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Blood, bone marrow and lymph nodes (B-lymphocyte malignancy)

Chronic lymphocytic leukaemia

How clinical staging, genetic risk markers, chemoimmunotherapy and BTK and BCL2 inhibitors shaped chronic lymphocytic leukaemia care.

5-year relative survival · United States, SEER 8 registries

69.49%→93.35%

1975 (observed value; first year in the table) to 2018 (observed value; last observed year in the table). Read these with the caveats under “Then and now”.Source

23 milestones, by decade

  • A 1975 paper in Blood proposed a clinical staging system for CLL based on the idea that the disease is a progressive accumulation of lymphocytes: stage 0 for lymphocytosis in blood and marrow only, then stages I to IV by enlarged nodes, enlarged spleen or liver, anaemia and thrombocytopenia. In its 125 patients, median survival from diagnosis was more than 150 months for stage 0 and 19 months for each of stages III and IV, and 71 months for the whole series. The figures come from the abstract of a single series published in 1975 and are not comparable with outcomes today.
  • In 1999 two papers in Blood linked the mutation status of the immunoglobulin heavy-chain variable (IGHV) genes of the leukaemia cells to outcome. One sequenced the IGHV genes of 84 patients; among those with stage A disease, median survival was 95 months with unmutated genes and 293 months with mutated genes (P = 0.0008). The other reported that patients with unmutated genes responded poorly to continuous multiregimen chemotherapy and had shorter survival. The numbers are from the abstracts.
  • On the SEER Cancer Stat Facts page for CLL, the US age-adjusted death rate is 1.40 per 100,000 in 1975, 1.71 in 1993 and 0.96 in 2024, while observed five-year relative survival in the SEER 8 series is 69.49% for 1975 and 93.35% for 2018. These are different series (US mortality data and a limited set of registries), and the page does not say how much of the change reflects treatment, earlier detection or diagnostic practice. Survival after diagnosis and population death rates answer different questions.

Evidence current to October 2026 · Checked against primary sources to the extent possible

A guided tour of 11 milestones. You can pause or step through it yourself.

Filter milestonesshowing all 23
Treatment type
Setting

Chemotherapy

  1. 1955 · Treatment · Chemotherapy⚑ needs reviewChlorambucil: the oral alkylating-agent reference for CLLChlorambucil is an oral chemotherapy tablet. A 1955 clinical report of the drug in lymphoma is cited here by title only and may not cover CLL. In terms of survival, a 1999 pooled analysis of randomised trials in CLL supported no treatment for most early-stage patients and chlorambucil alone as first-line treatment for most advanced disease.Chlorambucil (CB 1348) in malignant lymphoma: Galton 1955, title only. CLL Trialists' Collaborative Group meta-analysis (1999): 2048 early-stage patients, six trials, 10-year survival 44% immediate vs 47% deferred chemotherapy (difference -3%, 95% CI -10% to 4%); 2022 patients, ten trials, 5-year survival 48% with combination chemotherapy and with chlorambucil (difference 0%, 95% CI -6% to 5%). FDA original action on Leukeran: 18 March 1957.
  2. 1975 · Understanding · UnderstandingRai staging: lymphocytosis plus anatomy predicts survivalIn 1975 Rai and colleagues proposed sorting CLL into five stages using blood counts and a physical examination: lymphocytes alone, then swollen glands, an enlarged spleen or liver, low red cells, and low platelets. In their 125 patients, median survival ranged from over 12 years at the earliest stage to under 2 years at the last two.Rai et al., Blood 1975, proposed clinical staging of CLL as progressive accumulation of lymphocytes: stage 0 lymphocytosis only; I with enlarged nodes; II spleen or liver; III anaemia; IV thrombocytopenia. In 125 patients, median survival from diagnosis (months) was above 150 (stage 0), 101, 71, 19 and 19 (stage IV); 71 for the series. Stage remained prognostic after adjustment for age and sex.

Molecular origins

  1. 1981 · Understanding · UnderstandingBinet staging for CLL: three prognostic groups (A, B, C)In 1981 Binet and colleagues proposed three prognostic groups for CLL: A with few involved areas, B with more, and C with anaemia or low platelets. Median survival was about 7 years in group B and 2 years in group C. A 1977 Binet paper on clinical staging is cited by title only.Binet 1977 (title only, no abstract): a clinical staging system for CLL. Binet 1981: 99 retrospective and 196 prospective patients; Cox analysis; three groups. C: anaemia (Hb under 10 g) or platelets under 100,000/mm3, about 15%, median survival 2 years. B: three or more involved areas, about 30%, 7 years. A: fewer areas, about 55%. Confirmed in a series of 146 patients.
  2. 1991 · Treatment · ChemotherapyFludarabine: 1991 US approval and a 2000 trial against chlorambucilFludarabine, a drug that interferes with DNA building blocks in lymphocytes, was first approved by the US FDA in 1991; the approved use then is not documented here. In a randomised trial of 509 untreated people reported in 2000, it gave more remissions and longer time without progression than chlorambucil (20 against 14 months), but survival was not significantly different.Fludarabine: FDA original approval action 18 April 1991 (indication not read). Rai 2000 (509 randomised, untreated CLL): fludarabine vs chlorambucil CR 20% vs 4% (P<0.001), median PFS 20 vs 14 months (P<0.001), median OS 66 vs 56 months, not significantly different; fludarabine-plus-chlorambucil arm stopped early. French trial (938, Binet B/C): fludarabine, CAP and ChOP median survival 69, 70 and 67 months.

