A lthough chronic lymphocytic leukemia (CLL) is a low-grade lymphoproliferative disorder of mature B-lymphocytes, approximately 5-10 percent of patients develop an aggressive lymphoma during the course of their disease. Maurice Richter, a pathologist from Bellevue Hospital in New York, initially described this transformation to a high-grade lymphoma in 1928 and, therefore, this condition is also referred to as Richter's transformation or Richter syndrome. The most common histology at the time of transformation is diffuse large B-cell lymphoma (~95%, DLBCL), followed by Hodgkin lymphoma (<5%) and B-prolymphocytic leukemia (<1%).
The median time from CLL diagnosis to development of Richter's transformation varies, but has been estimated to be between 2-5 years. This is in contrast to the prevailing notion that Richter's transformation is a late event in CLL. There are several known risk factors for development of the transformation in a CLL patient. These include clinical factors such as bulky lymphadenopathy (>5cm) and advanced Rai stage (Rai III-IV), and biological characteristics such as unmutated immunoglobulin heavy chain (IGHV) genes; positive expression of CD38, CD49d, and ZAP-70; and stereotyped B-cell receptors. CLL patients who have high-risk genetic features such as del17p13 or del11q23 (by FISH) are also at a higher risk of developing Richter's transformation.
Recent studies using whole-exome analysis have shown transformation occurs due to TP53 disruption, c-Myc activation, and CDKN2A inactivation in ~50 percent patients. In ~30 percent patients, trisomy 12 and activating NOTCH1 mutations contribute to the development of Richter's transformation; and in the remaining 20 percent, there are heterogeneous genomic aberrations that lead to transformation.
The vast majority of DLBCL arising in patients with CLL are of the activated B-cell subtype (ABC) according to the Hans-Choi algorithm. More recent data have shown that DLBCL arising in the context of CLL can be either “clonally related” to CLL (representing 80% of cases) or be “clonally unrelated” to the underlying CLL (remaining 20% cases). The clonal relationship of the DLBCL to the underlying CLL can be determined by comparing IGHV sequencing of both the CLL and DLBCL samples or by performing clonal immunoglobulin rearrangement studies (although these techniques are not routinely available at most centers). Clonally unrelated DLBCL also can be considered to be de novo DLBCL occurring in a CLL patient. The distinction between clonally related and clonally unrelated DLBCL has important prognostic and therapeutic implications—the median survival of clonally unrelated Richter's transformation is similar to de novo DLBCL, whereas the median survival of clonally related Richter's transformation is <6-12 months.
It is unlikely that traditional chemoimmunotherapy or novel agents such as ibrutinib and idelalisib increase the risk of Richter's transformation. After a median follow-up of 13 years, ~8 percent of CLL patients treated with fludarabine, cyclophosphamide, and rituximab (FCR) at MD Anderson Cancer Center developed Richter's transformation. In the German CLL8 trial that compared fludarabine and cyclophosphamide to FCR, the risk of Richter's transformation was ~3 percent in both treatment arms after a median follow-up of 6 years.
In a randomized phase III trial comparing ibrutinib to ofatumumab in patients with relapsed/refractory CLL (RESONATE trial, n=391), transformation to diffuse large B-cell lymphoma occurred in two patients (1%) on each arm, suggesting that therapy with ibrutinib is unlikely to increase the risk of transformation. Although the risk of Richter's transformation appeared to be numerically higher in patients with relapsed/refractory CLL treated with venetoclax (18/116 patients, ~15%), the single-arm design of this phase II study makes it difficult to interpret whether therapy with venetoclax contributed to transformation. There is little data on the risk of Richter's transformation in patients who were treated with idelalisib (phosphoinositide 3-kinase delta inhibitor).
Management of Richter's Transformation
All patients suspected of having developed Richter's transformation should undergo a PET scan. An excision lymph node biopsy should be pursued to confirm a diagnosis of transformation (the most FDG avid lymph node should be targeted for an excisional biopsy; typically, the SUV uptake in these nodes is >10). If the lymph node is not accessible for an excisional biopsy, a core needle biopsy may be performed.
Treatment options for patients with Richter's transformation are limited; there are no randomized studies in this context. In a phase II study of 15 patients with Richter's transformation who were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the overall response rate was 67 percent, the median progression-free survival (PFS) was 10 months and median overall survival (OS) was 21 months.
