Treatments

Treatment Guidelines

Clinicians should consider multiple parameters before recommending a treatment for CLL, including the clinical stage of the disease, the symptoms of the patient, the fitness and concomitant diseases of the patient, genetic risks, line of treatment, and response to previous therapy.1 Using the assessment of these parameters, the following treatment recommendations have been published. Clinicians should consider these treatment guidelines and discuss the risks and benefits of each option with patients and families before arriving at a treatment decision.

 

Suggested Treatment Regimens for Chronic Lymphocytic Leukemia without del(17p)/TP53 mutation2,23

Line of Therapy      Patient Factors Preferred Regimens Other Recommended Regimens

First-Line Therapy

(CLL without del(17p)/TP53 mutation)

Frail patient with significant comorbidities OR age >65 y and younger patients with significant comorbidities

·  Ibrutinib
(category 1)

 

·  Venetoclax + obinutuzumab

·  Bendamustine + anti-CD20 monoclonal antibody* (Not for frail patients)

·  Chlorambucil + anti-CD20 monoclonal antibody

·  High-dose methylprednisolone (HDMP) + rituximab (category 2B)

·  Ibrutinib + obinutuzumab (category 2B)

·  Obinutuzumab (category 2B)

·  Chlorambucil (category 3)

·  Rituximab (category 3)

Age <65 y without significant comorbidities

·  Ibrutinib
(category 1)

 

·  Venetoclax + obinutuzumab

·  Bendamustine + CD20 monoclonal antibody

·  FCR (fludarabine, cyclophosphamide, rituximab)

·  FR (fludarabine, rituximab)

·  HDMP + rituximab (category 2B)

·  Ibrutinib + rituximab (category 2B)

·  PCR (pentostatin, cyclophosphamide, rituximab) [category 3]

Relapsed/Refractory Therapy

(CLL without del(17p)/TP53 mutation)

Frail patient with significant comorbidity OR age >65 y and younger patients with significant comorbidities (CrCl ˂70 mL/min)

·  Acalabrutinib (category 1)

·  Ibrutinib
(category 1)

·  Venetoclax + rituximab
(category 1)

·  Duvelisib

·  Idelalisib + rituximab

·  Alemtuzumab + rituximab

·  Chlorambucil + rituximab

·  Reduced-dose FCR

·  HDMP + rituximab

·  Idelalisib

·  Lenalidomide + rituximab

·  Obinutuzumab

·  Ofatumumab

·  Reduced-dose PCR

·  Venetoclax

·  Dose-dense rituximab (category 2B)

·  Bendamustine, rituximab +ibrutinib, or idelalisib (category 2B for BR and BR + ibrutnib; category 3 for BR + idelalisib)

Age <65 y without significant comorbidities

·  Acalabrutinib (category 1)

·  Ibrutinib
(category 1)

·  Venetoclax + rituximab
(category 1)

·  Duvelisib

·  Idelalisib + rituximab

·  Alemtuzumab + rituximab

·  Bendamustine + rituximab

·  FC + ofatumumab

·  FCR

·  HDMP + rituximab

·  Idelalisib

·  Lenalidomide + rituximab

·  Obinutuzumab

·  Ofatumumab

·  PCR

·  Venetoclax

·  Bendamustine, rituximab + ibrutinib (category 2B)

·  Bendamustine, rituximab + idelalisib (category 2B)

NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated.

*Anti-CD monoclonal antibody options include rituximab, obinutuzumab, or ofatumumab.

 

Suggested Treatment Regimens for CLL with del(17p)/TP53 mutation2,23

First-Line Therapy

 

·  Ibrutinib

·  Venetoclax + obinutuzumab

·  Alemtuzumab + rituximab

·  HDMP + rituximab

·  Obinutuzumab

Relapsed/Refractory Therapy

 

·  Acalabrutinib (category 1)

·  Ibrutinib (category 1)

·  Venetoclax + rituximab (category 1)

·  Duvelisib

·  Idelalisib +rituximab

·  Venetoclax

·  Alemtuzumab +rituximab

·  HDMP + rituximab

·  Idelalisib

·  Lenalidomide + rituximab

·  Ofatumumab

NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise indicated.

 

Studies of early-stage disease have not shown a benefit of early therapeutic intervention. As up to one third of CLL patients have slow-progressing indolent disease, the decision to initiate treatment depends on the presence of active or symptomatic disease. Asymptomatic patients with early stage disease (Rai 0 or Binet A) should be monitored for the development of aggressive disease. Treatment should be initiated when patients progress or present with symptomatic or active disease. According to guidelines published by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL), some conditions that indicate symptomatic or active disease include:3

 

  • Progressive marrow failure (anemia and/or thrombocytopenia; usually Binet C or Rai stage III or IV)
  • Massive (>6cm below the left costal margin) or progressive or symptomatic splenomegaly
  • Massive nodes (>10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
  • Progressive lymphocytosis with an increase of >50% over a 2-month period
  • Lymphocyte doubling time (LDT) of <6 months; patients with initial blood lymphocyte counts of <30,000/µL may require a longer observation period to determine LDT
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapies
  • Disease-related symptoms, such as unintentional weight loss >10% within the previous 6 months, significant fatigue, fevers of >100.5ºF or 38.0ºC for 2 or more weeks without other evidence of infection; or night sweats for more than 1 month without evidence of infection.

