Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Symptoms and General Pathology

Rare Diseases

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Chromosome 17p Deletion

Antineoplastic Agents

All Drugs and Chemicals

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Fludarabine

Fludarabine phosphate

Dexamethasone

Dexamethasone acetate

Alemtuzumab

Antineoplastic Agents, Immunological

30 mg alemtuzumab will be administered subcutaneously 3 times weekly for 4 weeks (total of 12 doses of 30 mg alemtuzumab) with premedication (as needed) and infection prophylaxis; combined with oral dexamethasone 40 mg total dose for 4 days every 2 weeks; evaluation at end of cycle (i.e. after 12 doses of 30 mg alemtuzumab).

If CR is documented after week 4 (12 doses of 30 mg alemtuzumab) or 8 (24 doses of 30 mg alemtuzumab), maintenance treatment with alemtuzumab or withdrawal from the study and stem cell transplantation will be instituted at this time point.

After a maximum of three 4-week cycles (total of 36 doses of 30 mg alemtuzumab, in case of interruptions this may take longer than 12 weeks), maintenance treatment with alemtuzumab or withdrawal from the study and stem cell transplantation will be instituted. Maintenance treatment with alemtuzumab will continue for a maximum of two years, with evaluation every three months, unless there is PD.

Alemtuzumab 30 mg s.c. 3 × weekly for 28 days (Days 1, 3, 5; 8, 10, 12; etc.)

Stephan Stilgenbauer, Prof Dr med

Aims and objectives

* Assessment of the efficacy of the study treatment in the study population in terms of response rate, progression-free survival, failure-free survival and overall survival.
* Acquisition of further data to expand the data base on the toxicity of the study treatment.
* Assessment of the efficacy of the study treatment in biological risk groups.
* Assessment of response in terms of minimal residual disease. Number of patients and estimated duration Total no. of patients: 122 (\~29 with 17p deletion for first-line therapy, \~29 with 17p deletion for second- or higher-line treatment, \~65 fludarabine-refractory irrespective of 17p status).

Duration for each patient: Max. 12 weeks of treatment in three 4-week cycles, then up to two years maintenance treatment.

CLL refractory to therapy based on fludarabine or with 17p deletion has a poor prognosis. Patients with F-refractory CLL have a remission rate of 20% after various salvage regimens and a median overall survival (OS) of \<12 months (Keating et al., 2002a). CLL patients with 17p deletion have a median OS of 16 months after first-line treatment with fludarabine or FC in the CLL4 trial of the GCLLSG (Figure 2; Stilgenbauer et al., 2005b; Eichhorst et al., 2006).

Alemtuzumab is the most active single agent in fludarabine-refractory CLL, with remission rates of 30-40% and median OS of 16-28 months (Keating et al., 2002b, Rai et al., 2002). Furthermore, alemtuzumab is of proven efficacy in CLL with 17p deletion and the subcutaneous administration is as effective as the intravenous application (Stilgenbauer \& Döhner, 2002, Lozanski et al., 2004, Stilgenbauer et al., 2004).

However, the outcome of fludarabine-refractory CLL is still poor, owing to the facts that the majority of patients do not achieve a remission and that the average duration of remission is short. Therefore, the current trial aims at achieving: (i) a higher remission rate, by adding high-dose dexamethasone to alemtuzumab, and (ii) prolongation of remission duration and survival by alemtuzumab maintenance or allogeneic stem-cell transplantation (SCT). High-dose steroids have shown activity independently of 17p and p53 status, and are effective in debulking large lymph nodes, a weakness of alemtuzumab (Bellosillo et al., 2002, Thornton et al., 2003, Pettitt et al., 2006). Maintenance treatment with alemtuzumab improved remission duration in the CLL4B trial and allogeneic SCT resulted in disease control in high-risk CLL in the CLL3X trial (Wendtner et al., 2004, Dreger et al., 2005).

This is a prospective, open, multi-center Phase II study conducted by the Deutsche CLL Studiengruppe (DCLLSG; German CLL Study Group, GCLLSG). There will be only one treatment group and thus no randomization. The study will be conducted at approximately 40 investigation sites in Germany, Austria and France.

