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Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

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Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Amino Acids

Nilotinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Administered orally at the dose of 300 mg twice daily (total daily dose 600 mg daily) for 24 months (study core), and indefinitely if it is in the interest of the patient (the drug will be given free-of-charge after 24 months to all those patients achieving the CMR4 at 24 months and in absence of safety concerns). Nilotinib dose is increased to 400 mg BID in case of suboptimal response or failure (with the exception of patients who will fail for progression to ABP: in case of progression to ABP, the patient will not be treated with study drug and the choise of the treatment will be up to the physician).

Gianantonio Rosti

This study is an open-label, multicentric, phase IIIb study of NILOTINIB administered orally twice daily for 24 months and indefinitely if it is in the interest of the patient.

The primary objective of the trial is to evaluate the efficacy of nilotinib, 300 mg twice daily with dose increase to 400 mg twice daily in case of suboptimal response or failure (excluding patients who will fail for progression to ABP), in a population of patients with Ph-positive, BCR-ABL positive CML in early CP.

This study is an open-label, multicentric, phase IIIb study of NILOTINIB administered orally at the dose of 300 mg twice daily (total daily dose 600 mg daily) for 24 months (study core), and indefinitely if it is in the interest of the patient (the drug will be given free-of-charge after 24 months to all those patients achieving the CMR4 at 24 months and in absence of safety concerns). Nilotinib dose is increased to 400 mg BID in case of suboptimal response or failure (with the exception of patients who will fail for progression to ABP: in case of progression to ABP, the patient will not be treated with study drug and the choice of the treatment will be up to the physician).

Study duration is estimated in 6 years, 1 year of estimated enrollment, 2 years therapy duration. Thereafter, information on course and survival is due for other 3 years.

The main data analysis will be performed when all patients will complete 24 months of treatment (or discontinued earlier). Safety and tolerability profile will be assessed by collecting hematologic and non-hematologic adverse events, laboratory examinations and ECG data. The molecular response will be assessed using the GIMEMA standardized molecular laboratories (Labnet network).

Nilotinib in PH+, BCR-, ABL+ CML Patients

The Protein Tyrosine Kinase Inhibitor Nilotinib as First-line Treatment of Ph+, BCR-, ABL+ Chronic Myeloid Leukemia (CML) in Early Chronic Phase: a Phase IIIb, Multicenter Study to Assess the Complete Molecular Response

To assess the complete molecular response (CMR4) rate at 24 months of treatment. For the purpose of this protocol, CMR is defined as a negative results of quantitative RT-PCR for BCR-ABL transcripts in a peripheral blood sample of at least 10 ml with a minimum sensitivity of 1:10,000, that corresponds to at least a 4-log reduction (hence, CMR4)

Number of fully compliant patients and number of patients who do not comply with treatment

From the date of the first nilotinib dose to death

From the date of the first nilotinib dose to progression to AP or BP or death

From the date of the first nilotinib dose to failure\* or progression or death

From the date of the first nilotinib to any event. Including treatment discontinuation for adverse events, failure, progression to AP or BP, or death, whichever comes first.

Gruppo Italiano Malattie EMatologiche dell'Adulto

A cohort of adult patients with CML who were treated with TKIs were identified using the IBM® MarketScan® Commercial and Medicare Supplemental databases (commercial claims; the MarketScan database)

The study included patients with CML who were previously treated with TKIs, who are relapsed/refractory to/intolerant of TKIs on third or later lines of therapy in the US.

Tyrosine Kinase Inhibitors (TKIs)

Novartis Pharmaceuticals

Retrospective, non-interventional observational cohort study conducted among patients with CML.

A retrospective, non-interventional cohort study was used to address the study objectives. A cohort of adult patients with CML who were treated with TKIs were identified using the IBM® MarketScan® Commercial and Medicare Supplemental databases (commercial claims; the MarketScan database) to have a better understanding of real-world treatment patterns, HRU and healthcare costs among patients with CML treated with later lines of therapy (i.e., third line or later).

For Phase I, the IBM® MarketScan® Commercial Claims and Encounters and Medicare Supplemental Databases were used (commercial claims). The commercial claims covered the period from 01/01/2001 to 06/30/2019.

The study consisted of the following periods:

* The baseline period was defined as the 6-month period before the first line therapy initiation for CML.
* The observation period was defined as the period of at least 12 months from the first CML diagnosis to the end of data availability or end of health plan coverage, whichever occurs first; the observation period varied by patient.

Study Conducted Among Patients With CML

Real-World Treatment Patterns, Healthcare Resource Utilization and Associated Costs Among Patients With Chronic Myeloid Leukemia in Later Lines of Therapy

Number of patients across all lines of therapy were reported to evaluate treatment sequences among the patients.

