Immunochemotherapy for Richter syndrome: current insights

Figures & data

Figure 1 CLL transformation into DLBCL.

Notes: (A) Large cells of DLBCL (lower left) next to infiltration by small CLL cells (upper right) HE, ×200 magnification. (B) DLBCL with centroblastic morphology (upper right); few small CLL cells (lower left); HE staining, ×400 magnification. (C) DLBCL cells reveal stronger membrane CD20 expression than that of CLL cells. (D) MIB1 staining in 80% of the DLBCL cells and in 3% of the CLL cells. (E) CD23 membrane expression in CLL cells; DLBCL cells are negative. (F) BCL6 nuclear expression in DLBCL cells; CLL is negative; EnVision staining, ×400 magnification.
Abbreviations: CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; HE, hematoxylin and eosin.

Figure 2 Morphological and phenotypic spectrum of CLL transformation into HL may strongly differ upon histopathological examination.

Notes: Type I – CLL with Hodgkin transformation (A–C). (A) Reed–Sternberg cells are sparsely dispersed in the background of small CLL cells; HE staining. (B) CD15 membrane and “dot-like” expression in HRS cell. (C) CD23 expression in CLL cells; the Reed–Sternberg cell is negative. EnVision staining, ×400 magnification. Type II – CLL transformation in HL (D–F). (D) The numerous HRS cells among histiocytes, eosinophils, and small lymphocytes in the background; a few CLL cells in the lower right; HE staining, ×200 magnification. The HRS cells reveal membrane CD30 expression (E) and “dot-like” expression of CD15 (F); EnVision staining, ×400 magnification.
Abbreviations: CLL, chronic lymphocytic leukemia; HE, hematoxylin and eosin; HL, Hodgkin’s lymphoma; HRS cell, Hodgkin and Reed–Sternberg cell.

Figure 3 Management algorithm for patients with a clinical suspicion of RS.

Notes: In CLL patients characterized by chromosome 12 trisomy or NOTCH1 mutations, or classified as subset #8, and especially in those with the presence of constitutional symptoms or asymmetrical lymph node enlargement, caution is advised due to the increased risk of RS transformation. In case RS is suspected, a PET/CT should be performed and regions with SUV >5 were qualified for excisional biopsy. If the biopsy reveals no transformation, CLL treatment may be initiated. However, in cases with a strong suspicion of RS, a secondary biopsy should be considered. Once the histopathological diagnosis of RS-DLBCL is confirmed, a patient should be qualified for clonality assessment. In case of no clonal relationship between CLL and DLBCL, the patient should be treated as having de novo DLBCL. In contrast, for clonally related cases, the enrollment into clinical trial with novel compounds is advised due to poor prognosis with a standard immunochemotherapy. Fit and transplant-eligible patients with clonally related disease should be qualified for allogeneic stem cell transplantation or, if not possible, for autologous stem cell transplantation. In case of relapsed disease, platinum-based salvage regimens or participation in clinical trials is recommended. Transformation to Hodgkin’s lymphoma should be treated with ABVD regimen. Shading relates to administered therapies or treatment as final points of the algorithm. Other non-shaded fields represent the diagnostic activities and results.
Abbreviations: ABVD, adriamycin, bleomycin, vinblastine, and dacarbazine; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; HSCT, hematopoietic stem cell transplantation; LDH, lactate dehydrogenase; PET/CT, positron emission tomography/computed tomography; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RS, Richter syndrome; SUV, standardized uptake value.

Table 1 Summary of the published retrospective studies assessing the efficacy and safety of induction regimens for patients with DLBCL-RS

Regimen	Reference	Patients with RS	ORR (%)	CR (%)	Median PFS (months)	Median OS (months)	Grade 3–4 adverse events			Negative prognostic factors
							Infections (%)	Thrombocytopenia (%)	Neutropenia (%)
R-EPOCH	^Citation79	46	39	NA	3.5	5.9	NA	NA	NA	Complex CLL karyotype
DHAP/ESHAP/OFAR ± R	^Citation83	28	43	25	6.9	8.3	43a	82a	83a	Serum albumin level <3.5 g/La

Note:

a Data for the entire study population which included 47 patients with relapsed/refractory CLL and 28 patients with RS.

Abbreviations: CLL, chronic lymphocytic leukemia; CR, complete response; DHAP, dexamethasone, cytarabine, and cisplatin; DLBCL, diffuse large B-cell lymphoma; ESHAP, etoposide, methylprednisolone, cytarabine, and cisplatin; NA, not available; OFAR, oxaliplatin, fludarabine, cytarabine, and rituximab; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; R-EPOCH, rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, and prednisone; RS, Richter syndrome.

Table 2 Summary of the published prospective studies assessing the efficacy and safety of induction regimens for patients with DLBCL-RS

Regimen	Reference	Patients with RS	ORR (%)	CR (%)	Median PFS (months)	Median OS (months)	Grade 3–4 adverse events			Negative prognostic factors
							Infections (%)	Thrombocytopenia (%)	Neutropenia (%)
R-CHOP	^Citation77	15	67	7	10	21	28a	65a	55a	del17pa; ECOG ps ≥2a
CHOP-O	^Citation78	37	46	27	6.2	11.4	56	25	33	TP53 disruption; pretreated CLL
OFAR1	^Citation82	20	50	20	6-month PFS, 27%	6-month OS, 59%	12b	94b	84b	NA
OFAR2	^Citation81	35	38.7	6.5	3	6.6	17	77	89	NA
R-hyperCVXD/R-MA	^Citation80	30	43	27	NA	12-month survival rate, 28%	Sepsis, 39%c	40c	100c	NA

Note:

a Data for the entire study population which included 26 patients with high-risk relapsed/refractory CLL, 19 patients with CLL plus autoimmune cytopenia, and 15 patients with RS;

b data for the entire study population which included 30 patients with relapsed/refractory CLL and 20 patients with RS;

c data for the entire study population which included 19 patients with relapsed/refractory CLL and 30 patients with RS.

Abbreviations: CHOP-O, cyclophosphamide, doxorubicin, vincristine, prednisone, and obinutuzumab; CLL, chronic lymphocytic leukemia; CR, complete response; del17p, deletion of chromosome 17p; DLBCL, diffuse large B-cell lymphoma; ECOG ps, the Eastern Cooperative Oncology Group performance status; FFS, failure-free survival; NA, not available; OFAR, oxaliplatin, fludarabine, cytarabine and rituximab; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-hyperCVXD/R-MA, rituximab, fractioned cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone alternating with rituximab, methotrexate, and cytarabine; RS, Richter syndrome; TP53 disruption, TP53 deletion or mutation.

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