Richter's Transformation Research Articles

Richter transformation of chronic lymphocytic leukaemia: a British Society for Haematology Good Practice Paper.

Richter transformation of chronic lymphocytic leukaemia: a British Society for Haematology Good Practice Paper.

S2623 Chronic Lymphoid Leukemia With Extensive Liver Infiltration in the Absence of Leukemic Transformation

Introduction: Chronic lymphoid leukemia (CLL) is the most common hematologic cancer diagnosed in the elderly. Its association with liver dysfunction secondary to leukemic infiltration ranges from mild elevations in liver enzymes (LE) to acute liver failure. Severe hepatic infiltration is typically associated with acute leukemic transformation. Here we report an atypical manifestation of CLL with rising LE and white blood cell (WBC) count mimicking leukemic transformation. Case Description/Methods: 62-year-old male with history of CLL not on therapy presented to clinic for abnormal LE and rising leukocytosis. Patient reported fatigued, jaundice, right upper quadrant pain and 25lb weight loss over five months attributed to dietary modifications. Patient reported taking glimepiride, atorvastatin and herbal supplements (GNC50+ multivitamin, fertility and prostate multivitamin) that were stopped five months prior to encounter due to concerns of drug-induced liver injury (DILI). Labs were significant for absolute lymphocytosis >53,000/uL, AST 156U/L, ALT 336U/L, total bilirubin 4.4 mg/dl, direct bilirubin 3.57mg/dl and gamma-glutamyl transferase of 94U/L from previously normal LE. Additional work up was negative for viral and autoimmune etiologies. NASH Fibrosure was consistent with F4 Fibrosis. Computer tomography (CT) of abdomen did not demonstrate fatty changes but did show significant abdominal lymphadenopathy. Patient was hospitalized for rapidly rising WBC and LE. Abdominal ultrasound doppler showed patent liver vasculature. Transjugular liver biopsy was negative for acute leukemic transformation, but did identify extensive, >60% sinusoidal infiltration by CLL with hepatic venous pressure gradient (HVPG) of 11 mmHG attributed to periportal and peripancreatic adenopathy observed on CT imaging (Imaging A-D). Patient was initiated on Venetoclax and Obinutuzumab as an outpatient. LE peaked two months after chemotherapy initiation. Liver synthetic function remained normal (Table 1). Discussion: After ruling out DILI with failed improvement upon discontinuation of suspected agents and liver biopsy, extensive CLL extranodal liver involvement was attributed to have caused liver dysfunction and subsequent portal hypertension. Severe pattern of involvement is rare without Richter Transformation, which can be seen in 8% of CLL patients. Due to severe pattern of liver infiltration, worsening LE, portal hypertension, and hepatosplenomegaly it was ultimately decided to start patient on chemotherapy.Figure 1.: Image A:CT abdomen and pelvis with IV contrast depicting an enlarged 33.4x42.9mm periportal lymph node Image B: CT abdomen and pelvis with IV contrast depicting 11.7x18.3mm pancreatic lymph node Image C: : H&E (400x) section demonstrates an atypical lymphoid follicle surrounding bile ductules, with adjacent liver parenchyma. Characteristic immunohistochemical staining of the neoplastic cells shows positivity for CD20 (dim), CD5, CD23, and is negative for CD3 Image D: ZAP 70 (400x) staining (brown) of neoplastic cells has been associated with a poor prognosis.Table 1.: Patient laboratory information from date of diagnosis to most recent outpatient follow up. Footnote: *Represents laboratory data for time of hospital admission for elevated liver enzyme work up **Represents the laboratory data prior to initiation of chemotherapy ***Represents peak liver enzyme abnormality ****Represents most recent outpatient follow up laboratory data.