The study will be conducted according to the EG Directive on Good Clinical Practice, the German Arzneimittelgesetz (AMG, 12. Novelle) as well as - with respect to the local activities and regulations - to the corresponding laws in France and Austria.

A total of 122 patients (adults, males and females, in-patients and out-patients; 2 to 10 patients are expected to be recruited by each of the centers) will be recruited, with stratification by detailed diagnosis. The distribution of female and male patients is not relevant for the study as both sexes are affected by CLL and treatment effects are not different in both groups (GCP-V § 7, 2). Recruiting will stop when the 122th. patient has completed the first four-week cycle of treatment. The study will be concluded when the last patient has completed treatment with alemtuzumab according to this protocol. The retrieval of additional follow-up data may be appropriate to achieve mature data in the survival endpoints.

Subcutaneous alemtuzumab (30 mg) will be administered three times weekly (days 1, 3 and 5) along with oral dexamethasone (40 mg/day, days 1-4, every 2 weeks) for at least 4 weeks (corresponding to 12 doses of alemtuzumab, in case of treatment interruption this may take longer than 4 weeks) and, for patients who show at least SD, a maximum of 12 weeks (36 doses of alemtuzumab, in case of treatment interruption this may take longer than 12 weeks). Thereafter, maintenance therapy with alemtuzumab will be instituted for a maximum of two years. If CR (including bone marrow histology and imaging (chest X-ray and ultrasound, CT if indicated) is documented before week 12, i.e. after week 4 (12 doses of 30 mg alemtuzumab) or 8 (24 doses of 30 mg alemtuzumab), maintenance treatment with alemtuzumab will be instituted at this time point.

In this study it is recommended to start the dose of alemtuzumab directly at 30 mg. However, the dose of alemtuzumab can be increased gradually (3 mg day -2, 10 mg day -1 and 30 mg day 1, as in earlier studies), according to the investigators discretion.

Staging will be performed at inclusion to the study and after 12 doses of alemtuzumab (aim: at the end of Week 4), after 24 doses of alemtuzumab (aim: at the end of Week 8), and after 36 doses of alemtuzumab (aim: at the end of Week 12) of treatment. Patients showing progressive disease (PD) (according to NCI criteria) will be withdrawn from the study. If hematological or other toxicity is seen, treatment will be interrupted and the dose will be reduced according to the prescription information.

If after 12 weeks there is stable disease (SD), partial response (PR) or complete response (CR), then maintenance treatment will be given, with continued subcutaneous alemtuzumab (30 mg every 14 days). Patients for whom stem-cell transplantation is a realistic treatment option will be offered the possibility of receiving allogeneic stem-cell treatment in another clinical trial (CLLX2 or other GCLLSG trial). The latter will however only be offered if (1) the patient is eligible according to protocol and (2) a HLA-compatible donor is available who has given his/her informed consent. There should be a treatment-free period of at least 2 months before SCT, details are specified in the corresponding protocol.

Appropriate premedication and infection prophylaxis will be administered. After each disease staging (i.e. every three months during the maintenance phase), if there is SD, PR or CR, then patients will continue study therapy (alemtuzumab maintenance). Maintenance therapy will be stopped after two years.

During the study, continual monitoring of efficacy and toxicity will be performed. Early stopping rules will be applied if major intolerability is observed.

Response will be assessed by clinical examination, blood counts, clinical chemistry, chest X-ray (plain radiograph of the chest), ultrasound of the abdomen, CT scanning (if indicated), bone marrow cytology and histology (only in cases of possible CR), and assessment of MRD (for molecular response rate only). Time points for response evaluation according to NCI criteria will be after 12 doses, 24 doses, and 36 doses of alemtuzumab. For an uninterrupted treatment course, this will be after 4, 8 and 12 weeks respectively. (If treatment with alemtuzumab is interrupted, then the time points for all subsequent doses, assessments and other procedures will be delayed correspondingly; i.e., the number of doses is the determining factor for elapsed treatment time, and not the calendar date; see above, "Staging will be performed...".) Follow-up assessment will continue at three-month intervals for at least three years.

