**7. Richter's transformation**

*Advances in Hematologic Malignancies*

**5. Role of transplant in CLL**

treatment and the regimens' expected toxicities.

Patients with CLL experience serial relapses and many will be treated with each of these agents at some point during their disease course. A preferred order for their use has not been established. A choice is primarily made based on the patient's prior

In the setting of approval of novel agents in the treatment of CLL the number of transplants that are being performed in Europe and the United States are decreasing. In the chemoimmunotherapy era, patients with TP53 deletion/mutation, fludarabine refractoriness, early relapse (<24 months) after FCR treatment were in the highest risk group. Allogeneic Stem Cell Transplant (SCT) would be considered in these patients as the only viable treatment option. Today however, these patients have ibrutinib, idelalisib and venetoclax and various combination of novel agents with immunotherapy as possible treatment options. There are no randomized clinical trials that compare the outcomes of allogeneic SCT with conventional chemotherapy, chemoimmunotherapy or novel therapy regimens. Most transplants offered for CLL use reduced intensity conditioning (RIC), however no trials have been conducted to compare it to myeloablative conditioning. RIC resulted in reduced toxicity without compromising engraftment and anti-tumor activity [60]. Follow up results for studies with RIC indicate that about 40% of patients achieve long term disease control and RIC also overcomes the negative prognostic effect of TP53, fludarabine refractoriness as well as that of SF3B1 and NOTCH gene mutations [61–63]. Generally, allogeneic transplants are no longer offered to patients with del(17p) in first remission. In the relapsed setting the role of SCT must be weighed against the comorbidities, prior therapies, and duration of response to prior therapies as well as current mutation status including TP53, NOTCH1 and SF3B1. Patient must be informed about the side effect profile and non-relapse mortality associated with allogeneic transplant compared to the toxicity and side

**108**

**Figure 2.**

*Hematopoietic SCT for CLL by year [64, 65].*

**6. Role of minimal residual disease (MRD) testing in CLL**

MRD in CLL is assessed most commonly using multiparametric flow cytometry with a sensitivity to detect <1 CLL cell in 10,000 leukocytes. MRD – undetectable (MRD-U) has been defined detection of <1 CLL cell per 10,000 leukocytes [2].

effect profile of novel agents. (**Figure 2**).

Maurice Richter initially described the transformation of CLL into an more aggressive form of lymphoma and since then this has been recognized as Richter's Transformation (RT) [67]. In most cases RT consists of transformation of CLL into Diffuse Large B Cell Lymphoma (DLBCL), however other aggressive lymphomas have been reported. As of now the reported incidence of RT in the era of novel agents is not very different from the incidence of RT in the chemoimmunotherapy era [68, 69] with incidence rates varying from 3–20% among various studies. RT is suspected when there is rapid clinical deterioration, worsening discordant lymphadenopathy to new onset cytopenia. However, its presentation can be varied. When RT is suspected a comprehensive evaluation with a PET/CT, image guided biopsy as well as a bone marrow biopsy is required. SUV of greater than 10 can distinguish RT form CLL with high sensitivity (91%) and specificity (95%) [70]. However, this has been disputed in the setting of novel agents and thus a concern for RT necessitates a biopsy of the index lesion preferably. RT primarily arises in the background of TP53 disruption and complex karyotype. MYC activation and CDKN2A/B likely play an important role in RT. Clonally related RT patients (>80% of RT DLBCL) respond very poorly to traditional chemotherapy for DLBCL, whereas clonally unrelated DLBCL RT patients respond to traditional chemotherapy just as de novo DLBCL. Thus, determination of clonal evolution is important but difficult to determine [71].Trials performed prior to the use of novel agents used R-CHOP or similar

**Figure 3.** *Richter transformation. Adapted by ASH education handbook [73].*

regimens as the standard therapy to treat RT. Fit patients who achieve a complete response or good partial response achieve benefit from a post induction strategy involving stem cell transplant [72]. Novel combinations, PDL-1 blockade and CAR-T or bispecific antibodies are being currently investigated as potential treatment options [72]. **Figure 3** below shows a suggested treatment approach algorithm for suspected patients with RT.