S2745 Chronic Lymphocytic Leukemia: An Unusual Cause of Hepatic Granulomas

Introduction: Hepatic granulomas (HG) are localized collections of inflammatory cells, found in 2 to 10% of patients who undergo liver biopsy. HG has a wide differential and, in some cases, may not lead to a definitive diagnosis. We present a rare case of chronic lymphoid leukemia (CLL) presenting as HG. Case Description/Methods: 70-year-old male with past history of CLL presented with fever, chills and night sweats for 2 weeks. Admission labs were significant for WBC count 25 and elevated LFTs with total bilirubin 3.67, Alkaline phosphatase 281, AST 41 and ALT 144. CT liver protocol showed diffuse hypodense liver lesions, classified as LIRADs 3 indeterminate lesions. MRI was contraindicated due to incompatible hardware. Infectious work up including cultures, viral and tick serologies, and acute and chronic liver serologies were negative and patient was observed off antibiotics and discharged. Subsequent liver biopsy revealed nodules of necrotizing granulomas but negative for CLL, Richter transformation, fungal or TB on special stains. Work up was expanded to rule out autoimmune causes, fungal, atypical viral, TB infections, hemochromatosis and sarcoidosis as a cause of HG, all of which resulted negative. Due to unclear diagnosis and persistent abnormal liver imaging, repeat liver biopsy was performed which revealed periportal and sinusoidal atypical lymphoid infiltrate with necrotizing granulomatous inflammation. Flow cytometry showed small CD 19+ B cells, consistent with CLL. This upstaged patient’s disease to Rai stage 2 and he was started on chemotherapy, which normalized LFTs and improved symptoms. Discussion: HG remains a diagnostic challenge for many clinicians. Common malignancies associated with hepatic granulomas are lymphoma, renal cell carcinoma and liver metastasis. CLL is not a well defined cause of hepatic granuloma. Other causes include drugs, bacterial, fungal, viral or parasitic infections, autoimmune disorders, TB and sarcoidosis. The histologic subtypes (caseating vs non caseating) may give a clue to the diagnosis. Progressive fibrosis, portal hypertension, and cirrhosis can rarely develop if not identified early. In patients with CLL, liver involvement may upstage the disease, necessitating more aggressive treatment. Assessment for associated clinical symptoms, targeted lab and radiological investigations, and characterization of the morphology and localization of granulomas will usually lead to a definitive diagnosis and appropriate treatment.

Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition

AbstractCovalent Bruton tyrosine kinase inhibitors (BTKi's) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n = 5). The cohort was heavily pretreated (median lines of prior therapy, 4) and enriched for adverse disease genetics (complex karyotype, 12 of 12 tested [100%]; del(17p)/TP53 mutations, 15 of 17 [88%]). The median time to progression on prior venetoclax was 24 months (range, 6-94 months) and was 25 months (range, 1-55 months) on prior BTKi. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in 6. The median overall survival after progression on second-line TA was 3.6 months (95% confidence interval, 2-11 months). Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.

CLL-115: First Results of a Head-to-Head Trial of Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia

Context: Increased selectivity of the Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib versus ibrutinib may improve tolerability. Objective: To compare acalabrutinib versus ibrutinib in patients with chronic lymphocytic leukemia (CLL). Design: Open-label, randomized, noninferiority, phase 3 trial. Patients: Previously treated CLL patients with del(17p) or del(11q) by central lab. Interventions: Oral acalabrutinib 100 mg twice daily (BID) or ibrutinib 420 mg once daily (QD) (stratified by del(17p) status, Eastern Cooperative Oncology Group performance status [2 vs ≤ 1], and number of prior therapies [1–3 vs ≥4]) until progression or unacceptable toxicity. Main Outcome Measures: Primary endpoint was progression-free survival (PFS), as assessed by independent review committee; secondary endpoints of all-grade atrial fibrillation (AF), grade ≥3 infection, Richter transformation, and overall survival (OS) were assessed in hierarchical order. Results: 533 patients (acalabrutinib, n=268; ibrutinib, n=265) were randomized (median age 66 years; median 2 prior therapies; del(17p) 45.2%; del(11q) 64.2%). At a median follow-up of 40.9 months (range 0.0–59.1), acalabrutinib was noninferior to ibrutinib with a median PFS of 38.4 months in both arms (HR: 1.00; 95% CI: 0.79–1.27). Acalabrutinib was statistically superior to ibrutinib in all-grade AF incidence (9.4% vs 16.0%; P=0.023). Among other secondary endpoints, incidences of grade ≥3 infection (acalabrutinib: 30.8%, ibrutinib: 30.0%) and Richter transformation (acalabrutinib: 3.8%, ibrutinib: 4.9%) were comparable between arms. Median OS was not reached in either arm (HR: 0.82; 95% CI: 0.59–1.15), with 63 (23.5%) deaths in the acalabrutinib arm and 73 (27.5%) in the ibrutinib arm. Among any-grade adverse events (AEs) in ≥20% of patients in either arm, acalabrutinib was associated with lower incidence of hypertension (9.4%, 23.2%), arthralgia (15.8%, 22.8%), and diarrhea (34.6%, 46.0%) but a higher incidence of headache (34.6%, 20.2%) and cough (28.9%, 21.3%). AEs led to treatment discontinuation in 14.7% of acalabrutinib- versus 21.3% of ibrutinib-treated patients. Any-grade AEs of clinical interest that were less frequent with acalabrutinib included cardiac (24.1% vs 30.0%), hypertension (above), and bleeding events (38.0% vs 51.3%). Conclusions: In this first head-to-head trial of BTKis in CLL, acalabrutinib demonstrated noninferior PFS with less cardiotoxicity and fewer discontinuations due to AEs versus ibrutinib.

