INC424 for Patients With Primary Myelofibrosis, Post Polycythemia Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis.

Myelofibrosis Clinical Trial

— JUMP  

Official title:

An Open-label, Multicenter, Expanded Access Study of INC424 for Patients With Primary Myelofibrosis (PMF) or Post Polycythemia Myelofibrosis (PPV MF) or Post-essential Thrombocythemia Myelofibrosis (PET-MF).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01493414
• Other study ID #: CINC424A2401
• Secondary ID: 2010-024473-39
• Status: Completed
• Phase: Phase 3
• Start date: August 16, 2011
• Est. completion date: January 26, 2017

Study information

• Verified date: October 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study was to collect additional safety of INC424 in patients with Primary Myelofibrosis, Post Polycythemia Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis, who either received prior treatment with commercially available agents or who have never received treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2233
• Est. completion date: January 26, 2017
• Est. primary completion date: January 26, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Main Inclusion Criteria:

1. Patients must not be eligible for another ongoing INC424 clinical trial.

2. Patients must be diagnosed with PMF, PPV MF or PET-MF, according to the 2008 revised International Standard Criteria, irrespective of JAK2 mutation status..

3. Patients with PMF requiring therapy must be classified as high risk (3 prognostic factors) OR intermediate risk level 2 (2 prognostic factors, no more), OR intermediate risk level 1 (1 prognostic factor, no more) with an enlarged spleen (assessment to occur at the Screening Visit).

The prognostic factors, defined by the International Working Group are:

• Age > 65 years;

• Presence of constitutional symptoms (weight loss, fever, night sweats);

• Marked anemia (Hgb < 10g/dL)*;

• Leukocytosis (history of white blood cell (WBC) > 25 x109/L);

• Circulating blasts > 1%. * A hemoglobin value < 10 g/dL must be demonstrated during the Screening Visit for patients who are not transfusion dependent. Patients receiving regular transfusions of packed red blood cells will be considered to have hemoglobin < 10 g/dL for the purpose of evaluation of risk factors.

4. Patients with Intermediate-1 disease and splenomegaly must have a palpable spleen measuring 5 cm or greater from the costal margin to the point of greatest splenic protrusion.

5. Patients must have a peripheral blood blast count of < 10%.

6. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

7. Fedratinib pretreated patients with documented complete physical examination including full neurologic examination and cardiology assessment, thiamine level testing, and MRI of the brain if indicated based on signs or symptoms. Patients pretreated with fedratinib should have completed or be receiving thiamine supplementation according to the investigator's instructions.

Main Exclusion Criteria:

1. Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available).

2. Patients with history of malignancy in past 3 years except for treated, early-stage squamous or basal cell carcinoma in situ.

3. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral INC424 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).

4. Patients with cardiac disease which in the Investigator's opinion may jeopardize the safety of the patient or the compliance with the protocol.

5. Patients with currently uncontrolled or unstable angina, rapid or paroxysmal atrial fibrillation or recent (approximately 6 months) myocardial infarction or acute coronary syndrome.

6. Patients with clinically significant bacterial, fungal, parasitic or viral infection which require therapy. Patients with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.

7. Patients with known active hepatitis A, B, C or who are HIV-positive.

8. Patients with inadequate bone marrow reserve at the Baseline visit as demonstrated by:

• Absolute neutrophil count (ANC) = 1000/µL.

• Platelet count < 50,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.

9. Patients with any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason.

10. In the case of ruxolitinib pretreated patients, ruxolitinib primary resistant patients defined as:

• No spleen reduction within the first 12 weeks after front line therapy with ruxolitinib.

AND

• No reduction in symptoms within the first 12 weeks after first-line treatment with ruxolitinib.

11. In the case of ruxolitinib pretreated patients, patients discontinuing ruxolitinib due to a Grade 4 Adverse event (AE) related or suspected to be related to ruxolitinib.

Related Conditions & MeSH terms

• Myelofibrosis
• Polycythemia
• Primary Myelofibrosis
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Drug:
• INC424
All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.

