Richter s Syndrome: Risk, Predictors and Treatment 10/23/2015 John N. Allan MD Assistant Professor of Medicine Division of Hematology and Medical Oncology CLL Research Center Weill Cornell Medicine
Agenda Richter s Syndrome (RS) Background Epidemiology Clinical and Biological Risk Factors Comparison CLL->RS Comparison to de novo DLBCL Clinical Predictors of Outcome to Therapy Impact of Transplantation RS in era of Novel Agents New Directions
Background First described in 1928 by Maurice Richter, MD 1897-1988 Professor of Pathology (Columbia and NYU) Chairman 1949-1951 Richter s Syndrome (RS) is coined years later in 1964 Am J Pathol, 1928. 4(4): p. 285-292 Our Dermatol Online. 2013; 4(3): 385-388
Richter s Transformation Statistics Term should be restricted to CLL transformations 90% -> DLBCL >90% are of the non-gcb subtype ~60-80% are clonally related >80% lack association with EBV ~10%->Hodgkin Variant (HVRS) Outcomes are worse than de novo HL, better than transformed DLBCL 3.9 yrs median OS ABVD remains standard 10 yr risk is about 0.5% at 10 years ~70% EBV positive Parikh et al. Am J Hematol. 2015 Apr;90(4):334-8
Annual Incidence Rate Parikh et al Br J Haematol. 2013 September ; 162(6): 774 782.
Clinical and Biological Risk Factors for Transformation Common Biological Predictors when corrected for Rai Stage Parikh et al. Br J Haematol. 2013 Sep; 162(6): 774 782. Effect of Chemotherapy: Univariate Drug Class Purine analogue without alkylating agent Alkylating agent without purine analogue Combination therapy of purine analogue and alkylating agent Odds Ratio for Developing RS p-value 0.72 (0.04-12.08) 0.42 0.49 (0.06-3.67) 0.48 3.26 (1.67-6.37) 0.003 Alemtuzumab +/- Rituximab 2.15 (0.62-7.49) 0.21 Telomere Length Clinical Risk Factors: Multivariate Analysis with multiple factors Parikh et al. Br J Haematol. 2013 Sep; 162(6): 774 782. Clinical variables Lymph node size 3 cm Biological and clinical variables Lymph node size 3 cm HR 95% CI P 9 07 3 27 25 15 <0 001 6 51 2 26 18 73 0 001 No del13q14 4 08 1 13 14 69 0 031 Rossi et al. Br J Haematol. 2008 Jun;142(2):202-15 Rossi et al Leukemia. 2009 Jun;23(6):1062-72
IgH stereotypy, IgHV gene usage and Transformation risk C. Rossi et al Clin Cancer Res. 2009 Jul 1;15(13):4415-22
Notch1 Mutations Increase RS Risk Rossi et al. Br J Haematol. 2012 Aug;158(3):426-9.
Comparison RS to CLL Fabbri et al J Exp Med. 2013 Oct 21;210(11):2273-88. Mutational Differences Cytogenetics Promoter Methylation Differences Fabbri et al J Exp Med. 2013 Oct 21;210(11):2273-88. Rinaldi et al Br J Haematol. 2013 Oct;163(2):194-204
Comparison to De Novo DLBCL Mutational Profiling Promoter Methylation Profiling Fabbri et al J Exp Med. 2013 Oct 21;210(11):2273-88. Rinaldi et al Br J Haematol. 2013 Oct;163(2):194-204
Predictors of Outcome to Therapy: Clonality and RS Score Risk Factors RR P Performance status (0 or 1 v 2-4) 2.02.006 Lactate dehydrogenase (< 1.5 normal v > 1.5 normal) Platelet count (> 100 10 9 /L v < 100 10 9 /L) 1.82.003 1.69.012 Tumor size (< 5 cm v > 5 cm) 1.61.022 Prior therapies (0-1 v > 1) 1.62.024 Tsimberadou et al.j Clin Oncol. 2006 May 20;24(15):2343-51 Rossi et al. Blood. 2011 Mar 24;117(12):3391-401
Chemo immunotherapy Regimens for RS: Parikh et al Blood. 2014 Mar 13;123(11):1647-57.
Impact of Stem Cell Transplantation on RS N=20 Autologous Transplant N=35 Allogeneic Transplant N=20 Tsimberidou et al. J Clin Oncol. 2006 May 20;24(15):2343-51 Kate Cwynarski et al. JCO 2012;30:2211-2217
Outcomes After Allogeneic Transplant Failure: SCT performed for RS Uri Rozovski et al. JCO 2015;33:1557-1563 Uri Rozovski et al. JCO 2015;33:1557-1563
Ibrutinib Failure and RS Maddocks et al. JAMA Oncol. 2015;1(1):80-87. Farooqui et al Lancet Oncol. 2015 Feb;16(2):169-76
New Directions Need for Novel Targeted Agents Current Available Clinical Trials allowing RS or designed specifically for RS KPT-330 (selinexor)-xpo1 Inhibitor PNT2258-Liposomal encapsulated DNA oligonucleotide targeting BCL-2 CC-486 (oral azacytidine)+rchop ACP-196 ACP-196 + Pembrolizumab CART cells
Summary RS is a distinct biological entity from de novo DLBCL and other transformed lymphomas Transformation is associated with specific recurrent mutational, chromosomal and promoter methylation changes compared to paired CLL samples Clinical, biological and genomic information is now established for RS risk factors and predictors of outcome Current chemo immunotherapy paradigms are relatively ineffective Transplantation can improve outcomes however few patients (~10-15%) are eligible (comorbidities, response etc) Few targeted approaches are available, but have proven effective in achieving responses in refractory patients.
John N. Allan MD Assistant Professor of Medicine Division of Hematology and Medical Oncology CLL Research Center Weill Cornell Medicine