The following time schedule is anticipated for the study:

* Start of recruitment: January 2008
* End of recruitment: September 2011
* End of study procedures (conclusion of maintenance therapy): December 2013 (plus eventual additional follow-up)

Subcutaneous Alemtuzumab Combined With Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allo-SCT in CLL With 17p- or Refractory to Fludarabine

A Prospective, Multi-center Phase II Study of Subcutaneous Alemtuzumab Combined With Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Stem-cell Transplantation, in Chronic Lymphocytic Leukemia Which is Associated With 17p Deletion or is Refractory to Fludarabine

Time points for response evaluation according to NCI criteria will be:

* The end of each treatment cycle: after 12 doses (4 weeks actual treatment), 24 doses (8 weeks actual treatment), and 36 doses (12 weeks actual treatment) of alemtuzumab
* During maintenance therapy, every three months
* During follow-up, every three months
* A final response assessment will be made at the end of study treatment if the patient's participation is ended at a point other than one of those specified above.

Progression-free survival: time from study entry to the detection of progressive disease according to NCI criteria or death of any cause, whichever occurs first.

Failure-free survival: time from study entry until next treatment, detection of progressive disease according to NCI criteria or death of any cause, whichever occurs first.

Time from study entry to death of any cause.

Acquisition of further data to expand the data base on the toxicity of the study treatment. (Type, frequency, severity, timing and relatedness of AEs and laboratory abnormalities observed during different treatment cycles)

Technical University of Munich

WiSP Wissenschaftlicher Service Pharma GmbH

German CLL Study Group

University of Ulm

Prof. Dr. med.

Syndrome

Lymphoma

Tumor Lysis Syndrome

Lymphosarcoma

Venetoclax

Obinutuzumab

Bendamustine Hydrochloride

Antineoplastic Agents, Alkylating

Alkylating Agents

Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen.

After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.

Obinutuzumab (100 mg on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen.

Bendamustine (90 mg/m\^2 ) was to be administered to those with nodes or nodal mass \> 10 cm, or with del(11q) and \> 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg.

Bendamustine

The venetoclax dose was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. Participants were instructed to take venetoclax tablets with a meal and water at approximately the same time each day. Venetoclax tablets were to be swallowed whole and not chewed, crushed, or broken prior to swallowing.

ABBVIE INC.

This is a multi-cohort, open-label study in previously untreated participants with chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), excluding those with the 17p deletion, to evaluate a debulking strategy that would enable all participants to receive subsequent venetoclax as outpatients, with lower risk of tumor lysis syndrome.

Safety and efficacy data through 13 October 2021 are included in the interim analysis, which was conducted after all participants completed the post-treatment Week 65 visit or discontinued from the study.

A Study in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Subjects, Excluding Those With the 17p Deletion, to Evaluate Debulking Regimens Prior to Initiating Venetoclax Combination Therapy

A Phase 3b Study in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Subjects, Excluding Those With the 17p Deletion, to Evaluate Debulking Regimens Prior to Initiating Venetoclax Combination Therapy

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.

Low tumor burden is defined as absolute lymphocyte count (ALC) \< 25 × 10\^9 /L and all lymph nodes \< 5 cm per computed tomography (CT) scans.

Complete response rate is defined as the percentage of participants achieving complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria.

CR required all of the following:

* Peripheral blood lymphocytes \<4000/μL
* Absence of lymphadenopathy by physical examination and computed tomography scan
* No hepatomegaly or splenomegaly by physical examination
* Absence of disease or constitutional symptoms (unexplained fevers \>38°C, drenching night sweats, ≥10% weight loss in last 6 months)
* Blood counts above the following:

  * Neutrophils \>1500/μL
  * Platelets \>100,000/μL
  * Hemoglobin \>11.0 g/dL
* Bone marrow at least normocellular for age, \<30% lymphocytes

CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity.

ORR is defined as the percentage of participants who achieved a best response of complete remission (CR), complete remission with incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR) based on the 2008 Modified IWCLL NCI-WG criteria at any time during the study as assessed by investigator up through the completion of the 65-week disease response assessment after the start of venetoclax. Participants who did not respond were considered non-responders.

