Richter transformation (RT) represents an uncommon (2% to 10%) but feared complication of chronic lymphocytic leukemia (CLL). The disease is characterized by rapid disease kinetics, a high-risk genetic mutational profile, chemoimmunotherapy resistance, and consequent poor survival. The typical overall survival (OS) from the pre-Bruton tyrosine kinase (BTK)/B-cell lymphoma 2 (BCL2) inhibitor CLL era is 6–12 months, and recent series of RT complicating progression on a BTK or BCL2 inhibitor in heavily pretreated relapsed CLL patients suggests an OS of only 3–4 months. Despite these sobering survival statistics, novel agents have the potential to impact the natural RT disease course. This article reviews recent therapeutic developments, focusing on inhibitors of BTK, BCL2, the PD1-PDL1 axis, and T-cell–activating/engaging therapies. Herein, I discuss the importance of randomized clinical trials in a disease where small single-arm studies dominate; industry engagement, including the role of registrational studies; and the need to integrate prospectively planned correlative biological studies embedded within future clinical trials to help discover which patient benefits most from each class or combination of novel targets.

1.
Al-Sawaf
O
,
Robrecht
S
,
Bahlo
J
, et al.
Richter transformation in chronic lymphocytic leukemia (CLL)-a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials
.
Leukemia
.
2021
;
35
(
1
):
169
-
176
.
doi:10.1038/s41375-020-0797-x
.
Google Scholar
Crossref
Search ADS
PubMed
 
2.
Rossi
D.
XIII. Molecular pathogenesis of transformed lymphomas
.
Hematol Oncol
.
2015
;
33
(
suppl 1
):
70
-
74
.
doi:10.1002/hon.2221
.
Google Scholar
PubMed
 
3.
Klintman
J
,
Appleby
N
,
Stamatopoulos
B
, et al.
Genomic and transcriptomic correlates of Richter transformation in chronic lymphocytic leukemia
.
Blood
.
2021
;
137
(
20
):
2800
-
2816
.
doi:10.1182/blood.2020005650
.
Google Scholar
Crossref
Search ADS
PubMed
 
4.
Ten Hacken
E
,
Sewastianik
T
,
Yin
S
, et al.
In vivo modeling of CLL transformation to Richter syndrome reveals convergent evolutionary paths and therapeutic vulnerabilities
.
Blood Cancer Discov
.
2023
;
4
(
2
):
150
-
169
.
doi:10.1158/2643-3230.BCD-22-0082
.
Google Scholar
Crossref
Search ADS
PubMed
 
5.
Parry
EM
,
Ten Hacken
E
,
Wu
CJ
.
Richter syndrome: novel insights into the biology of transformation
.
Blood
.
2023
;
142
(
1
):
11
-
22
.
doi:10.1182/blood.2022016502
.
Google Scholar
PubMed
 
6.
Smyth
E
,
Eyre
TA
,
Cheah
CY
.
Emerging therapies for the management of Richter transformation
.
J Clin Oncol
.
2023
;
41
(
2
):
395
-
409
.
doi:10.1200/JCO.22.01028
.
Google Scholar
Crossref
Search ADS
PubMed
 
7.
Eyre
TA
,
Clifford
R
,
Bloor
A
, et al.
NCRI phase II study of CHOP in combination with ofatumumab in induction and maintenance in newly diagnosed Richter syndrome
.
Br J Haematol
.
2016
;
175
(
1
):
43
-
54
.
doi:10.1111/bjh.14177
.
Google Scholar
Crossref
Search ADS
PubMed
 
8.
Langerbeins
P
,
Busch
R
,
Anheier
N
, et al.
Poor efficacy and tolerability of R-CHOP in relapsed/refractory chronic lymphocytic leukemia and Richter transformation
.
Am J Hematol
.
2014
;
89
(
12
):
E239
-
E243
.
doi:10.1002/ajh.23841
.
Google Scholar
Crossref
Search ADS
PubMed
 
9.
Rogers
KA
,
Huang
Y
,
Ruppert
AS
, et al.
A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor
.
Br J Haematol
.
2018
;
180
(
2
):
259
-
266
.
doi:10.13039/100006928
.
Google Scholar
Crossref
Search ADS
PubMed
 
