CML, 7 ADV]; 3L, n=11 [10 CP-CML, 1 accelerated-phase (AP)]); 63 pts were treated with BOS (median [range] age: 55 [20-78] y; 62% male; entry diagnosis: CP-CML, n=58; AP-CML, n=3; blast phase [BP]-CML, n=2). Median follow-up was 132 wk for 2L pts and 37 wk for 3L pts. In the CP-CML 2L cohort in Part 2 (n=28), the MCyR rate by wk 24 was 36% (10/28 pts; complete [CCyR], n=8; partial [PCyR], n=2) (primary endpoint); maintained MCyR at wk 24 was 64% (18/28 pts; CCyR, n=16; PCyR, n=2); median time to MCyR was 12.3 wk. Only 1 of 13 CP-CML 2L pts who attained MCyR at any point during the study lost it. Cumulative major molecular response (MMR) rate through the study was 43% (12/28 pts). AP/BP transformation occurred in 1 CP-CML 2L pt; at wks 48 and 96, progression-free survival (PFS) rates were 100% and 94%, respectively, and overall survival (OS) rate was 96% (both). Of 7 ADV 2L pts, 1 had confirmed complete hematologic response (cCHR) at wk 84 with duration of 95 wk (cCHR lost). AP/BP transformation occurred in 1 ADV 2L pt; at wks 48 and 96, PFS rate was 21% (both), and OS rate was 43% (both). In the 3L cohort, the cumulative MCyR rate by wk 24 and maintained MCyR rate at wk 24 were 18% (2/11 pts) and 64% (7/11 pts [CCyR, n=6; PCyR, n=1]); cumulative MMR rate through the study was 18% (2/11 pts). The only 3L pt with AP-CML attained cCHR at 12 wk with a duration of 24 wk as of the date of this analysis (censored due to data cutoff). No AP/BP transformation occurred in the 3L cohort; treatment duration was inadequate for assessment of PFS and OS. Overall, the most common treatment-emergent AEs (TEAEs) were diarrhea (95%), rash (57%), nasopharyngitis (51%), nausea (38%), vomiting (38%), increased alanine aminotransferase (ALT; 38%), lymphopenia (35%), thrombocytopenia (30%), and increased aspartate aminotransferase (30%). Grade 3/4 TEAEs were reported in 54 (86%) pts, most commonly lymphopenia (21%), increased lipase (19%), neutropenia (18%), thrombocytopenia (18%), and increased ALT (18%). 16 (25%) pts discontinued treatment due to AEs. No deaths occurred within 30 d of last BOS dose. Conclusions The safety and PK profiles of BOS up to 600 mg/d was confirmed in Japanese pts with Ph+ CML resistant/intolerant to IM. BOS 500 mg/d demonstrated clinical activity and an acceptable safety profile in this population. Disclosures: Kobayashi: Ariad: Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Research Funding; Ohtsuka: Research Funding; Onconova: Research Funding. Shibata:Pfizer Japan Inc: Employment. Fujii:Pfizer Japan Inc: Employment. Ono:Pfizer Japan Inc: Employment.

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The Prospective Analysis Of Clinical Efficacy and Adverse Events In Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Patients With Imatinib Resistance Or Intolerance, Evaluated By European Leukemia Net (ELN) 2013 Criteria

Blood ◽

10.1182/blood.v122.21.4027.4027 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4027-4027

Author(s):

Kazunori Murai ◽

Tomoaki Akagi ◽

Kenji Shimosegawa ◽

Kenichi Ishizawa ◽

Tomohiro Sugawara ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Molecular Response ◽