DoR is defined as the number of days from the date of first response (CR, CRi, nPR, or PR per the 2008 Modified IWCLL NCI-WG criteria) to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless whether the event occurred during or after the participant was taking any study drug (either venetoclax, obinutuzumab, or bendamustine). Duration of response was analyzed by Kaplan-Meier (K-M) methodology.

PFS is defined as the number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless whether the event occurred during or after the participant was taking any study drug. Progression-free survival was analyzed by Kaplan-Meier methodology.

TTP is defined as the number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to date of disease progression. All disease progression was to be included regardless of whether the event occurred during or after the participant was taking any study drug.The distribution of the time to progression was estimated using Kaplan-Meier methodology.

OS is defined as number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of death. If a participant had not died, their data was censored at the date when they were last known to be alive prior to the cutoff date.The distribution of OS was estimated using Kaplan-Meier methodology.

The level of MRD was assessed in the peripheral blood of all participants at 5 months after last dose of obinutuzumab, and at 3 months after last dose of venetoclax/end of treatment (including early study termination) to determine the rate of UMRD. Undetectable Minimal Residual Disease is defined as less than one CLL cell per 10,000 leukocytes (\< 10\^-4 ).

AbbVie

Participants who received obinutuzumab during the debulking regimen period

Obinutuzumab_Debulk

Participants who received obinutuzumab and bendamustine during the debulking regimen period

Obinutuzumab_Bendamustine_Debulk

Participants who received obinutuzumab and venetoclax during the post debulking period

Obinutuzumab_Venetoclax_Postdebulk

Participants who received venetoclax monotherapy during the post debulking period; safety data were collected starting 30 days after the last dose of obinutuzumab

Venetoclax_MONO_Postdebulk

Obinutuzumab/Bendamustine

Total

Age, Continuous

Sex: Female, Male

White

Black or African American

Asian

American Indian/Alaska Native

Native Hawaiian or Other Pacific Islander

Other

Missing

Race/Ethnicity, Customized

All Treated Participants: all enrolled participants who received at least one dose of any study drug

Global Medical Services

From Baseline to the End of Cycle 2

From Baseline to the End of Cycle 4

From Baseline to the End of Cycle 6

Participants who completed debulking and were subsequently treated with venetoclax with available data

Percentage of Participants Achieving Low Tumor Burden Status With Induction of Obinutuzumab or Obinutuzumab Plus Bendamustine (Debulking Period)

All treated participants who received at least 1 dose of any study drug

Complete Response Rate

Overall Response Rate (ORR)

All treated participants who received at least 1 dose of any study drug and who had a record of first response (CR, CRi, PR, or nPR)

Duration of Response (DoR)

Progression-Free Survival (PFS)

Time to Progression (TTP)

Overall Survival (OS)

At Week 38

At Week 65

Undetectable Minimal Residual Disease (UMRD) Rate

Overall Study

Venetoclax will be administered orally once daily (QD) beginning with a dose-titration phase. The initial venetoclax dose is 20 mg QD. After 1 week of treatment at 20 mg QD, the dose will be escalated to 50 mg QD followed by subsequent increases, each after 1 week, to 100 mg QD, 200 mg QD and the maximum dose of 400 mg QD. Participants may continue to receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator's assessment), do not have unacceptable toxicity, and do not meet any of the criteria for discontinuation.

In countries where venetoclax is not commercially available, participants who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 2 additional years, plus one additional year until the venetoclax extension study was open, determined on a case by case basis.

AbbVie Inc.

The purpose of this study is to evaluate the efficacy of venetoclax monotherapy in participants with relapsed/refractory CLL with or without the 17p deletion or TP53 mutation, including those who have received prior treatment with a B-cell receptor inhibitor.

Following the Screening period, all eligible participants initiate venetoclax on a once daily (QD) dosing schedule. To mitigate the risk for tumor lysis syndrome (TLS), dosing will start with a 5-week dose titration phase.

Participants may receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator assessment), do not have unacceptable toxicity and do not meet any of the criteria for subject discontinuation. In countries where venetoclax is not commercially available, participants who continued to derive benefit after 2 years of treatment may extend their treatment for up to 2 additional years in an extended access phase. Participants in the extended access phase of this study who continue to derive benefit from venetoclax after the 2-year extension and are transferring to the venetoclax extension study, Study M19-388 (NCT03844048), may remain in Extended Access for up to 1 additional year or until the extension study is approved and initiated at the site, whichever is sooner.