Number of patients with the use of pre-treatment hydroxyurea were reported to evaluate treatment patterns in patients.

Number of patients Treatment received and initial dose at each line were reported to evaluate treatment patterns in patients.

Number of patients as per the calendar year of line of therapy initiation were reported to evaluate treatment patterns in patients.

Duration of the line of therapy was reported to evaluate treatment patterns in patients.

Treatment-free period among those with an observed subsequent line of therapy was reported to evaluate treatment patterns in patients.

Number of patients who discontinued treatment were reported to evaluate treatment patterns in patients.

Number of patients: All cause Health Resource Utilization were reported to estimate HRU among patients with three lines of therapy or more.

Healthcare costs among patients with three lines of therapy or more were reported.

Prevalence was defined as the number of cases alive per year of patients with CML who were currently or previously treated on later lines of therapy (third line or later), by calendar year from 2006 to 2018

Healthcare costs among patients with earlier lines of therapy were reported.

Number of patients: All cause Health Resource Utilization among patients with earlier lines of therapy were reported.

Blast Crisis

Cell Transformation, Neoplastic

Carcinogenesis

Neoplastic Processes

Antineoplastic Agents

Imatinib Mesylate

Multi-center, open-label, non-randomized trial to evaluate long-term safety and efficacy of nilotinib. Approximately 20 patients will be enrolled in this trial at 3 centers in Mexico, which means all ongoing patients participating on \[CAMN107A2109\] excluding discontinued patients. During this study, patients will receive nilotinib orally, at a dose of 400 mg b.i.d. Patients will normally receive nilotinib on an outpatient basis. This trial will have a maximum of 24 months of follow-up time.

Nilotinib in Adult Patients With Imatinib-resistant or Intolerant Chronic Myeloid Leukemia in Blast Crisis, Accelerated Phase or Chronic Phase

An Open-label, Multicenter Study Providing Continuation of Nilotinib in Adult Patients With Imatinib-(Glivec®/Gleevec®) - Resistant or - Intolerant Chronic Myeloid Leukemia in Blast Crisis, Accelerated Phase or Chronic Phase

Bosutinib

Dasatinib

Ponatinib

Patients who initiated third-line treatment (3L) therapy. Treatments received in 3L were dasatinib, nilotinib, imatinib, ponatinib, bosutinib, and allo-SCT

Patients with chronic myeloid leukemia with T315I mutation

Treatments received in 3L were dasatinib, nilotinib, imatinib, ponatinib, bosutinib, and allo-SCT

3L Therapy

T315I

A retrospective multi-center cohort study design was used to address the study objectives, using medical records obtained from three clinical centers in France.

The index date for patients in the 3L cohort was defined as the date of initiation of 3L therapy. The index date for the T315I cohort was defined as the date of treatment initiation with TKI or allogeneic stem cell transplantation (allo-SCT) after identification of T315I mutation status. The baseline (i.e., pre-index) period was defined as the 6 months prior to the index date, and the post-index period was defined as the time from the index date to the date of last patient contact or patient death. Patients who were alive at the end of the follow-up period were censored at the date of last contact.

French Study to Highlight the Unmet Treatment Needs of 3L+ CP-CML and With T315I-mutated CML Patients

A Multi-Center Retrospective Chart Review Study Examining the Patient Characteristics, Treatment Patterns, Clinical Outcomes, and Burden of Illness Among Patients With Chronic Myeloid Leukemia in Third-line Treatment or With T315I Mutation in France (CML 3L+ & T315I)

Following categories included:

Before 2010 2010-2014 2015-2019 2020-2021

Duration of third-line treatment was reported

Time from 2L discontinuation to third-line treatment initiation was reported

Number of patients still on 3L therapy as of data collection date was reported

Number of patients who discontinued 3L treatment were reported

* Treatment switch due to AEs or intolerance
* Treatment switch due to resistance
* Treatment switch due to signs of ineffectiveness
* Treatment switch due to other reasons

Number of lines of therapy for patients with chronic myeloid leukemia in third-line treatment were reported

Number of most frequent treatment sequences for patients with chronic myeloid leukemia in third-line treatment were reported

Number of last line of therapy for patients with chronic myeloid leukemia in third-line treatment were reported

Following categories included:

Before 2010 2010-2014 2015-2019

Duration of the line identified as T315I line of interest was reported

Number of patients still on line of therapy identified as T315I line of interest as of data collection date were reported

* Adverse events or intolerance
* Resistance
* Signs of ineffectiveness Suboptimal response Progression to accelerated phase or blast phase
* Other reasons Acquired mutations

Number of lines of therapy for patients with chronic myeloid leukemia with T315I mutation were reported

Number of line identified as T315I line of interest were reported

Number of treatment sequence for patients with chronic myeloid leukemia with T315I mutation were reported

Number of last line of therapy for patients with chronic myeloid leukemia with T315I mutation were reported

CCyR, defined as an absence of Philadelphia chromosome-positive (Ph+) metaphases in bone marrow cytogenetics

Proportion of patients achieving response among patients with chronic myeloid leukemia in third-line treatment in 12 months were reported

Proportion of patients achieving response among patients with chronic myeloid leukemia in third-line treatment in 24 months were reported.

