Dr. Vinayak Maka and Dr. Vishwanath Sathyanarayanan pick 4 major studies on chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), presented at this year's American Society of Hematology Annual Meeting, summarising them and providing their expert take on each for Indian Oncologists.

ASH 2019 was held between December 7 to 10, 2019 in USA and the premier event included many recent updates in malignant and non-malignant haematology. Here are a few selected abstracts in Chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) which are relevant to Indian practice.

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ELEVATE TN: Acalabrutinib ± Obinutuzumab vs Obinutuzumab + Chlorambucil in treatment-naive Chronic Lymphocytic Leukemia (CLL)

Phase III ELEVATE TN (ACE-CL-007) was a phase III randomised trial which compared Acalabrutinib 100 mg PO BID + Obinutuzumab (n = 179) with Acalabrutinib 100 mg PO BID (n=179) and Obinutuzumab+ Chlorambucil 0.5 mg/kg PO D1, 15 (n = 177). The patients were stratified by del(17p) status, ECOG PS 0/1 vs 2, geographic region.

• Primary endpoint: PFS by IRC with acalabrutinib + obinutuzumab vs obinutuzumab + chlorambucil
• Key secondary endpoints: PFS of acalabrutinib vs obinutuzumab + chlorambucil, ORR by IRC and investigators, time to next treatment, overall survival (OS), safety

All the baseline characteristics were evenly matched in all the sub-groups. At a median follow-up of 28.3 months, the median PFS was not reached in the acalabrutinib+obinutuzumab and the acalabrutinib monotherapy arms as compared to 22.6 months in the obinutuzumab with chklorambucil arm.

1. The ORR and CR rates were better in the acalabrutinib arms and best in the acalabrutinib with obinutuzumab arm.
2. The 24 months PFS was 93% vs. 87% vs. 47% in the acalabrutinib+obinutuzumab, acalbrutinib monotherapy arms and in the obinutuzumab with chlorambucil arms respectively.
3. PFS benefit of acalabrutinib was consistent across subgroups, including bulky disease (< 10 cm or ≥ 10 cm), presence or absence of del(17p) or TP53 mutations, presence or absence of del(11q)(q22.3), IGHV mutated or unmutated, and presence or absence of complex karyotype.
4. Acalabrutinib ± obinutuzumab was associated with tolerable safety profile.
5. There were fewer deaths in either acalabrutinib treatment arm vs obinutuzumab + chlorambucil, but longer follow-up was needed to assess OS.

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Venetoclax + Ibrutinib in treatment-naive Chronic Lymphocytic Leukemia (CLL)

This phase II study was done to evaluate venetoclax + ibrutinib as first-line, fixed-duration treatment for patients with high-risk CLL/SLL. Eighty patients with treatment-naive high-risk CLL/SLL (≥65 yrs of age, del[17p], mutated TP53, del[11q], and/or unmutated IGHV); adequate organ function were selected. In the first 3 cycles, Ibrutinib 420 mg/day was given followed by Ibrutinib 420 mg/day + Venetoclax 400 mg/day from cycle 4-27. Subsequently if the MRD was positive, ibrutinib was continued until disease progression.

• Primary endpoint: Best response (CR, CRi)
• Secondary endpoints: Safety, time to response, OS, PFS, CR/CRi by IGHV and FISH subgroups

Responses were assessed per 2008 iwCLL criteria every 3 months in year 1, every 6 months in year 2. MRD was assessed in bone marrow by flow cytometry (sensitivity 10-4) and the median follow-up was 27 months.

1. 92% of patients had either a TP53 mutation, unmutated IGHV, or del(11q). In this trial, venetoclax + ibrutinib combination was effective and well tolerated in treatment-naive high-risk CLL
2. Responses improved with ongoing therapy, especially during year 2, with best MRD response of 75% in ITT population.
3. Main safety concerns were neutropenia, infection, and atrial fibrillation.

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Combination of lenalidomide and obinutuzumab in relapsed follicular lymphoma (FL)

Nathan Fowler from MD Anderson Cancer Center presented the data from a phase 1/2 study in which dose escalation of lenalidomide led to treatment with the combination of lenalidomide (Revlimid, Celgene) with obinutuzumab (Gazyva, Genentech). Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible.