A Study to Evaluate the Efficacy of Venetoclax Monotherapy in Relapsed/Refractory Participants With Chronic Lymphocytic Leukemia (CLL)

Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating the Efficacy of Venetoclax (ABT 199) in Relapsed/Refractory Subjects With Chronic Lymphocytic Leukemia (CLL)

Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria.

CR required all of the following:

* Peripheral blood lymphocytes \< 4000/μL
* Absence of lymphadenopathy by physical examination and computed tomography scan
* No hepatomegaly or splenomegaly by physical examination
* Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months)
* Blood counts above the following:

  * Neutrophils \> 1500/μL
  * Platelets \> 100,000/μL
  * Hemoglobin \> 110 g/L
* Bone marrow at least normocellular for age, \< 30% lymphocytes.

CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.

Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria.

CR required all of the following:

* Peripheral blood lymphocytes \< 4000/μL
* Absence of lymphadenopathy by physical examination and computed tomography scan
* No hepatomegaly or splenomegaly by physical examination
* Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months)
* Blood counts above the following:

  * Neutrophils \> 1500/μL
  * Platelets \> 100,000/μL
  * Hemoglobin \> 110 g/L
* Bone marrow at least normocellular for age, \< 30% lymphocytes

CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.

Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 modified IWCLL NCI-WG criteria assessed by the investigator.

CR and CRi are defined above. nPR is defined as for CR but bone marrow nodules could be identified histologically.

For PR at least 2 of the following must be met:

* 50% decrease in peripheral blood lymphocyte count from the Baseline value;
* 50% reduction in lymphadenopathy;
* 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy);

In addition at least 1 of the following criteria must be met:

* Neutrophils \> 1,500/μL or ≥ 50% improvement over Baseline;
* Platelets \> 100,000/μL or ≥ 50% improvement over Baseline;
* Hemoglobin \> 11.0 g/dL or ≥ 50% improvement over Baseline without transfusions or exogenous growth factors.

PR must have been confirmed at least 7 weeks later.

Duration of response was defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) was objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding the data were censored at the date of the last available disease assessment prior to the data cutoff date.

Time to progression was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.

Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.

Overall survival (time to death) was defined as the time from the first dose date of venetoclax to the date of death. If a participant had not died the data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.

The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (\< 10-⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.

Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria.

CR required all of the following:

* Peripheral blood lymphocytes \< 4000/μL
* Absence of lymphadenopathy by physical examination and computed tomography scan
* No hepatomegaly or splenomegaly by physical examination
* Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months)
* Blood counts above the following:

  * Neutrophils \> 1500/μL
  * Platelets \> 100,000/μL
  * Hemoglobin \> 110 g/L
* Bone marrow at least normocellular for age, \< 30% lymphocytes.

CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.

The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess health-related quality of life (HRQoL) and leukemia-specific symptoms using a core set of questions (Functional Assessment of Cancer Therapy-General; FACT-G), and a cancer site-specific leukemia subscale. Questions are scored on a scale from 0 (not at all) to 4 (very much).

FACT-G consists of 27 general items divided into 4 primary HRQoL domains: Physical Well-being (PWB; 7 items; score range 0-28), Social/Family Well-being (SWB; 7 items; score range 0-28), Emotional Well-being (EWB; 6 items; score range 0-24), Functional Well-being (FWB; 7 items; score range 0-28). The leukemia subscale consists of 17 items (score range 0-68) that assess patient concerns relating to leukemia. Three summary scales were calculated: FACT-Trial Outcome Index composed of the PWB, FWB, and leukemia subscale (score range 0-124); FACT-G (score range 0-108) and the FACT-Leu Total (range 0-176). Higher scores reflect better HRQoL.

The FACIT-Fatigue questionnaire measures fatigue and its effect on functioning and daily activities. The FACIT-Fatigue includes 13 items answered on a 5-point rating scale based on a 7-day recall period. Scores range from 0 to 52, with lower scores reflecting greater fatigue.