 

Clinical Trial Data

Ibrutinib

Oral Bruton tyrosine kinase inhibitor that antagonizes B-cell receptor signaling, homing, and adhesion.4

  • In a phase I/II clinical trial of 101 patients with relapsed/refractory CLL and 31 treatment naïve patients, a 5-year PFS of 92%, an ORR of 87%, and a CR rate of 29% was noted in the treatment-naïve cohort. For relapsed/refractory patients, an ORR of 89% with a 10% CR rate was observed, with a median PFS of 52 months. This is significantly longer than the 15 months median PFS observed with bendamustine plus rituximab and the 21 to 31 months median PFS noted with FCR treatment.5,6
  • In a phase III trial (RESONATE-2), 269 treatment-naïve patients aged 65 years or older were randomized to receive ibrutinib or chlorambucil. The median PFS was not reached for the ibrutinib arm compared to 18.9 months for those who received chlorambucil. Additionally, the 2-year PFS was significantly longer for ibrutinib compared to chlorambucil (89% vs 34%).7,8 Ibrutinib is associated with an increase in the risk of atrial fibrillation and hemorrhage.7
  • The RESONATE-17 trial enrolled 145 patients with relapsed/refractory del(17p) CLL/SLL and found the 24-month PFS was 63% and the 24-month overall survival was 75% after treatment with ibrutinib. The most commonly reported grade 3 or 4 adverse events included neutropenia, hypertension, pneumonia, and anemia. Adverse events leading to death occurred in 18 patients with extended follow-up.9
  • In a phase III trial comparing ibrutinib to ofatumumab in 391 patients with relapsed or refractory CLL or SLL, ibrutinib significantly improved PFS, with the median not reached after 9.4 months of follow-up for ibrutinib and a median PFS of 8.1 months with ofatumumab (HR for progression or death, 0.22; 95% CI, 0.15-0.32; P<0.001). After 6 months, 88% of ibrutinib treated patients did not have disease progression compared to 65% of patients in the ofatumumab group. Ibrutinib significantly prolonged the rate of overall survival compared to ofatumumab (HR for death, 0.43; 95% CI, 0.24-0.79; P=0.005). Overall, 57% of ibrutinib patients and 47% of ofatumumab patients experienced at least one adverse event of grade 3 or higher.4

 

Venetoclax

Oral BH3-mimetic drug that triggers apoptosis by antagonizing the anti-apoptotic protein BCL-2.10

