Richter's Transformation Research Articles

NOTCH1 Signalling: A key pathway for the development of high-risk chronic lymphocytic leukaemia.

NOTCH1 is a cell surface receptor that releases its intracellular domain as transcription factor upon activation. With the advent of next-generation sequencing, the NOTCH1 gene was found recurrently mutated in chronic lymphocytic leukaemia (CLL). Here, virtually all NOTCH1 mutations affect the protein’s PEST-domain and impair inactivation and degradation of the released transcription factor, thus increasing NOTCH1 signalling strength. Besides sequence alterations directly affecting the NOTCH1 gene, multiple other genomic and non-genomic alterations have by now been identified in CLL cells that could promote an abnormally strong NOTCH1 signalling strength. This renders NOTCH1 one of the key signalling pathways in CLL pathophysiology. The frequency of genomic alterations affecting NOTCH1 signalling is rising over the CLL disease course culminating in the observation that besides TP53 loss, 8q gain and CDKN2A/B loss, NOTCH1 mutation is a hallmark genomic alteration associated with transformation of CLL into an aggressive lymphoma (Richter transformation). Both findings associate de-regulated NOTCH1 signalling with the development of high-risk CLL. This narrative review provides data on the role of NOTCH1 mutation for CLL development and progression, discusses the impact of NOTCH1 mutation on treatment response, gives insight into potential modes of NOTCH1 pathway activation and regulation, summarises alterations that have been discussed to contribute to a de-regulation of NOTCH1 signalling in CLL cells and provides a perspective on how to assess NOTCH1 signalling in CLL samples.

CLL-129 BRUIN CLL-313: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative, and the majority of patients will require additional treatment. Covalent BTKi shares pharmacologic liabilities (e.g., low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. Determine whether pirtobrutinib is superior to bendamustine plus rituximab in treatment naïve CLL/SLL patients with retained 17p. BRUIN CLL-313 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus bendamustine plus rituximab (BR) in treatment naïve CLL/SLL patients with retained 17p. Approximately 250 patients will be randomized 1:1. Randomization will be stratified by IGHV mutation status (mutated vs unmutated), and Rai stage (low/intermediate vs high). Patients in the BR arm are eligible to crossover to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 and confirmed by an independent review committee (IRC). Global; community hospitals, academic medical centers. Eligible patients are adults with confirmed diagnosis of CLL/SLL and who require therapy per iwCLL 2018 criteria. Key exclusion criteria include CNS involvement by CLL/SLL, Richter's transformation to DLBCL, prolymphocytic leukemia or Hodgkin lymphoma any time pre-enrollment, presence of 17p deletion, prior systemic therapy for CLL/SLL, and significant cardiovascular disease. Oral pirtobrutinib monotherapy versus bendamustine plus rituximab. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an independent review committee. Secondary endpoints include investigator-assessed PFS, overall survival (OS), overall response rate (ORR), duration of response (DoR), safety and tolerability, and patient-reported outcomes. The global study is currently enrolling patients (NCT05023980). Trial in Progress. Trial in Progress.

CLL-506 Clinical Outcomes Beyond Progression on Ibrutinib in Patients With Chronic Lymphocytic Leukemia

Patients with chronic lymphocytic leukemia (CLL) with disease progression on ibrutinib have worse outcomes compared to patients stopping ibrutinib due to toxicity. To analyze survival estimates of patients with CLL following true disease progression (per iwCLL 2018 criteria) on ibrutinib. Retrospective. Academic. Patients with CLL who received ibrutinib therapy for CLL at a Mayo Clinic Cancer Center site (Arizona, Florida, Minnesota) between 4/2012-6/2021. Treatment-free survival (TFS) was analyzed as the duration from the start of treatment immediately after ibrutinib failure to the start of the subsequent line of therapy or death, whichever occurred earlier. Overall survival (OS) was analyzed as the time from date of progression while on ibrutinib and from subsequent therapy start date until date of death or last known to be alive. OS was analyzed using the Kaplan-Meier method (with comparisons of OS by characteristics analyzed by the log rank test). Among 144 patients with CLL identified to have disease progression on ibrutinib, the median age was 68 years and 74% were male. Unmutated IGHV (90%) and TP53 disruption (50%) were common in evaluable patients at the time of progression on ibrutinib. The median OS for the entire cohort following progression on ibrutinib was 25.5 months; 29.8 months and 8.3 months following CLL progression (n=104) and Richter's transformation (n=38), respectively. Longer OS was observed among patients with CLL progression who had received ibrutinib in the frontline (n=23) compared to relapsed/refractory setting (not reached versus 28.5 months; p=0.04), but was similar amongst patients treated with 1, 2, or ≥3 prior lines (18.5, 30.9, and 26.0 months, respectively, p=0.24). Among patients with CLL disease progression on ibrutinib, next-line treatment with chimeric antigen receptor T-cell therapy or venetoclax-based treatment was associated with significantly longer median OS and TFS compared to other approved treatments (OS: not-reached, 29.8 months, and 9.1 months, respectively, p=0.034; TFS: 30.4 months, 20.1 months, and 4.4 months, respectively, p<0.001) Conclusions: These findings suggest an unmet need for this growing patient population while supporting the current practice of next-line venetoclax and participation in clinical trials.