Targeted therapy

  1. 1999 · Understanding · UnderstandingIGHV mutation status separates two clinical coursesIn 1999 two papers in the same journal issue showed that CLL cells differ in whether their antibody genes carry mutations. People whose cells had unmutated genes had shorter survival. Among 84 patients in one study, early-stage patients with unmutated genes had a median survival of about 8 years, against about 24 years with mutated genes.Two Blood papers (1999). Hamblin et al.: IGHV sequencing in 84 patients, 54.8% mutated (>2%); unmutated status associated with advanced stage and progressive disease; stage A median survival 95 vs 293 months (P=.0008). Damle et al.: IGHV mutation status and CD38 (30% cut-off) predicted response to chemotherapy and survival. CLL-IPI 2016 (n=3472): IGHV status is one of five factors; 5-year OS 93.2% to 23.3% (training dataset).
  2. 2000 · Understanding · UnderstandingFISH and TP53: genomic aberrations predict survival in CLLIn 2000, researchers used a laboratory method called FISH to look for chromosome changes in the leukaemia cells of 325 people. Changes were found in 82 in 100 and were linked to survival: median survival was 32 months with a 17p deletion and 133 months with a lone 13q deletion. A 2010 study linked TP53 mutation to poor outcomes.Dohner 2000: FISH in 325 patients, aberrations in 268 (82%); median survival 32 months (17p deletion), 79 (11q), 114 (trisomy 12), 111 (normal karyotype), 133 (13q sole); 17p and 11q deletion, age, Binet stage, LDH and white-cell count independent. Zenz 2010 (CLL4, n=375): TP53 mutation 28 of 328 (8.5%); median PFS 23.3 vs 62.2 months, OS 29.2 vs 84.6.
  3. 2001 · Treatment · ImmunotherapyAlemtuzumab: accelerated approval, then CAM307 against chlorambucilAlemtuzumab, an antibody against the CD52 marker on lymphocytes, was approved in the US in 2001 for CLL after other treatments had failed, under rules for accelerated approval. A published single-group study of 93 such people found 33 in 100 responded. A later randomised trial in 297 untreated people found longer time without progression than with chlorambucil.FDA accelerated approval 7 May 2001 (BL 103948) for B-CLL after alkylating agents and failure of fludarabine; the FDA review describes three single-arm studies (149 patients), the pivotal one with 93. Published 93-patient study: ORR 33% (CR 2%, PR 31%), median OS 16 months. CAM307 (297 randomised, untreated; vs chlorambucil): PFS HR 0.58 (P=.0001), ORR 83% vs 55%, CR 24% vs 2%. Supplement approved 19 September 2007 fulfilling the commitment.
  4. 2008 · Understanding · UnderstandingiwCLL criteria and MRD as a response measureDoctors need shared rules to judge whether CLL treatment has worked. An international workshop updated them in 2008 and 2018, adding guidance on measuring tiny amounts of remaining leukemia cells (MRD). A single-centre study linked undetectable MRD with longer survival, and MRD became a trial endpoint.iwCLL 2008 updated the NCI-WG 1996 guidelines for diagnosis, response assessment and treatment; iwCLL 2018 added revised response criteria and an update on MRD use. In a retrospective single-institution analysis (up to 18 years of follow-up), MRD negativity (fewer than 1 CLL cell per 10,000 leukocytes) correlated with PFS and OS; in frontline patients 10-year PFS was 65% vs 10% and 10-year OS 70% vs 30% (MRD-negative vs MRD-positive). A 174-member panel (2021) proposed uniform MRD nomenclature.
  5. 2010 · Treatment · ChemotherapyCLL8: rituximab added to fludarabine and cyclophosphamideIn a randomised trial of 817 people with untreated CLL who were fit for intensive treatment, adding the antibody rituximab to the chemotherapy pair fludarabine and cyclophosphamide helped. Three years after randomisation, 65 in 100 were free of progression compared with 45 in 100 on chemotherapy alone, and 87 in 100 compared with 83 in 100 were alive.CLL8 (NCT00281918): open-label phase 3 in untreated, physically fit, CD20-positive CLL, aged 30 to 81 years; FC with or without rituximab for six courses; n=817, ITT, primary endpoint PFS. At 3 years PFS 65% vs 45% (HR 0.56, 95% CI 0.46-0.69; p<0.0001); OS 87% vs 83% (HR 0.67, 0.48-0.92; p=0.01). Grade 3-4 neutropenia 34% vs 21%. FDA approved rituximab with FC on 18 February 2010.

Immunotherapy

  1. 2011 · Treatment · Cell therapy & transplantCAR T cells in CLL: 2011 report to 2024 liso-cel approvalIn 2011 doctors reported a complete remission in a patient with refractory CLL treated with CAR T cells made from the person's own T cells. In a 2023 trial of people whose CLL had progressed on a BTK inhibitor and venetoclax, fewer than one in five had a complete response or remission. The FDA gave accelerated approval in March 2024.Porter 2011: CD19-directed 4-1BB CAR T cells in a patient with refractory CLL; complete remission ongoing at 10 months; delayed tumour lysis syndrome. TRANSCEND CLL 004 (phase 1-2, single arm; 117 treated after a BTK inhibitor, 70 also after venetoclax): in the primary efficacy analysis set at dose level 2 (49 patients), CR/CRi rate 18% (95% CI 9 to 32; P=0.0006). Grade 3 CRS 9%, grade 3 neurological events 18%. FDA accelerated approval 14 March 2024.
  2. 2013 · Treatment · TargetedIbrutinib: BTK inhibition for relapsed CLL, approved in 2014Ibrutinib is an oral medicine, taken once daily, that blocks BTK, a protein CLL cells rely on. In 2013 a study of 85 people with relapsed disease reported high response rates. In 2014 a randomised trial found people stayed free of progression longer than on an antibody drug, and the US regulator approved ibrutinib for relapsed CLL.Phase 1b-2 (n=85, single arm): ORR 71% at 420 mg and at 840 mg; estimated 26-month PFS 75%, OS 83%. RESONATE (phase 3, n=391, ibrutinib vs ofatumumab, relapsed/refractory CLL/SLL): median follow-up 9.4 months; PFS HR 0.22 (P<0.001), median 8.1 months with ofatumumab, not reached with ibrutinib; OS HR 0.43 (P=0.005); ORR 42.6% vs 4.1%. FDA accelerated approval 12 February 2014; accelerated-approval requirements fulfilled 28 July 2014.
  3. 2013 · Treatment · ImmunotherapyCLL11: anti-CD20 plus chlorambucil in patients with comorbiditiesIn people with untreated CLL and other health conditions, adding an antibody to the tablet chemotherapy chlorambucil delayed progression. In a three-arm trial of 781 people, median time without progression was about 27 months with obinutuzumab, 16 months with rituximab and 11 months with chlorambucil alone.CLL11 (NCT01010061): three-arm open-label phase 3, 781 randomised, untreated CLL with CIRS >6 or creatinine clearance 30-69 ml/min; primary endpoint investigator-assessed PFS. Median PFS 26.7 months with obinutuzumab-chlorambucil, 16.3 with rituximab-chlorambucil, 11.1 with chlorambucil; HR 0.18 (95% CI 0.13-0.24) and 0.44 (0.34-0.57). Obinutuzumab vs rituximab HR 0.39 (0.31-0.49). OS vs chlorambucil HR 0.41 (0.23-0.74). FDA approval 1 November 2013.
  4. 2015 · Treatment · TargetedIbrutinib as first-line therapy: RESONATE-2, A041202, E1912Ibrutinib was tested as first treatment for CLL in four randomised trials, against chlorambucil, bendamustine-rituximab and fludarabine-based chemoimmunotherapy. In each trial, ibrutinib treatment delayed progression for longer than its own comparator did. The US regulator approved ibrutinib for first-line CLL in 2016.RESONATE-2 (n=269, age 65 or older): median PFS not reached vs 18.9 months with chlorambucil, HR 0.16. A041202 (n=547): 2-year PFS 87% ibrutinib and 88% ibrutinib-rituximab vs 74% BR (HR 0.39 and 0.38). E1912 (n=529, 70 or younger): 3-year PFS 89.4% vs 72.9% with FCR, HR 0.35. FLAIR (n=771, interim): PFS HR 0.44 vs FCR. Different controls; not pooled.
  5. 2015 · Treatment · TargetedVenetoclax: BCL2 inhibition, from phase 1 to MURANOVenetoclax blocks BCL2, a protein that helps leukemia cells survive. A phase 1 study in people, reported in 2015, found responses in most people with relapsed CLL. In MURANO, two years of venetoclax with six months of rituximab left about 85% free of progression at two years, versus about 36% with bendamustine plus rituximab.Phase 1 (116 patients with relapsed or refractory CLL or SLL): response 79%, complete remission 20%. Single-arm phase 2, del(17p) CLL (107 patients): response 79.4% (95% CI 70.5 to 86.6). MURANO (389 randomised): venetoclax-rituximab vs bendamustine-rituximab, 24-month investigator-assessed PFS 84.9% vs 36.3% (HR 0.17, 95% CI 0.11 to 0.25; P<0.001). Final analysis: median PFS 54.7 vs 17.0 months; 7-year OS 69.6% vs 51.0%.
  6. 2019 · Treatment · TargetedAcalabrutinib: ELEVATE-TN, ASCEND, ELEVATE-RRAcalabrutinib is an oral BTK inhibitor tested in three randomised trials: untreated CLL against chemotherapy plus an antibody, relapsed CLL against two standard regimens, and head-to-head with ibrutinib. Progression-free survival was longer than with the comparators in the first two and similar to ibrutinib in the third. The US regulator approved it for CLL in 2019.ELEVATE-TN (n=535, untreated): 24-month PFS 93% acalabrutinib-obinutuzumab and 87% acalabrutinib vs 47% obinutuzumab-chlorambucil; HR 0.1 and 0.20. ASCEND (n=310, relapsed/refractory): median PFS not reached vs 16.5 months, HR 0.31. ELEVATE-RR (n=533, del(17p) or del(11q)): noninferior to ibrutinib, median PFS 38.4 months in both arms, HR 1.00 (0.79 to 1.27).
  7. 2019 · Treatment · TargetedCLL14: fixed-duration venetoclax-obinutuzumab for comorbid patientsCLL14 tested a one-year course of venetoclax plus obinutuzumab against chlorambucil plus obinutuzumab in people with untreated CLL and other health conditions. After two years, about nine in ten on venetoclax-obinutuzumab were free of progression, versus about six in ten. The US regulator approved the combination in May 2019.CLL14 (open-label phase 3; 432 randomised, 216 per group; CIRS score above 6 or creatinine clearance below 70 ml/min): 12 cycles of venetoclax with 6 of obinutuzumab vs chlorambucil-obinutuzumab. Investigator-assessed PFS at median 28.1 months: HR 0.35 (95% CI 0.23 to 0.53; P<0.001); 24-month PFS 88.2% vs 64.1%. At 6 years: median PFS 76.2 vs 36.4 months (HR 0.40); OS 78.7% vs 69.2% (HR 0.69, 95% CI 0.48 to 1.01; P=0.052).

