Richter’s Transformation in Chronic Lymphocytic Leukemia

2006 ◽  
Vol 33 (2) ◽  
pp. 250-256 ◽  
Author(s):  
A TSIMBERIDOU ◽  
M KEATING
2017 ◽  
Vol 5 (4) ◽  
pp. 232470961773513 ◽  
Author(s):  
Parita Soni ◽  
Nidhi Aggarwal ◽  
Anand Rai ◽  
Vivek Kumar ◽  
Kamholz Stephan ◽  
...  

The incidence rate of chronic lymphocytic leukemia (CLL) in the United States is approximately 0.005%; men are at slightly higher risk than women. Bony involvement or pathological fracture rarely occurs in CLL, and it may be the initial presentation. An 85-year-old woman presented with acute respiratory failure secondary to pneumonia. Symptomatology included dyspnea. She was found to have pathological fracture of the femur caused by CLL. The diagnosis of CLL had been made 6 years previously, but the patient had refused therapy. On admission, the patient required endotracheal intubation, mechanical ventilation, and admission to the medical intensive care unit. Endotracheal intubation extubation was successful after 48 hours. The patient then complained of severe left knee pain. Bone radiograph and femoral computed tomography scan revealed acute pathological fracture of the left distal femur. There was no history of trauma. The fracture was stabilized with extension lock splint. Pathological fracture in patients with CLL is associated with hypercalcemia, Richter’s transformation, or multiple myeloma. This patient exemplifies the fact that pathological fracture can be caused by CLL in the absence of hypercalcemia, Richter’s transformation, or multiple myeloma and can be the initial presentation of CLL.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3929-3929
Author(s):  
Michael J. Keating ◽  
Constantine S Tam ◽  
William G. Wierda ◽  
Susan O'Brien ◽  
Deborah A. Thomas ◽  
...  

Abstract Abstract 3929 Introduction Up until now, Chronic Lymphocytic Leukemia (CLL) has been considered incurable except with an allogeneic stem cell transplant. In the last 10 years, evidence has demonstrated that chemo-immuotherapy with fludarabine, cyclophosphamide, and rituximab, (FCR) has significantly improved CR rates, overall survival (OS), and progression free survival 1. Long term follow up data for FCR at MDACC demonstrated that a significant proportion of patients (pts.) were free at 8 years2 raising the question of whether pts. are potentially cured. Definition of cure in a chronic disease such as CLL has not been addressed. To investigate this possibility we evaluated the outcome characteristics of 222 of the 300 patients (who commenced FCR more than 10 years ago) in our previously reported study of initial therapy with FCR in CLL2. Seventy eight (35%) pts were free of relapse and 127 (58%) were alive at 10 years (Fig. 1). Thirty three patients died in CR/PR of infection (5), second malignancies (8), Richter's transformation (8). MDS (9), and other causes (3). One hundred and sixty three pts. (73%) achieved CR, 22 pts. (10%) a nodular PR (nPR), 27 pts. (12%) a PR, and 10 (5%) failed treatment. The 10 year PFS correlates strongly with response, CR (41%), nPR+PR (15%) (Fig. 2). None of these patients were transplanted in remission. FISH analysis was not available at the time of this study. Conventional karyotyping demonstrated +12 (24 pts), del 11q (15), del 17p (4), other abnormalities (15), diploid (105), and in 59 patients the test was not done or had no metaphases. The worst outcomes were del 17p and del 11q each significantly inferior to diploid (+12) patients had the best time-to-treatment failure (TTF) with P<.09 compared to diploid. The 10-year TTF was significantly higher for Rai <3 versus 3 – 4 (P=.02), serum beta-2-microglobulin (β2M) value of ≤ 4 mg/L (p<.001), mutation status of IgVh (P<.001) and number of courses of FCR received. (Table 1) The causes for receiving <6 courses of FCR were persistent cytopenia (15), infections (6), resistance (5), Richter's transformation and other malignancies (9), autoimmune hemolysis (5), and other causes and lost to follow-up (16). Of the 77 patients who are still in remission at 10 years, two have relapsed and one developed Richter's transformation. Four of 21 patients checked had no residual disease in their blood at 10 years by 4-parameter flow cytometry. All other 10 yr. TTF patients are being contacted to provide blood for 4-parameter flow residual disease. Conclusion The present data suggest that one-third of patients treated with chemoimmunotherapy are potentially cured of CLL. The characteristics most strongly associated with 10 yr. TTF were Rai stage, serum β2M level, mutation status, and tolerance of chemotherapy. Second malignancies and transformations are emerging as significantly impairing the likelihood of cure. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 927-927
Author(s):  
Lorenzo Falchi ◽  
Long Xuan Trinh ◽  
Edith M. Marom ◽  
Mylene Truong ◽  
Ellen Schlette ◽  
...  