Proportion of patients achieving sustained molecular responses among patients with chronic myeloid leukemia in third-line treatment in 12 months were reported.

Proportion of patients achieving sustained molecular responses among patients with chronic myeloid leukemia in third-line treatment in 24 months were reported.

Time to MMR was defined as the time from third-line (3L) treatment initiation to the time patients achieved MMR (i.e., 0.01% IS \< BCR::ABL1 transcript level ≤ 0.1% IS). Patients were censored at the earliest of treatment discontinuation or switch, loss to follow-up, end of data availability, or death.

Time to MR4.0 was defined as the time from third-line (3L) treatment initiation to the time patients achieved MR4.0 (i.e., 0.0032% IS \< BCR::ABL1 transcript level ≤ 0.01% IS). Patients were censored at the earliest of treatment discontinuation or switch, loss to follow-up, end of data availability, or death.

Time to sustained MR4.0 was defined as the time from third-line (3L) treatment initiation to the time patients achieved sustained MR4.0 or better (i.e., BCR::ABL1 ≤ 0.01%) in all consecutive assessments performed for at least 12 months (i.e., 365.25 days). Patients were censored at the earliest of treatment discontinuation or switch, loss to follow-up, end of data availability, or death.

Time to MR4.5 was defined as the time from third-line (3L) treatment initiation to the time patients achieved MR4.5 (i.e., 0.001% IS ≤ BCR::ABL1 transcript level ≤ 0.0032% IS). Patients were censored at the earliest of treatment discontinuation or switch, loss to follow-up, end of data availability, or death.

Time to sustained MR4.5 was defined as the time from third-line (3L) treatment initiation to the time patients achieved sustained MR4.5 or better (i.e., BCR::ABL1 ≤ 0.0032%) in all consecutive assessments performed for at least 2 years (i.e., 730.5 days). Patients were censored at the earliest of treatment discontinuation or switch, loss to follow-up, end of data availability, or death.

Time to PFS was defined as the time from third-line treatment initiation to earliest occurrence of documented disease progression to accelerated phase or blast crisis, or the date of death from any cause. Patients were censored at the earliest of treatment discontinuation or switch, loss to follow-up, or end of data availability.

Time to OS was defined as the time from third-line treatment initiation to death from any cause. Patients were censored at the earliest of treatment discontinuation or switch, date of last follow-up, or end of data availability.

TTD was defined as the time from third-line treatment initiation to treatment discontinuation or switch. Patients were censored at the earliest of loss to follow-up, or end of data availability, or death

Proportion of patients with Adverse Events (AEs) were reported to evaluate the safety profile of third-line treatments for chronic myeloid leukemia

Year of CML-CP diagnosis of patients with chronic myeloid leukemia in third-line treatment was reported.

The following centers were included:

Centre Léon Bérard, Lyon Hématologie Institut Bergonié, Bordeaux Institut Universitaire du Cancer Toulouse, Toulouse

Length of follow-up was defined as time from index date to the date of last known contact with patient or patient death.

Smoking status at index date of patients with chronic myeloid leukemia in third-line treatment was reported.

Time from CML-CP diagnosis to index date (month) of patients with chronic myeloid leukemia in third-line treatment was reported.

Low risk (≤780) Intermediate risk (\>780 to ≤1480) High risk (\>1480) Not assessed Unknown / not sure

Low risk (\<0.8) Intermediate risk (≥0.8 to ≤1.2) High risk (\>1.2) Not assessed Unknown / not sure

ELTS: EUTOS long-term survival Low risk (≤1.5680) Intermediate risk (\>1.5680 to ≤2.2185) High risk (\>2.2185) Not assessed Unknown / not sure

Number of comorbid conditions prior to the index date in patients with chronic myeloid leukemia in third-line treatment were reported.

Cardiovascular disease Pulmonary disease/pulmonary arterial hypertension Gastrointestinal issues Renal disease Diabetes Liver disease Other No comorbidities Unknown / not sure

Cardiovascular disease Cerebrovascular disease Peripheral arterial

Hypertension Hyperlipidemia/dyslipidemia Diabetes Obesity

Laboratory and clinical results were reported.