Imatinib Treatment ◽

Efficacy And Safety ◽

Major Molecular Response ◽

First Line ◽

Imatinib Resistance ◽

Grade 3 ◽

Dasatinib Treatment

Abstract Background Dasatinib is a highly potent BCR-ABL inhibitor, with a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. Across a series of phase II and III trials with more than 2 years of follow-up, dasatinib has demonstrated durable efficacy in patients with CML following resistance or intolerance to imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib resistance or intolerance CML. Methods Fifty- five CML-CP patients from 2009 to 2011 with resistance (n=40) or intolerance (n=26) to imatinib were registered to dasatinib administration (100mg once daily). Eleven among 26 patients with intolerance also showed resistance to imatinib at the registration. Imatinib resistance was defined as a lack of partial cytogenetical response at 3 months, a lack of complete cytogenetic response at 6 months or a lack of a major molecular response at 12 months of imatinib treatment. This criteria was identical to the criteria in ELN 2013 recommendation for first line. In another words, the resistance in this study means non-optimal criteria (warning and failure) of definition of the response to TKIs, first line, in ELN 2013 recommendation. Efficacy and safety were assessed using rates of major molecular response (MMR)/ 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) at 12 months and drug-related adverse events (AEs) respectively. All analyses were based on the modified to intension-to treat. Results One patient was withdrawal before dasatinib administration. The median duration of imatinib therapy was 545 days. The overall incidence of MMR (primary endopoint) and MR4.5 at 12 months was 67.2% (95% confidence interval, 53.3-81.1%), and 20.2 % (95% CI, 8.4–32.0 %), respectively. Forty patients with resistance to imatinib, who were warning and failure patients judged by ELN 2013 criteria, were reassessed. Cumulative MMR and MR4.5 rate were 63.4% (95% CI: 46.3-80.6) and 18.0% (95% CI: 4.9-31.1) respectively at 12 months. Eleven patients, who showed more than 1% IS at 3 months of dasatinib treatment, did not reach to MMR at 12 months or discontinued dasatinib due to insufficient efficacy in this resistance cohort. However, progression to the accelerated or blastic phase had not been observed. When imatinib were changed to dasatinib, 5 patients showed the mutations, which were effective in dasatinib therapy. New mutations have not been observed during the treatment of dasatinib. Among 54 patients, most non-hematological AEs were in grade 1/2. including diarrhea (12.7%), rash (7.3%), myalgia (5.5%) and vomiting (3.6%). Grade 3/4 non-hematological AEs were infrequent, including decreased potassium (3.6%), and increased creatinine (3.6%). Grade 1/2 fluid retention AEs were shown in 9.1% of patients, including edema (3.6%). Pleural effusion, which was only in Grade 1/2, was shown in 32.7% of patients. Grade 3/4 hematological toxicities included anemia (7.3%) and thrombocytopenia (3.6 %). Only 3 patients have permanently discontinued dasatinib treatment due to AEs. Conclusions The patients with non-optimal responses (warning and failure) judged by ELN 2013 criteria should have early intervention to dasatinib, which is less toxicity in CML-CP patients. This intervention might induce good prognosis. The BCR-ABL1 IS less than 1% at 3 months of dasatinib administration will be the valuable landmark for outcome. Disclosures: No relevant conflicts of interest to declare.

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Real-World Ponatinib Prescribing Patterns and Outcomes in US Patients

Blood ◽

10.1182/blood.v126.23.1591.1591 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1591-1591

Author(s):

Michael J. Mauro ◽

Lisa J. McGarry ◽

Mo Yang ◽

Stephanie Lustgarten ◽

Hui Huang

Keyword(s):

