Richter's transformation
CLL/SLL is the most common adult leukemia in Western countries, accounting for 1.2% of the new cancers diagnosed each year in the United States.
[12] In 1928, Maurice Richter reported that a patient with CLL developed an aggressive generalized swelling of his lymph nodes, liver, and spleen due to their infiltration by rapidly growing "sarcoma-like cells."
"[13] In 1964, Lortholary et al. described the occurrence of DLBCL in CLL patients and named the condition Richter's transformation.
[14] Subsequent studies have combined SLL with CLL and included HL-RT with DLBCL-RT in the definition of CLL/SLL RTs.
[16] Individuals with CLL/SLL that develop RT typically present with a rapid increase in the size of their superficial (i.e. cervical, axillary, inguinal, and/or retropharyngeal) lymph nodes; this may be the only sign of the transformation.
These symptoms are often accompanied by the development of extra-nodal disease, i.e. swelling or tumors due to the infiltration of malignant B lymphocytes into the gastrointestinal tract,[17] bone, skin, central nervous system, spleen, liver,[2] urinary bladder, thyroid gland, and/or pulmonary pleurae.
[2][12][18] Individuals presenting with RT at the time of CLL/SLL diagnosis will show these symptoms and signs along with microscopic histopathological evidence of CLL/SLL concurrently with DLBCL-RT or HL-RT.
Individuals with CLL/SLL are considered to be at an increased risk for developing RT if they have: 1) enlarged lymph nodes, liver, and/or spleen; 2) advanced stage disease; 3) low blood platelet counts and/or elevated serum beta-2-microglobulin levels; 4) CLL/SLL cells which develop deletions in the CDKN2A gene, disruptions of the TP53 gene, activation of the C-MYC gene, trisomy (i.e. extra) chromosome 12, or mutations in the NOTCH1 gene;[12] and/or 5) prior CLL/SLL treatment with chemotherapy regimens combining purine analogues and alkylating agents, multiple different types of chemotherapy,[12] and/or combinations of fludarabine, cyclophosphamide, and rituximab (the latter regimen has been associated with a 2.38-fold higher risk of CLL/SLL developing an RT).
[19] The RS cells in HL-RT are spread throughout 1) a CLL/SLL-like background of variably shaped, small lymphocytes or 2) an inflammatory cell-like background of epithelioid histiocytes, eosinophils, and plasma cells that is similar to that found in many cases of Hodgkin's lymphoma not due to RT (here termed HL-not RT).
The virus then goes into a latency phase in which infected individuals become lifetime asymptomatic carriers of EBV in their B lymphocytes.
[22] EBV infection in CLL/SLL malignant B lymphocytes is often diagnosed using In situ hybridization to detect Epstein–Barr virus–encoded small RNAs (i.e. EBERs) made by the virus.
[1] There is an important distinction in DLBCL-RTs based on the similarities of their antibody-producing genes to those in their preceding CLL/SLL's malignant B lymphocytes.
[1][19] One study found that 53% of 14 type 2 HL-RT cases had, and 47% did not have, antibody-producing gene changes in their RS cells that were related to those in their predecessor CLL/SLL malignant B lymphocytes while 29% of 14 type 1 HL-RT cases had, and 71% did not have, antibody-producing genes that were related to their preceding CLL/SLL B lymphocytes.
[11] Individuals with accelerated CCL/SLL show worsening symptoms and signs as well as a microscopic histopathology of their involved tissues that can be difficult to distinguish from RTs.
The modified CHOP chemoimmunotherapy regimen termed [R]-CHOEP, which consists of rituximab (an immunotherapy antibody preparation that binds to CD20 cell surface protein), cyclophosphamide, doxorubicin, vincristine, and prednisone, has given overall response rates of 50–60% with median overall survival times of 15–21 months.
R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin), R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, and cisplatin), and dose-intensified regimens such as R-hyper-CVAD (rituximab with hyper-fractionated [i.e. intensive treatment with small doses given more than once per day] cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine as described elsewhere[25]) have given higher complete response rates but also higher adverse events, higher treatment-related mortality, and shorter overall survival times compared to [R]-CHOEP.
[12] Chemotherapy combined with immunotherapy is and will remain the gold standard for treating DLBCL-RT until future studies report on more effective regimens.
In these procedures, hematopoietic stem cells are isolated from the patient for an autologous or from a donor for allogenic transplant.
The patients are then treated with an "ablation therapy regimen", i.e. high-dose chemotherapy with or without immunotherapy and radiotherapy to eradicate or at least stop or reduce further growth of his or her malignant B lymphocytes.
[1] Further studies, preferably randomized controlled trials, are needed to determine if this treatment regimen improves the outcome of such highly selected DLBCL-RT patients.
[29] A retrospective review study of type 1 HL-RT cases (which have a poorer prognoses than type 2 HL-RT) found that individuals who received therapy regimens directed against HL-not RT had a median overall survival time of 57 months, significantly higher than those treated with regimens used to treat CLL/CSS (medium overall survival time of 8.4 months).