Locations

Country	Name	City	State
Algeria	Novartis Investigative Site	Alger
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Corrientes
Argentina	Novartis Investigative Site	Paraná	Entre Rios
Austria	Novartis Investigative Site	Graz
Austria	Novartis Investigative Site	Innsbruck	Tyrol
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Wien
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Antwerpen
Belgium	Novartis Investigative Site	Arlon	Luxembourg
Belgium	Novartis Investigative Site	Brugge
Belgium	Novartis Investigative Site	Brussel
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Charleroi
Belgium	Novartis Investigative Site	Edegem
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Hasselt
Belgium	Novartis Investigative Site	Kortrijk
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Belgium	Novartis Investigative Site	Roeselare
Belgium	Novartis Investigative Site	Wilrijk
Belgium	Novartis Investigative Site	Yvoir
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Campinas	SP
Brazil	Novartis Investigative Site	Curitiba	PR
Brazil	Novartis Investigative Site	Goiania	GO
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Ribeirao Preto	SP
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	São Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	Halifax	Nova Scotia
Canada	Novartis Investigative Site	Hamilton	Ontario
Canada	Novartis Investigative Site	Moncton	New Brunswick
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Québec	Quebec
Canada	Novartis Investigative Site	Saskatoon	Saskatchewan
Canada	Novartis Investigative Site	St. John's	Newfoundland and Labrador
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
Canada	Novartis Investigative Site	Windsor	Ontario
Colombia	Novartis Investigative Site	Bogota	Cundinamarca
Colombia	Novartis Investigative Site	Medellín
Czechia	Novartis Investigative Site	Brno	Czech Republic
Czechia	Novartis Investigative Site	Hradec Kralove	Czech Republic
Czechia	Novartis Investigative Site	Olomouc
Czechia	Novartis Investigative Site	Praha 2	Czech Republic
Germany	Novartis Investigative Site	Aachen
Germany	Novartis Investigative Site	Aschaffenburg
Germany	Novartis Investigative Site	Bamberg
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bochum
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Bottrop
Germany	Novartis Investigative Site	Bremen
Germany	Novartis Investigative Site	Chemnitz
Germany	Novartis Investigative Site	Darmstadt
Germany	Novartis Investigative Site	Dortmund
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Duisburg
Germany	Novartis Investigative Site	Düsseldorf
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Frankfurt, Oder
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Friedrichshafen
Germany	Novartis Investigative Site	Goslar
Germany	Novartis Investigative Site	Göttingen
Germany	Novartis Investigative Site	Greifswald
Germany	Novartis Investigative Site	Halle
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hamm
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Hildesheim
Germany	Novartis Investigative Site	Ingolstadt
Germany	Novartis Investigative Site	Jena
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Köln
Germany	Novartis Investigative Site	Leer
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Magdeburg
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Mannheim	Baden-Württemberg
Germany	Novartis Investigative Site	Marburg
Germany	Novartis Investigative Site	Marburg
Germany	Novartis Investigative Site	Minden
Germany	Novartis Investigative Site	Moers
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	München
Germany	Novartis Investigative Site	Nuernberg
Germany	Novartis Investigative Site	Oldenburg
Germany	Novartis Investigative Site	Rostock
Germany	Novartis Investigative Site	Stuttgart
Germany	Novartis Investigative Site	Ulm
Germany	Novartis Investigative Site	Wuerzburg
Greece	Novartis Investigative Site	Athens	GR
Greece	Novartis Investigative Site	Athens	GR
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Patras
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Kaposvár
Hungary	Novartis Investigative Site	Szeged
Hungary	Novartis Investigative Site	Szombathely
Ireland	Novartis Investigative Site	Cork City	Cork
Israel	Novartis Investigative Site	Afula
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Ramat Gan
Israel	Novartis Investigative Site	Tel-Aviv
Italy	Novartis Investigative Site	Alessandria	AL
Italy	Novartis Investigative Site	Ancona	AN
Italy	Novartis Investigative Site	Avellino	AV
Italy	Novartis Investigative Site	Bari	BA
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Cagliari	CA
Italy	Novartis Investigative Site	Cagliari	CA
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Catanzaro	CZ
Italy	Novartis Investigative Site	Cona	FE
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Lecce	LE