Dose Reduction ◽

Real World ◽

Dose Adjustment ◽

Prescribing Patterns ◽

Employment Equity ◽

Line Therapy ◽

Starting Dose ◽

The Us ◽

Equity Ownership ◽

Over Time

Abstract Background: In Jan 2014, ponatinib was reintroduced to the US market after an 11 week withdrawal to review data on arterial thrombotic events, revise US prescribing information (USPI) and implement a risk evaluation and mitigation strategy (REMS). The USPI was revised to narrow the indicated population and recommend a starting dose of 45 mg, with consideration of 1) lower doses in patients with selected comorbidities or to manage adverse events, 2) dose reduction in chronic phase (CP) and accelerated phase (AP) chronic myeloid leukemia (CML) patients achieving major cytogenetic response, and 3) discontinuation if response has not occurred at 3 months. In the US, ponatinib is available exclusively through a specialty pharmacy that maintains prescribing data for all US ponatinib-treated patients since reintroduction. Examining these data provides insight into practitioners' patient selection and prescribing patterns, and real-world ponatinib outcomes. Methods: We performed a retrospective analysis of patients starting treatment with ponatinib between 01 January 2014 and 25 March 2015 using data from referring physicians, patient intake forms and pharmacy dispensing records. Patient and prescriber characteristics, and dosing and dose modifications were documented. Clinical, demographic and physician characteristics were examined as predictors of initial dose and dose modification using logistic regression; therapy duration was assessed using Kaplan-Meier techniques and proportional hazard regression. Results: 758 US patients initiated treatment with ponatinib over this 15-month period, (58% male; median age 55 years [range: 11-98]). Among 730 patients with a specified diagnosis, 80% had CML and 4% Philadelphia chromosome positive (Ph+) acute lymphocytic leukemia (ALL); the remainder had unspecified ALL (10%), other hematologic malignancies (3%), and solid tumors (3%). Of 411 CML patients reporting disease phase, 61% were in CP, 18% AP and 21% blast phase (BP). 12% of CML and 8% of Ph+ ALL patients had a reported T315I mutation. 21% of CP, 34% of AP, 12% of BP and 31% of Ph+ ALL patients were receiving ponatinib as 2nd-line therapy, with the remainder in 3rd line or later. Most recent prior TKI was dasatinib for 48%, nilotinib for 23%, bosutinib for 17%, and imatinib for 12% of patients in all therapy lines. 50% received 45 mg as their initial dose, 33% 30 mg and 17% 15 mg. Prescribers' practice setting was 49% community and 51% academic. Most prescribers (82%) had only 1 ponatinib patient; only 7% had 3 or more. Prescribers with >1 ponatinib patient were less likely to prescribe 45 mg starting dose (OR=0.53 for those with 2 patients; OR=0.25 for 3+ patients.) 23% of patients had at least one dose adjustment, including 17% with dose reduction. Among CP patients initially on 45 mg, with at least 6 months of therapy, 42% reduced dose (29% to 30 mg; 13% to 15 mg). Dose reduction decreased significantly for later therapy lines in CP, but did not differ by disease phase. Median time on therapy was >15 months for CP, 10.6 months for AP, 7.0 months for BP, and >14 months for Ph+ ALL. CP patients' time on therapy was longer for those started on 15 mg, although this difference was not significant (p=0.14) (Figure.) Reasons for dose adjustment and discontinuation were not well documented, but they appeared to occur at a relatively constant rate over time rather than at time points recommended for response monitoring. Conclusions: Real-world US data shows ponatinib is prescribed across disease phase, therapy line, and mutation status. While a majority of patients were in their 3rd line of therapy or later, a substantial proportion of patients, especially in AP CML and Ph+ ALL, received ponatinib as 2nd line therapy. Physicians appear to be selecting patients who are younger than those enrolled in registrational trial for ponatinib (55 years vs. PACE trial median age, 64 years), and mitigating against potential risk using lower starting doses and dose reduction. Most prescribers have only 1 ponatinib patient, but physicians with >1 ponatinib patient favor lower starting doses. Dose reduction and discontinuation occurred steadily over time rather than clustered at routine response milestone time points. CP CML Patients starting at 15 mg appear to have similar or better treatment duration compared with those started at higher doses. Disclosures Mauro: Ariad: Consultancy; Pfizer: Consultancy; Novartis Pharmaceutical Corporation: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. McGarry:ARIAD: Employment, Equity Ownership. Yang:ARIAD Pharmaceuticals, Inc: Employment. Lustgarten:ARIAD Pharmaceuticals Inc.: Employment, Equity Ownership, Other: Stock. Huang:ARIAD: Employment, Equity Ownership.

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Real-Life Analysis of Dasatinib in Chronic Phase CML Patients Aged > 60 Years Resistant/Intolerant to Imatinib.

Blood ◽

10.1182/blood.v114.22.2211.2211 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2211-2211

Author(s):

Roberto Latagliata ◽

Massimo Breccia ◽

Fabio Stagno ◽

Luigiana Luciano ◽

Antonella Gozzini ◽

...

Keyword(s):