10.
Tsimberidou
AM
,
O'Brien
SM
,
Cortes
JE
, et al.
Phase II study of fludarabine, cytarabine (ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) in patients with Richter's syndrome or refractory lymphoproliferative disorders
.
Leuk Lymphoma
.
2002
;
43
(
4
):
767
-
772
.
doi:10.1080/10428190290016872
.
Google Scholar
Crossref
Search ADS
PubMed
 
11.
Tsimberidou
AM
,
Kantarjian
HM
,
Cortes
J
, et al.
Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia
.
Cancer
.
2003
;
97
(
7
):
1711
-
1720
.
doi:10.1002/cncr.11238
.
Google Scholar
Crossref
Search ADS
PubMed
 
12.
Tsimberidou
AM
,
Wierda
WG
,
Wen
S
, et al.
Phase I-II clinical trial of oxaliplatin, fludarabine, cytarabine, and rituximab therapy in aggressive relapsed/refractory chronic lymphocytic leukemia or Richter syndrome
.
Clin Lymphoma Myeloma Leuk
.
2013
;
13
(
5
):
568
-
574
.
doi:10.1016/j.clml.2013.03.012
.
Google Scholar
Crossref
Search ADS
PubMed
 
13.
Woyach
JA
,
Ruppert
AS
,
Guinn
D
, et al.
BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia
.
J Clin Oncol
.
2017
;
35
(
13
):
1437
-
1443
.
doi:10.1200/JCO.2016.70.2282
.
Google Scholar
Crossref
Search ADS
PubMed
 
14.
Davids
MS
,
Huang
Y
,
Rogers
KA
, et al.
Richter's syndrome (RS) in patients with chronic lymphocytic leukemia (CLL) on novel agent therapy
.
J Clin Oncol
.
2018
;
35
(
suppl 15
):
7505
.
doi:10.1200/JCO.2017.35.15_suppl.7505
.
Google Scholar
 
15.
Rossi
D
,
Spina
V
,
Deambrogi
C
, et al.
The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation
.
Blood
.
2011
;
117
(
12
):
3391
-
3401
.
doi:10.1182/blood-2010-09-302174
.
Google Scholar
Crossref
Search ADS
PubMed
 
16.
Wang
Y
,
Tschautscher
MA
,
Rabe
KG
, et al.
Clinical characteristics and outcomes of Richter transformation: experience of 204 patients from a single center
.
Haematologica
.
2020
;
105
(
3
):
765
-
773
.
doi:10.3324/haematol.2019.224121
.
Google Scholar
Crossref
Search ADS
PubMed
 
17.
Abrisqueta
P
,
Delgado
J
,
Alcoceba
M
, et al.
Clinical outcome and prognostic factors of patients with Richter syndrome: real-world study of the Spanish Chronic Lymphocytic Leukemia Study Group (GELLC)
.
Br J Haematol
.
2020
;
190
(
6
):
854
-
863
.
doi:10.1111/bjh.16748
.
Google Scholar
Crossref
Search ADS
PubMed
 
18.
Cwynarski
K
,
Van Biezen
A
,
De Wreede
L
, et al.
Autologous and allogeneic stem-cell transplantation for transformed chronic lymphocytic leukemia (Richter's syndrome): a retrospective analysis from the chronic lymphocytic leukemia subcommittee of the chronic leukemia working party and lymphoma working party of the European Group for Blood and Marrow Transplantation
.
J Clin Oncol
.
2012
;
30
(
18
):
2211
-
2217
.
doi:10.1200/JCO.2011.37.4108
.
Google Scholar
Crossref
Search ADS
PubMed
 
19.
Herrera
AF
,
Ahn
KW
,
Litovich
C
, et al.
Autologous and allogeneic hematopoietic cell transplantation for diffuse large B-cell lymphoma-type Richter syndrome
.
Blood Adv
.
2021
;
5
(
18
):
3528
-
3539
.
doi:10.1182/bloodadvances.2021004865
.
Google Scholar
Crossref
Search ADS
PubMed
 
20.
Khurana
A
,
Mwangi
R
,
Nowakowski
GS
, et al.
Impact of organ function-based clinical trial eligibility criteria in patients with diffuse large B-cell lymphoma: who gets left behind?
J Clin Oncol
.
2021
;
39
(
15
):
1641
-
1649
.
doi:10.1200/JCO.20.01935
.
Google Scholar
Crossref
Search ADS
PubMed
 