CLL-069: Incidence of Second Cancer in Patients with Chronic Lymphocytic Leukemia: The Indian Scenario

Context: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the west; however, it is relatively infrequent in India. Patients with CLL have two times higher incidence of second malignancies (SM) than the general population. Objective: Our study aims to evaluate the incidence of SM in Indian patients. Design and Setting: We retrospectively screened 589 patients with CLL registered in the Department of Medical Oncology at All India Institute of Medical Sciences (AIIMS), New Delhi, India, over a period of 20 years (2000–2019) and found 60 cases of SM. SM was defined as another malignancy or transformation at the time of diagnosis or during follow-up. SM was divided into two categories: hematologic malignancies and solid tumors. Results: With a median follow-up of 48 months, a total of 60 SM cases were identified. Forty-eight cases (80%) were hematological malignancies, and 12 cases (20%) were solid tumors. The median age was 55 years (28–72 years). There were 43 males and 17 females. The median total leukocyte count at presentation was 55×109/L. The clinical Rai stage distribution was stage 0 – 3 (5%), stage I – 9 (15%), stage II – 23 (38.3%), stage III – 9 (15%), and stage IV –19 (31.6%). Forty (66.6%) patients received treatment at presentation for CLL. The most common regimens were chlorambucil-based, in 45%; bendamustine and rituximab, in 40%; and fludarabine-based, in 9% of cases. Forty-three cases (71.6%) progressed to Richter transformation (RT). RT developed as diffuse, large B-cell lymphoma in 40 cases and as Hodgkin lymphoma in 3 cases. The other SM were myelodysplastic syndrome –2, myelofibrosis – 1, multiple myeloma – 1, chronic myeloid leukemia – 1, basal cell carcinoma –1, carcinoma of larynx – 1, carcinoma of tongue – 1, breast cancer – 2, adenocarcinoma of lung – 2, prostate cancer – 1, renal cell carcinoma – 1, carcinoma of urinary bladder – 1, gallbladder – 1, and pancreatic cancer – 1 case. Median time to progression to SM was 39 months. Conclusion: The incidence of SM is 10.1% in our population. The most common SM is RT, which accounts for 71.6% of cases. Secondary solid tumors constitute 20% of cases without any site specification.

Approaches to Therapy of Richter Syndrome

Richter transformation (RT) is defined as the evolution of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) into an aggressive lymphoma. Occurring mostly in elderly and frail patients with multiple comorbidities, RT may be treated only with limited approaches. Under the progressive development of knowledge regarding the molecular bases of RT evolution, novel treatment strategies are being explored.

ABCL-040: Pirtobrutinib (LOXO-305), a Next-Generation, Highly Selective, Non-Covalent Bruton's Tyrosine Kinase Inhibitor in Previously Treated Mantle Cell Lymphoma and Other Non-Hodgkin Lymphomas: Phase 1/2 BRUIN Study Results