Research Funding ◽

Haematological Toxicity ◽

Real Life ◽

Elderly Subjects ◽

Molecular Response ◽

Imatinib Treatment ◽

Secondary Resistance ◽

Pericardial Effusions ◽

Median Period ◽

Grade 3

Abstract Abstract 2211 Poster Board II-188 Dasatinib is a 2nd generation tyrosine-kinase inhibitor active in CML patients resistant or intolerant to Imatinib; at present there is no data on its toxicity and efficacy in unselected elderly patients. To highlight this issue, 97 patients treated with Dasatinib when aged > 60 years were retrospectively evaluated from 16 Italian Centers on a “real-life” basis, including all patients treated at each Center independently from enrolment or not in controlled clinical trials.There were 52 males and 45 females, median age at Dasatinib start was 69.5 years (IR 65.0 – 73.3), Sokal Risk at diagnosis was low in 26 patients, intermediate in 37, high in 15 and not valuable in 19. Forthy-five patients (46.4%) were primarily resistant, 11 (11.4%) were intolerant and 41 (42.2%) had secondary resistance to Imatinib; all patients were in CP when Dasatinib was started. Median time from diagnosis to Dasatinib treatment was 85.0 months (IR 44.8 – 120.0); 53/97 patients (54.6%) had been pretreated with IFN ± Ara-C before Imatinib, all patients received Imatinib at standard dose (400 mg/day) followed in 50/97 (51.5%) by increased dose (600 – 800 mg/day) with an overall median period of Imatinib treatment of 48.6 months (IR 26.9 – 67.0). In addition, 28/97 patients (28.8%) received other 2nd line treatment (10 Nilotinib, 14 HU +/- other drugs, 3 Imatinib + HU or IFN and 1 allogeneic transplant) before Dasatinib. Starting dose of Dasatinib was 140 mg/day in 47 patients, 100 mg/day in 44 patients and ≥ 50 mg/day in 6 patients, respectively. After a median period of treatment of 15.6 months (IR 7.6 – 23.0) all patients were evaluable for toxicity; on the whole, grade 3 – 4 hematological and extra-hematological toxicities were reported in 36/97 (37.1%) and 27/97 (27.8%) patients, respectively. A grade 3 – 4 hematological toxicity occurred in 25/47 (53.1%) patients receiving 140 mg as compared to 10/44 (22.7%) patients receiving 100 mg (p<0.01); a grade 3 – 4 extra-haematological toxicity occurred in 16 (34.0%) patients receiving 140 mg as compared to 10/44 (22.7%) patients receiving 100 mg (p=0.09). Pleuro-pericardial effusions of all WHO grades occurred in 30/97 patients (30.9%): according to starting dosage, pleuro-pericardial effusions occurred in 19/47 patients (40.4%) treated with 140 mg and in 11/44 patients (25.0%) treated with 100 mg. Overall, 11/97 patients (7 treated with 140 mg, 3 with 100 mg and 1 with < 100 mg) permanently discontinued Dasatinib due to toxicity; a dose reduction was needed in 56/97 patients [43/47 (91.5%) treated with 140 mg and 12/44 (27.3%) with 100 mg (p<0.001)]. As to response, 91 patients were considered evaluable (≥ 3 months of treatment) and 6 were considered as too early; 11 patients (12.0%) did not have any response (including 6 patients with early Dasatinib discontinuation for toxicity and 1 patient died from unrelated 2nd neoplasia), 26 (28.6%) achieved Hematological Response only, 54 (59.4%) achieved Cytogenetic Response (CyR) (Major CyR in 10, Complete CyR in 44). Among 44 patients in Complete CyR, 29 (31.8% of all 91 evaluable patients) also achieved Molecular Response (MolR) (Major MolR in 14, Complete MolR in 15). According to starting dosage, CyR was achieved in 26/47 patients (55.3%) treated with 140 mg compared with 27/39 patients (69.2%) treated with 100 mg. The mean Overall Survival and Event-Free Survival of the whole cohort of patients were 44.6 months (CI95% 41.2 - 47.9) and 24.8 months (CI95% 20.4 – 29.2), respectively. Present analysis shows that Dasatinib could have a major role in the treatment of unselected patients aged > 60 years resistant/intolerant to Imatinib; in particular, when employed at the current recommended dose of 100 mg/day, it is very effective and has a favourable safety profile also in heavily pretreated elderly subjects. Disclosures: Vitolo: Roche: . Pane:Novartis: Research Funding; Ministero dell'Università/PRIN: Research Funding; Regione Campania: Research Funding; Ministero della Salute/Progetto integrato Oncologia: Research Funding.

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Pegylated Interferon-ALFA-2A (PEG-IFN-α-2A; PEGASYS) Therapy Renders High Clinical and Molecular Response Rates in Patients with Essential Thrombocythemia (ET) and Polycythemia VERA (PV)

Blood ◽

10.1182/blood.v112.11.658.658 ◽

2008 ◽

Vol 112 (11) ◽

pp. 658-658 ◽

Cited By ~ 4

Author(s):

Alfonso Quintas-Cardama ◽

Hagop M. Kantarjian ◽

Guillermo Garcia-Manero ◽

Jorge Cortes ◽

Marie Ann Richie ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Jak2 V617f ◽