CLL-116 BRUIN CLL-322: A Phase 3 Open-Label, Randomized Study of Fixed-Duration Pirtobrutinib Plus Venetoclax and Rituximab Versus Venetoclax and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Currently, the majority of patients with chronic lymphocytic leukemia (CLL) who require treatment receive a covalent Bruton's tyrosine kinase inhibitor (BTKi) as their first standard of care targeted therapy. The MURANO study established the time-limited combination of venetoclax plus rituximab (2 years) as a standard of care regimen for patients with relapsed/refractory (R/R) CLL or small lymphocytic lymphoma (SLL). MURANO enrolled very few patients who were previously treated with a covalent BTKi. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild-type and C481-mutated BTK with equally low nM potency. Adding fixed-duration pirtobrutinib to the MURANO regimen may allow for deeper remissions and longer disease control and generate a clinically relevant dataset in a population of patients with BTKi-pretreated R/R CLL/SLL. BRUIN CLL-322 is a randomized, open-label, global phase 3 trial comparing fixed duration pirtobrutinib plus venetoclax and rituximab with standard venetoclax and rituximab in patients with R/R CLL/SLL. Approximately 600 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (yes/no) and prior BTKi experience (discontinuation due to progressive disease vs. due to other reasons vs. no prior BTKi exposure). Global; community hospitals, academic medical centers. Eligible patients are adults with a diagnosis of CLL/SLL who require therapy per iwCLL 2018 criteria and who received prior therapy that may or may not include a covalent BTKi. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time pre-enrollment, history of allogeneic or autologous stem cell transplant or chimeric antigen receptor (CAR) T-cell therapy within 60 days, and prior therapy with a BCL2 inhibitor or non-covalent BTKi. There will be no exclusion based on the number of lines of prior therapy. Fixed-duration pirtobrutinib plus venetoclax and rituximab versus venetoclax and rituximab. The primary endpoint is progression-free survival per iwCLL criteria assessed by an independent review committee. Secondary endpoints include overall response rate, overall survival, time to next treatment, event-free survival, safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04965493). This study is a trial in progress. This study is a trial in progress.

CLL-114 BRUIN CLL-321: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in BTK Inhibitor–Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Covalent Bruton tyrosine kinase (BTK) inhibitors (BTKi) have transformed the management of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative. Covalent BTKi share pharmacologic liabilities (e.g., low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild-type (WT) and C481-mutated BTK with equally low nM potency, was developed. Demonstrate the superiority of continued BTK pathway inhibition with pirtobrutinib compared with other available therapies in patients with BTKi-treated CLL/SLL. BRUIN CLL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus the investigator's choice of idelalisib plus rituximab or bendamustine plus rituximab in patients with CLL/SLL who have been treated with a prior covalent BTKi. Approximately 250 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (yes/no) and prior venetoclax (yes/no). Patients receiving the investigator's choice are eligible to cross over to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 (determined by an independent review committee [IRC]). Global; community hospitals, academic medical centers. Eligible patients are adults aged ≥18 years with a diagnosis of CLL/SLL who require therapy per iwCLL 2018 criteria and who have received prior covalent BTKi. An unlimited number of lines of prior therapy is allowed. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time pre-enrollment, a major bleeding event on prior covalent BTKi, and a history of allogeneic or autologous stem cell transplant or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization. Pirtobrutinib monotherapy versus investigator's choice of idelalisib plus rituximab or bendamustine plus rituximab. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an IRC. Secondary endpoints include overall survival, overall response rate, duration of response, safety and tolerability, and patient-reported outcomes. The global study is currently enrolling patients (NCT04666038). This study is a trial in progress. This study is a trial in progress.