The EQ-5D-5L is a generic measure of health status consisting of two parts: a descriptive system consisting of 5 items and a visual analog scale (VAS).

The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The participant is asked to rate each dimension on 5 levels of severity (1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, 5: extreme problems).

The scores for the 5 dimensions are used to compute a single health utility index score representing the general health status of the individual. The health index score ranges from zero (defined as a health state equivalent to being dead) to 1 (full health).

The EQ-5D-5L is a generic measure of health status consisting of two parts, a descriptive system consisting of 5 items and a visual analog scale (VAS).

The VAS assesses the participant's self-rated overall health on a scale from 0 (worst health imaginable) to 100 (best health imaginable).

Participants received venetoclax on a once daily dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants who continued to derive benefit after 2 years of treatment may have continued venetoclax therapy for up to 3 additional years.

Age, Customized

Ethnicity (NIH/OMB)

Geographic Region

Prior Treatment With B-cell Receptor Inhibitor (BCRi)

The null hypothesis stated that the CR rate for BCRi-naïve participants would be ≤ 6%, based on the CR rate reported for current therapies at the time the study was designed, with an alternative hypothesis that the CR rate would be \> 6%. If the p-value for this test was \< 0.025, the null hypothesis would be rejected.

All enrolled participants treated with at least one dose of venetoclax who had not previously received treatment with BCRi

Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Primary Analysis

All enrolled participants treated with at least one dose of venetoclax who were previously treated with BCRi

Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Primary Analysis

All enrolled participants treated with at least one dose of venetoclax

Overall Response Rate (ORR) - Primary Analysis

Enrolled participants treated with at least one dose of venetoclax who had an overall response of CR, CRi, nPR, or confirmed PR.

Duration of Overall Response (DOR) - Primary Analysis

Enrolled participants treated with at least one dose of venetoclax

Time to Progression (TTP) - Primary Analysis

Progression-Free Survival (PFS) - Primary Analysis

Overall Survival (OS) - Primary Analysis

Physical well-being - Week 48

Physical well-being - Week 108

Social/family well-being - Week 48

Social/family well-being - Week 108

Emotional well-being - Week 48

Emotional well-being - Week 108

Functional well-being - Week 48

Functional well-being - Week 108

Leukemia subscale - Week 48

Leukemia subscale - Week 108

FACT-G total score - Week 48

FACT-G total score - Week 108

FACT-leukemia trial outcome index - Week 48

FACT-leukemia trial outcome index - Week 108

FACT-leukemia total score - Week 48

FACT-leukemia total score - Week 108

All enrolled participants treated with at least one dose of venetoclax with available data at each time point.

Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu)

Week 48

Week 108

Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue)

Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Health Index Score

Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Visual Analog Scale Score

Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Final Analysis

Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Final Analysis

Overall Response Rate (ORR) - Final Analysis

Duration of Overall Response (DOR) - Final Analysis

Time to Progression (TTP) - Final Analysis

Progression-Free Survival (PFS) - Final Analysis

Overall Survival (OS) - Final Analysis

Peripheral blood

Bone marrow

All enrolled participants who received at least one dose of venetoclax

Minimal Residual Disease (MRD) Negativity Rate - Primary Analysis

Minimal Residual Disease (MRD) Negativity Rate - Final Analysis

Participants received venetoclax on a once daily (QD) dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.

In countries where venetoclax was not commercially available, participants who continued to derive benefit after 2 years of treatment could extend their treatment for up to two additional years plus one additional year until the venetoclax extension study was open.

Behaviors and Mental Disorders

Disease Progression

Quality of Life

Venetoclax was administered orally once daily (QD) for a planned duration of up to 2 years or until disease progression; median time on treatment was 127 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.

Venetoclax tablets were to be taken orally once daily with a meal and water in the morning at approximately the same time each day. Tablets were to be swallowed whole and not chewed, crushed, or broken prior to swallowing.