Clinical Activity ◽

Molecular Response ◽

Significant Activity ◽

Recombinant Interferon ◽

Starting Dose ◽

Grade 3 ◽

Initial Starting

Abstract Patients with high-risk essential thrombocythemia (ET) and polycythemia vera (PV) are typically managed with cytoreductive agents such as recombinant interferon-alpha (IFN-α), hydroxyurea (HU), and anagrelide (AG). Despite the significant activity of IFN-α in ET and PV, this agent is frequently hindered by poor tolerance and inconvenient dosing schedules. PEG-IFN-α is formulated by covalently attaching polymers of ethylene glycol to the native IFN-α molecule, resulting in decreased renal excretion and increased serum half-life that allows for weekly administration. On this basis, we are conducting a phase II study of subcutaneous PEG-IFN-α-2a (Pegasys) for patients with ET or PV. A total of 76 patients have been enrolled and treated thus far (36 ET, 40 PV). Median age is 53 years (range, 18–77), time from diagnosis to PEG-IFN-α-2a 49 months (range, 0–355), WBC count 8.7×109/L (range, 3.7–27.8), hemoglobin 13.5 g/dL (range, 8.9–18.8), and platelet count 554×109/L (range, 140–1641). Prior therapies (median 1; range 0–6) included HU (n=44), AG (n=29), IFN-α (n=11: 5 oral and 6 sc), imatinib (n=7), and dasatinib (n=1). PEG-IFN-α-2a was the initial therapy in 13 patients that refused therapy with HU. The JAK2 V617F mutation was detected in 20 (56%) of 36 ET and in 37 (92.5%) of 40 PV patients. Nine (12%) patients had abnormal cytogenetics. Initial starting dose of PEG-IFN-α-2a was 450 mcg/week, but that was modified to the current starting dose of 90 mcg/week. Dose modifications are allowed according to response or toxicity. Patients are currently receiving 450 mcg (n=1), 270 mcg (n=3), 180 mcg (n=14), 135 mcg (n=8), 90 mcg (n=27), and 45 mcg (n=7). After a median follow-up of 23 months (range, 2–38), 63 (85%) of 74 assessable patients have responded. The median time to response was 4 weeks (range, 0.5–26). Complete response (CR) was achieved by 60 (81%) patients (for ET: platelets <440×109/L, off HU and AG, in the absence of thromboembolic events; for PV: Hb <15 g/dL, off HU and AG, no phlebotomy, with disappearance of splenomegaly) whereas 3 (4%) patients (1 PV, 2 ET) had a partial response ([PR]; no phlebotomy, off HU and AG, but still palpable spleen). Of 5 assessable patients with abnormal karyotype at the start of the study, 2 reverted to diploid cytogenetics. The mutant JAK2 V617F to total JAK2 ratio was determined by quantitative pyrosequencing assay in all 76 patients prior to PEG-IFN-α-2a and was repeated at least once during therapy in 41 JAK2 V617F-positive patients. Overall, 23 (56%) had >10% reduction in JAK2 V617F expression, including 14 (34%) who had a >50% reduction. In 5 (11%) of the latter the mutant allele became undetectable. PEG-IFN-α-2a was well tolerated in most patients. Thirty-nine episodes of grade 3–4 toxicity were reported: neutropenia (n=15), elevated transaminases (n=5), infection (n=4), fatigue (n=3), pain (n=3), cardiac (n=2), and anemia, thrombocytopenia, depression, shortness of breath, pruritus, thrombosis, and dizziness in 1 case each. Sixteen (21%) patients were taken off study after a median of 8 months (range, 2–26) on PEG-IFN-α-2a but only 7 (9%) of them due to due to therapy-related toxicities: grade 3 neutropenia, anorexia, depression, ischemic retinopathy, dyspnea, confusion, and pruritic rash. In conclusion, PEG-IFN-α-2a therapy results in remarkable clinical activity with an acceptable toxicity profile in advanced, previously treated, patients with ET or PV. Clinical responses are frequently accompanied by significant reduction of JAK2 V617F allele burden, which becomes undetectable in a proportion of them, suggesting selective targeting of the malignant clone.

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The Real World Use of Bosutinib in Patients with Chronic Myeloid Leukaemia

Blood ◽

10.1182/blood.v128.22.5435.5435 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5435-5435

Author(s):

Jane F. Apperley ◽

Jenny L. Byrne ◽

Graeme Smith ◽

Simone Claudiani ◽

Andrea Viqueira ◽

...