Emerging Therapies for the Management of Richter Transformation.

Richter transformation (RT) refers to the development of an aggressive lymphoma in patients with underlying chronic lymphocytic leukemia/small lymphocytic lymphoma. Aside from a small subgroup of patients with clonally unrelated and previously untreated chronic lymphocytic leukemia, the disease responds poorly to standard therapies and prognosis is dismal. Recent developments in the understanding of the biology of RT and the advent of several targeted agents may result in improved outcomes for these patients. The purpose of this review is to analyze recent data on the pathogenesis and treatment of RT. We reviewed studies addressing the pathophysiology of RT and analyzed the data for frontline chemoimmunotherapy and emerging targeted therapies likely to play a significant role in the future management of RT. Several biologic and clinical factors may help identify those who are unlikely to respond to conventional chemoimmunotherapy; where possible, these patients should be managed with a novel approach. Emerging therapies for the management of RT include chimeric antigen receptor T-cell therapy, noncovalent Bruton tyrosine kinase inhibitors, and T-cell-engaging bispecific antibodies. The use of less toxic and more effective targeted therapies may result in improved outcomes. Larger, prospective clinical trials are required to confirm efficacy and safety of novel agents for the management of RT, particularly when used in combination with other targeted therapies and in addition to chemoimmunotherapy regimens.

649TiP A phase I/Ib study evaluating the safety, pharmacokinetics, and preliminary efficacy of LP-118 in subjects with relapsed or refractory haematological malignancies

Newave Pharmaceutical is developing an investigational compound LP-118, a next generation selective B-cell lymphoma 2 (BCL-2) inhibitor with tuned B-cell lymphoma extra-large (BCL-XL) activity to improve antitumor efficacy and reduce risk for thrombocytopenia. Clinical development of LP-118 includes targeting of relapsed or refractory hematological malignancies. BCL-2 and BCL-XL are important anti-apoptotic proteins in the intrinsic apoptotic pathway and are involved in the pathophysiology of many hematologic malignancies, including Non-Hodgkin’s Lymphoma (NHL), Richter transformation (RT), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), etc. (Valentin, Grabow et al. 2018). Considering that concern about acquired resistance to venetoclax (the first FDA-approved BCL-2 selective inhibitor indicated for the treatment of AML has been an obstacle in the treatment of AML patients, a promising strategy for overcoming BCL-2 acquired resistance mutation is urgently needed (Tahir, Smith et al. 2017) The inhibitory effect of LP-118 on the targets BCL-2 and BCL-XL is carefully adjusted to be between that of navitoclax and venetoclax with the aim of minimizing BCL-XL on-target platelet toxicity while retaining and improving antitumor efficacy. Newave Pharmaceutical, Inc. intends to conduct the first in human study of LP-118 in hematologic malignancies with a primary focus on relapsed or refractory NHL, RT, MM, T-PLL, AML, ALL, MDS, MDS/MPN, and MF. Phase Ia dose-escalation will begin with Group 1 until DLT is observed and MTD is established, or until an RP2D or OBD is established. Once the MTD, RP2D, or OBD is established for Group 1, the phase Ia dose escalation can proceed for Group 2 (hight risk). Group 1 relapsed/refractory: low risk tumor lysis CLL/SLL; MF, MDS/MPN, CMML-2, MPN-BP, MDS, AML; NHL, RT, MM, T-PLL; ALL A classic “3+3” design will be used in this study. The safe starting dose of LP-118 calculated from non-clinical toxicity studies is 50 mg/d. To mitigate risk of TLS, an accelerated step-up dosing schedule of LP-118 will be used to reach the target dose for each cohort. NCT04771572. Newave Pharmaceutical Inc.