Context Despite the marked efficacy of covalent BTK inhibitors (BTKi) in MCL, WM, and MZL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Low oral bioavailability or short half-life of these agents can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). Pirtobrutinib (LOXO-305) is a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal, low nM potency. Objective To evaluate safety and efficacy of pirtobrutinib in pts with MCL/NHLs. Design BRUIN is an ongoing multi-center phase 1/2 trial (NCT03740529). Enrollment was initiated 21 March 2019. Setting Global: community hospitals, academic medical centers. Patients Previously treated pts with advanced B-cell malignancies. Interventions Oral pirtobrutinib (7 dose escalation levels: 25–300mg once daily) in 28-day cycles. Main Outcomes Measures Determining the maximum tolerated dose/recommended phase 2 dose (RP2D), safety profile, and efficacy based on response assessment using disease-specific criteria per protocol. Results As of 27 September 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were treated on 7 dose levels (25–300mg QD). Pirtobrutinib demonstrated high oral exposures, with doses ≥100 mg QD exceeding the BTK IC90 for the entirety of the dosing interval. No DLTs occurred. The only TEAEs, regardless of attribution or grade in ≥10% of pts (n=323), were fatigue (20%), diarrhea (17%) and contusion (13%). A RP2D of 200mg QD was selected. At the efficacy cutoff date, 35 (57%) MCL pts, 18 (69%) WM pts, and 34 (52%) other NHL pts remained on therapy. Among the 52 efficacy evaluable prior BTKi treated MCL pts, the ORR was 52%. Among the 19 efficacy evaluable pts with WM, the ORR was 68%. For the other 55 efficacy evaluable NHL pts, ORR was 24% (DLBCL), 50% (FL), 22% (MZL), and 75% (Richter's transformation). Conclusion Pirtobrutinib demonstrated promising efficacy in MCL and other NHL pts, was well-tolerated and exhibited a wide therapeutic index.

Case Presentations – Management of the Most Difficult Cases of Chronic Lymphocytic Leukemia: Relapse After BTK Inhibitor and BCL2 Inhibitor Therapy and Richter Transformation

AbstractTremendous progress has been made in the management of chronic lymphocytic leukemia (CLL) in recent years. Anti-CD20 antibodies, inhibitors of Bruton tyrosine kinase (BTK), an inhibitor of B-cell lymphoma 2 (BCL2), and inhibitors of phosphoinositide 3-kinase (PI3K) have all translated into improved outcomes for patients with CLL. Patients are living longer, in remission longer, and experiencing fewer toxicities than in the era of chemoimmunotherapy.

Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter's transformation

Allogeneic hematopoietic stem cell transplantation (HSCT) may potentially cure patients with chronic lymphocytic leukemia (CLL) and Richter's transformation (CLL-RT) or CLL without RT, but the impact of novel agents on HSCT is unclear. CLL-RT patients have a grave prognosis, and their outcomes after HSCT are uncertain. We conducted a retrospective analysis of all 58 CLL patients, including 23 CLL-RT patients, who underwent reduced intensity conditioning (RIC) HSCT at Memorial Sloan Kettering Cancer Center (New York, NY) between September 2006 and April 2017. With a median follow-up of 68 months (range, 24-147 months), 5-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 28%-56%), and overall survival (OS) was 58% (95% CI, 48%-74%). The 1-year graft-versus-host disease/relapse-free survival (GRFS) was 38% (95% CI, 25%-50%). Patients with CLL-RT and CLL patients without RT had comparable outcomes. In both cohorts, treatment-sensitive response and ≤3 previous lines of therapy produced superior PFS and OS. Outcomes were agnostic to adverse cytogenetic and molecular features. Novel agents did not have a negative impact on HSCT outcomes. Total body irradiation (TBI)-containing RIC yielded inferior PFS, OS, and GRFS. CLL-RT patients older than age 55 years who had an HSCT Comorbidity Index score of ≥2 demonstrated inferior OS. This study, which is the largest series of RIC-HSCT for patients with CLL-RT, provides evidence supporting RIC-HSCT in early remission courses for patients with CLL-RT and poor-risk CLL patients. TBI-containing RIC should be considered with caution.

Outcomes of Richter’s transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): an analysis of the SEER database

Richter's transformation (RT) is a rare complication arising in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is associated with an overall dismal outcome. The rarity of this entity poses many challenges in understanding its biology and outcomes seen and the optimal treatment approach. We utilized the SEER (Surveillance, Epidemiology and End Results) database to identify patients diagnosed with CLL/SLL between 2000 and 2016 and subsequently had a diagnosis of diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL), thus capturing those who experienced an RT event. We compared the outcomes of those patients to those of patients in the database diagnosed with DLBCL without a preceding CLL/SLL diagnosis. We identified 530 patients who developed RT out of 74,116 patients diagnosed with CLL/SLL in the specified period. The median age at RT diagnosis was 66years, and the median time from CLL/SLL diagnosis to RT development was roughly 4years. Patients with RT had a dismal outcome with median overall survival of 10months. We identified advanced Ann Arbor stage (III/IV) and prior treatment for CLL as predictors of worse outcome in patients with RT. Our study represents the largest dataset of patients with CLL/SLL and RT and adds to the existing literature indicating the poor outcomes for those patients.