Keyword(s):

Clinical Practice ◽

Data Collection ◽

Chronic Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Real World ◽

Molecular Response ◽

Major Molecular Response ◽

The Real ◽

Advisory Boards ◽

Grade 3

Abstract Objectives.Bosutinib is a second-generation tyrosine kinase inhibitor (TKI) indicated for patients with previously treated Philadelphia chromosome positive chronic myeloid leukaemia (CML) when imatinib, nilotinib and dasatinib are not appropriate. Data describing the use of bosutinib in patients with CML in the real world clinical setting are limited. The objective of this study was to describe the efficacy and safety of bosutinib in patients with CML used under routine clinical practice. Methods.An international, multi-centre, retrospective, non-interventional study in hospitals in the UK (n=7) and the Netherlands (n=2). Fifty-three patients (32 [60%] male) with CML, aged ≥18 years at bosutinib initiation and with ≥3 months data available post-initiation were recruited. Surviving patients provided written informed consent for data collection; data from deceased patients were collected by a member of the direct care team to preserve confidentiality. Data were analysed using descriptive statistics with no imputation of missing values (denominators presented where data are missing). Results.Median age at bosutinib initiation was 63.6 (range: 25.5 to 90.1) years; median time from CML diagnosis to bosutinib initiation was 7.1 (range: 0.5 to 35.7) years; 74% (39/53) of patients had one or more co-morbidities at initiation. Bosutinib was 3rd-line TKI in 32% (17/53) of patients and 4th-line TKI in 53% (28/53) of patients. Fifty-seven percent (30/53) of patients switched to bosutinib due to intolerance and 26% (14/53) due to resistance to a previous TKI. The most common bosutinib starting dose was 300 mg/day (28% [15/53] of patients). Median bosutinib treatment duration was 15.6 (range: 0.4 to 66.0) months. The proportions of patients with cumulative complete cytogenetic response (CCyR), major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) with bosutinib were 62%, 54%, 34% and 26%, respectively (see figure). At data collection (median follow-up 25.1 [range: 3.0 to 66.0] months), 38% (20/53) of patients had discontinued bosutinib; 2% (1/53) discontinued due to progression, 8% (4/53) due to treatment failure, 15% (8/53) due to adverse events (AE), 6% (3/53) due to loss of response, and 4% (2/53) due to patient request. Ninety-two percent (49/53) of patients experienced ≥1 AE, most commonly diarrhoea (55% [29/53] of patients); 26% (14/53) of patients had grade 3/4 AEs (diarrhoea grade 3/4: 4% [2/53] of patients). Conclusions.Bosutinib used in normal clinical practice in pre-treated patients with CML demonstrates high rates of cytogenetic and major molecular response similar to those seen in clinical trials. Bosutinib is generally well tolerated, with the majority of patients not experiencing grade 3/4 AEs, despite most patients having pre-existing co-morbidities. Disclosures Apperley: Pfizer: Honoraria, Speakers Bureau; Ariad: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Byrne:Bristol Myers Squipp: Consultancy, Speakers Bureau. Smith:Pfizer: Honoraria, Other: Advisory boards and talks at regional sponsored meetings. Viqueira:Pfizer: Employment. Ferdinand:Pfizer: Employment. Carter:pH Associates: Employment. Nock:pH Associates: Employment. Milojkovic:Ariad: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

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Real-World Dosing Patterns of Ruxolitinib in Patients with Polycythemia Vera Who Are Resistant to or Intolerant of Hydroxyurea

Blood ◽

10.1182/blood-2019-127442 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4192-4192

Author(s):

Ivy Altomare ◽

Anna Nguyen ◽

Shreekant Parasuraman ◽

Dilan Paranagama ◽

Jonathan K. Kish ◽

...