Abstract Abstract 927 Introduction. Richter's transformation (RT) occurs in 2–8% of pts with chronic lymphocytic leukemia (CLL) and is associated with poor prognosis. Moreover, pts with CLL often show clinical and/or histologic features of aggressive disease, but do not fulfill the histological criteria for RT. FDG/PET is a diagnostic tool in hematologic malignancies. Standardized uptake values (SUV) measured by FDG/PET correlates with tumor cell proliferation and aggressiveness. FDG/PET is increasingly used to evaluate pts suspicious for RT. We therefore reviewed the experience with FDG/PET in the diagnosis and management of pts with aggressive CLL and RT seen at our Institution and correlated FDG/PET data, histology, and clinical outcomes in these pts. Methods. We studied pts assessed with FDG/PET and concurrent lymph node biopsy (or marrow diagnosis of transformation). According to the histological characteristics pts were grouped in 3 categories: chronic phase (CP), increased aggressiveness (IA) or overt RT. IA was defined for this report by the presence of either increased number of large cells or ≥10% prolymphocytes in the tissue specimen. The extent of disease was assessed by FDG/PET and defined: limited = hypermetabolic sites with SUVbwmax≥5 on one side of the diaphragm; extensive = hypermetabolic sites with SUVbwmax≥5 on both sides of the diaphragm. After therapy, restaging FDG/PET was analyzed, when available, for response assessment. Results. 750 pts with CLL had at least 1 complete FDG/PET report, 422 were excluded from this analysis because of: no biopsy in 341 pts, no FDG/PET at time of biopsy in 34, concurrent cancer in 25, benign histology in 18, CP histology in pt with past RT/IA in 4. 328 pts had both FDG/PET and histological characterization and are the focus of this report. 93 pts had RT, 116 had IA and 119 had CP. Patient characteristics are summarized in table 1. We analyzed FDG/PET results in these 328 pts. Median highest SUV (SUVbwmax) was 17.9 (0-56.3) for pts with RT, 6.7 (0-37.8) for pts with IA and 3.6 (0-14.3) for pts with CP. Using an SUVbwmax cutoff of 5 sensitivity, specificity, positive and negative predictive value for the detection of RT were 88%, 48%, 40% and 91%, respectively. We next correlated FDG/PET result, histology and survival. Median overall survival (OS) was 7.9, 19.7, and 77.3 months in pts with RT, IA and CP, respectively. SUVbwmax correlated with OS. An SUVbwmax cutoff of 10 showed the highest discriminatory power: median OS was 56.4 months (95% CI: 36.4 – 71.3) in pts with SUVbwmax<10 vs 7.3 months (95% CI: 5.0 – 8.6) in pts with SUVbwmax≥10. OS of pts with RT or IA was similar for pts with SUVbwmax<10 (29.5 vs 21.4 months, p=.62) or ≥10 (7.6 vs. 5.9 months, p=.71). Sixty %, 38% and 13% of pts with RT, IA, and CP, respectively, had extensive disease. OS was not significantly different between pts with limited vs extended disease within pt groups with SUVbwmax<10 or ≥10 (p=.45 vs .06, respectively). Factors independently associated with inferior OS in multi variable analysis were: RT histology, age ≥65 ys, PS ≥2, bulky disease, prior therapy, and SUVbwmax≥10. All pts with RT or IA, and 71% of pts with CP received treatment. 95 pts had a FDG/PET performed as restaging. In these pts OS was not reached in pts with ≥66% reduction in SUVbwmax after therapy and 15.3 months in those without such reduction (p <.0001). Conclusion. In our experience, FDG/PET accurately suggested the presence of RT in pts with CLL. SUVbwmax correlates with OS in pts with transformed CLL, independently of disease histology and extension. Restaging FDG/PET also predicted OS in pts with RT or IA. Prospective studies to validate the role of FDG/PET in the evaluation and management of pts with CLL are ongoing Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3198-3198
Author(s):  
Cecelia R. Miller ◽  
Amy S. Ruppert ◽  
Nyla A. Heerema ◽  
Kami J. Maddocks ◽  
Jadwiga Labanowska ◽  
...  