Abstract 915: Preclinical evaluation of anti-CD37 antibody-targeted amanitin conjugates (ATAC) in B-cell malignancies

Abstract Background: ATACs (antibody-targeted amanitin conjugates) comprise a new class of antibody-drug conjugates (ADCs) using amanitin as a toxic payload. Amanitin binds to the RNA pol II and thereby efficiently inhibits the cellular transcription process. In the current study, in vitro and in vivo data of ATACs targeting CD37 (member of the tetraspanin family) are presented. CD37 is a transmembrane protein expressed exclusively on cells of the immune system and mainly on mature B-cells, as well as in many B-cell malignancies, including Richter's Syndrome (RS) or Richter´s transformation. RS is a transformation of B cell chronic lymphocytic leukemia, refractory to treatment and carries a poor prognosis, and hence is considered an ideal target for amanitin-based ADCs. Material and methods: Cell lines: CD37-positive: Mec-2 (B-chronic lymphocytic leukaemia); Raji-Luc, Ramos (Burkitt´s lymphoma); CD37-negative: HL-60 (acute lymphocytic leukemia) Antibody: anti-CD37 engineered monoclonal antibody produced at Heidelberg Pharma Toxic warhead: Cysteine reactive amanitin-linker constructs were synthesized at Heidelberg Pharma and conjugated site-specifically to the antibody. Cell proliferation assay: Quantitative determination of cell viability was performed by CellTiter Glo 2.0 assay (Promega). Animal models: Disseminating Mouse xenograft tumor models (Mec-2 and Raji-Luc) and CD37-positive patient derived xenograft (PDX; Richter's Syndrome) models were performed in single-dose experiments. Tolerability was assessed in non-human primates (NHP). Results: All tested anti-CD37 ATACs showed in vitro cytotoxicity in the picomolar range on CD37-positive cell lines. No cytotoxic activity was observed on CD37-negative cells. In mouse xenograft models, 80 - 100% overall survival was achieved with two anti-CD37 ATACs at doses of 1/16 MTD (Mec-2 model) and 1/64 MTD (Raji Luc Model). Single-dose treatment caused rapid and complete tumor remission already 7 days after treatment. The tested ATACs revealed good tolerability in mice. In NHP, the anti CD37 ATACs revealed good tolerability. Hematology and clinical chemistry parameters were unaffected except liver transaminases and LDH: A mild to moderate and transient increase was observed. Conclusions: Targeted cytotoxic drug delivery to CD37 positive cell lines was achieved by using anti-CD37 ATACs. The mode of action of the payload amanitin led to an efficient anti-tumor potential in vitro and in vivo with good tolerability in non-human primates. Using ADCs in the therapy of B-cell lymphomas, including malignancies that underwent Richter's transformation, is a promising approach, especially by using a payload whose mode of action differs from other commonly used toxins, like ATACs. Citation Format: Stephanie Voss, Aniko Palfi, Christoph Mueller, Andreas Pahl, Torsten Hechler, Michael Kulke. Preclinical evaluation of anti-CD37 antibody-targeted amanitin conjugates (ATAC) in B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 915.

Abstract 1612: Tumor intrinsic changes determine immune-checkpoint response in Richter's transformation