Precision & engineered

  1. 2020 · Reversal · ChemotherapyEarly treatment of asymptomatic CLL: FCR (CLL7), ibrutinib (CLL12)Two randomised trials tested treating early-stage CLL before symptoms appear, one with chemoimmunotherapy and one with ibrutinib. Both reported longer event-free survival with early treatment, but neither showed longer overall survival. The authors of both concluded that watching and waiting should remain the standard.CLL7 (800 enrolled; 201 high-risk patients randomised to FCR, n=100, or watch and wait, n=101): median EFS not reached vs 18.5 months (P<0.001); 5-year OS 82.9% vs 79.9% (P=0.864). CLL12 (n=363; ibrutinib 182, placebo 181): median EFS not reached vs 47.8 months, HR 0.25 (95% CI 0.14 to 0.43) at 31 months; final analysis: no survival benefit at median observation 69.3 months, 26 deaths; 5-year survival 93.3% vs 93.6%.
  2. 2021 · Reversal · TargetedPI3K inhibitors: CLL approvals, lymphoma indications withdrawnTwo PI3K-blocking drugs, idelalisib and duvelisib, delayed progression in randomised trials of relapsed CLL and were approved in the US in 2014 and 2018. Their accelerated approvals for lymphoma uses were later withdrawn, in 2021 and 2022, and the February 2022 idelalisib label restricts how it is combined and used.Idelalisib-rituximab vs placebo-rituximab (n=220, relapsed CLL with coexisting conditions; stopped early at first interim analysis): median PFS 5.5 months with placebo, not reached with idelalisib, HR 0.15; ORR 81% vs 13%; 12-month OS 92% vs 80%. DUO (n=319, duvelisib vs ofatumumab): median PFS 13.3 vs 9.9 months, HR 0.52; ORR 74% vs 45%. FDA withdrew accelerated lymphoma indications on 17 December 2021 and 18 February 2022.
  3. 2022 · Treatment · TargetedFixed-duration combinations: GLOW and CLL13 (GAIA)Two trials tested fixed-length venetoclax combinations as first treatment. GLOW, in older or less fit people, found ibrutinib plus venetoclax kept people free of progression longer than chlorambucil plus obinutuzumab. CLL13, in fit people, found venetoclax with obinutuzumab (with or without ibrutinib) did better than chemoimmunotherapy; venetoclax with rituximab was not significantly better.GLOW (211 randomised; age 65 or older, or coexisting conditions): ibrutinib-venetoclax vs chlorambucil-obinutuzumab, IRC-assessed PFS HR 0.216 (95% CI 0.131 to 0.357; P<0.001) at median 27.7 months. CLL13 (926 fit patients without TP53 aberrations): undetectable MRD at month 15 86.5% (venetoclax-obinutuzumab) and 92.2% (plus ibrutinib) vs 52.0% with chemoimmunotherapy; 3-year PFS 87.7% and 90.5% vs 75.5%; venetoclax-rituximab 57.0% and 80.8%, not significantly better.
  4. 2022 · Treatment · TargetedZanubrutinib: SEQUOIA and the ALPINE head-to-head with ibrutinibZanubrutinib is an oral BTK inhibitor tested against bendamustine-rituximab in untreated CLL and against ibrutinib in relapsed disease. Progression-free survival was longer with zanubrutinib in both trials. In the head-to-head trial more people responded, and fewer had atrial fibrillation. The US regulator approved it for CLL in 2023.SEQUOIA (n=590; 241 vs 238 randomised, no del(17p)): PFS by independent review HR 0.42 (95% CI 0.28 to 0.63) vs bendamustine-rituximab at median follow-up 26.2 months. ALPINE (n=652, vs ibrutinib): ORR (primary, first 415 patients) 78.3% vs 62.5% (P<.001); final investigator-assessed PFS HR 0.65 (0.49 to 0.86), 24-month PFS 78.4% vs 65.9%.
  5. 2023 · Treatment · Targeted⚑ needs reviewPirtobrutinib: non-covalent BTK inhibitor after covalent BTK failurePirtobrutinib is a BTK blocker that binds reversibly, tested in people whose CLL had stopped responding to earlier BTK drugs. A 2023 study reported responses in about three of four such people, and later randomised trials found longer progression-free survival than standard comparators. The US regulator granted accelerated approval in December 2023 and traditional approval followed in December 2025.BRUIN phase 1-2 (CLL/SLL after a BTK inhibitor, n=247): ORR 73.3% (95% CI 67.3 to 78.7), median PFS 19.6 months. CLL-321 (n=238, vs idelalisib-rituximab or bendamustine-rituximab; updated analysis): PFS HR 0.54, median 14 vs 8.7 months; OS HR 1.09. CLL-313 (n=282, untreated, no del(17p), vs bendamustine-rituximab): PFS HR 0.199, 24-month PFS 93.4% vs 70.7%. FDA: accelerated 1 December 2023; fulfilled 3 December 2025; untreated CLL 2 October 2026.
  6. 2025 · Treatment · TargetedAMPLIFY: fixed-duration acalabrutinib-venetoclax vs chemoimmunotherapyAMPLIFY compared two fixed-length regimens built on acalabrutinib and venetoclax with chemoimmunotherapy in fit people with untreated CLL. At three years, about three in four on acalabrutinib plus venetoclax were free of progression, versus about two in three on chemoimmunotherapy. The US regulator approved the pair in February 2026.AMPLIFY (open-label phase 3; 867 randomised; fit patients without 17p deletion or TP53 mutation): acalabrutinib-venetoclax vs FCR or BR, BICR-assessed PFS HR 0.65 (95% CI 0.49 to 0.87; P=0.004); 36-month PFS 76.5% vs 66.5% at median follow-up 40.8 months; 83.1% with the obinutuzumab triplet (P<0.001 vs chemoimmunotherapy). Estimated 36-month OS 94.1%, 87.7% and 85.9%.
  7. 2026 · Treatment · TargetedBRUIN CLL-322: pirtobrutinib added to venetoclax-rituximabIn people with previously treated CLL, adding the BTK inhibitor pirtobrutinib to a fixed course of venetoclax plus rituximab left more people free of progression at two years (about 87% versus 72%). Most had taken a covalent BTK inhibitor before. This is an interim analysis of an ongoing trial.BRUIN CLL-322 (open-label phase 3; 639 randomised, 321 vs 318): pirtobrutinib-venetoclax-rituximab vs venetoclax-rituximab, IRC-assessed PFS at a prespecified interim analysis (median follow-up 27.3 months): HR 0.547 (95% CI 0.400 to 0.748; P=0.0001); 24-month PFS 87% vs 72%; median PFS not reached vs 39.7 months. 80% had prior covalent BTK inhibitor exposure. Grade 3 or higher adverse events 79% vs 73%.