Philadelphia Chromosome

This was an open-label, single-arm, prospective, multi-center, Phase IIIb clinical study with nilotinib 300 mg bid treatment in newly diagnosed CML-CP patients not previously treated with imatinib therapy and diagnosed within 6 months of study entry. For patients insufficiently responding to nilotinib 300 mg bid, the dose may have been increased to 400 mg bid. Among patients with adverse events who had dose reduction, this study also allowed a possible re-escalation to 300 mg bid.

This study will further investigate the safety and efficacy of nilotinib in newly diagnosed chronic myeloid leukemia patients in the chronic phase

Safety and Efficacy of Nilotinib in Newly Diagnosed Chronic Myeloid Leukemia Patients

Extending Molecular Responses With Nilotinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients in Chronic Phase

MMR is defined as BCR-ABL ratio (%) on IS \<= 0.1% (corresponds to \>=3 log reduction of BCR-ABL transcripts from standardized baseline value). Clopper-Pearson method

Estimated median time to first MMR by Kaplan-Meier method

Kaplan-Meier estimates of duration of first MMR among patients who achieved MMR (FAS) Duration of first MMR (months) = (Minimum date of (loss of first MMR , CML-related death, progression to AP/BC during study treatment, censoring) - date of first MMR + 1) / 30.4375

Complete cytogenetic response (CCyR) is defined as a value of 0% Ph+ metaphases in bone marrow.

\* CCyR = 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics.

Duration of first CCyR (months) = (date of CCyR loss or censoring - date of first CCyR +1) / 30.4375

OS was defined as the time between date of study entry and date of death due to any cause at any time during the study, including the follow-up period after discontinuation of treatment.

PFS was defined as the time from the date of study entry to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause occurring on treatment.

Time to event (months) = (date of event or censoring - date of study entry + 1) / 30.4375. Date of event is the earliest date of the following events during treatment : discontinuation of nilotinib for nilotinib-related adverse events, death due to any cause, progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR. Time is censored at the date of last assessment in the trial for patients without event.

Age, Categorical

Age, Continuous

Sex: Female, Male

Newly diagnosed CML-CP patients not previously treated with imatinib and diagnosed within 6 months of study entry, except for hydroxyurea, and/or anagrelide . In emergent cases where the patient requires disease management Gleevec/Glivec at any dose may be prescribed to the patient for no longer than 2 weeks in duration

Clinical Disclosure Office

The Percentage of Patients Achieving MMR by 12 Months

Time to Molecular Response at 24 Months

K-M Estimate for 3 Month Duration

K-M Estimate for 6 Month Duration

K-M Estimate for 9 Month Duration

K-M Estimate for 12 Month Duration

K-M Estimate for 15 Month Duration

18 months

K-M Estimate for 21 Month Duration

K-M Estimate for 24 Month Duration

Full Analysis set, Number of events / censored 29/312.

Duration of Major Molecular Response

Complete Cytogenetic Response

6 mos after the first CCyR was achieved

12 mos after the first CCyR was achieved

18 mos after the first CCyR was achieved

24 mos after the first CCyR was achieved

Percentage of Participants Estimated to Maintain Their First CCyR for 6, 12, 18, and 24 Months After the First CCyR Was Achieved as Determined by Kaplan Meier Estimatation.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nilotinib in PH+, BCR-, ABL+ CML Patients	NCT01535391	Chronic Myeloid...	Nilotinib	18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto
Study Conducted Among Patients With CML	NCT05476562	Chronic Myeloid...	Tyrosine Kinase...	18 Years - 85 Years	Novartis
Nilotinib in Adult Patients With Imatinib-resistant or Intolerant Chronic Myeloid Leukemia in Blast Crisis, Accelerated Phase or Chronic Phase	NCT00905593	Chronic Myeloid...	Nilotinib	18 Years - 60 Years	Novartis
Study Conducted Among Patients With CML	NCT05476562	Chronic Myeloid...	Tyrosine Kinase...	18 Years - 85 Years	Novartis
French Study to Highlight the Unmet Treatment Needs of 3L+ CP-CML and With T315I-mutated CML Patients	NCT05619978	Chronic Myeloid...	3L Therapy T315I	18 Years - 99 Years	Novartis
Safety and Efficacy of Nilotinib in Newly Diagnosed Chronic Myeloid Leukemia Patients	NCT01254188	Chronic Myeloid...	Nilotinib	18 Years -	Novartis

Spots Global Cancer Trial Database for chronic myeloid leukemia,