21.
Soilleux
EJ
,
Wotherspoon
A
,
Eyre
TA
, et al.
Diagnostic dilemmas of high-grade transformation (Richter's syndrome) of chronic lymphocytic leukaemia: results of the phase II National Cancer Research Institute CHOP-OR clinical trial specialist haemato-pathology central review
.
Histopathology
.
2016
;
69
(
6
):
1066
-
1076
.
doi:10.1111/his.13024
.
Google Scholar
Crossref
Search ADS
PubMed
 
22.
Eyre
TA
,
Schuh
A
,
Wierda
WG
, et al.
Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1-2 study
.
Lancet Haematol
.
2021
;
8
(
12
):
e912
-
e921
.
doi:10.1016/S2352-3026(21)00305-7
.
Google Scholar
Crossref
Search ADS
PubMed
 
23.
Tsang
M
,
Shanafelt
TD
,
Call
TG
, et al.
The efficacy of ibrutinib in the treatment of Richter syndrome
.
Blood
.
2015
;
125
(
10
):
1676
-
1678
.
doi:10.1182/blood-2014-12-610782
.
Google Scholar
Crossref
Search ADS
PubMed
 
24.
Tam
C
,
Munoz
J
,
Cull
G
, et al.
Zanubrutinib, alone and in combination with tislelizumab, for the treatment of Richter transformation of chronic lymphocytic leukemia
.
HemaSphere
.
2023
;
7
(
4
):
e870
.
doi:10.1097/hs9.0000000000000870
.
Google Scholar
Crossref
Search ADS
PubMed
 
25.
Al-Sawaf
O
,
Robrecht
S
,
Stumpf
J
, et al.
The CLL-RT1 trial: a multicenter phase-2 trial of zanubrutinib, a BTK inhibitor, plus tislelizumab, a PD-1 inhibitor, for patients with Richter transformation
.
Hematol Oncol
.
2021
;
39
(
S2
).
doi:10.1002/hon.161_2880
.
Google Scholar
 
26.
Appleby
N
,
Eyre
TA
,
Cabes
M
, et al.
The STELLAR trial protocol: a prospective multicentre trial for Richter's syndrome consisting of a randomised trial investigation CHOP-R with or without acalabrutinib for newly diagnosed RS and a single-arm platform study for evaluation of novel agents in relapsed disease
.
BMC Cancer
.
2019
;
19
(
1
):
471
.
doi:10.1186/s12885-019-5717-y
.
Google Scholar
Crossref
Search ADS
PubMed
 
27.
Mato
AR
,
Shah
NN
,
Jurczak
W
, et al.
Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study
.
Lancet
.
2021
;
397
(
10277
):
892
-
901
.
doi:10.1016/S0140-6736(21)00224-5
.
Google Scholar
Crossref
Search ADS
PubMed
 
28.
Wierda
WG
,
Lewis
DJ
,
Ghia
P
, et al.
Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: results from the phase 1/2 BRUIN study
.
Blood
.
2022
;
140
(
suppl 1
):
846
-
849
.
doi:10.1182/blood-2022-157058
.
Google Scholar
 
29.
Ding
W
,
LaPlant
BR
,
Call
TG
, et al.
Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL
.
Blood
.
2017
;
129
(
26
):
3419
-
3427
.
doi:10.1182/blood-2017-02-765685
.
Google Scholar
Crossref
Search ADS
PubMed
 
30.
Jain
N
,
Senapati
J
,
Thakral
B
, et al.
A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL
.
Blood Adv
.
2023
;
7
(
10
):
1958
-
1966
.
doi:10.1182/bloodadvances.2022008790
.
Google Scholar
Crossref
Search ADS
PubMed
 
31.
Rogers
KA
,
Huang
Y
,
Dotson
E
, et al.
Use of PD-1 (PDCD1) inhibitors for the treatment of Richter syndrome: experience at a single academic centre
.
Br J Haematol
.
2019
;
185
(
2
):
363
-
366
.
doi:10.1111/bjh.15508
.
Google Scholar
Crossref
Search ADS
PubMed
 
32.
Armand
P
,
Murawski
N
,
Molin
D
, et al.
Pembrolizumab in relapsed or refractory Richter syndrome
.
Br J Haematol
.
2020
;
190
(
2
):
e117
-
e120
.
doi:10.1111/bjh.16762
.
Google Scholar
Crossref
Search ADS
PubMed
 