Then and now

  • 5-year relative survival · United States, SEER 8 registries

    • 69.49%

      1975 (observed value; first year in the table)

    People with chronic lymphocytic leukemia, all races, both sexes (chart note); the SEER 8 five-year relative survival series (1975-2018) on the SEER Cancer Stat Facts CLL page. The page states no age range, stage mix or treatment status for this series, and says there is no standard staging system for leukemia.

    Relative survival excludes deaths from other causes. 'Observed' is the table's label for the yearly value, as opposed to the Joinpoint modeled-trend value in the adjacent column. The column is headed 'Year' and the chart note says only 'SEER 8 5-Year Relative Survival Percent from 1975-2018'; the page does not say the year is the year of diagnosis. SEER 8 covers a limited set of registries, and single-year values fluctuate (for example 62.21% in 1981 and 78.54% in 1985 in the same series). Survival measured from diagnosis can change through earlier detection (lead time), changes in diagnostic practice and case definition as well as through treatment, and the page does not apportion the change in this series between them; read it beside the mortality values. SEER's site recode (ICD-O-3/WHO 2008) puts histology code 9823 at the blood, bone marrow and hematopoietic NOS sites (C420, C421, C424) in its 'Chronic Lymphocytic Leukemia' category and lists the same code under non-Hodgkin lymphoma at other sites; the Stat Facts page does not say that it uses this recode or whether small lymphocytic lymphoma is counted. Compare only with other values from this same SEER 8 series, not with the SEER 21 value. The modeled-trend value for 1975 is 66.15%.

    Source

  • 5-year relative survival · United States, SEER 8 registries

    • 93.35%

      2018 (observed value; last observed year in the table)

    Same series as above: all races, both sexes, SEER 8, five-year relative survival.

    Observed single-year value (modeled trend for 2018: 93.02%). The entries for 2019-2023 in the table are modeled-trend values only (93.40% to 94.73%) and are not used. Relative survival excludes deaths from other causes. 'Observed' is the table's label for the yearly value, as opposed to the Joinpoint modeled-trend value in the adjacent column. The column is headed 'Year' and the chart note says only 'SEER 8 5-Year Relative Survival Percent from 1975-2018'; the page does not say the year is the year of diagnosis. SEER 8 covers a limited set of registries, and single-year values fluctuate (for example 62.21% in 1981 and 78.54% in 1985 in the same series). Survival measured from diagnosis can change through earlier detection (lead time), changes in diagnostic practice and case definition as well as through treatment, and the page does not apportion the change in this series between them; read it beside the mortality values. SEER's site recode (ICD-O-3/WHO 2008) puts histology code 9823 at the blood, bone marrow and hematopoietic NOS sites (C420, C421, C424) in its 'Chronic Lymphocytic Leukemia' category and lists the same code under non-Hodgkin lymphoma at other sites; the Stat Facts page does not say that it uses this recode or whether small lymphocytic lymphoma is counted. Compare only with other values from this same SEER 8 series, not with the SEER 21 value.

    Source

  • 5-year relative survival · United States, SEER 21 (excluding IL)

    • 90.2%

      2016-2022

    People with chronic lymphocytic leukemia, all races, both sexes; the headline figure on the SEER Cancer Stat Facts CLL page. The page states no age range beside the figure; median age at diagnosis on the same page is 71 (SEER 21, 2019-2023).

    A different registry set and a multi-year period from the SEER 8 series above, so it is not a continuation of that series and must not be subtracted from it. The page labels the period '2016-2022' and does not say whether it is the diagnosis period. Relative survival, with the same lead-time and case-definition limits as above.

    Source

  • Age-standardised mortality · United States (U.S. mortality data, not SEER registries)

    • 1.4per 100,000

      1975 (observed value; first year in the table)

    Death rate for chronic lymphocytic leukemia, all races, both sexes, age-adjusted; the page labels the series 'U.S. Mortality' and does not state the standard population in the text read.

    Underlying-cause-of-death data, a different series from the SEER 8 survival values; do not combine the two. The page does not describe how cause-of-death coding changed between 1975 and 2024. SEER's cause-of-death recode assigns ICD-10 C91.1 (ICD-9 204.1) to its 'Chronic Lymphocytic Leukemia' category, but the page does not say that it uses this recode. The rate was higher in the early 1990s (1.71 in 1993, the highest value in the table) before it fell. The modeled-trend value for 1975 is 1.43. The page attributes no change in this series to a cause.

    Source

  • Age-standardised mortality · United States (U.S. mortality data, not SEER registries)

    • 0.96per 100,000

      2024 (observed value; last year in the table)

    Same series as above; the page text gives 1.0 per 100,000 for 2020-2024 deaths and states that age-adjusted death rates fell on average 1.9% a year over 2015-2024.

    Same series and limits as the 1975 value. The modeled-trend value for 2024 is 1.00. A falling death rate and a rising survival percentage answer different questions, and the page assigns neither to a single cause.

    Source

Survival figures are affected by earlier detection (lead time) and overdiagnosis, and by changes in who is diagnosed. For screened cancers, read them alongside mortality.

Evidence chains

A lane follows one defined population and setting, where each new trial tests against what was then standard. Compare only within a lane, and read every comparison as illustrative.

Untreated CLL, fit for intensive treatment: progression-free survival at 3 years

Previously untreated CLL in people fit for chemotherapy-based treatment: CLL8 (age 30 to 81, CD20-positive), E1912 (age 70 or younger), CLL13 (low burden of coexisting conditions, no TP53 aberration) and AMPLIFY (ECOG 0 to 2, no 17p deletion or TP53 mutation). The earlier fludarabine trials enrolled broader populations. · Metastatic · endpoint: PFS

Results are not comparable across trials.