Clinical outcomes in patients with chronic lymphocytic leukemia with disease progression on ibrutinib

Patients with chronic lymphocytic leukemia (CLL) with disease progression on ibrutinib have worse outcomes compared to patients stopping ibrutinib due to toxicity. A better understanding of expected outcomes in these patients is necessary to establish a benchmark for evaluating novel agents currently available and in development. We evaluated outcomes of 144 patients with CLL treated at Mayo Clinic with 2018 iwCLL disease progression on ibrutinib. The median overall survival (OS) for the entire cohort was 25.5 months; it was 29.8 months and 8.3 months among patients with CLL progression (n = 104) and Richter transformation (n = 38), respectively. Longer OS was observed among patients with CLL progression who had received ibrutinib in the frontline compared to relapsed/refractory setting (not reached versus 28.5 months; p = 0.04), but was similar amongst patients treated with 1, 2, or ≥3 prior lines (18.5, 30.9, and 26.0 months, respectively, p = 0.24). Among patients with CLL disease progression on ibrutinib, OS was significantly longer when next-line treatment was chimeric antigen receptor T-cell therapy (median not reached) or venetoclax-based treatment (median 29.8 months) compared to other approved treatments, such as chemoimmunotherapy, phosphoinositide 3’-kinase inhibitors, and anti-CD20 monoclonal antibodies (9.1 months; p = 0.03). These findings suggest an unmet need for this growing patient population.

Richter Transformation in Chronic Lymphocytic Leukemia with Hypercalcemia and Acute Kidney Injury Presenting as Altered Mental Status: A Case Report

Introduction: Richter’s transformation is a deadly complication of chronic lymphocytic leukemia (CLL) associated with high mortality. This transformation involves the development of an aggressive, diffuse large B cell lymphoma in the setting of a chronic, underlying case of CLL. Although it is rare, Richter’s transformation is important to identify in patients with a history of CLL because of its significant mortality if left untreated. In the setting of CLL, there are many ways in which patients can present if they are currently undergoing a Richter’s transformation. Case Description: Patients may present with symptoms common to CLL which include but are not limited to fatigue, easy bruising, weight loss, etc., or they may present more unusually, as in the case that will be presented here: with altered mental status, fall, hypercalcemia and acute kidney injury (AKI). Discussion: With the current state of affairs due to COVID-19, it is also important to recognize the potential complications of patients with this disease state that are positive for COVID-19, leading to further complications such as disseminated intravascular coagulation (DIC). Recognizing these patients, and directing their care appropriately is important for their disease progression and outlook.

Early Clones Expand in Richter Transformation of Chronic Lymphocytic Leukemia.

Subclones that drive Richter transformation (RT) in chronic lymphocytic leukemia are seeded early.

Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial

Although BTK inhibitors provide long-term disease-control in patients with chronic lymphocytic leukaemia, they need to be combined with BCL2 inhibitors or antibodies to achieve deep responses with undetectable minimal residual disease (uMRD), which allows for time-limited treatment. This trial aims to evaluate the triple combination of obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine. This multicentre, open-label, investigator-initiated, phase 2 study evaluates a sequential treatment consisting of a debulking with two cycles of bendamustine for patients with a higher tumour load (70 mg/m2 intravenously on days 1 and 2, repeated after 28 days), followed by an induction and a maintenance with obinutuzumab (1000 mg intravenously on days 1-2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2-6 and every 12 weeks in the maintenance phase), acalabrutinib (100 mg orally twice daily continuously from induction cycle 2 day 1 onwards) and venetoclax (starting in induction cycle 3 with 20 mg per day with a weekly dose ramp-up over 5 weeks to the target dose of 400 mg per day). Eligible patients were aged 18 years or older with an ECOG performance score 0-2 and had relapsed or refractory chronic lymphocytic leukaemia requiring treatment according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria. The primary endpoint was uMRD (<10-4) in peripheral blood at the end of induction treatment assessed centrally at the final restaging, 12 weeks after the start of the last induction cycle. As per protocol, all patients with more than two induction cycles were included in the analyses. This study is registered with ClinicalTrials.gov, number NCT03787264, and is ongoing. Between Jan 14, 2019, and June 25, 2020, 45 evaluable patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled; 13 (29%) were female, 32 (71%) were male, 21 (47%) had already received a targeted agent, and 14 (32%) had del(17)(p13.1) or TP53 mutation. Ethnicity-race data was not collected. At data cutoff (Feb 25, 2021), all patients had completed the induction treatment. 34 patients (76%; 95% CI 61-87, p=0·26) had uMRD in peripheral blood after 6 months of triple therapy. Until data cutoff, 32 (71%) patients started maintenance and nine (28%) were able to stop with uMRD. After a median observation time of 13·8 months (IQR 10·4-18·4), there were two (4%) Richter transformations, but no progressions and no deaths observed. The most common adverse events of grade 3 and 4 during the entire treatment were thrombocytopenia and neutropenia (12 [27%] of 45 patients each), tumour lysis syndrome and infections (five [11%] of 45 patients each, grade 3 adverse events only), infusion-associated reactions (four [9%] of 45 patients) and anaemia (four [9%] of 45 patients). With 76% of patients achieving uMRD in peripheral blood, this trial did not reach the prespecified activity threshold. Triple therapy with obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine regimen requires further evaluation in larger trials to define its value compared with double treatment with a BTK or BCL2 inhibitor combined with obinutuzumab or a combination of the two oral targeted drugs. Until these trials show a clear benefit, the use of the triple combination in routine practice cannot be recommended. Acerta, AstraZeneca, F Hoffmann-La Roche, and AbbVie.