  • In a phase 3 trial, 389 patients with relapsed or refractory CLL were randomized to receive either venetoclax plus rituximab or bendamustine plus rituximab. Venetoclax plus rituximab showed a significantly higher rate of 2-year PFS than bendamustine plus rituximab (84.9% vs 36.3%, respectively; HR for progression or death, 0.17; 95% CI, 0.11-0.25; P<0.001). This improvement in 2-year PFS for venetoclax-rituximab versus bendamustine-rituximab was observed for patients with chromosome 17p deletions (81.5% vs 27.7%; HR, 0.13; 95% CI, 0.05-0.29) and those without the deletion (85.9% vs 41.0%; HR, 0.19; 95% CI, 0.12-0.32). Although the rate of grade 3 or 4 neutropenia was higher in the venetoclax treatment group, the rate of grade 3 or 4 febrile neutropenia and infections was lower for venetoclax. The rate of grade 3 or 4 tumor lysis syndrome was 3.1% in the venetoclax combination group.10
  • A phase I dose-escalation study found that venetoclax was effective in all risk categories, including del(17p) CLL (ORR, 71%), heavily pretreated with at least four prior therapies (ORR, 73%), bulky disease (ORR, 78%), unmutated IGHV (ORR, 76%), and fludarabine-resistant disease (ORR, 79%).11 Previous studies have found that the combination of venetoclax with rituximab can overcome microenvironment-induced resistance to venetoclax.12
  • A phase 2 trial of venetoclax monotherapy in 91 patients with relapsed or refractory CLL previously treated with ibrutinib found an investigator-assessed overall response rate of 65% (95% CI, 53-74), with 51 patients achieving a partial response and 8 patients with a complete response. Median PFS was 24.7 months (95% CI, 19.2-not reached) and estimated 12-month PFS was 75%. Median OS was not reached (27.8-not reached) and estimated 12-month OS was 91%.13
  • Another phase 2 study found an ORR of 67% with venetoclax monotherapy in 36 patients with refractory or relapsed CLL after previous idelalisib treatment. Median PFS had not been reached and estimated 12-month PFS was 79%. The most common adverse events were neutropenia (56%), diarrhea (42%), upper respiratory tract infection (39%), thrombocytopenia (36%), nausea (31%), fatigue (28%), cough (22%), rash (22%) and anemia (22%). Grade 3 and 4 AEs were mostly hematologic [neutropenia (50%), thrombocytopenia (25%), and anemia (17%)]. No patients experienced tumor lysis syndrome.14
  • A retrospective cohort analysis of CLL patients from a large multicenter retrospective study investigated the optimal sequencing of agents after disease progression with ibrutinib. After ibrutinib discontinuation, the top three regimens administered were: anti-CD20 ± chlorambucil 32.6%, venetoclax 18%, alternate kinase inhibitor 12.6%; venetoclax-treated patients had a higher response rate (ORR, 89%) than patients given monoclonal antibody-based therapies (ORR, 58%) or an alternate kinase inhibitor (ORR, 40%).15
  • An open-label, phase 3 trial, investigating fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions found that venetoclax–obinutuzumab was associated with longer progression-free survival (primary end point) than chlorambucil–obinutuzumab. 432 patients underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax–obinutuzumab group versus 77 in the chlorambucil–obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan–Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax–obinutuzumab group than in the chlorambucil–obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) versus 64.1% (95% CI, 57.4 to 70.8), respectively. This benefit was also observed in patients with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. There were no significant differences in all-cause mortality or occurrences in grade 3 or 4 neutropenia or infections between groups.24

 

Idelalisib

Phosphoinositide 3-kinase delta (PI3K-δ) inhibitor that blocks B-cell receptor signaling and promotes apoptosis.16

  • In relapsed disease, one study found that idelalisib and rituximab had superior ORR (81% vs 13%; P<0.001), PFS (median, not reached vs 5.5 months; 93% vs 46%; P<0.001), and 12-month OS (92% vs 80%; P=0.02) compared with rituximab monotherapy. Patients in this study were heavily pretreated (median of 3 prior therapies), had high-risk disease (42% del(17p) or TP53 mutated), and had significant comorbidities (median CIRS score of 8).17
  • A phase II study of 125 patients with indolent non-Hodgkin’s lymphoma refractory to rituximab and an alkylating agent found a response rate of 57% with idelalisib monotherapy, with 6% of patients achieving a complete response. The median PFS was 11 months, with 47% of patients remaining progression-free at 48 weeks. The overall survival at 1 year was estimated to be 80% and the median duration of response was 12.5 months. The most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).16

 

Duvelisib

Oral, dual inhibitor of phosphatidylinositol 3-kinase delta and gamma (PI3K-δ,γ) that prevents B-cell proliferation and survival in clonal B-cell malignancies.18

  • In the phase 3 DUO trial, 319 patients with relapsed or refractory CLL were randomized to receive duvelisib or ofatumumab. Duvelisib was associated with a longer PFS (13.3 vs 9.9 months; HR, 0.52; P<0.0001) and higher overall response rate (74% vs 45%; P=0.0001) than ofatumumab in all patients, including those with del(17p) or TP53 mutations. The most common adverse events with duvelisib treatment were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough, and for ofatumumab, the most common AEs were neutropenia and infusion reactions.18
  • In an extension study of patients who had disease progression following ofatumumab therapy in the DUO study, a higher ORR (73% vs 28%) and median PFS (15 vs 9 months) were achieved with duvelisib compared to prior ofatumumab. A >50% reduction in target nodal lesions was observed in 83% of evaluable patients receiving duvelisib.19

 

Obinutuzumab

Glycoengineered type II anti-CD20 monoclonal antibody that stimulates increased direct cellular cytotoxicity of B cells.20