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Novara
Italy	Novartis Investigative Site	Orbassano	TO
Italy	Novartis Investigative Site	Padova	PD
Italy	Novartis Investigative Site	Pagani	SA
Italy	Novartis Investigative Site	Palermo	PA
Italy	Novartis Investigative Site	Pavia	PV
Italy	Novartis Investigative Site	Pavia
Italy	Novartis Investigative Site	Perugia
Italy	Novartis Investigative Site	Pesaro	PU
Italy	Novartis Investigative Site	Pescara	PE
Italy	Novartis Investigative Site	Pisa	PI
Italy	Novartis Investigative Site	Ravenna	RA
Italy	Novartis Investigative Site	Reggio Calabria	RC
Italy	Novartis Investigative Site	Reggio Emilia	RE
Italy	Novartis Investigative Site	Rionero in Vulture	PZ
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Ronciglione	VT
Italy	Novartis Investigative Site	San Giovanni Rotondo	FG
Italy	Novartis Investigative Site	Siena	SI
Italy	Novartis Investigative Site	Taranto	TA
Italy	Novartis Investigative Site	Terni	TR
Italy	Novartis Investigative Site	Torino	TO
Italy	Novartis Investigative Site	Treviso	TV
Italy	Novartis Investigative Site	Udine	UD
Italy	Novartis Investigative Site	Varese	VA
Italy	Novartis Investigative Site	Venezia	VE
Italy	Novartis Investigative Site	Verona	VR
Italy	Novartis Investigative Site	Vicenza	VI
Mexico	Novartis Investigative Site	Guadalajara	Jalisco
Mexico	Novartis Investigative Site	Hermosillo	Sonora
Mexico	Novartis Investigative Site	Mexico	Distrito Federal
Mexico	Novartis Investigative Site	Monterrey	Nuevo León
Mexico	Novartis Investigative Site	Puebla
Morocco	Novartis Investigative Site	Marrakech
Poland	Novartis Investigative Site	Gdansk
Poland	Novartis Investigative Site	Katowice
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Opole
Poland	Novartis Investigative Site	Torun
Poland	Novartis Investigative Site	Warszawa
Portugal	Novartis Investigative Site	Coimbra
Portugal	Novartis Investigative Site	Faro
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Porto
Portugal	Novartis Investigative Site	Vila Real
Russian Federation	Novartis Investigative Site	Irkutsk
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Nizhnii Novgorod
Russian Federation	Novartis Investigative Site	Novosibirsk
Russian Federation	Novartis Investigative Site	Rostov-on-Don
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	St Petersburg
Saudi Arabia	Novartis Investigative Site	Jeddah
Saudi Arabia	Novartis Investigative Site	Riyadh
Slovakia	Novartis Investigative Site	Bratislava
South Africa	Novartis Investigative Site	Cape Town	Western Province
South Africa	Novartis Investigative Site	Johannesburg
South Africa	Novartis Investigative Site	Pretoria
South Africa	Novartis Investigative Site	Pretoria
South Africa	Novartis Investigative Site	Soweto	Gauteng
Spain	Novartis Investigative Site	Alcala de Henares	Madrid
Spain	Novartis Investigative Site	Alicante	Comunidad Valenciana
Spain	Novartis Investigative Site	Badalona	Catalunya
Spain	Novartis Investigative Site	Baracaldo	Vizcaya
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Bilbao	Pais Vasco
Spain	Novartis Investigative Site	Burgos	Castilla Y Leon
Spain	Novartis Investigative Site	Cadiz	Andalucía
Spain	Novartis Investigative Site	El Palmar	Murcia
Spain	Novartis Investigative Site	Ferrol	A Coruna
Spain	Novartis Investigative Site	Girona	Catalunya
Spain	Novartis Investigative Site	Granada	Andalucia
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	Jaen	Andalucía
Spain	Novartis Investigative Site	La Laguna	Santa Cruz De Tenerife
Spain	Novartis Investigative Site	Las Palmas de Gran Canaria	Las Palmas De G.C
Spain	Novartis Investigative Site	Las Palmas de Gran Canaria
Spain	Novartis Investigative Site	Logrono	Rioja
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Majadahonda	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Oviedo	Asturias
Spain	Novartis Investigative Site	Palma De Mallorca	Islas Baleares
Spain	Novartis Investigative Site	Pamplona	Navarra
Spain	Novartis Investigative Site	Pozuelo de Alarcón	Madrid
Spain	Novartis Investigative Site	Sabadell	Barcelona
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
Spain	Novartis Investigative Site	San Sebastian	Pais Vasco
Spain	Novartis Investigative Site	San Sebastian de los Reyes	Madrid
Spain	Novartis Investigative Site	Santander	Cantabria
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Tarragona	Catalunya
Spain	Novartis Investigative Site	Toledo	Castilla La Mancha
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Valladolid	Castilla Y Leon
Spain	Novartis Investigative Site	Zaragoza
Spain	Novartis Investigative Site	Zaragoza
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Chiang Mai
Tunisia	Novartis Investigative Site	Sfax	Tunisie
Tunisia	Novartis Investigative Site	Sousse
Tunisia	Novartis Investigative Site	Tunis
Tunisia	Novartis Investigative Site	Tunis