Controls differ by era: FC in CLL8, FCR in E1912, and FCR or bendamustine-rituximab in CLL13 and AMPLIFY; the experimental regimens range from a continuous BTK inhibitor with rituximab (E1912) to fixed-duration venetoclax or acalabrutinib combinations (CLL13, AMPLIFY). Eligibility differs (age limits, TP53 and 17p exclusions), the E1912 figure is from a planned interim analysis, and PFS was assessed by investigators in CLL13 and by blinded independent review in AMPLIFY. All plotted values are PFS at 3 years from randomisation, but follow-up differs. CLL13 and AMPLIFY each have more than one experimental arm against the same control. The 1991 to 2000 fludarabine trials and CLL4 report median PFS rather than a landmark rate, so they are not on the 3-year axis (CLL4 is listed, not plotted); FLAIR reports only a hazard ratio and one median, so it is not plotted. Compare only each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080100PFS at 36 months (%)2010201520222022202220252025CLL8E1912GAIAGAIAGAIAAMPLIFYAMPLIFY
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS at 36 months, rate, across 7 trials in this lane. CLL8 (2010): experimental 65 % vs control 45 %; E1912 (2015): experimental 89.4 % vs control 72.9 %; GAIA (2022): experimental 87.7 % vs control 75.5 %; GAIA (2022): experimental 90.5 % vs control 75.5 %; GAIA (2022): experimental 80.8 % vs control 75.5 %; AMPLIFY (2025): experimental 76.5 % vs control 66.5 %; AMPLIFY (2025): experimental 83.1 % vs control 66.5 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
CLL82010PFS45 %65 %
E19122015PFS72.9 %89.4 %
GAIA2022PFS75.5 %87.7 %
GAIA2022PFS75.5 %90.5 %
GAIA2022PFS75.5 %80.8 %
AMPLIFY2025PFS66.5 %76.5 %
AMPLIFY2025PFS66.5 %83.1 %
CLL42010PFS (not plotted: different measure or time point)20 months48 months

Untreated CLL, older or with coexisting conditions: chlorambucil-based comparators

Previously untreated CLL or SLL in people considered unsuitable for intensive chemoimmunotherapy: CLL11 (CIRS above 6 or creatinine clearance 30 to 69 mL/min, median age 73), RESONATE-2 (age 65 or older), CLL14 (CIRS above 6 or creatinine clearance below 70 mL/min, median age 72) and GLOW (age 65 or older, or 18 to 64 with CIRS above 6 or creatinine clearance below 70 mL/min). · Metastatic · endpoint: PFS

Results are not comparable across trials.

The control is chlorambucil in CLL11 and RESONATE-2 and chlorambucil-obinutuzumab in CLL14 and GLOW. The plotted points are median PFS (months) from CLL11 (investigator-assessed, primary analysis) and the 6-year CLL14 update; the CLL14 value comes from a much longer follow-up than CLL11's, and eligibility, region and era differ. RESONATE-2 (7-year PFS rate, continuous ibrutinib) and GLOW (PFS rate at 42 months, fixed-duration ibrutinib-venetoclax) report landmark rates rather than medians, so they are listed beside the chart but not on the median axis. ELEVATE-TN is not plotted: its control median is reported but the acalabrutinib arms are given only as 24-month rates, so no like-for-like pair exists. Continuous (ibrutinib, acalabrutinib) and fixed-duration regimens are not equivalent exposures. Compare only each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080PFS, median (months)201320132019CLL11CLL11CLL14
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS, median, across 3 trials in this lane. CLL11 (2013): experimental 26.7 months vs control 11.1 months; CLL11 (2013): experimental 16.3 months vs control 11.1 months; CLL14 (2019): experimental 76.2 months vs control 36.4 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
CLL112013PFS11.1 months26.7 months
CLL112013PFS11.1 months16.3 months
CLL142019PFS36.4 months76.2 months
RESONATE-22015PFS (not plotted: different measure or time point)9 %59 %
GLOW2022PFS (not plotted: different measure or time point)24.8 %74.6 %

Untreated CLL: bendamustine-rituximab as comparator, PFS at 2 years

Previously untreated CLL or SLL: Alliance A041202 (age 65 or older), SEQUOIA (no del(17p) in the randomised groups) and BRUIN CLL-313 (no del(17p)). · Metastatic · endpoint: PFS

Results are not comparable across trials.

All three trials used bendamustine-rituximab as the control, with a continuous BTK inhibitor as the experimental drug (ibrutinib, zanubrutinib, pirtobrutinib). The plotted values are PFS rates at 2 years: A041202 is an age 65 or older population; BRUIN CLL-313 is by independent review with the milestone marked for clinical review; follow-up and assessment methods differ. SEQUOIA reported a hazard ratio without arm-level values in the record, so it is a milestone in this lane but not plotted. Compare only each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080100PFS at 24 months (%)201520152023A041202A041202BRUIN CLL-313
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS at 24 months, rate, across 3 trials in this lane. A041202 (2015): experimental 87 % vs control 74 %; A041202 (2015): experimental 88 % vs control 74 %; BRUIN CLL-313 (2023): experimental 93.4 % vs control 70.7 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
A0412022015PFS74 %87 %
A0412022015PFS74 %88 %
BRUIN CLL-3132023PFS70.7 %93.4 %

Relapsed or refractory CLL: antibody or chemoimmunotherapy comparators

Previously treated CLL or SLL: RESONATE (ibrutinib vs ofatumumab), the idelalisib-rituximab trial (vs rituximab), DUO (duvelisib vs ofatumumab), MURANO (venetoclax-rituximab vs bendamustine-rituximab) and ASCEND (acalabrutinib vs idelalisib-rituximab or bendamustine-rituximab). · Relapsed / refractory · endpoint: PFS

Results are not comparable across trials.

Controls are antibody monotherapy in RESONATE, DUO and the idelalisib trial, chemoimmunotherapy in MURANO and investigator's choice in ASCEND; prior-therapy counts, del(17p) mix and era differ. The plotted values are median PFS: MURANO's from its final analysis at about 7 years (investigator-assessed) and DUO's from its primary analysis. RESONATE, the idelalisib-rituximab trial and ASCEND are not plotted because the experimental arm's median is not reported (not reached) or is reported as a rate while the control is a median, so no like-for-like pair exists. The PI3K inhibitors' lymphoma indications were later withdrawn (see the milestone). Compare only each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

0102030405060PFS, median (months)20152021MURANODUO
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS, median, across 2 trials in this lane. MURANO (2015): experimental 54.7 months vs control 17 months; DUO (2021): experimental 13.3 months vs control 9.9 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
MURANO2015PFS17 months54.7 months
DUO2021PFS9.9 months13.3 months

Relapsed or refractory CLL: BTK inhibitor head-to-head trials

ELEVATE-RR (previously treated, centrally confirmed del(17p) or del(11q); noninferiority) and ALPINE (relapsed or refractory CLL or SLL after at least one previous course of therapy). · Relapsed / refractory · endpoint: PFS

Results are not comparable across trials.