33.
Davids
MS
,
Roberts
AW
,
Seymour
JF
, et al.
Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma
.
J Clin Oncol
.
2017
;
35
(
8
):
826
-
833
.
doi:10.1200/JCO.2016.70.4320
.
Google Scholar
Crossref
Search ADS
PubMed
 
34.
Davids
MS
,
Rogers
KA
,
Tyekucheva
S
, et al.
Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome
.
Blood
.
2022
;
139
(
5
):
686
-
689
.
doi:10.1182/blood.2021011386
.
Google Scholar
Crossref
Search ADS
PubMed
 
35.
Davids
MS
,
Rogers
KA
,
Jain
N
, et al.
Initial results of a multicenter phase 2 study of venetoclax in combination with R-CHOP (VR-CHOP) for patients with Richter syndrome
.
Hematol Oncol
.
2023
;
41
(
S2
):
466
-
468
.
doi:10.1002/hon.3164_343
.
Google Scholar
Crossref
Search ADS
 
36.
Hampel
P
,
Parikh
S
,
Wierda
W
, et al.
P651: venetoclax-based treatment of patients with Richter syndrome: outcomes from a multicenter retrospective study
.
HemaSphere
.
2022
;
6
:
549
-
550
.
doi:10.1097/01.HS9.0000845488.18043.aa
.
Google Scholar
Crossref
Search ADS
 
37.
Kater
AP
,
Ye
JC
,
Sandoval-Sus
J
, et al.
Subcutaneous epcoritamab in patients with Richter's syndrome: early results from phase 1b/2 trial (EPCORE CLL-1)
.
Blood
.
2022
;
140
(
suppl 1
):
850
-
851
.
doi:10.1182/blood-2022-158298
.
Google Scholar
 
38.
Carlo-Stella
C
,
Hutchings
M
,
Offner
F
, et al.
Glofitamab mono therapy induces durable complete remissions and has a manageable safety profile in patients with Richter's transformation
.
Hematol Oncol
.
41
(
S2
):
63
-
65
.
doi:10.1002/hon.3163_28
.
Crossref
Search ADS
 
39.
Neelapu
SS
,
Jacobson
CA
,
Ghobadi
A
, et al.
5-year follow-up supports curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1)
.
Blood
.
2023
;
141
(
19
):
2307
-
2315
.
doi:10.1182/blood.2022018893
.
Google Scholar
PubMed
 
40.
Wang
M
,
Munoz
J
,
Goy
A
, et al.
Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study
.
J Clin Oncol
.
2022
;
94
.
doi:10.1200/JCO.21.02370
.
Google Scholar
 
41.
Jacobson
CA
,
Chavez
JC
,
Sehgal
AR
, et al.
Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial
.
Lancet Oncol
.
2022
;
23
(
1
):
91
-
103
.
doi:10.1016/S1470-2045(21)00591-X
.
Google Scholar
Crossref
Search ADS
PubMed
 
42.
Kittai
AS
,
Bond
DA
,
William
B
, et al.
Clinical activity of axicabtagene ciloleucel in adult patients with Richter syndrome
.
Blood Adv
.
2020
;
4
(
19
):
4648
-
4652
.
doi:10.1182/bloodadvances.2020002783
.
Google Scholar
Crossref
Search ADS
PubMed
 
43.
Benjamini
O
,
Shimoni
A
,
Besser
M
, et al.
Safety and efficacy of CD19-CAR T cells in Richter's transformation after targeted therapy for chronic lymphocytic leukemia
.
Blood
.
2020
;
136
(
suppl 1
):
40
.
doi:10.1182/blood-2020-138904
.
Google Scholar
 
44.
Eyre
TA
,
Riches
JC
,
Patten
PEM
, et al.
Richter transformation of chronic lymphocytic leukaemia: a British Society for Haematology Good Practice Paper
.
Br J Haematol
.
2022
;
196
(
4
):
864
-
870
.
doi:10.1111/bjh.17882
.
Google Scholar
Crossref
Search ADS
PubMed
 
45.
Dubovsky
JA
,
Beckwith
KA
,
Natarajan
G
, et al.
Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes
.
Blood
.
2013
;
122
(
15
):
2539
-
2549
.
doi:10.1182/blood-2013-06-507947
.
Google Scholar
Crossref
Search ADS
PubMed
 
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