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Algeria,  Argentina,  Austria,  Belgium,  Brazil,  Canada,  Colombia,  Czechia,  Germany,  Greece,  Hungary,  Ireland,  Israel,  Italy,  Mexico,  Morocco,  Poland,  Portugal,  Russian Federation,  Saudi Arabia,  Slovakia,  South Africa,  Spain,  Thailand,  Tunisia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) up to 5 Years	An adverse event (AE) is any untoward medical occurrence in a clinical trial participant regardless of causal relationship to study drug and regardless whether study drug has been administered. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. A non-serious AE is any AE that does not meet the criteria above.	Baseline up to approximately 5 years
Secondary	Percentage of Participants With at Least 50% Reduction in Spleen Length	Spleen length was assessed by manual palpation. Assessment of spleen response was repeated until early discontinuation of the study drug and also at study completion (28 days post end of treatment visit).	Baseline up to approximately 5 years
Secondary	Number of Participants With Best Overall Response (BOR) up to 5 Years According to Spleen Length	Overall response is analyzed using the spleen response, as assessed by the investigator and also by deriving the response using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria.; Participants with spleen length at baseline between 5 and 10 cm were reported as Responders if reporting non palpable spleen; Stable disease does not meet criteria for response or disease progression and Progressive disease with an increase of 100% from baseline in spleen length.; Participants with spleen length at baseline more than 10 cm were reported as Responders with spleen reduction of 50% from baseline; Stable disease does not meet criteria for response or disease progression and Progressive disease with an increase of 50% from baseline in spleen length.	Baseline up to approximately 5 years
Secondary	Change in Eastern Cooperative Oncology Group (ECOG) Performance Status From Baseline to Worst Post-baseline ECOG Status up to 5 Years	ECOG Performance Score has 5 grades. 0 = Fully active, able to carry out all pre-disease activities; 1 = Restricted in strenuous activity but ambulatory and able to carry out work of light or sedentary nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Active about 50% of waking hours; 3 = Capable of limited self-care, confined to bed/chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on self-care. Totally confined to bed/chair. 5 = Death.	Baseline up to approximately 5 years
Secondary	Change in Functional Assessment of Cancer Therapy (FACT-TOI, FACT-G) and FACT-Lymphoma (FACT-Lym) Total Scores Measured at Baseline and Week 48	The FACT-Lym questionnaire consists of a total of 42 questions divided between five subscales (i.e., physical well-being, social/family well-being, emotional well-being, functional well-being and lymphoma subscale). Each subscale questionnaire rates each question on a 5-point scale from 0 = Not at all to 4 = Very much. These scores were summed to three total sum scores, namely FACT-Lym score, FACT-Lym Trial Outcome Index (TOI), FACT-General (FACT-G) and FACT-Lym total score. Total scores: FACT-Lym=0-60, FACT-TOI=0-116, FACT-G total=0-108, FACT-Lym Total= 0-168. Higher scores are reflective of better HRQoL.	Baseline and Week 48
Secondary	Time to First Improvement in FACT-Lym, FACIT-Fatigue Score and ECOG Performance Status	Improvement was defined by the upper limit of the minimally important difference (MID). Patients with the best possible score at Baseline were excluded from this analysis because their HRQoL cannot be further improved. Responders and non-responders for each endpoint were defined based on change from baseline scores using pre specified cut-off points. Patients with an improved score compared to Baseline, for which the magnitude of the change was at least the cutoff value, were classified as responders; otherwise, as non-responders. The responder cutoff: ECOG cutoff=1, range=0 to 5, FACT-Lym cutoff=5.4, range 0-60, FACIT-Fatigue =5 and range=0-52.The median time to first improvement was estimated using the Kaplan Meier method and time to improvement event was determined based on upper bound of the MID. The time to improvement was calculated from the date of first study drug administration.	Baseline up to approximately 5 years
Secondary	Medical Resource Utilization up to 5 Years	Percentage of patients requiring medical resources (blood transfusions, hospitalization, emergency room visits, general practitioners or specialists consultations, urgent care or splenic irradiation) up to 5 years.	Baseline up to approximately 5 years.