  • In a phase III trial of 781 patients with previously untreated CLL and coexisting conditions, subjects were randomized to receive obinutuzumab plus chlorambucil, rituximab plus chlorambucil, or chlorambucil monotherapy. A significant improvement in median PFS was associated with obinutuzumab-chlorambucil (26.7 months) and rituximab-chlorambucil (16.3 months) compared to chlorambucil alone (11.1 months). This benefit was observed in all subgroups, except in patients with del(17p). The rate of negative testing for minimal residual disease was significantly higher after obinutuzumab-chlorambucil therapy than after rituximab-chlorambucil treatment (bone marrow, 19.5% vs 2.6%; peripheral blood, 37.7% vs 3.3%, respectively). Treatment with obinutuzumab-chlorambucil improved overall survival as compared to chlorambucil alone (hazard ratio for death, 0.41; 95% CI, 0.23-0.74; P=0.002), with death rates of 9% and 20%, respectively. No significant benefit was noted for rituximab-chlorambucil over chlorambucil monotherapy (HR, 0.66; 95% CI, 0.39-1.11; P=0.11). The rate of infusion-related reactions and neutropenia was higher with obinutuzumab-chlorambucil than with rituximab-chlorambucil.21
  • In a phase I/II study of obinutuzumab monotherapy in relapsed/refractory CLL, median PFS was 10.7 months (95% CI, 7.1-11.7) and the median duration of response was 8.9 months (range, 0.8-26.1 months) for any patient with complete or partial responses to obinutuzumab. Overall, 62% of patients in the phase I arm of the study achieved partial responses and the best ORR of the phase II arm was 30%.20
  • A phase II trial investigated the efficacy and safety of 1000-mg or 2000-mg doses of obinutuzumab in symptomatic, previously untreated CLL patients. In the 2000-mg dose arm, the ORR was 67%, and 20% of patients achieved a compete response or complete response with incomplete cytopenia response. The ORR was 49% for the 1000-mg dose arm, with 5% of patients achieving a complete response or complete response with incomplete cytopenia response. Infusion-related events (89.5%-95%) and cytopenias (34.2%-42.5%) were the most common adverse events.22

 

Acalabrutinib

Acalabrutinib (ACP-196) is a highly selective, potent, covalent Bruton tyrosine kinase (BTK) inhibitor25

  • In 2 updated analyses of the Phase 1/2 ACE-CL-001 study, treatment with acalabrutinib was associated with high response rates and durable remissions in patients with R/R CLL/SLL, including those with high-risk disease,25 and in treatment-naïve CLL.26 Reported AEs indicated a tolerable safety profile.
  • ASCEND, a randomized, global, multicenter, open-label phase 3 trial, evaluated the efficacy and safety of acalabrutinib vs investigator’s choice of rituximab/idelalisib or rituximab/bendamustine in patients with relapsed or refractory CLL. At a median follow-up of 16.1 months, acalabrutinib significantly prolonged progression-free survival vs rituximab/idelalisib or rituximab/bendamustine (median = not reached vs 16.5 months; HR = 0.31; 95% CI = 0.20–0.49; P<.0001). This represented a 69% reduction in risk of progression or death. Progression-free survival was improved with acalabrutinib across subgroups including del(17p), TP53 mutation, and Rai stage.27,28
  • According to topline results of the randomized phase 3 ELEVATE-TN trial, acalabrutinib alone or in combination with obinutuzumab significantly prolonged PFS compared with a chemotherapy-based chlorambucil-obinutuzumab combination for patients with previously untreated CLL. Detailed results from ELEVATE-TN are forthcoming.
  • As of September 2019, acalabrutinib has received FDA breakthrough therapy designation for CLL and is approved for use in mantle cell lymphoma.

References

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  5. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32- 42.
  6. O’Brien S, Furman RR, Coutre SE, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128:233.
  7. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-2437.
  8. Barr P, Robak T, Owen CJ, et al. Updated efficacy and safety from the phase 3 Resonate-2 study: ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128:234.
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  10. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-Rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107-1120.
  11. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322.
  12. Thijssen R, Slinger E, Weller K, et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica. 2015;100(8):e302-e306.
  13. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicenter, open-label, phase 2 trial. Lancet. 2018;19(1):65-75.
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  15. Mato AR, Allan JN, Pagel JM, et al. Front-line ibrutinib therapy for chronic lymphocytic leukemia (CLL) in the real world: responses, toxicity, outcomes and subsequent therapies. Presented at: 59th Annual Meeting of the American Society of Hematology. Atlanta, GA; 2017. Abstract 3011.
  16. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-1018.
  17. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007.
  18. Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446-2455.
  19. Kuss B, Davids M, Hillmen P, et al. The efficacy of duvelisib monotherapy following disease progression on ofatumumab monotherapy in patients with relapsed/refractory CLL or SLL in the DUO crossover extension study [abstract]. J Clin Oncol. 2018;36:Abstract 7533.
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  26. Byrd JC, Woyach JA, Furman RR, et al. Acalabrutinib in treatment-naive (TN) chronic lymphocytic leukemia (CLL): Updated results from the phase 1/2 ACE-CL-001 study. Blood. 2018;132(Suppl 1):692.
  27. The ASCO Post. EHA 2019: ASCEND trial compares acalabrutinib vs investigator’s choice in relapsed or refractory CLL. https://www.ascopost.com/News/60168. Accessed September 6, 2019.
  28. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plub idelalisib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at the 24th Annual Congress of the European Hematology Association (EHA), Amsterdam, Netherlands; Abstract LB2606.