Patients were enrolled in three predefined dose cohorts of lenalidomide (10 mg,15 mg, 20 mg) given on days 2-22 of a 28-day cycle. Obinutuzumab was given at a fixed dose (1000 mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding patients.

In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for a maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose-limiting toxicities (DLT) assessed during cycle 1. Once the maximum tolerated dose (MTD) was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Sixty-six patients were enrolled between May 2014 until March 2019, and all were eligible for safety and response assessment. No dose-limiting toxicities (DLTs) were observed in dose escalation, and 60 patients were enrolled in the phase II portion of the study at 20 mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of patients, the combination represented the third or greater line of treatment.

1. The overall response (OR) rate for all patients was 98% with 72% attaining a complete response (CR).
2. Eighteen patients (27%) had a partial response, and stable disease was noted in 1 (2%).
3. At a median follow up of 17 months, 14 patients had progressed, with an estimated 24 months progression-free survival (PFS) of 73% (57-83% 95% CI).
4. The estimated 24 months PFS for third line patients was 63%.
5. Twenty five patients (38%) remain on treatment and 95% remained alive at last follow up.
6. The most common grade ≥3 non-hematologic toxicities included fatigue (5 patients), rash (4 patients), and cough (3 patients).
7. Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) patients respectively.
8. Two patients stopped treatment due to adverse events, including one transient bradycardia and one grade 3 fatigue.

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RELEVANCE: Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumour Burden Follicular Lymphoma (FL)

This was a phase II trial to explore the efficacy and safety of obiunutuzumab-lenalidomide (O-len) in previously untreated, stage II, III, or IV, high tumour burden (defined by Groupe d'Etude des Lymphomes Folliculaires [GELF]) FL (grade 1, 2 or 3A).

Patients received 1000 mg of obiunutuzumab on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, and day 1 of even numbered cycles, cycle 8-30. Cycle length was 28 days. Lenalidomide was administered as 20 mg on days 1-21 of cycles 1-6. Patients in a complete response (CR) after 6 cycles received reduced dose lenalidomide (10 mg on days 1-21) for cycles 7-18. Among patients in a partial response (PR) after 6 cycles, lenalidomide was continued at 20 mg for the next 3-6 cycles or until CR, whichever occurred first, lenalidomide was then dose reduced to 10 mg on days 1-21 for the remainder of 18 cycles.

• The primary endpoint was progression-free survival (PFS) at 2 years (according to Lugano 2014 criteria)
• Secondary endpoints included: safety, CR, PR, overall response (ORR), and overall survival (OS)

Ninety patients with high tumor burden FL were enrolled. The median age was 58 years (range 33-84), 52% (N=47) were male, 67 (74%) had an ECOG performance status of 0, 9 (10%) had stage II, 23 (26%) stage III, and 58 (64%) had stage IV disease. The majority had grade 1/2 FL (80%). Twenty-one percent had low risk Follicular Lymphoma International Prognostic Index (FLIPI) scores; 37% were intermediate risk and 42% were high risk.

1. With a median follow-up of 22 months (range 1-30 months), the 2-year PFS estimate was 96% (95% CI 92-100%) with only 2 patients experiencing progression to date.
2. The overall response rate (ORR) was 98% (85 complete response [CR], 1 partial response [PR]); 92% achieved a CR at the first response assessment (cycle 4, day 1).
3. Eleven patients (12%) discontinued therapy as a result of an adverse event (AE), upper respiratory infection was the most common reason (N=5). Other reasons included bradycardia with sick sinus syndrome, urinary tract infection, constipation, abdominal pain, fatigue, foot neuroma (N=1 for each instance). The most common grade 3 or higher AEs include neutropenia (16%, grade 3 N=5, grade 4 N= 9), rash (10%), lung infection (4%), neutropenic fever (1%).

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. Vinayak Maka is a Senior Medical Oncologist who teaches and practice at the MS Ramaiah Medical College and the HCG MSR Cancer Centre, Bangalore.

Dr. Vishwanath Sathyanarayan is a Medical Oncologist from Apollo Hospitals, Bangalore with a fellowship from MD Anderson Cancer Center.