Keyword(s):

Real World ◽

Treatment Duration ◽

Chart Review ◽

Dose Increase ◽

Employment Equity ◽

Skin Ulcers ◽

Starting Dose ◽

Equity Ownership ◽

Dose Modifications ◽

Dosing Patterns

Background Polycythemia vera (PV) is a myeloproliferative neoplasm affecting >100,000 people in the United States annually. Patients (pts) with PV are at risk for thromboembolic events (TEs), premature death, and high symptom burden. Hydroxyurea (HU) is recommended for high-risk pts with PV; however, up to 40% of pts become resistant and/or intolerant to the drug (Demuynck T, et al. Ann Hematol. 2019;98:1421-1426). Ruxolitinib (RUX), a Janus kinase (JAK) 1/JAK2 inhibitor, is currently the only FDA-approved treatment option for pts with PV who are resistant to or intolerant of HU. We conducted a retrospective chart review to characterize the reasons pts were switched from HU to RUX and to describe the real-world dosing patterns of RUX in pts with PV. Methods This retrospective medical chart review was conducted at US community hematology/oncology practices in the Cardinal Health Oncology Provider Extended Network. Eligible pts were ≥18 y old, initiated RUX therapy during the index period (January 1, 2015, to December 31, 2016), were previously treated with HU for ≥3 mo, and were seen at least twice during the 6 mo following RUX initiation. Data were collected for the 12 mo prior to RUX initiation (including near the time of HU discontinuation), near the time of RUX initiation (index), and up to the last provider visit. Pt and clinical characteristics were collected, including blood counts, symptoms, TEs, cardiovascular disease risk factors, phlebotomy, and HU and RUX treatment patterns. Target enrollment was 250 pts; interim results are presented here. Results Providers identified 99 pts for inclusion; mean (SD) age was 64 (9.9) y, 56% were male, and 68% had high-risk PV (ie, age ≥60 y and/or history of TE). All pts had been tested for the JAK2V617F mutation, and 99% were positive. At the time of HU discontinuation, 28% of pts had reached an HU dose of ≥2 g/d; median (range) HU treatment duration was 9.7 (3.6-182.4) mo. Causes of HU discontinuation were resistance (63%), intolerance (17%), resistance and intolerance (11%), and other reasons (9%; Table). The most frequent reasons for HU discontinuation due to resistance were hematocrit (Hct) ≥45% (79%), symptoms (45%), leukocytosis (32%), thrombocytosis (31%), and splenomegaly (22%). The most frequent intolerance signs and symptoms were nausea (43%), stomatitis (25%), fever (18%), and skin ulcers (14%). With respect to the RUX starting dose, 44 pts (44%) initiated RUX at the US package insert-recommended dose of 10 mg twice daily (BID); median (range) treatment duration for these pts was 26.4 (3.2-52.0) mo (Table). During the first 6 mo of RUX treatment, dose modification was noted in 19 pts (43%) who initiated at 10 mg BID (dose increase, n=13 [30%]; dose decrease, n=5 [11%]; dose interruption, n=1 [2%]). The most common reasons for dose increase were continued need for phlebotomy (39%) and symptoms (39%). Five pts required a dose reduction; the most common reason was low hemoglobin levels (n=3). Overall, pts starting at 10 mg BID had more dose modifications in the first 6 mo of RUX treatment (43%), with fewer dose modifications needed after 6 mo (25%). Hct control (Hct <45%) at initiation and after 6 mo of RUX treatment was 14% and 75%, respectively. At the time of the last visit, 48% of pts were still taking RUX. The majority of pts (65%) who discontinued RUX had no dosing changes from the time of initiation to discontinuation. Conclusions In this interim analysis of real-world data pertaining to pts with PV who discontinued HU and were subsequently treated with RUX, the most common resistance events leading to HU discontinuation were Hct ≥45%, uncontrolled symptoms, leukocytosis, thrombocytosis, and splenomegaly. Discontinuations due to intolerance were most commonly attributed to nausea, stomatitis, fever, and skin ulcers. Of pts who were switched from HU to RUX, the duration of HU treatment was shorter and the proportion of pts treated with HU doses of ≥2 g/d was higher than has been reported for all pts discontinuing HU, irrespective of their next line of therapy (Grunwald MR, et al. ASH Annual Meeting 2017. Poster 1633). Less than half of pts initiated RUX at the recommended dose of 10 mg BID; 41% of pts dosed in accordance with the recommended starting dose experienced dosing modifications (primarily dose increases); however, the majority of pts who discontinued RUX had no dosing modifications during their treatment. Results from the entire cohort of 250 pts will be presented. Disclosures Altomare: Amgen: Consultancy; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy; Rigel: Consultancy. Nguyen:Incyte: Employment, Equity Ownership. Parasuraman:Incyte: Employment, Equity Ownership. Paranagama:Incyte: Employment, Equity Ownership. Kish:Cardinal Health: Employment. Lord:Cardinal Health: Employment, Equity Ownership. Colucci:Incyte: Employment, Equity Ownership.

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