The purpose of this open-label, single-arm study was to evaluate the impact of venetoclax on the quality of life of participants including those with with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL; a type of cancer affecting the blood and the bone marrow) with or without the 17p deletion or TP53 mutation, including participants with an unknown status, as well as R/R CLL participants who had been previously treated with B-cell receptor inhibitor (BCRi) therapy. The starting dose of venetoclax was 20 mg once daily. The dose must have been gradually increased over a period of 5 weeks up to the daily dose of 400 mg. Participants may have continued receiving venetoclax for up to 2 years. After the treatment period, participants may have continued on into a 2-year follow-up period.

A Study Evaluating the Impact of Venetoclax on the Quality of Life for Subjects With Relapsed (Your Cancer Has Come Back) or Refractory (no Response to Previous Cancer Treatments) Chronic Lymphocytic Leukemia (CLL) While Receiving Venetoclax Monotherapy (a Single Agent).

Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating the Impact of Venetoclax on the Quality of Life of Relapsed/Refractory Subjects With Chronic Lymphocytic Leukemia (CLL) (VENICE II)

EORTC QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a global health status/quality of life (GHS/QoL) scale. Participants rate items and a score ranging from 0 to 100 is calculated. A higher score on the global health status/quality of life scale indicates a better level of functioning, and positive changes from baseline indicate improvement. A change of 5 - 10 points is considered a small change, and a change of 10 - 20 points is considered a moderate change.

EORTC QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a physical functioning scale. Participants rate items and a score ranging from 0 to 100 is calculated. A higher score on the physical functioning scale indicates a better level of functioning, and positive changes from baseline indicate improvement. A change of 5 - 10 points is considered a small change, and a change of 10 - 20 points is considered a moderate change.

EORTC QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a role functioning scale. Participants rate items and a score ranging from 0 to 100 is calculated. A higher score on the role functioning scale indicates a better level of functioning, and positive changes from baseline indicate improvement. A change of 5 - 10 points is considered a small change, and a change of 10 - 20 points is considered a moderate change.

EORTC QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including an emotional functioning scale. Participants rate items and a score ranging from 0 to 100 is calculated. A higher score on the emotional functioning scale indicates a better level of functioning, and positive changes from baseline indicate improvement. A change of 5 - 10 points is considered a small change, and a change of 10 - 20 points is considered a moderate change.

EORTC QLQ-C30 is a 30-item participant self-report questionnaire composed of both multi-item and single scales, including a cognitive functioning scale. Participants rate items and a score ranging from 0 to 100 is calculated. A higher score on the cognitive functioning scale indicates a better level of functioning, and positive changes from baseline indicate improvement. A change of 5 - 10 points is considered a small change, and a change of 10 - 20 points is considered a moderate change.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Subcutaneous Alemtuzumab Combined With Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allo-SCT in CLL With 17p- or Refractory to Fludarabine	NCT01392079	Chronic Lymphoc...	Alemtuzumab	18 Years -	University of Ulm
A Study in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Subjects, Excluding Those With the 17p Deletion, to Evaluate Debulking Regimens Prior to Initiating Venetoclax Combination Therapy	NCT03406156	Chronic Lymphoc... Small Lymphocyt...	Obinutuzumab Bendamustine Venetoclax	18 Years - 99 Years	AbbVie
A Study to Evaluate the Efficacy of Venetoclax Monotherapy in Relapsed/Refractory Participants With Chronic Lymphocytic Leukemia (CLL)	NCT02756611	Chronic Lymphoc...	Venetoclax	18 Years - 99 Years	AbbVie
Subcutaneous Alemtuzumab Combined With Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allo-SCT in CLL With 17p- or Refractory to Fludarabine	NCT01392079	Chronic Lymphoc...	Alemtuzumab	18 Years -	University of Ulm
A Study Evaluating the Impact of Venetoclax on the Quality of Life for Subjects With Relapsed (Your Cancer Has Come Back) or Refractory (no Response to Previous Cancer Treatments) Chronic Lymphocytic Leukemia (CLL) While Receiving Venetoclax Monotherapy (a Single Agent).	NCT02980731	Chronic Lymphoc...	Venetoclax	18 Years - 99 Years	AbbVie
A Study of Venetoclax in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma	NCT02966756	Chronic Lymphoc... Small Lymphocyt...	Venetoclax	18 Years -	AbbVie

Spots Global Cancer Trial Database for 17p deletion

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