In another study of 46 patients with Richter's transformation, treatment with R-EPOCH (rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, and prednisone), a more intensified cytotoxic therapy program, led to an ORR of 38 percent (complete response [CR] in 20%), and a median PFS of 3.5 months and median OS of ~5 months. Platinum containing cytotoxic chemotherapy regimens such as OFAR (oxaliplatin, fludarabine, cytarabine, and rituximab) also have been tested with similarly poor efficacy (ORR of ~50%), with median OS <6 months. Intensive multi-agent chemotherapy has considerable toxicity with grade 3/4 hematologic toxicity occurring in virtually all patients, and grade 3/4 infection in ~40 percent patients. For patients who are able to achieve a response and have a donor, an allogeneic stem cell transplant is the only potentially curative therapeutic modality and should be considered in these patients. Given the advanced age of CLL patients, an allogeneic stem cell transplant may not be an option in many patients; and in these circumstances, an autologous stem cell transplant in responding patients may be appropriate.
Single-agent ibrutinib has been shown to have activity in patients with Richter's transformation. In a small series of four patients with relapsed/refractory Richter's transformation treated with 420 mg ibrutinib, one patient had a CR and three patients had stable disease. The median duration of response was ~6 months. In a recently presented phase II study, 29 patients with Richter's transformation were treated with 100 mg twice daily acalabrutinib, a second generation BTK inhibitor. The ORR was 38 percent and the median PFS was 3.2 months. Although single-agent BTK inhibitors do not appear to have impressive responses in this patient population, it is hoped that combination therapy (with either chemoimmunotherapy or other novel agents such as PD1 inhibitors) will improve their efficacy.
Selinexor, a selective inhibitor of nuclear export, blocks XPO1, which transports several proteins including TP53 from the nucleus into the cytoplasm. Cancer cells upregulate this mechanism and it is thought that by blocking this transporter, proteins such as TP53 may be retained in the nucleus, which may lead to cell death. Selinexor was administered to three patients with relapsed/refractory Richter's transformation, and a partial response was seen in one patient. This has now led to the initiation of an expanded phase II study of selinexor in patients with Richter's transformation. Among seven patients with relapsed/refractory Richter's transformation who received single-agent venetoclax, the ORR was 43 percent, suggesting that BCL2 inhibitors may also play an important role in the treatment of Richter's transformation.
The interaction of programmed death 1 (PD1) with its ligands represents a major immune checkpoint utilized by tumor cells to overcome immune surveillance by T cells. There is strong preclinical data to suggest this mechanism of tumor evasion is active in Non-Hodgkin lymphoma, including small lymphocytic lymphoma.
In a phase II study of single-agent pembrolizumab, a PD1 inhibitor, 16 patients with relapsed/refractory CLL and nine patients with Richter's transformation were treated with pembrolizumab 200 mg IV every 3 weeks. Although the response rate in the CLL cohort was 0 percent, among the nine patients with relapsed/ refractory Richter's transformation, the ORR was 44 percent (one patient had a CR, three had partial responses, and three patients had stable disease).
After a median follow-up of 10 months, the median OS was not reached in these patients. Two-thirds of these patients with transformation had previously been treated with ibrutinib, and these results compare extremely favorably to ibrutinib-treated CLL with Richter's transformation where the median survival was 4 months. In another study combining nivolumab (PD1 inhibitor) with ibrutinib in five patients with Richter's transformation, the ORR was 80 percent (one patient had a CR and three patients had partial responses). Therapy with PD1 inhibitors was well tolerated in both these studies, with immune-mediated adverse events occurring in <5 percent of patients. These data indicate that therapy with PD1 blocking agents (as single agent or in combination with other novel agents) appears to be most promising in the treatment of this difficult-to-treat complication of CLL.
In summary, Richter's transformation is a devastating complication in patients with CLL, particularly those who have progressed on ibrutinib and idelalisib. Our understanding of the molecular mechanisms that drive this disease continues to evolve. With the advent of novel therapeutic strategies such as second generation BTK inhibitors, BCL2 antagonists, selinexor, PD1 inhibitors, and combinations thereof, it is hoped we will be able to improve the outcomes of these patients.
SAMEER A. PARIKH, MD, is a hematologist at Mayo Clinic, Rochester, Minn. Mayo Clinic is a top 10 cancer hospital according to U.S. News & World Report.