Abstract Richter's transformation (RT) is a clinically challenging and aggressive transformation of CLL (Chronic lymphocytic leukemia) to lymphoma. Immune-checkpoint therapy has improved outcomes in selective lymphoma types. Nearly 40% of RT patients respond to anti-PD1, while the underlying CLL do not show any response, and 10% of CLL patients progress post-anti-PD1 treatment. Previous studies mostly focused on T-cell responses elicited by anti-PD1, however, intrinsic changes in CLL and RT B-cells induced by the treatment remains elusive. We hypothesized that pre-existing active transcriptional circuitry and distinct B-cell subsets in the CLL and RT B-cells may determine the response to anti-PD1 treatment. Peripheral blood mononuclear cells (PBMCs) from 3 patients who received pembrolizumab(anti-PD1) as a single agent. Samples were obtained at baseline and 3 months post-treatment initiation. Among these patients, 2 are progressors while 1 is a responder. We performed single-cell RNAseq (10X Genomics) on B-cells enriched from PBMCs derived from 3 samples (1 Responder: RS2, 2 progressors: CLL14 and CLL17) before and after treatment using chromium single cell 3' gene expression library. A total of ~10000 cells were captured with an average detection of 1000 genes/sample. To delineate the transcriptional changes upon the anti-PD1 treatment, we first integrated the single-cell data from 6 samples (before and after Pembro) and performed unsupervised clustering analysis using UMAP (Uniform Manifold Approximation and projection). We identified 8 different clusters based on highly expressed marker genes. Cluster 2(C2) was increased in the responder as compared to the progressors post-pem treatment. To determine the activated pathways in each cluster, we performed gene-set enrichment analysis (GSEA) using the Enrichr method. This analysis revealed upregulation of distinct pathways related to IFNG/MYC(C1), IFNG(C2), ER stress(C3), B-cell dependent T cell activation related pathway(C4), MYC targets/TNFα(C5,6,7) indicating intra-tumor transcriptional heterogeneity. To decipher the intratumor cell differentiation changes, we performed pseudotime trajectory analysis using Monocle 2 coupled with B cell developmental stage markers. We identified 7 different states, with distinct changes of state in responder sample RS2 (State 4,5, 6, and 7 were increased in RS2 post-treatment) while CLL samples(progressors) did not have distinct changes. Integration with B cell development revealed that aggressive B cells with CD38 expression were highly induced upon anti-PD1 in responder RS2 while regulatory (CD1d) and memory B cells (CD27) remained the same, suggesting PD1 induced intrinsic changes contributing to the disease response. We identified distinct transcriptional states in B cells within responders and progressors which may govern the intra-tumor and inter-tumor heterogeneity to the anti-PD1 response. Citation Format: Prajish Sundaram Iyer, Lu Yang, Yang Zhi Zhang, Hyo Jin Kim, Charla Secreto, Sutapa Sinha, Neil Kay, Stephen Ansell, Wei Ding, Lili Wang. Tumor intrinsic changes determine immune-checkpoint response in Richter's transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1612.

Is There a Role for Cellular Therapy in Chronic Lymphocytic Leukemia?

Despite multiple advances in the treatment landscape of chronic lymphocytic leukemia (CLL) during recent years, cellular therapies, such as allogeneic hematopoietic cell transplantation and chimeric antigen-engineered T cells, represent valuable therapeutic options for patients with multiply relapsed or poor-risk disease. This brief overview will summarize current results of cellular therapies in CLL including Richter transformation, suggest an indication algorithm and strategies for performing cellular therapies in these conditions, and discuss the impact of COVID-19 (coronavirus disease 2019) on allogeneic hematopoietic cell transplantation and chimeric antigen-engineered T cells in CLL.

Clinical Outcomes of Chronic Lymphocytic Leukemia (CLL) Patients with Richter's Transformation (RT) to Aggressive Non-Hodgkin Lymphoma (aNHL): a Single-Institution Experience