Ibrutinib is the control in both trials. ELEVATE-RR was a noninferiority trial in a high-risk population with median PFS reported by independent review; ALPINE's primary endpoint was overall response, with PFS a key secondary endpoint reported as a 24-month rate (investigator-assessed) and is listed but not on the median axis. The two trials were not designed to be compared with each other, and no trial compared acalabrutinib with zanubrutinib. Compare only each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

010203040PFS, median (months)2019ELEVATE-RR
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS, median, across 1 trial in this lane. ELEVATE-RR (2019): experimental 38.4 months vs control 38.4 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
ELEVATE-RR2019PFS38.4 months38.4 months
ALPINE2022PFS (not plotted: different measure or time point)65.9 %78.4 %

CLL after a covalent BTK inhibitor

BRUIN CLL-321 (relapsed or refractory CLL or SLL previously treated with a covalent BTK inhibitor) and BRUIN CLL-322 (relapsed or refractory CLL or SLL; most but not all randomised patients had earlier covalent BTK inhibitor exposure). · Relapsed / refractory · endpoint: PFS

Results are not comparable across trials.

CLL-321 compared continuous pirtobrutinib with investigator's choice of idelalisib-rituximab or bendamustine-rituximab; the plotted median PFS is the 2024 updated descriptive analysis (independent review), and the 2023 primary analysis is a separate result. CLL-322 added pirtobrutinib to fixed-duration venetoclax-rituximab and reported 24-month rates for one arm and a median for the other in an interim analysis, so it is a milestone in this lane but not plotted. The pirtobrutinib records are marked for clinical review. Compare only each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

05101520PFS, median (months)2023BRUIN CLL-321
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
PFS, median, across 1 trial in this lane. BRUIN CLL-321 (2023): experimental 14 months vs control 8.7 months.
Data table
TrialYearEndpointControl (months)Experimental (months)
BRUIN CLL-3212023PFS8.7 months14 months

Asymptomatic early-stage CLL: early treatment vs watch and wait, overall survival at 5 years

Untreated Binet stage A CLL at increased risk of progression: CLL7 (FCR vs watch and wait in 201 high-risk patients with two or more risk features) and CLL12 (ibrutinib vs placebo in 363 patients). · Localised · endpoint: OS

Results are not comparable across trials.

The lane shows 5-year overall survival because event-free survival cannot be drawn like for like: CLL7 and CLL12 report a control median but not an experimental median, and their event definitions differ. CLL7 was open-label against observation; CLL12 was double-blind against placebo, and its non-randomised low-risk watch-and-wait cohort is not a control arm. Risk definitions differ between the trials. The authors of both reports concluded that watch and wait should remain the standard. Compare only each trial's own arms.

Each pair shows one trial: its control arm and its experimental arm. Yesterday's experimental arm is often today's control. Populations, definitions and follow-up differ.

020406080100OS at 60 months (%)20202020CLL7CLL12
  • experimental arm
  • control arm
  • different endpoint from the lane's
  • step line through experimental values
OS at 60 months, rate, across 2 trials in this lane. CLL7 (2020): experimental 82.9 % vs control 79.9 %; CLL12 (2020): experimental 93.3 % vs control 93.6 %.
Data table
TrialYearEndpointControl (%)Experimental (%)
CLL72020OS79.9 %82.9 %
CLL122020OS93.6 %93.3 %

Standard of care, then and now

How the usual sequence of treatment changed for one setting. Choose a point in time; each step links to the milestone behind it.

Untreated CLL: first-line treatment

Adults with previously untreated CLL or SLL needing treatment (trial populations differ by age, fitness and 17p or TP53 status) · Metastatic

  1. Immunotherapy1FCR (comparator in later trials)CLL8: rituximab added to fludarabine and cyclophosphamide (2010)
  2. Targeted2IbrutinibIbrutinib as first-line therapy: RESONATE-2, A041202, E1912 (2015)
  3. Targeted3AcalabrutinibAcalabrutinib: ELEVATE-TN, ASCEND, ELEVATE-RR (2019)
  4. Targeted4ZanubrutinibZanubrutinib: SEQUOIA and the ALPINE head-to-head with ibrutinib (2022)
  5. Targeted5Venetoclax-obinutuzumab (fixed duration)CLL14: fixed-duration venetoclax-obinutuzumab for comorbid patients (2019)
  6. Targeted6Fixed-duration pairs (GLOW, CLL13)Fixed-duration combinations: GLOW and CLL13 (GAIA) (2022)
  7. Targeted7Acalabrutinib plus venetoclax (fixed)AMPLIFY: fixed-duration acalabrutinib-venetoclax vs chemoimmunotherapy (2025)
2026. Based only on the trials cited in each step; guidelines and local practice vary. Fixed-duration combinations and zanubrutinib were added; FCR remained the comparator in later trials.
Text version
  • 2000: Chlorambucil → Fludarabine
  • 2010: Chlorambucil → FC plus rituximab (FCR), fit patients
  • 2019: FC plus rituximab (FCR), fit patients → Obinutuzumab plus chlorambucil → Ibrutinib → Acalabrutinib → Venetoclax-obinutuzumab (fixed duration)
  • 2026: FCR (comparator in later trials) → Ibrutinib → Acalabrutinib → Zanubrutinib → Venetoclax-obinutuzumab (fixed duration) → Fixed-duration pairs (GLOW, CLL13) → Acalabrutinib plus venetoclax (fixed)

Relapsed or refractory CLL: treatment

Adults with CLL or SLL who had received earlier treatment (trial populations differ by prior therapy and genetic risk) · Relapsed / refractory

  1. Targeted1IbrutinibIbrutinib: BTK inhibition for relapsed CLL, approved in 2014 (2013)
  2. Targeted2Venetoclax plus rituximabVenetoclax: BCL2 inhibition, from phase 1 to MURANO (2015)
  3. Targeted3AcalabrutinibAcalabrutinib: ELEVATE-TN, ASCEND, ELEVATE-RR (2019)
  4. Targeted4ZanubrutinibZanubrutinib: SEQUOIA and the ALPINE head-to-head with ibrutinib (2022)
  5. Targeted5Idelalisib or duvelisib (PI3K inhibitors)PI3K inhibitors: CLL approvals, lymphoma indications withdrawn (2021)
  6. Targeted6Pirtobrutinib after a covalent BTK inhibitorPirtobrutinib: non-covalent BTK inhibitor after covalent BTK failure (2023)
  7. Cell therapy & transplant7CAR T cells (lisocabtagene maraleucel)CAR T cells in CLL: 2011 report to 2024 liso-cel approval (2011)
2026. Based only on the trials cited in each step; guidelines and local practice vary. Zanubrutinib, pirtobrutinib (marked for review) and CAR T cells were added.
Text version
  • 2010: Alemtuzumab after fludarabine failure
  • 2015: Ibrutinib → Venetoclax plus rituximab
  • 2021: Ibrutinib → Venetoclax plus rituximab → Acalabrutinib → Idelalisib or duvelisib (PI3K inhibitors)
  • 2026: Ibrutinib → Venetoclax plus rituximab → Acalabrutinib → Zanubrutinib → Idelalisib or duvelisib (PI3K inhibitors) → Pirtobrutinib after a covalent BTK inhibitor → CAR T cells (lisocabtagene maraleucel)

Reversals and dead ends

Approaches that were abandoned or withdrawn, and trials whose results were later questioned, are part of the story.

  • 2020

    Early treatment of asymptomatic CLL: FCR (CLL7), ibrutinib (CLL12)

    Two randomised trials tested treating early-stage CLL before symptoms appear, one with chemoimmunotherapy and one with ibrutinib. Both reported longer event-free survival with early treatment, but neither showed longer overall survival. The authors of both concluded that watching and waiting should remain the standard.