Clinical analysis of 20 cases of small B lymphocyte proliferative disease with t (14;19) (q32;q13)

Objective: The clinical characteristics and prognosis of 20 patients with small B-lymphocyte proliferative disease with t (14;19) (q32; q13) were analyzed to improve the understanding of such rare cases. Methods: The clinical data of 20 patients with t (14; 19) (q32; q13) small B lymphocyte proliferative disease treated in the First Affiliated Hospital of Nanjing Medical University from April 2013 to December 2020 were retrospectively collected and analyzed. Among them, 10 cases were chronic lymphocytic leukemia (CLL) and 10 cases were other small B-cell malignancies. Results: Among the 20 cases, 10 were male and 10 were female, and the median age at diagnosis was 53.5 (35-88) years old. All patients had absolute lymphocytosis, 19 patients had lymphadenopathy, and 10 patients had splenomegaly. With a median follow-up of 36 (4-163) months, three patients died, and 11 patients had a time to treatment (TTT) ≤12 months. Ten patients (50%) were accompanied by +12, two patients (2/17, 12%) were accompanied by 13q-. Moreover, we found that t (14;19) was associated with unmutated immunoglobulin heavy-chain variable (IGHV) somatic mutation (17/19, 89%) and a biased use of IGHV4-39 (7/17, 41%) was observed. Next-generation sequencing detected one or more gene mutations in 14 (14/17, 82%) cases and a total of 25 gene mutations had been revealed, of which the most frequent were NOTCH1 (35%) , followed by SF3B1 (24%) and KMT2D (18%) . For 10 CLL patients, five (50%) were defined as Rai Ⅲ/Binet C. It is noteworthy that among the 20 cases, two cases actually involved Richter transformation. Conclusions: Small B-cell malignant tumors with abnormal t (14; 19) show unique clinical biological characteristics, often accompanied by a variety of adverse prognostic factors, and tend to have an aggressive clinical course.

Minimal residual disease–driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL

AbstractUndetectable measurable residual disease (uMRD) is achievable in patients with chronic lymphocytic leukemia (CLL) with the BCL2-inhibitor venetoclax alone or combined with the Bruton’s tyrosine kinase inhibitor ibrutinib. This phase 2, multicenter, MRD-driven study was designed to discontinue treatment upon reaching uMRD4 (<10−4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary end point of the study was proportion of uMRD4 with venetoclax ± ibrutinib. Secondary end points were overall response rate, partial response, complete response, progression-free survival, duration of response, overall survival, and safety of venetoclax ± ibrutinib. Patients with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle 24 Day 28/uMRD4/progression/toxicity. After Cycle 24 Day 28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53 aberrations; 79% with unmutated IGHV) started venetoclax. Overall response rate with venetoclax was 36 (95%) of 38 patients (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7 months (range, 3-10 months) of combined treatment, 16 (84%) of 19 achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median progression-free survival was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, and 1 dropped out). Seven (22%) of 32 patients remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent grade 3 to 4 adverse event; no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33 (87%) of 38 patients, with venetoclax monotherapy or combined with ibrutinib, delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. This trial was registered at www.clinicaltrials.gov as # NCT04754035.

Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high–B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.

Artificial intelligence-assisted mapping of proliferation centers allows the distinction of accelerated phase from large cell transformation in chronic lymphocytic leukemia

AbstractChronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is characterized morphologically by numerous small lymphocytes and pale nodules composed of prolymphocytes and paraimmunoblasts known as proliferation centers (PCs). Patients with CLL can undergo transformation to a more aggressive lymphoma, most often diffuse large B-cell lymphoma (DLBCL), known as Richter transformation (RT). An accelerated phase of CLL (aCLL) also may be observed which correlates with subsequent transformation to DLBCL, and may represent an early stage of transformation. Distinguishing PCs in CLL from aCLL or RT can be diagnostically challenging, particularly in small needle biopsy specimens. Available guidelines pertaining to distinguishing CLL from its' progressive forms are limited, subject to the morphologist's experience and are often not completely helpful in the assessment of scant biopsy specimens. To objectively assess the extent of PCs in aCLL and RT, and enhance diagnostic accuracy, we sought to design an artificial intelligence (AI)-based tool to identify and delineate PCs based on feature analysis of the combined individual nuclear size and intensity, designated here as the heat value. Using the mean heat value from the generated heat value image of all cases, we were able to reliably separate CLL, aCLL and RT with sensitive diagnostic predictive values.

Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T therapy for Richter-transformed DLBCL

The advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of refractory B-cell malignancies. Real-world evidence has highlighted the high incidence of hematological toxicity, including prolonged and profound cytopenia. Here, we present a case of bone marrow (BM) failure in a 57-year old man with DLBCL-type Richter transformation receiving tisagenlecleucel in a standard-of-care setting. His clinical course was notable for underlying BM infiltration, severe cytokine release syndrome, and multiple infectious complications in the setting of prolonged, profound neutropenia. Cytokine profiling revealed a signature consistent with acquired aplastic anemia - including downregulation of CD40-L and EGF. Flow cytometric analyses demonstrated migration of CAR T-cells to the BM, as well as peripheral blood expansion of both CAR and non-CAR bearing CD8+CD57+ T-cells, an immunophenotype linked to oligoclonality in aplastic anemia. From single-cell level transcriptomics, this cytotoxic T-cell population was characterized by T-cell receptor Vβ oligoclonal expansion and post-CAR clonal drift. Gene expression profiling revealed upregulation of exhaustion markers on (CAR) T-cells and decreased expression of genes involved in STAT signalling and inflammatory response. In conclusion, this case highlights the complex nature of CAR-T-related hematological toxicity and introduces oligoclonal (CAR) T-cell expansion as a potential contributing pathophysiologic mechanism.

An Approach to Diagnosis of Richter Transformation in Chronic Lymphocytic Leukemia.

Richter transformation (RT) is the development of high-grade lymphoma in patients with B-cell chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). CLL/SLL is a heterogenous disease with a highly variable clinical course. Disease progression in patients with CLL continues to occur even in the era of novel therapies. A small percentage of CLL patients will develop aggressive histologic transformation to diffuse large B-cell lymphoma (DLBCL), commonly known as RT. It is known that certain genetic aberrations predispose patients to RT, including mutations in NOTCH1, TP53, CDKN2A, and unmutated IGHV somatic mutations. Historically, challenges existed in making a definitive diagnosis of RT. More recently, clonal relationships between the underlying CLL and DLBCL-RT are primarily diagnosed by sequencing immunoglobulin genes. Yet, RT continues to present challenges to health-care providers in managing patients with CLL/SLL, even with novel agents. This article aims to increase advanced practitioner awareness of predictive factors for RT, clinical manifestations, and diagnostic criteria to promote early recognition and intervention. Advanced practitioners need to be cognizant of clinical signs of RT and of diagnostic criteria for an appropriate and rapid diagnosis. In doing so, the advanced practitioner can promote early diagnosis and intervention, which may improve patient outcomes, given the dismal prognosis of RT.

Richter Transformation: Clinical Manifestations, Evaluation, and Management.

Richter transformation is a devastating and rare but not uncommon development of an aggressive B-cell lymphoma in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Prognosis is dismal, with survival generally in the realm of months to a couple of years. Many patients progress quickly after traditional first-line immunochemotherapy. Nonetheless, novel therapies are on the horizon. It is important that the advanced practitioner have awareness and knowledge of this condition in order to furnish a crucial timely diagnosis and to provide appropriate treatment.