Background: Patients (pts) with RT from CLL have poor long-term outcomes with standard treatments. We examined the pt outcomes and the impact of different treatment options of standard therapy alone, standard therapy followed by autologous (autoSCT) or allogeneic stem cell transplant (alloSCT) or CAR-T cell therapy. Methods: Between 1998 and 2016, 47 pts were identified who had a diagnosis of CLL and transformed to aNHL. Multivariable models were used to test for independent predictors of overall survival (OS) by including the following factors: age at RT diagnosis, presence of del17p, high CD38, high ZAP-70, prior treatment for CLL (none/any), more than 2 treatments for CLL, ibrutinib therapy for CLL, complete response to first line of treatment for RT (CR1), autoSCT, alloSCT and CAR-T cell treatments for RT. Results: Median age at the time of RT diagnosis was 63 (35 - 91) years and 38% of pts were female. High risk CLL features included del17p (32%), del11q (15%), complex karyotype (11%), high CD38 (38%) and high ZAP-70 (28%). Fifteen pts (32%) had required no therapy for CLL before the RT diagnosis. Median number of CLL treatments was 1 (range: 0 -5). Most commonly used CLL treatments were fludarabine-based regimens (57%), bendamustine-based regimens (13%), ibrutinib (11%) and RCHOP (11%). Four percent had received alloSCT for CLL. Median time interval from CLL to RT diagnosis was 26 months (range 0 - 301). For RT therapy, pts received median three lines of treatment (range: 1 - 8). Fourteen pts (30%) achieved CR after first line treatment (CR1). CR1s were achieved using RCHOP (9), REPOCH (4) and HyperCVAD (1). Five patients (11%) received autoSCT only, 7 (15%) had alloSCT only and 7 (15%) received autoSCT followed by alloSCT. Six (13%) had treatment with CAR-T cells. Two of the CAR-T pts also had an autoSCT (1 before and 1 after) and 2 had alloSCT (both before CAR-T treatment). Median follow-up after RT diagnosis was 15 months (0.9 - 150) and median OS was 23.8 months (range 0.9 - 150). Overall, 3-year-OS was 47% (95% CI: 32-60). The 3-year OS rate was significantly higher in patients who achieved CR1: 86% (95% CI: 54-96) vs. 30% (95% CI: 16-46); p =.001. Among pts with CR1, 6 patients subsequently received transplant (autoSCT only= 1, alloSCT only=2, both =3) and all these pts were alive after median follow-up of 43 months (range: 20 -132). Outcome of these pts was not statistically different from those in CR1 who did not have a subsequent transplant (n=8) and had a 3-year OS of 75% (95% CI 31-93); p = .20. On the other hand, in patients who did not achieve CR1, there was a trend towards a better 3-year OS in patients who subsequently received transplant (autoSCT only=3, alloSCT only=6, both, =4) compared to those who did not (n=20): 46% (95% CI: 19-49) vs. 20% (95% CI: 6 -39); p = .05. Among all patients and in a multivariable model, only achievement of CR1 (HR 0.13; p .003) and having an alloSCT (HR 0.28; p 0.02) were associated with an improved OS. Among patients who did not achieve CR1 and in the multivariate analysis, there was a trend for improved OS only in patients who received an alloSCT (HR 0.35; p 0.06). Conclusion: Pts with RT have poor clinical outcome especially if they fail to achieve a CR after first line of treatment. Novel combinations are needed to increase the likelihood of achieving CR1. AlloSCT is associated with an improved OS in those pts and in RT pts in general and should be considered for treatment of RT pts. [Display omitted] DisclosuresShadman:Pharmacyclics: Other: advisory board, Research Funding; TG Therapeutics: Research Funding; Celgene: Research Funding; Acerta Pharma: Research Funding; Genentech: Consultancy, Research Funding; Merck: Research Funding; PLEXXIKON: Research Funding; Gilead: Research Funding; Emergent: Research Funding; AbbVie: Other: advisory board. Till:Genentech: Research Funding; Mustang Bio: Patents & Royalties, Research Funding. Holmberg:Seattle Genetics: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Millennium: Research Funding; JAZZ: Consultancy; Up To Date: Patents & Royalties. Maloney:Celgene: Other: Advisory board; Juno Theraapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Roche/Genetech: Other: Advisory board; Kite Pharmaceuticals: Other: Advisory board. Gopal:Seattle Genetics: Consultancy, Research Funding. Press:Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Smith:Genentech: Research Funding; Merck: Research Funding; Acerta: Research Funding; Sharp: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Dohme Corp: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding.

Real-World Results on Ibrutinib in Relapsed/Refractory CLL: A 21-Month Follow-up of 95 Swedish Patients Treated in a Compassionate Use Program