    CLL7 (800 enrolled; 201 high-risk patients randomised to FCR, n=100, or watch and wait, n=101): median EFS not reached vs 18.5 months (P<0.001); 5-year OS 82.9% vs 79.9% (P=0.864). CLL12 (n=363; ibrutinib 182, placebo 181): median EFS not reached vs 47.8 months, HR 0.25 (95% CI 0.14 to 0.43) at 31 months; final analysis: no survival benefit at median observation 69.3 months, 26 deaths; 5-year survival 93.3% vs 93.6%.

  • 2021

    PI3K inhibitors: CLL approvals, lymphoma indications withdrawn

    Two PI3K-blocking drugs, idelalisib and duvelisib, delayed progression in randomised trials of relapsed CLL and were approved in the US in 2014 and 2018. Their accelerated approvals for lymphoma uses were later withdrawn, in 2021 and 2022, and the February 2022 idelalisib label restricts how it is combined and used.

    Idelalisib-rituximab vs placebo-rituximab (n=220, relapsed CLL with coexisting conditions; stopped early at first interim analysis): median PFS 5.5 months with placebo, not reached with idelalisib, HR 0.15; ORR 81% vs 13%; 12-month OS 92% vs 80%. DUO (n=319, duvelisib vs ofatumumab): median PFS 13.3 vs 9.9 months, HR 0.52; ORR 74% vs 45%. FDA withdrew accelerated lymphoma indications on 17 December 2021 and 18 February 2022.

Today and tomorrow

Standard of care today

Any setting

Diagnosis, indications for treatment and risk assessment. Guideline documents are cited by identifier only; their recommendations were not read for this page, and whether each is the current edition was not checked:

  • the iwCLL guidelines for diagnosis, indications for treatment, response assessment and supportive management (Blood 2018, PMID 29540348
  • the 2008 iwCLL guidelines are PMID 18216293)
  • the international prognostic index for CLL (CLL-IPI
  • Lancet Oncol 2016, PMID 27185642), whose abstract names five independent prognostic factors (TP53 status, IGHV mutational status, serum beta-2 microglobulin, clinical stage and age) and four risk groups
  • NCCN Guidelines Insights, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2026 (J Natl Compr Canc Netw 2026, PMID 41825137)
  • the EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation (HemaSphere 2026, PMID 42293463)
  • and the ESMO Clinical Practice Guideline interim update on new targeted therapies in the first line and at relapse (Ann Oncol 2024, PMID 38969011)
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al 2018Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al 2008International CLL-IPI working group 2016Wierda WG, Brown J, Abramson JS, Awan F, Bociek G, Boyer D, et al 2026Eichhorst B, Ghia P, Bosch F, Clifford R, Gregor M, Guieze R, et al 2026Eichhorst B, Ghia P, Niemann CU, Kater AP, Gregor M, Hallek M, et al 2024
Any setting
Early-stage disease without symptoms. No FDA or EMA action on treating asymptomatic early-stage CLL was read. Two randomised trials of early treatment (CLL7, fludarabine-cyclophosphamide-rituximab versus watch and wait in high-risk patients; CLL12, ibrutinib versus placebo) reported longer event-free survival with early treatment and no longer overall survival, and the CLL12 final report states that watch and wait remains the standard of care (see the milestone timeline). The randomised EVOLVE CLL/SLL trial of early versus delayed venetoclax-obinutuzumab in high-risk disease is recruiting (see the horizon list). Guideline text was not read.
Herling CD, Cymbalista F, Groß-Ophoff-Müller C, Bahlo J, Robrecht S, Langerbeins P, et al 2020Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, et al 2022Langerbeins P, Robrecht S, Nieper P, Cramer P, Fürstenau M, Al-Sawaf O, et al 2025
Any setting

Untreated CLL or SLL needing treatment, regulatory documents read. FDA approval letters:

  • rituximab with fludarabine and cyclophosphamide for previously untreated CD20-positive CLL (18 February 2010)
  • obinutuzumab with chlorambucil (1 November 2013)
  • ibrutinib, frontline indication (4 March 2016)
  • venetoclax with obinutuzumab (15 May 2019)
  • acalabrutinib (21 November 2019) and zanubrutinib (19 January 2023), whose letters name CLL or SLL without stating a line of therapy
  • acalabrutinib and venetoclax as a new combination regimen (19 February 2026, one letter to each sponsor)
  • pirtobrutinib for previously untreated CLL or SLL with no known 17p deletion (2 October 2026). None of these letters uses accelerated-approval wording for the CLL indication, so 'regular' approval is an inference. The February 2026 Calquence and Venclexta labels describe the AMPLIFY acalabrutinib-venetoclax-obinutuzumab cohort as an unapproved regimen in previously untreated CLL/SLL. Whether the FDA has an indication for ibrutinib with venetoclax was not established. EMA procedural-steps documents list European Commission decisions extending Imbruvica to combination treatment with venetoclax in previously untreated CLL (2 August 2022), Calquence to venetoclax with or without obinutuzumab (2 June 2025), and Venclyxto to combination with acalabrutinib with or without obinutuzumab and with ibrutinib (both 27 May 2026). The initial EU authorisations of the other first-line drugs were not read. Guideline sequencing was not read
U 2010U 2013US Food and Drug Administration 2016US Food and Drug Administration 2019US Food and Drug Administration 2019US Food and Drug Administration 2023US Food and Drug Administration 2026US Food and Drug Administration 2026US Food and Drug Administration 2026US Food and Drug Administration 2026US Food and Drug Administration 2026European Medicines Agency 2026European Medicines Agency 2026European Medicines Agency 2026
Relapsed / refractory

Relapsed or refractory CLL or SLL, regulatory documents read. FDA:

  • ibrutinib, accelerated approval on 12 February 2014 for CLL after at least one prior therapy, and a supplement letter of 28 July 2014 that states approval of the supplement fulfils the accelerated-approval requirement (it carries a Subpart H fulfilled section
  • the word converted is not used)
  • idelalisib with rituximab, approved on 23 July 2014 for relapsed CLL in people for whom rituximab alone would be considered appropriate because of other medical conditions, with the separate accelerated approvals of idelalisib for relapsed follicular lymphoma and small lymphocytic lymphoma given a withdrawal date of 18 February 2022 on the FDA list of withdrawn cancer accelerated approvals (the list gives no reason)
  • duvelisib, approved on 24 September 2018 for relapsed or refractory CLL or SLL after at least two prior therapies
  • venetoclax, accelerated approval on 11 April 2016 for CLL with 17p deletion after at least one prior therapy, followed by a letter of 8 June 2018 (supplements S-004 and S-005) with a Subpart H fulfilled section that describes regular approval. EMA: Venclyxto received a conditional authorisation (5 December 2016)
  • a Commission decision of 20 November 2018 followed fulfilment of the specific obligation, and an extension to venetoclax with rituximab was decided on 29 October 2018. Alemtuzumab (Campath) received accelerated approval on 7 May 2001 for B-cell CLL after alkylating-agent treatment and fludarabine failure, and a supplement dated 19 September 2007 fulfilled the commitment
  • its current US availability for CLL was not established. No regulatory document for ofatumumab was read. Guideline text was not read
US Food and Drug Administration 2014US Food and Drug Administration 2014US Food and Drug Administration 2014US Food and Drug Administration 2026US Food and Drug Administration 2018US Food and Drug Administration 2016US Food and Drug Administration 2018European Medicines Agency 2026European Medicines Agency 2026U 2001U 2007
Relapsed / refractory