PB1882: RICHTER TRANSFORMATION FEATURES, SURVIVAL AND TREATMENT OUTCOME IN HEMATOLOGY CLINIC OF CRAIOVA, ROMANIA

Background: Richter transformation is a rare but potential lethal complication in patients diagnosed with chronic limphocytic leukemia. The most common histological transformation is of Hodgkin lymphoma or Diffuse Large B-cell lymphoma type. Aims: The aim is to assess the clinicopathological characteristics survival and treatment in Richter transformation patients diagnosed and treated in Hematology Clinic of Craiova in the last 10 years. Methods: Between January 2012 and January 2022, 453 patients with chronic lymphocytic leukemia (CLL) were diagnosed and treated in our clinic, 121 female and 332 male. Results: Median age of the patients was 68 years and the male:female ratio was 2,74. The majority were diagnosed in A stage (52%), 27% in B stage and 21% in C stage. 29% of patients required treatment initiation upon diagnosis. Richter transformation occurs in 1,76 % cases (8/453) of all CLL. The transformation occurred as follows: 5 diffuse large B-cell lymphoma (DLBCL)-type pacients and 3 Hodgkin lymphoma-type pacients. In all cases the mutational status was unmutated, CD38 was positive in 6 patients and 3 patients were positive for TP53 mutation. The time until transformation lasted between 6 and 42 months, measured from treatment initiation. In 6 patients, transformation involved peripheral lymphadenopathy and in 2 patients, intraabdominal lymphadenopathy. The treatment received was ABVD regimen in Hodgkin transformation and R CHOP in DLBCL-type. On average, survival was 16 months in Hodgkin transformation and 7,8 months in DLBCL transformation. Summary/Conclusion: The Richter transformation is a rare complication of CLL, an indolent lymphoproliferative disorder. Only 8 patients were diagnosed with Richter transformation in our clinic in the last 10 years. Chemotherapy response was poor and survival was short.

PB1881: IBRUTINIB REDUCES THE RISK OF RICHTER’S TRANSFORMATION IN PREVIOUSLY TREATED CLL PATIENTS: A POPULATION-BASED STUDY IN BRITISH COLUMBIA

Background: Richter Transformation (RT) presents in approximately 5% of Chronic Lymphocytic Leukemia (CLL) patients. Richter transformation is a rare and aggressive complication of CLL, with little information in current literature regarding possible predictive factors. In this study we assessed the possible factors for incidence of Richter’s transformation. This is a population-based study in British Columbia, Canada. Aims: To evaluate the possibility of Ibrutinib reducing the incidence of Richter transformation in patients with Chronic Lymphocytic Leukemia. Evaluating risk factors for Richter’s transformation can help implement Ibrutinib in widespread usage as a first-line treatment for cases presenting the evaluated risk factors. Methods: An electronic database search of 1056 patients with confirmed diagnosis of CLL who presented at St Paul’s Hospital, Vancouver, Canada over 30 years and between 1991 and 2021 was performed with 520 having a complete data set. 197 have undergone at least one treatment. 48 received Ibrutinib (Ibr group), and 149 patients received other non-novel therapies (non-Ibr group). Their Transformation-Free Survival (TFS) is then calculated using SPSS and incorporated in the Kaplan Meier Method. Results: The median age at diagnosis of CLL and RT was 61 y (range 34-86 y) and 64.5 y (range 33-84 y) respectively. The median lymphocyte count at diagnosis was 12 x109/L. The median time to transformation for Richter Patients was 60.1 months. By 5 years, the percentage of CLL patients who transformed in the non-Ibr group is 9%, while for the Ibr-group is 0%. By 10 years, the percentage of CLL patients who transformed in the non-ibr group is 17%, while for the Ibr group is 2% (p = 0.012). Other factors such as age, gender, and lymphocyte count at diagnosis were not significant predictors for RT on univariate analysis. On multivariate analysis, previous ibrutinib therapy retained its significance and lowered the risk of RT. Image:Summary/Conclusion: Previous Ibrutinib therapy reduced the risk for RT in CLL patients. Incorporating Ibrutinib based therapy in management of CLL is a reasonable strategy in reducing the risk of RT.