Background: Ibrutinib is current standard of care for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) based on phase 3 clinical trials. There is often a discrepancy between data obtained in clinical trials with strict inclusion criteria and those later obtained in routine health care. We have previously reported the 10-month follow-up of real-world results on ibrutinib in consecutive Swedish CLL patients treated in a compassionate use program (CUP) (Winqvist et al., 2016). Here we present follow-up data at 21-month follow-up with extended PFS, OS and safety.Methods: Inclusion/exclusion criteria of the CUP have been described earlier (Winqvist et al., 2016). All patients were identified for follow-up. CRFs were updated after a second round of in-depth analyses of individual patient files and data were cross-checked. Patients received 420 mg oral ibrutinib once daily until progression. Dose modifications were allowed as needed.Results: The 95 patients had a median age of 69 years, 63% had del17p/ TP53 mutation and had received a median of 3 prior therapies. 27% had PS grade 2 or 3 (Winqvist et al., 2016). The median treatment duration at this 2nd data analysis was 19.6 months (range 0.6-30.4 months) and 54 patients (57%) remained on ibrutinib therapy. The overall response rate (ORR) was 85% including 63% PR, 14% PR with lymphocytosis and 8% CR. The median PFS and OS had not yet been reached. At a median follow-up time of 21.4 months (range 1.2-30.4 months) the OS rate was 72% and the PFS rate was 65% (Fig 1 and 2).Toxicity was similar as in the first report (Winqvist et al., 2016) with 38% grade 3-4 neutropenia, 28% grade 1-2 diarrhea (1 grade 3) and 16% arthralgia /muscle pain (4 grade 3-4). Hemorrhage occurred in 52% (1 grade 5) and 13% had atrial fibrillation. Richter transformation (RT) occurred in 13% after a median time of 12.0 months (range 3.7-19.8); in contrast to another report (Woyach et al., 2016), no clearcut RT plateau was observed (Fig 3).27% of the patients have died due to RT (n=8), infection (n=5), secondary malignancy (n=4), CLL progression on therapy (n=3), CLL progression after ibrutinib cessation (n=3), congestive heart failure (n=1), subdural hematoma (n=1) and unknown (n=1).Ibrutinib was permanently stopped in 41 patients (43%). The most common reasons were RT (n=11), infection (n=7), other malignancy (n=4), allogeneic SCT (n=4), CLL progression (n=4), cutaneous AE (n=3), or drug interaction (n=2). Fifteen patients had totally 20 treatment breaks longer than 14 days (median 22 days). In contrast to others (Barr et al., 2017; Forum, 2016) we found no impact of breaks >14 days on PFS or OS.We also analyzed whether our patients would have fulfilled the inclusion criteria of the pivotal phase 3 study (RESONATE) (Byrd et al., 2014): 44% had at least 1 exclusion criteria, further supporting the real-world representativity of our cohort. However, neither ORR, PFS nor OS was significantly different between CUP patients matching vs not matching the RESONATE criteria (Fig 4, p=0.29 for OS).In contrast to the first report (Winqvist et al., 2016), the negative impact on del17p was no longer significant but del17p patients who had 3 or more previous therapies had a short OS on ibrutinib (median 19.6 months). In univariate and multivariate analysis OS was associated with baseline comorbidities (CIRS) and PFS was associated with CIRS and number of prior therapies.Conclusions: The 21-month follow-up of the Swedish real-world analysis on ibrutinib treatment of CLL patients with poor prognosis baseline characteristics showed that 57% of patients remained on therapy, but there were still no signs of an emerging plateau of the PFS or OS curves. New RTs were still occurring. Ibrutinib was well tolerated by most patients. Updated results including a markedly longer follow-up will be presented at the meeting. [Display omitted] DisclosuresAndersson:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; GSK: Speakers Bureau. Karlsson:Janssen-Cilag: Honoraria; Abbvie: Honoraria. Lundin:Janssen-Cilag: Research Funding; Celgene: Research Funding. Mattsson:Janssen-Cilag: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Roche: Honoraria. Hansson:Gilead: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Abbvie: Honoraria. Österborg:Pfizer: Honoraria; Abbvie: Honoraria; Celgene: Research Funding; Janssen-Cilag: Honoraria, Research Funding; Gilead: Honoraria, Research Funding.

Venetoclax (VEN) Is Active in Chronic Lymphocytic Leukemia (CLL) Relapsed or Refractory to More Than One B-Cell Receptor Pathway Inhibitor (BCRi)

Venetoclax (VEN) Is Active in Chronic Lymphocytic Leukemia (CLL) Relapsed or Refractory to More Than One B-Cell Receptor Pathway Inhibitor (BCRi)

Phase I/II Study of Pembrolizumab in Combination with Ublituximab (TG-1101) and Umbralisib (TGR-1202) in Patients with Relapsed/Refractory CLL

Phase I/II Study of Pembrolizumab in Combination with Ublituximab (TG-1101) and Umbralisib (TGR-1202) in Patients with Relapsed/Refractory CLL

A Retrospective Analysis of 450 TP53 Mutations in a Real Life Cohort of CLL from the French Innovative Leukemia Organization (FILO) Group

A Retrospective Analysis of 450 TP53 Mutations in a Real Life Cohort of CLL from the French Innovative Leukemia Organization (FILO) Group

Disease and Patient Characteristics, Patterns of Care, Toxicities, and Outcomes of Chronic Lymphocytic Leukemia (CLL) Patients Treated with Venetoclax: A Multicenter Study of 204 Patients

Disease and Patient Characteristics, Patterns of Care, Toxicities, and Outcomes of Chronic Lymphocytic Leukemia (CLL) Patients Treated with Venetoclax: A Multicenter Study of 204 Patients