After a covalent BTK inhibitor, regulatory documents read. FDA:

  • pirtobrutinib (a non-covalent BTK inhibitor) received accelerated approval on 1 December 2023 for CLL or SLL after at least two prior lines of therapy including a BTK inhibitor and a BCL-2 inhibitor
  • the supplement letter signed 3 December 2025 (openFDA lists 2 December) describes support for conversion from accelerated to traditional approval, carries a Subpart H fulfilled section and states the indication as relapsed or refractory CLL or SLL previously treated with a covalent BTK inhibitor. Lisocabtagene maraleucel (a CAR T-cell product) received accelerated approval on 14 March 2024 for relapsed or refractory CLL or SLL after at least two prior lines including a BTK inhibitor and a BCL-2 inhibitor
  • a replacement letter of 21 March 2024 keeps that effective date. EMA: the Jaypirca EPAR page (updated 15 September 2026) shows a conditional marketing authorisation issued on 30 October 2023 (CHMP opinion adopted 26 April 2023) and lists pirtobrutinib monotherapy for adults with CLL
  • dates of later EU indication changes and any conversion from conditional status were not established, and no EMA document on lisocabtagene maraleucel in CLL was read. Guideline text was not read
US Food and Drug Administration 2023US Food and Drug Administration 2025US Food and Drug Administration 2024European Medicines Agency 2026

Trials to watch

  • EVOLVE CLL/SLL (SWOG S1925) NCT04269902

    In newly diagnosed, asymptomatic, high-risk CLL or SLL (registry criteria: diagnosed within 18 months, and a CLL-IPI score of 4 or more and/or complex cytogenetics), does starting venetoclax-obinutuzumab early differ from starting it when iwCLL 2018 treatment indications are met, in overall survival and in the FACT-Leukemia total score at 2 years (the registry's two primary outcomes)? Registry record: randomised phase 3, 247 estimated, sponsor National Cancer Institute; registry status recruiting; primary completion 2028-10-01 (estimated); no results posted.

  • MAJIC NCT05057494

    In previously untreated CLL or SLL, does acalabrutinib plus venetoclax differ from venetoclax plus obinutuzumab in progression-free survival (the registry's primary outcome)? Registry record: randomised, open-label phase 3, 607 (actual), sponsor AstraZeneca; registry status active, not recruiting; primary completion 2027-07-15 (estimated); no results posted. A trial-in-progress paper (PMID 36102212) describes the design but reports no results.

  • Sonrotoclax plus zanubrutinib versus venetoclax-obinutuzumab (BGB-11417-301) NCT06073821

    In previously untreated CLL, does fixed-duration sonrotoclax plus zanubrutinib differ from venetoclax plus obinutuzumab in progression-free survival and in the rate of undetectable measurable residual disease (the registry's primary outcomes for cohort 1)? Registry record: randomised, open-label phase 3, 652 estimated, sponsor BeOne Medicines; registry status active, not recruiting; primary completion 2032-02 (estimated); no results posted. The registry gives no trial acronym.

  • BELLWAVE-011 NCT06136559

    In previously untreated CLL or SLL, does nemtabrutinib differ from investigator's choice of ibrutinib or acalabrutinib in objective response rate and progression-free survival, both per iwCLL 2018 criteria and assessed by blinded independent central review (the registry's primary outcomes; its stated hypotheses include noninferiority on objective response rate)? Registry record: randomised phase 3, 1200 estimated, sponsor Merck Sharp & Dohme LLC; registry status recruiting; primary completion 2032-09-07 (estimated); no results posted.

  • BELLWAVE-010 NCT05947851

    In relapsed or refractory CLL or SLL after at least one prior therapy, does nemtabrutinib plus venetoclax differ from venetoclax plus rituximab in progression-free survival by blinded independent central review (the registry's Part 2 primary outcome; Part 1 primary outcomes concern safety and dose-limiting toxicity)? Registry record: randomised, open-label phase 3, 735 estimated, sponsor Merck Sharp & Dohme LLC; registry status recruiting; primary completion 2032-06-01 (estimated); no results posted.

  • CaDAnCe-302 NCT06846671

    In CLL or SLL previously exposed to both a BTK inhibitor and a BCL2 inhibitor, does tacabrutideg (BGB-16673) differ from investigator's choice (idelalisib plus rituximab for CLL only, bendamustine plus rituximab, or venetoclax plus rituximab retreatment) in progression-free survival by independent review committee (the registry's primary outcome)? Registry record: randomised, open-label phase 3, 250 estimated, sponsor BeOne Medicines; registry status recruiting; primary completion 2028-05-15 (estimated); no results posted.

References

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Every figure was checked against its primary source to the extent possible. Items that could not be fully confirmed are marked “needs review”. Educational history, not medical advice.

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2019TreatmentTargeted

majorMetastaticRelapsed / refractory

Acalabrutinib: ELEVATE-TN, ASCEND, ELEVATE-RR

Acalabrutinib is an oral BTK inhibitor tested in three randomised trials: untreated CLL against chemotherapy plus an antibody, relapsed CLL against two standard regimens, and head-to-head with ibrutinib. Progression-free survival was longer than with the comparators in the first two and similar to ibrutinib in the third. The US regulator approved it for CLL in 2019.

ELEVATE-TN (n=535, untreated): 24-month PFS 93% acalabrutinib-obinutuzumab and 87% acalabrutinib vs 47% obinutuzumab-chlorambucil; HR 0.1 and 0.20. ASCEND (n=310, relapsed/refractory): median PFS not reached vs 16.5 months, HR 0.31. ELEVATE-RR (n=533, del(17p) or del(11q)): noninferior to ibrutinib, median PFS 38.4 months in both arms, HR 1.00 (0.79 to 1.27).

Standard before

Comparators were obinutuzumab-chlorambucil (ELEVATE-TN), investigator's choice of idelalisib-rituximab or bendamustine-rituximab (ASCEND) and ibrutinib (ELEVATE-RR).

What changed

FDA approved acalabrutinib for adults with CLL or SLL on 21 November 2019 (supplement approval letter).

Why it mattered

ELEVATE-RR's abstract describes it as the first direct comparison of a more and a less selective BTK inhibitor in CLL, with noninferior PFS and a lower rate of atrial fibrillation or flutter with acalabrutinib. ELEVATE-TN and ASCEND each reported significantly longer PFS than their comparators.

Caveats

  • ELEVATE-RR is a noninferiority trial in patients with del(17p) or del(11q), not a superiority claim, and it did not compare acalabrutinib with zanubrutinib.
  • Comparators and populations differ across the three trials; each is compared only with its own control and results are not pooled.
  • ELEVATE-TN's primary comparison was acalabrutinib-obinutuzumab against obinutuzumab-chlorambucil; the acalabrutinib-monotherapy comparison is reported alongside it.
  • ASCEND's primary analysis was in the intention-to-treat population; the abstracts of ELEVATE-TN and ELEVATE-RR do not state the analysis population.
  • In ELEVATE-RR, all-grade atrial fibrillation or flutter was 9.4% with acalabrutinib and 16.0% with ibrutinib (P=0.02); grade 3 or higher infections were 30.8% and 30.0%, and discontinuation because of adverse events 14.7% and 21.3%.