Abstract Ibrutinib is a promising targeted therapy for chronic lymphocytic leukemia (CLL). However, a small subset of patients progress on ibrutinib either through progressive CLL or Richter's transformation. Patients responding to ibrutinib and then progressing with Richter's transformation do so most commonly within the first 2 years of treatment and have an extremely poor prognosis. Identifying biomarkers associated with this transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas; however, its incidence in CLL has not been described. We investigated the prevalence of near-tetraploidy in CLL patients prior to starting ibrutinib and identified it as a pre-treatment biomarker for Richter's transformation. We examined near-tetraploidy in a large series of CLL patients enrolled across four ibrutinib clinical trials at the Ohio State University, for which extensive correlative studies and follow up data are available (previously described by Maddocks et al., JAMA Oncol, 2015). We identified this abnormality in 9 of 300 patients (3.0%, 95% CI: 1.4-5.6) in blood or bone marrow samples taken prior to starting therapy. Near-tetraploidy was detected by the presence of four signals with four or more fluorescence in situ hybridization (FISH) probes and confirmed in the metaphase karyotype of each patient in at least one cell. Near-tetraploidy was associated with aggressive disease characteristics including: Rai stage 3/4 (p=0.03), deletion 17p (p=0.03), and complex karyotype (p=0.01), as well as trisomy 12 (p=0.05). With a median follow-up time of 40.5 months, in patients positive with near-tetraploidy, one patient (11%) progressed with CLL on ibrutinib, six patients (67%) progressed with Richter's transformation, and two patients (22%) were still on treatment. Cumulative incidence of Richter's transformation was significantly higher in patients with near-tetraploidy (Figure; p<0.0001). Notably, near-tetraploidy was not associated with progression with CLL alone (p=0.53). In a multivariable model, both near-tetraploidy (HR 8.66, 95% CI 3.83-19.59, p<0.0001) and complex karyotype (HR 4.78, 95% CI 1.42-15.94, p=0.01) were independent risk factors for discontinuing ibrutinib due to Richter's transformation. Our results suggest that near-tetraploidy is a distinct biomarker to assess in patients initiating ibrutinib which would predict a high risk for Richter's transformation. As a biomarker it will be important to confirm this association in a second independent data set as well as interrogate the distinct pathophysiology of this genomic subset of CLL. Figure Figure. Disclosures Lozanski: Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding. Jones:Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Awan:Novartis Oncology: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Research Funding. Blum:Pharmacyclics: Research Funding. Woyach:Acerta: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding.


2005 ◽  
Vol 29 (4) ◽  
pp. 389-395 ◽  
Author(s):  
P.D. Thornton ◽  
C. Bellas ◽  
A. Santon ◽  
G. Shah ◽  
C. Pocock ◽  
...  

2007 ◽  
Vol 2 (4) ◽  
pp. 265-271 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
Michael J. Keating ◽  
William G. Wierda

Author(s):  
Silvia Montolio Breva ◽  
Rafael Sánchez Parrilla ◽  
Teresa Giménez Pérez ◽  
Carmen Araguás Arasanz

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